**Mindfulness Meditation — A New Preventive Intervention for ADHD**

Yi-Yuan Tang and Rongxiang Tang

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/61213

#### **Abstract**

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Meditation practice. Mind Brain J Psychiatr 2011;2(1):73–81.

Medication and behavioral treatments have been used for ADHD treatments; however, both have limitations. Mindfulness meditation has been shown to improve attention and self-control, (or self-regulation), which could help the core ADHD symptoms of inattention, impulsivity, and hyperactivity. This chapter aims to review the latest literature on the effectiveness of mindfulness meditation on ADHD, to explore the brain mechanism underlying ADHD intervention, and to propose a mindfulness-based preventive intervention for ADHD symptoms and treatments.

**Keywords:** Mindfulness meditation, attention, self-control, IBMT, brain mechanism

### **1. Introduction**

People with attention deficit/hyperactivity disorder (ADHD) have problems sustaining attention over prolonged periods of time, have difficulty to hold goals and plans in mind, and have difficulty inhibiting a prepotent response. Consequently, this neurodevelopmental disorder is characterized by symptoms of inattention, impulsivity, and hyperactivity and can influence brain structure and function [1]. Medication (mostly stimulants) and behavioral treatments (e.g., cognitive behavioral therapy) have been used for ADHD treatments; however, both have limitations. For example, medication works only short term and often has side effects, and treatment fidelity is often low [2].

Mindfulness meditation is often described as non-judgmental attention to experiences in the present moment [3, 4]. It has been suggested that mindfulness meditation involves a systematic

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

training of attention and self-control [3]. It is thus reasonable to suggest that the underlying brain mechanisms of mindfulness may involve similar brain regions and networks as these mental processes [3–5]. Mindfulness meditation has been shown to improve attention and selfcontrol [3, 6–10]. Since poor attention functioning is a core symptom of ADHD [11] and executive functioning deficits in ADHD are common [12–14], mindfulness meditation that purportedly strengthen these processes may help the ADHD symptoms and treatments.

In this chapter, we first introduce attention and self-control (or self-regulation) networks and the brain mechanism underlying ADHD intervention. We also summarize the latest literature on the effectiveness of mindfulness meditation on ADHD and then propose a mindfulnessbased preventive intervention for ADHD symptoms and treatments.

### **2. Attention and self-control networks**

Attention can be viewed as a system of anatomical areas that consists of three or more specialized networks. These networks carry out the functions of alerting, orienting and executive control, or resolving conflict [15]. Figure 1 illustrates what is known of the anatomy of attention networks that involves in mindfulness practice, especially executive control (attention) network [6,15]. The executive attention network shares with the brain circuits of self-regulation, mainly in the anterior cingulate cortex (ACC) and its adjacent medial prefrontal cortex (mPFC) and striatum/basal ganglia [16–18]. In mindfulness meditation, attentional control is required to stay engaged in the practice, and meditators often report improved attention control as an effect of repeated practice [6, 9]. Research has shown that the executive control (attention) network is heavily involved in mindfulness practice [3–6, 9,10]. In sum, ACC/mPFC and striatum play an important role in attention control and self-control following mindfulness.

### **3. Brain mechanism involved in ADHD**

Functional neuroimaging and structural neuroimaging have identified brain abnormalities involved in ADHD. The hypofunction of the brain regions, including the cingulo-frontal– parietal cognitive attention network, has been consistently observed across studies [19]. Metaanalysis has also shown a ventral–striatal hyporesponsiveness in ADHD [20]. These are major components of neural systems related to ADHD, including attention and self-control net‐ works, motor systems, and reward/feedback-based processing systems. The ADHD neuroi‐ maging research related to these network dysfunction is also associated with the core symptoms of inattention, impulsivity, and hyperactivity. This evidence suggests the biomark‐ ers of diagnosis and treatment in ADHD prevention and intervention. However, these network abnormalities are not the only factors responsible for ADHD; instead, they are only part of the pathophysiology of ADHD [20]. In order to fully characterize the disorder, we should not only consider the dysfunction of prefrontal–striatal circuitry but also consider the large-scale neural

training of attention and self-control [3]. It is thus reasonable to suggest that the underlying brain mechanisms of mindfulness may involve similar brain regions and networks as these mental processes [3–5]. Mindfulness meditation has been shown to improve attention and selfcontrol [3, 6–10]. Since poor attention functioning is a core symptom of ADHD [11] and executive functioning deficits in ADHD are common [12–14], mindfulness meditation that purportedly strengthen these processes may help the ADHD symptoms and treatments.

In this chapter, we first introduce attention and self-control (or self-regulation) networks and the brain mechanism underlying ADHD intervention. We also summarize the latest literature on the effectiveness of mindfulness meditation on ADHD and then propose a mindfulness-

Attention can be viewed as a system of anatomical areas that consists of three or more specialized networks. These networks carry out the functions of alerting, orienting and executive control, or resolving conflict [15]. Figure 1 illustrates what is known of the anatomy of attention networks that involves in mindfulness practice, especially executive control (attention) network [6,15]. The executive attention network shares with the brain circuits of self-regulation, mainly in the anterior cingulate cortex (ACC) and its adjacent medial prefrontal cortex (mPFC) and striatum/basal ganglia [16–18]. In mindfulness meditation, attentional control is required to stay engaged in the practice, and meditators often report improved attention control as an effect of repeated practice [6, 9]. Research has shown that the executive control (attention) network is heavily involved in mindfulness practice [3–6, 9,10]. In sum, ACC/mPFC and striatum play an important role in attention control and self-control following

Functional neuroimaging and structural neuroimaging have identified brain abnormalities involved in ADHD. The hypofunction of the brain regions, including the cingulo-frontal– parietal cognitive attention network, has been consistently observed across studies [19]. Metaanalysis has also shown a ventral–striatal hyporesponsiveness in ADHD [20]. These are major components of neural systems related to ADHD, including attention and self-control net‐ works, motor systems, and reward/feedback-based processing systems. The ADHD neuroi‐ maging research related to these network dysfunction is also associated with the core symptoms of inattention, impulsivity, and hyperactivity. This evidence suggests the biomark‐ ers of diagnosis and treatment in ADHD prevention and intervention. However, these network abnormalities are not the only factors responsible for ADHD; instead, they are only part of the pathophysiology of ADHD [20]. In order to fully characterize the disorder, we should not only consider the dysfunction of prefrontal–striatal circuitry but also consider the large-scale neural

based preventive intervention for ADHD symptoms and treatments.

**2. Attention and self-control networks**

294 ADHD - New Directions in Diagnosis and Treatment

**3. Brain mechanism involved in ADHD**

mindfulness.

**Figure 1.** The anatomy of attention and self-control networks. Square, alerting network; circle, orienting network; tri‐ angle, executive control network. Executive attention shares with the brain circuits of self-control, mainly in ACC/ mPFC. We call this as attention/self-control networks.

systems involved in ADHD based on recent advances in systems neuroscience-based ap‐ proaches to brain dysfunction [21].

### **4. Mindfulness-based preventive intervention for ADHD**

In addition to the pharmacological and behavioral treatments, mindfulness meditation has also been shown to improve attention and self-control [3, 6–10]. Given that poor attention functioning is a core symptom of ADHD [11] and self-control (executive functioning) deficits in ADHD are common [12–14], mindfulness meditation could strengthen these processes and may help the ADHD symptoms and treatments. We here propose the integrated translational model for mindfulness meditation as prevention strategies on ADHD [3]. As shown in Figure 2, mindfulness meditation includes at least three components that interact closely to constitute a process of enhanced self-regulation: enhanced attention control, improved emotion regula‐ tion, and altered self-awareness that targets the core symptoms of ADHD.

Previously in healthy population, we have applied one form of mindfulness meditation, the integrative body–mind training (IBMT) [3, 6], originating from an ancient eastern contempla‐ tive tradition, which involves body relaxation, mental imagery, and mindfulness training. Eighty undergraduates were randomly assigned to an experimental group (IBMT) or a control group (relaxation training) for 5 days of short-term training (20 min per day). The IBMT group showed significantly greater improvement of performance in executive attention as measured

**Figure 2.** Integrated translational model. Mindfulness meditation includes at least three components that interact close‐ ly to constitute a process of enhanced self-regulation: enhanced attention control, improved emotion regulation, and altered self-awareness that targets the core symptoms of ADHD.

by the attention network test (ANT). They also reported lower anxiety, depression, anger, and fatigue and higher vigor. In addition, we found that after a stressful task, IBMT participants showed significantly reduced stress responses, as measured by salivary cortisol, and increased immunoreactivity, as measured by salivary immunoglobulin A [6]. These results indicated that brief mindfulness meditation – IBMT – can improve attention and self-regulation ability. A similar study showed that in comparison with a book listening control group, 4 days of meditation training enhanced the ability to sustain attention [8]. If the participants practiced 1 month of IBMT (10 h in total), we found improved efficiency of executive attention, alertness (sustained attention), and basal cortisol and immune function [3, 22, 23].

We further studied the brain and body mechanisms of IBMT [18]. During and after 5 days of training, the IBMT group showed significantly better physiological responses, including heart rate, respiratory amplitude and rate, and skin conductance response than the relaxation control. In addition, the IBMT group has significant differences in heart rate variability (HRV) and EEG power during and after training, suggesting greater involvement of the autonomic nervous system (ANS). Imaging data demonstrated stronger subgenual/ventral ACC activity in the IBMT group, and ACC theta was correlated with high-frequency HRV, suggesting control by the ACC over parasympathetic activity. These results indicate that after 5 days of training, the IBMT group shows better regulation of the ANS through a ventral midline brain system than does the relaxation group. This altered state probably reflects training in the coordination of body and mind given in the IBMT, but not in the control group [18]. Other studies also showed the ACC involvement [3, 4, 24]. Taken together, these evidences suggest that mindfulness practice is associated with enhanced attention, self-control, and awareness involving neuroplasticity in the ACC/mPFC, striatum, insula, and other brain areas [3, 4]. These biomarkers can be the target of diagnosis and treatment of ADHD.

Children and adolescents with ADHD often receive different formats of mindfulness medita‐ tion (e.g., MYmind program), with either the patients receive training only, or the caregivers receive concurrent mindfulness training as well [25, 26]. Overall, results are promising and demonstrate feasibility of mindfulness meditation in ADHD population. However, methodo‐ logical issues pertaining to small samples, a lack of active comparison groups, and short followup periods limit generalizability suggest the need for longitudinal randomized rigorous trials [25, 26].

Studies in adult ADHD samples also provide promising preliminary support for mindfulness meditation (e.g., mindful awareness practices). In addition to mindfulness training, some studies have included mindfulness training as a component also showed the positive results related to ADHD symptoms (e.g., modified dialectical behavior therapy, mindfulness-based cognitive therapy). In sum, existing studies support the acceptability and feasibility in child, adolescent, and adult with ADHD and preliminary effectiveness of mindfulness in the treatment of ADHD [14]. Future studies are required to address methodological limitations of these studies.

### **5. Other factors in ADHD treatment**

by the attention network test (ANT). They also reported lower anxiety, depression, anger, and fatigue and higher vigor. In addition, we found that after a stressful task, IBMT participants showed significantly reduced stress responses, as measured by salivary cortisol, and increased immunoreactivity, as measured by salivary immunoglobulin A [6]. These results indicated that brief mindfulness meditation – IBMT – can improve attention and self-regulation ability. A similar study showed that in comparison with a book listening control group, 4 days of meditation training enhanced the ability to sustain attention [8]. If the participants practiced 1 month of IBMT (10 h in total), we found improved efficiency of executive attention, alertness

**Figure 2.** Integrated translational model. Mindfulness meditation includes at least three components that interact close‐ ly to constitute a process of enhanced self-regulation: enhanced attention control, improved emotion regulation, and

We further studied the brain and body mechanisms of IBMT [18]. During and after 5 days of training, the IBMT group showed significantly better physiological responses, including heart rate, respiratory amplitude and rate, and skin conductance response than the relaxation control. In addition, the IBMT group has significant differences in heart rate variability (HRV) and EEG power during and after training, suggesting greater involvement of the autonomic nervous system (ANS). Imaging data demonstrated stronger subgenual/ventral ACC activity in the IBMT group, and ACC theta was correlated with high-frequency HRV, suggesting control by the ACC over parasympathetic activity. These results indicate that after 5 days of training, the IBMT group shows better regulation of the ANS through a ventral midline brain system than does the relaxation group. This altered state probably reflects training in the coordination of body and mind given in the IBMT, but not in the control group [18]. Other studies also showed the ACC involvement [3, 4, 24]. Taken together, these evidences suggest that mindfulness practice is associated with enhanced attention, self-control, and awareness involving neuroplasticity in the ACC/mPFC, striatum, insula, and other brain areas [3, 4].

(sustained attention), and basal cortisol and immune function [3, 22, 23].

altered self-awareness that targets the core symptoms of ADHD.

296 ADHD - New Directions in Diagnosis and Treatment

These biomarkers can be the target of diagnosis and treatment of ADHD.

As one form of ADHD treatment, mindfulness meditation can be subdivided into methods involving focused attention and those involving open monitoring of present-moment experi‐ ence [3–5]. These two techniques involve different attention and self-control strategies that may help ameliorate different ADHD symptoms. For example, "attention deficit" means brain hypoactivity that could not support attention functioning (e.g., sustained attention), whereas "attention hyperactivity" indicates overactivity that includes impulsivity. Thus, focused attention and open monitoring mindfulness may sensitize two extremes of attention problems in clinical practice using mindfulness intervention.

Regarding the ADHD different subtypes in responding to mindfulness intervention, clinical observations showed that there are differences in the ease of engaging in mindfulness based on the ADHD subtypes. In general, inattentive subtypes have easier time with quiet sitting practice and combined or hyperactive types struggle more because of restlessness. The latter responds more to body movement-based practice over quiet observation. Once engaged in the mindfulness practices, there also may be differences in outcomes. So far, there has not been enough research (studies with enough power) to tease out the effects of subtypes.

In addition, many other factors such as cultural differences in clinical strategy and social support can further complicate ADHD treatment. For instance, at least 9% school-aged children in the United States have been diagnosed with ADHD and are taking medications because ADHD is thought as a biological disorder with biological causes and the preferred treatment is stimulant medications such as Ritalin [27]. However, only less than 1% kids in France are diagnosed and medicated for ADHD. The drastic difference may due to the fact that in France, ADHD is viewed as a medical condition that has psychosocial and situational causes. Therefore, instead of using medications to treat children, French doctors look for the underlying social issue that is causing the problematic behavior. The common treatment for these underlying social context problems is psychotherapy or family counseling. This is a very different perspective from the American doctors, who tend to attribute all symptoms to a biological dysfunction such as a chemical imbalance in the child's brain [27].

### **6. Future directions**

ADHD has often been thought to reflect dysfunction of prefrontal–striatal circuitry, but the involvement of other circuits has frequently been largely overlooked. Recent systems of neuroscience-based approaches to brain dysfunction have facilitated the development of models of ADHD pathophysiology, which include a number of different large-scale restingstate networks such as prefrontal–striatal, frontoparietal, dorsal attentional, motor, visual, and default networks. A better understanding of large-scale brain systems in ADHD could greatly advance our diagnosis and treatment of ADHD [21].

Recent commercial claims suggest that computer-based cognitive training (e.g., working memory) can remediate ADHD impairments and provide lasting improvement in attention, impulse control, and other cognitive and social functioning. However, the meta-analysis indicates that training attention or executive functions did not significantly improve attention and the targeted executive functions. The future rigorous RCT cognitive training studies may provide the possibility to improve executive function deficits and benefit ADHD [28]. We term this type of training as "network training" that exercises certain brain circuits using repeated cognitive tasks (e.g., working memory). In contrast, mindfulness meditation focuses on changing brain and body state that can affect many networks; we call it as "state training" [9, 10, 22]. Since network training and state training involve different brain networks, the combination of these two methods may be more effective [10]. In sum, a holistic approach to ADHD preventive intervention could be the trend in the field.

It should be noted that although the empirical evidences have shown the promising effects of mindfulness meditation on attention control, emotion regulation, and impulsivity reduction in healthy and ADHD populations, future research should consider the use of longitudinal randomized clinical trial to validate the effectiveness of mindfulness-based intervention for ADHD [29] and how this intervention could better transfer into school and workplace environment. If supported by rigorous studies, the practice of mindfulness meditation could serve as the treatment of clinical disorders and might facilitate the cultivation of a healthy mind and increased well-being.

### **Acknowledgements**

This work was supported by the U.S. Office of Naval Research.

### **Author details**

underlying social issue that is causing the problematic behavior. The common treatment for these underlying social context problems is psychotherapy or family counseling. This is a very different perspective from the American doctors, who tend to attribute all symptoms to a

ADHD has often been thought to reflect dysfunction of prefrontal–striatal circuitry, but the involvement of other circuits has frequently been largely overlooked. Recent systems of neuroscience-based approaches to brain dysfunction have facilitated the development of models of ADHD pathophysiology, which include a number of different large-scale restingstate networks such as prefrontal–striatal, frontoparietal, dorsal attentional, motor, visual, and default networks. A better understanding of large-scale brain systems in ADHD could greatly

Recent commercial claims suggest that computer-based cognitive training (e.g., working memory) can remediate ADHD impairments and provide lasting improvement in attention, impulse control, and other cognitive and social functioning. However, the meta-analysis indicates that training attention or executive functions did not significantly improve attention and the targeted executive functions. The future rigorous RCT cognitive training studies may provide the possibility to improve executive function deficits and benefit ADHD [28]. We term this type of training as "network training" that exercises certain brain circuits using repeated cognitive tasks (e.g., working memory). In contrast, mindfulness meditation focuses on changing brain and body state that can affect many networks; we call it as "state training" [9, 10, 22]. Since network training and state training involve different brain networks, the combination of these two methods may be more effective [10]. In sum, a holistic approach to

It should be noted that although the empirical evidences have shown the promising effects of mindfulness meditation on attention control, emotion regulation, and impulsivity reduction in healthy and ADHD populations, future research should consider the use of longitudinal randomized clinical trial to validate the effectiveness of mindfulness-based intervention for ADHD [29] and how this intervention could better transfer into school and workplace environment. If supported by rigorous studies, the practice of mindfulness meditation could serve as the treatment of clinical disorders and might facilitate the cultivation of a healthy mind

biological dysfunction such as a chemical imbalance in the child's brain [27].

**6. Future directions**

298 ADHD - New Directions in Diagnosis and Treatment

and increased well-being.

**Acknowledgements**

advance our diagnosis and treatment of ADHD [21].

ADHD preventive intervention could be the trend in the field.

This work was supported by the U.S. Office of Naval Research.


### **References**


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[10] Tang YY, Posner MI. Training brain networks and states. Trends Cogn Sci. 2014: 18:

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[21] Castellanos FX, Proal E. Large-scale brain systems in ADHD: beyond the prefrontal– striatal model. Trends Cogn Sci. 2012; 16:17–26. DOI: 10.1016/j.tics.2011.11.007.

[22] Tang YY, Rothbart MK, Posner MI. Neural correlates of establishing, maintaining and switching brain states. Trends Cogn Sci. 2012;16: 330–337. DOI: 10.1016/j.tics.

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**Chapter 14**

**Therapy for ADHD Directed Towards Addressing the Dual Imbalances in Mental Effort and Reward as Illustrated in the Mental Effort-Reward Imbalances Model (MERIM)**

Alison Poulton

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60814

#### **Abstract**

In this chapter we describe a clinical model for ADHD: the Mental Effort Reward Imbalances Model (MERIM). We use this model to explain some of the behaviour commonly observed in children with ADHD and to guide approaches to treatment. The MERIM views the behaviour associated with ADHD as an outcome of two unfavourable imbalances: 1.Imbalance of the level of mental effort required for achievement. 2.Imbalance in the level of reward experienced. These imbalances each contribute to lower levels of achievement and fewer rewarding experiences in ADHD. This results in a poorer mood with less tolerance for frustration, together with seeking rewards that do not involve high levels of effort. The concept of ADHD as dual imbalances in mental effort and reward gives a useful framework for understanding the behaviour and the strategies that individuals use to compensate and improve their mood.

**Keywords:** attention deficit hyperactivity disorder, oppositional defiant disorder, mental effort reward imbalances model, emotional self regulation, reward deficien‐ cy syndrome

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

In this chapter we describe a clinical model for ADHD: the Mental Effort-Reward Imbalances Model (MERIM) [1]. We use this model to explain some of the behaviour commonly observed in children with ADHD and to guide approaches to treatment. The MERIM is a clinical model which we have found useful for explaining some of the more difficult behaviour observed in individuals with ADHD. This is particularly valuable for parents and teachers because a better insight into the reason the behaviour works for the child helps promote understanding and empathy.

The MERIM views the behaviour associated with ADHD as an outcome of two unfavourable imbalances:


These imbalances each contribute to lower levels of achievement and fewer rewarding experiences in ADHD. This results in a poorer mood with less tolerance for frustration, together with seeking rewards that do not involve high levels of effort. The concept of ADHD as dual imbalances in mental effort and reward gives a useful framework for understanding the behaviour and the strategies that individuals use to compensate and improve their mood.

This chapter is structured with some clinical descriptions and some sections which outline the background and evidence. As much of the descriptive information is based on observation, it cannot be fully referenced. It is therefore up to the readers to draw on their own observations, experience and intuition for validation.

### **2. Background**

#### **2.1. What is ADHD?**

ADHD is a common condition with an estimated population prevalence of between 2.6% and 11% in children [2-5], being higher in boys and younger children. It is also common in adults, with estimates varying from 2.8% to 4.7% [6-8]. People with ADHD have impaired functioning due to difficulties with sustaining attention and with controlling impulsive behaviour [9]. They also often have a high level of physical activity.

There is evidence that individuals with ADHD have functional deficits in the prefrontal cortex, which is the part of the brain most involved in executive functioning [10]. Executive functions include working memory, reasoning, planning and resisting distractions [11]. ADHD is also associated with reduced motivation attributable to deficits in the striatum affecting the dopamine reward pathway and it may impact on the functioning of the amygdala, which is associated with the experience of emotions [12, 13]. The stimulant medications used in the treatment of ADHD increase the levels of the neurotransmitters noradrenaline and dopamine, and lead to improvement in the executive functioning deficits and the mood [14, 15].

ADHD is a clinical diagnosis and depends on an individual showing the behavioural features to a greater extent than would be expected for their age or developmental level and having associated problems in functioning. The features of ADHD are not specific, also occurring within the normal population but not with sufficient severity to cause significant impairment. ADHD typically results in difficulty completing tasks, which leads to underachievement and a less rewarding existence. A popular misconception is that individuals with ADHD will tend to be similar in their behaviour. However, within the normal population there is substantial variation in personality types, skills and abilities. When a diagnosis such as ADHD is super‐ imposed, it adds a further source of variability. ADHD can occur in people of all levels of intellectual ability. Intellectual ability is one of the most important personal attributes that modifies the expression of ADHD.

### *2.1.1. Inattention*

**1. Introduction**

304 ADHD - New Directions in Diagnosis and Treatment

empathy.

imbalances:

In this chapter we describe a clinical model for ADHD: the Mental Effort-Reward Imbalances Model (MERIM) [1]. We use this model to explain some of the behaviour commonly observed in children with ADHD and to guide approaches to treatment. The MERIM is a clinical model which we have found useful for explaining some of the more difficult behaviour observed in individuals with ADHD. This is particularly valuable for parents and teachers because a better insight into the reason the behaviour works for the child helps promote understanding and

The MERIM views the behaviour associated with ADHD as an outcome of two unfavourable

These imbalances each contribute to lower levels of achievement and fewer rewarding experiences in ADHD. This results in a poorer mood with less tolerance for frustration, together with seeking rewards that do not involve high levels of effort. The concept of ADHD as dual imbalances in mental effort and reward gives a useful framework for understanding the behaviour and the strategies that individuals use to compensate and improve their mood. This chapter is structured with some clinical descriptions and some sections which outline the background and evidence. As much of the descriptive information is based on observation, it cannot be fully referenced. It is therefore up to the readers to draw on their own observations,

ADHD is a common condition with an estimated population prevalence of between 2.6% and 11% in children [2-5], being higher in boys and younger children. It is also common in adults, with estimates varying from 2.8% to 4.7% [6-8]. People with ADHD have impaired functioning due to difficulties with sustaining attention and with controlling impulsive behaviour [9]. They

There is evidence that individuals with ADHD have functional deficits in the prefrontal cortex, which is the part of the brain most involved in executive functioning [10]. Executive functions include working memory, reasoning, planning and resisting distractions [11]. ADHD is also associated with reduced motivation attributable to deficits in the striatum affecting the dopamine reward pathway and it may impact on the functioning of the amygdala, which is associated with the experience of emotions [12, 13]. The stimulant medications used in the treatment of ADHD increase the levels of the neurotransmitters noradrenaline and dopamine,

and lead to improvement in the executive functioning deficits and the mood [14, 15].

**1.** Imbalance of the level of mental effort required for achievement

**2.** Imbalance in the level of reward experienced

experience and intuition for validation.

also often have a high level of physical activity.

**2. Background**

**2.1. What is ADHD?**

People with ADHD have more difficulty than others for tasks that involve sustained attention, particularly if the task is mentally demanding. Therefore, they would cope better for tasks that are shorter, easier or have a particular interest that stimulates attention. Individuals with ADHD may be able to concentrate for prolonged periods of time on electronic games. These typically do not involve the effort of independent or creative thought and also provide constant stimulation that catches and keeps the attention.

One characteristic of people with ADHD is that they are easily distracted. This may occur while they are talking and may lead to forgetting what they were going to say or losing the point while telling a story. Alternatively, becoming distracted during a task and then forgetting to go back and get it finished can lead to a person being inefficient and disorganised. People with ADHD often have difficulty ignoring distractions and this may make them particularly intolerant to background noise while trying to concentrate. Losing focus on schoolwork may lead to disruptive behaviour in class as a response to the boredom that comes with having nothing to do. Lack of attention predisposes to missing instructions and making careless mistakes. A child with ADHD may have difficulty with age appropriate play, quickly losing concentration and moving on to the next task or looking around for something more enter‐ taining to relieve boredom.

ADHD is more disabling in children who have learning difficulties. This is because they have to concentrate longer and harder to acquire the same skills. The more difficult the task is for them, the more quickly they will fatigue mentally and give up. Conversely, an able child with ADHD may have no difficulty achieving at school during the early years. However, as the work becomes more demanding in high school, intellectual ability by itself may no longer be sufficient; and if they are unable to concentrate in class and study consistently, their grades may decline. Once a person leaves school, they usually have more opportunity to follow their interests and strengths and ADHD may therefore be less of a problem. However, lack of organisational ability may become more disabling when an individual has to contend with the complexities of functioning in society as an adult.

### *2.1.2. Hyperactivity*

Hyperactivity is common in ADHD and is the most easily recognised feature. The hyperac‐ tivity often reflects the changing focus of attention as a child moves rapidly from one distrac‐ tion to another. The restless energy may make it difficult to remain seated for any length of time, increasing the challenge for table-based activities. A child with ADHD may also be excessively talkative, sometimes apparently talking just for the sake of it and may lack the patience to stop talking and listen. Hyperactivity tends to diminish with age [16] and although some adults with ADHD may be still hyperactive, a hyperactive young child may develop into an underactive, unmotivated adolescent.

### *2.1.3. Impulsivity*

People with ADHD often have quick reactions that occur without having time to stop, think and make a decision. Impulsivity can have an adverse effect on peer relationships as a child may unintentionally hurt or offend or repeatedly get into trouble for the same misdemeanour, such as impulsively calling out in class. Because of the lack of any active decision-making, these unregulated actions may be considered accidental by the child who may be inclined to deny responsibility. The lack of impulse control can lead to anxiety and low self-esteem as the child may suddenly be in trouble without any prior warning or intent.

#### *2.1.4. Oppositional Defiant Disorder (ODD)*

ODD is very frequently associated with ADHD. It is a common condition, with a community sample in the United Kingdom showing a prevalence of 2.2% in children aged 8–19 [2]. Among children with ADHD, about 38–52% also meet diagnostic thresholds for ODD [2, 17, 18], and of the remainder many will have symptoms of ODD but not of sufficient severity or consistency to meet the diagnostic criteria. People with ODD typically overreact with anger in response to minor frustrations [9]. The lack of control over impulsive behaviour in ADHD becomes even worse when associated with anger as such children may incorrectly interpret another child's actions as hostile [19]. For example, if accidently pushed, a child may automatically react by hitting. This can make individuals prone to involvement in physical fights and they may show no fear, even fighting with children who are much older and stronger. Other children may find this loss of control amusing and may deliberately provoke or bully such a child for a reaction. ODD is also associated with deliberately annoying people and sometimes with planned acts of spite. ODD is therefore a risk factor for bullying, either as the perpetrator, or the victim, or both. Children with ADHD sometimes consider the features of ODD to be an intrinsic part of their ADHD identity and may view the threat to their peers of their uncon‐ trolled aggression as a source of power or strength rather than a weakness [21]. ODD is also associated with a negative attitude and a tendency to blame others and deny responsibility, argue and oppose authority.

#### *2.1.5. Functional impairment in ADHD*

The key to diagnosis of ADHD is not simply a matter of expressing the symptoms but, more importantly, it relates to the consequent impairment in functioning. When assessing the extent of functional impairment, it is useful to consider the level of achievement in the following modalities: academic achievement in relation to ability; peer relationships; ability to function at home and/or at school without generating unreasonable levels of stress or disruption and level of self-esteem.

#### **2.2. Why is ADHD different from normal functioning? – The Mental Effort-Reward Imbalances Model (MERIM)**

*2.1.2. Hyperactivity*

*2.1.3. Impulsivity*

an underactive, unmotivated adolescent.

306 ADHD - New Directions in Diagnosis and Treatment

*2.1.4. Oppositional Defiant Disorder (ODD)*

argue and oppose authority.

*2.1.5. Functional impairment in ADHD*

Hyperactivity is common in ADHD and is the most easily recognised feature. The hyperac‐ tivity often reflects the changing focus of attention as a child moves rapidly from one distrac‐ tion to another. The restless energy may make it difficult to remain seated for any length of time, increasing the challenge for table-based activities. A child with ADHD may also be excessively talkative, sometimes apparently talking just for the sake of it and may lack the patience to stop talking and listen. Hyperactivity tends to diminish with age [16] and although some adults with ADHD may be still hyperactive, a hyperactive young child may develop into

People with ADHD often have quick reactions that occur without having time to stop, think and make a decision. Impulsivity can have an adverse effect on peer relationships as a child may unintentionally hurt or offend or repeatedly get into trouble for the same misdemeanour, such as impulsively calling out in class. Because of the lack of any active decision-making, these unregulated actions may be considered accidental by the child who may be inclined to deny responsibility. The lack of impulse control can lead to anxiety and low self-esteem as the

ODD is very frequently associated with ADHD. It is a common condition, with a community sample in the United Kingdom showing a prevalence of 2.2% in children aged 8–19 [2]. Among children with ADHD, about 38–52% also meet diagnostic thresholds for ODD [2, 17, 18], and of the remainder many will have symptoms of ODD but not of sufficient severity or consistency to meet the diagnostic criteria. People with ODD typically overreact with anger in response to minor frustrations [9]. The lack of control over impulsive behaviour in ADHD becomes even worse when associated with anger as such children may incorrectly interpret another child's actions as hostile [19]. For example, if accidently pushed, a child may automatically react by hitting. This can make individuals prone to involvement in physical fights and they may show no fear, even fighting with children who are much older and stronger. Other children may find this loss of control amusing and may deliberately provoke or bully such a child for a reaction. ODD is also associated with deliberately annoying people and sometimes with planned acts of spite. ODD is therefore a risk factor for bullying, either as the perpetrator, or the victim, or both. Children with ADHD sometimes consider the features of ODD to be an intrinsic part of their ADHD identity and may view the threat to their peers of their uncon‐ trolled aggression as a source of power or strength rather than a weakness [21]. ODD is also associated with a negative attitude and a tendency to blame others and deny responsibility,

The key to diagnosis of ADHD is not simply a matter of expressing the symptoms but, more importantly, it relates to the consequent impairment in functioning. When assessing the extent of functional impairment, it is useful to consider the level of achievement in the following

child may suddenly be in trouble without any prior warning or intent.

The most fundamental problem in ADHD is the inability to achieve consistently at a level appropriate to a person's ability. The individual would therefore be intellectually capable of higher achievement and have no physical disability sufficient to explain their level of ach‐ ievement. For normal people, getting through their daily routine involves a constant stream of tasks that require effort and lead to a series of achievements, most of them small. These achievements are each associated with the satisfaction of task completion – the feeling of a job done well – which all help to sustain a stable and amicable mood. Therefore, for example, you get up in the morning, you put some effort into getting dressed and ready to go. Your assessment is that you look presentable in your clothes. You have achieved and you feel good about yourself and ready to put further effort into the next challenge. Achievement therefore involves some level of effort and is associated with a feeling of satisfaction (reward) which contributes to a good mood and a readiness to attempt the next task. Good mood is important for normal functioning and it has been shown that individuals who have a greater tendency to react with positive emotions have better emotional, psychological and social well-being [22]. They have better physical health and fewer days off work. The cycle of achievement, reward, good mood and further achievement is represented in Figure 1.

**Figure 1.** Schematic representation of the achievement and reward sequence

In ADHD the sequential pathway shown in Figure 1 does not work as effectively as it should. According to the MERIM, there are two places where it can malfunction. The first is if the cost or effort required to achieve is disproportionately great, as occurs in association with executive functioning deficits leading to less efficient thought processes in ADHD. The second is if a person experiences an inadequate level of reward. The MERIM views ODD as a deficit in the experience of reward, caused by neurochemical underactivity in the reward pathway. The impact of these two deficits on achievement and reward is illustrated in Figure 2.

Figure reproduced with permission by Australasian Psychiatry [1]

**Figure 2.** Mental Effort-Reward Imbalances Model (MERIM)

### *2.2.1. Inefficient mental processes in ADHD leading to higher cost for achievement*

In ADHD, mental processes (executive functions) are less efficient and therefore achievement requires more mental effort. This is like a runner who has to run uphill. It is not that running is a task that is too difficult for him, but he will tire more quickly than others who are running along level ground. He will either keep going but run more slowly, or he will try and run as fast as the others and then have to stop to rest. It is like this for mental tasks for people with ADHD. The mental fatigue is genuine and may affect academic functioning, social interactions and managing the daily routine at home. Children with ADHD often develop various ways of disguising or adapting to it. Some of these could be considered as 'taking mental short-cuts'.

#### *2.2.1.1. Schoolwork*

A child with ADHD may rush to get work finished within a time span for which he can concentrate. Alternatively, he may work for a bit and then stop working and appear to daydream, as if his mind is going blank like a computer on standby. Some just limit their rate of mental effort to a manageable level by working slowly. This may be disguised by giving too much attention to neatness and therefore doing very little of the more cognitively demanding aspects of the work. Creating a distraction may also be an effective work avoidance strategy. For example, a little girl developed the pattern of turning around and giving her mother a cuddle whenever she felt under too much pressure to concentrate on her homework. Other more common avoidance strategies include changing the subject or asking an irrelevant question.

#### *2.2.1.2. Social interactions*

Conversation demands mental effort, both for listening and for thinking and formulating the sentences required for a response. Children with ADHD often use strategies which conserve their mental effort. If a child is asked about who they have played with at school, this involves the effort of thinking back to an earlier part of the day and it may be easier to respond: 'I don't remember'.

### *2.2.1.3. Routine tasks*

Figure reproduced with permission by Australasian Psychiatry [1]

*2.2.1. Inefficient mental processes in ADHD leading to higher cost for achievement*

In ADHD, mental processes (executive functions) are less efficient and therefore achievement requires more mental effort. This is like a runner who has to run uphill. It is not that running is a task that is too difficult for him, but he will tire more quickly than others who are running along level ground. He will either keep going but run more slowly, or he will try and run as fast as the others and then have to stop to rest. It is like this for mental tasks for people with ADHD. The mental fatigue is genuine and may affect academic functioning, social interactions and managing the daily routine at home. Children with ADHD often develop various ways of disguising or adapting to it. Some of these could be considered as 'taking mental short-cuts'.

A child with ADHD may rush to get work finished within a time span for which he can concentrate. Alternatively, he may work for a bit and then stop working and appear to daydream, as if his mind is going blank like a computer on standby. Some just limit their rate of mental effort to a manageable level by working slowly. This may be disguised by giving too much attention to neatness and therefore doing very little of the more cognitively demanding aspects of the work. Creating a distraction may also be an effective work avoidance strategy. For example, a little girl developed the pattern of turning around and giving her mother a cuddle whenever she felt under too much pressure to concentrate on her homework. Other more common avoidance strategies include changing the subject or asking an irrelevant

Conversation demands mental effort, both for listening and for thinking and formulating the sentences required for a response. Children with ADHD often use strategies which conserve

**Figure 2.** Mental Effort-Reward Imbalances Model (MERIM)

308 ADHD - New Directions in Diagnosis and Treatment

*2.2.1.1. Schoolwork*

question.

*2.2.1.2. Social interactions*

Children with ADHD often have difficulty carrying out instructions, particularly if given several together. A child may try to look as though he is listening, keeping his eyes on the speaker but not fully concentrating and therefore unable to follow an explanation or instruc‐ tion. Sometimes a child may only listen to part of a sentence and guess the rest. Remembering several instructions often involves the effort of repeating them mentally. Rehearsal strategies and recall may be less efficient in ADHD [23]. If a person is not putting in adequate mental effort or is distracted by other thoughts, instructions may easily be forgotten.

If a person is achieving less on account of the disproportionate or unsustainable effort they have to put into completing a task, they will experience less satisfaction. They may be less ready to put further effort into the next task, with a tendency to give up easily. Inefficient mental processes therefore contribute to the underachievement associated with ADHD and consequent low self-esteem. Some individuals attempt to preserve their self-esteem by reducing their goals in life to a level that is more achievable. This may lead to dropping out of school into unskilled work or state benefits. This may be framed as a deliberate choice rather than failure to achieve.

#### *2.2.2. Inadequate experience of reward from achievement leading to symptoms of ODD*

Getting pleasure from the little things in life is important as this helps to maintain a good mood and amicable outlook [24]. However, if the subjective experience of reward is inadequate, a person is likely to feel negative and dissatisfied. The resultant low mood may lead to lack of motivation stemming from the perception that tasks are not worth the effort. Alternatively, a person may compensate by seeking activities that are more highly rewarding or that give reward for less effort. The dissatisfaction associated with inadequate experience of reward predisposes to the characteristic behaviour of ODD.

In this chapter, the term ODD is being used to include all the disruptive, impulse control and conduct disorders (ODD, intermittent explosive disorder, antisocial personality disorder, disruptive mood dysregulation disorder, conduct disorder) [9]. These conditions are associated with temper outbursts (problems in emotional regulation) and with behav‐ iour problems including rule breaking and antisocial acts, with the specific diagnosis designated according to the main symptoms and the relative balance of the mood versus the behavioural dysfunction.

Deficits in reward do not only occur in ADHD/ODD but are also associated with other conditions such as addictions and obesity [25]. These are sometimes termed reward deficiency syndromes and are characterised by the strategies that people use to compensate for their inadequate experience of reward [26]. These may include comfort eating, compulsive gam‐ bling, internet or gaming addiction and drug abuse.

### **2.3. Relating the MERIM to the DSM and other models of ADHD**

A formal diagnosis of ADHD is usually made in accordance with specific diagnostic criteria, such as those published by the American Psychiatric Association in their Diagnostic and Statistical Manual of Mental Disorders (DSM), the current edition being DSM-5 [9]. The diagnosis is based on meeting a sufficient number of the DSM-5 criteria for inattention, hyperactivity and impulsivity, with associated impairment in functioning. ADHD is classified as combined type (meets sufficient criteria for inattention and for hyperactivity–impulsivity), predominantly inattentive ADHD (meets criteria for inattention but not for hyperactivity– impulsivity), or hyperactive–impulsive ADHD (does not meet criteria for inattention). The diagnosis of hyperactive–impulsive ADHD tends only to be made in preschool children, who are at a stage of life in which the lack of ability to sustain concentration may be less evident. A diagnosis of hyperactive–impulsive ADHD may therefore be revised to ADHD combinedtype as a child matures [27].

Several of the DSM-5 diagnostic criteria for ADHD are outcome-based and relate to lack of achievement in task completion. These do not dictate the causal mechanism and are therefore not specific to underachievement due to executive functioning deficits. Children who under‐ achieve due to inadequate experience of reward would also qualify. According to the MERIM, the dual deficits in executive functioning and reward experience contribute independently to the lack of achievement associated with ADHD (Figure 2). Because these two mechanisms are both highly prevalent and are additive in their effects on achievement, most people diagnosed with ADHD using the DSM are likely to have some degree of deficit in each. This provides an explanation for the substantial levels of diagnosable ODD among children with DSMdiagnosed ADHD. The MERIM would therefore consider the negative attitude and outlook that is frequently associated with ADHD as evidence of some degree of reward deficiency syndrome contributing to the symptoms of ADHD.

The MERIM is not the only model for ADHD that competes with that described in the DSM. The MERIM is probably the simplest model as it does not attempt to relate the symptoms of ADHD to specific testable modalities of executive functioning. Instead, it starts from the premise that unspecified executive functioning deficits mean that cognition is less efficient in ADHD and therefore requires more mental effort. It also does not really provide any explan‐ ation for the hyperactivity or the impulsivity. It has similarities with the model put forward by Douglas, which considers ADHD to be a result of four predispositions: the desire for immediate gratification, reluctance to invest mental effort, impaired impulse control and impairment in modulating arousal or alertness [28]. However, although it does not address arousal and impulse control, in the area of gratification the MERIM goes further than Douglas in that the desire for reward is explained as being an intrinsic deficit that reduces the individ‐ ual's subjective experience of reward and interacts with the motivation for mental effort.

Barkley postulated the primary problem in ADHD to be inadequate response inhibition [27]. He gave this as the underlying cause for deficits in executive functions that include working memory, inner speech and verbal reasoning, analysis of behaviour and also for deficits in emotional regulation. According to this model, the symptoms of ODD would be explainable as manifestations of the emotional dysregulation associated with ADHD. Therefore, with Barkley's model there is also no need for any additional diagnosis of ODD. However, although Barkley's model includes ODD in the overall symptomatology of ADHD, unlike the MERIM it does not explain the observation that the main emotional component of ADHD should be negative.

**2.3. Relating the MERIM to the DSM and other models of ADHD**

type as a child matures [27].

310 ADHD - New Directions in Diagnosis and Treatment

syndrome contributing to the symptoms of ADHD.

A formal diagnosis of ADHD is usually made in accordance with specific diagnostic criteria, such as those published by the American Psychiatric Association in their Diagnostic and Statistical Manual of Mental Disorders (DSM), the current edition being DSM-5 [9]. The diagnosis is based on meeting a sufficient number of the DSM-5 criteria for inattention, hyperactivity and impulsivity, with associated impairment in functioning. ADHD is classified as combined type (meets sufficient criteria for inattention and for hyperactivity–impulsivity), predominantly inattentive ADHD (meets criteria for inattention but not for hyperactivity– impulsivity), or hyperactive–impulsive ADHD (does not meet criteria for inattention). The diagnosis of hyperactive–impulsive ADHD tends only to be made in preschool children, who are at a stage of life in which the lack of ability to sustain concentration may be less evident. A diagnosis of hyperactive–impulsive ADHD may therefore be revised to ADHD combined-

Several of the DSM-5 diagnostic criteria for ADHD are outcome-based and relate to lack of achievement in task completion. These do not dictate the causal mechanism and are therefore not specific to underachievement due to executive functioning deficits. Children who under‐ achieve due to inadequate experience of reward would also qualify. According to the MERIM, the dual deficits in executive functioning and reward experience contribute independently to the lack of achievement associated with ADHD (Figure 2). Because these two mechanisms are both highly prevalent and are additive in their effects on achievement, most people diagnosed with ADHD using the DSM are likely to have some degree of deficit in each. This provides an explanation for the substantial levels of diagnosable ODD among children with DSMdiagnosed ADHD. The MERIM would therefore consider the negative attitude and outlook that is frequently associated with ADHD as evidence of some degree of reward deficiency

The MERIM is not the only model for ADHD that competes with that described in the DSM. The MERIM is probably the simplest model as it does not attempt to relate the symptoms of ADHD to specific testable modalities of executive functioning. Instead, it starts from the premise that unspecified executive functioning deficits mean that cognition is less efficient in ADHD and therefore requires more mental effort. It also does not really provide any explan‐ ation for the hyperactivity or the impulsivity. It has similarities with the model put forward by Douglas, which considers ADHD to be a result of four predispositions: the desire for immediate gratification, reluctance to invest mental effort, impaired impulse control and impairment in modulating arousal or alertness [28]. However, although it does not address arousal and impulse control, in the area of gratification the MERIM goes further than Douglas in that the desire for reward is explained as being an intrinsic deficit that reduces the individ‐ ual's subjective experience of reward and interacts with the motivation for mental effort.

Barkley postulated the primary problem in ADHD to be inadequate response inhibition [27]. He gave this as the underlying cause for deficits in executive functions that include working memory, inner speech and verbal reasoning, analysis of behaviour and also for deficits in emotional regulation. According to this model, the symptoms of ODD would be explainable as manifestations of the emotional dysregulation associated with ADHD. Therefore, with

#### **2.4. Striving for happiness: The balance between adequate reward and manageable effort**

According to the MERIM, the clinical presentation of a child with ADHD will vary according to the severity of the imbalances in the level of mental effort required for achievement and the level of reward experienced. The particular clinical problems depend partly on the behavioural outcomes resulting from the underlying neurochemical deficits and partly on the strategies an individual develops to compensate and cope with these deficits.

People who have deficits in their experience of reward may feel miserable and moody. However, many develop strategies that make their life more rewarding and result in improv‐ ing their mood and feeling happier. The particular strategies depend partly on the relative balance of deficits in executive functioning and reward experience and also on a person's intellectual strengths and weaknesses. Symptoms of reward deficit include arguing, deliber‐ ately annoying people and being spiteful or vindictive. Although these strategies might not initially appear to be obviously rewarding, there are study data that suggest otherwise. A study of adolescents with aggressive conduct disorder found that they showed an atypical response when observing inflicted pain, with activation in areas of the brain associated with pleasure [29]. Clinical observations also provide intuitive support: why would a child be deliberately spiteful if this were not pleasurable in some way? Humans are a social species and even more fundamental than communicating with language is communication that involves influencing and manipulating others' emotions. This can be done in a positive way, for example, telling a good joke that makes people laugh or giving someone a pleasant surprise that makes them happy. However, positive experiences can be difficult to organise and it is often easier to hurt or upset someone. Parents sometimes say that their child with ADHD will argue that black is white. This implies that arguing may not be a rational debate but rather an end in itself. Perceptive parents may observe that their child would start out in an angry mood but after a prolonged argument that frustrates or even hurts and upsets the parent, the child's mood may have improved. Therefore, the strategy works for the child, but clearly not for the parent. Winning is also a rewarding experience and older teenagers or adults may actively look for opportunities for starting an argument that they think they can win. Alternatively, children may become skilled at annoying or upsetting other family members, or playing one parent off against the other, and then quietly smiling at the resulting chaos. Children with less sophisti‐ cation may simply resort to unprovoked physical violence when they feel irritable. Eliciting a negative social response by being deliberately difficult may therefore be an effective strategy that compensates for deficits in the subjective experience of reward. In the present context, any such activity that is carried out with the intention of causing pain or distress to another person has been classified as bullying. Therefore, a child may bully a parent or a teacher. The positive impact of bullying on mood is shown in Figure 3.

Figure 3: Oppositional behaviour that compensates for lack of reward

Although the behaviour that is typically associated with ODD may be effective for compensating for deficits in reward **Figure 3.** Oppositional behaviour that compensates for lack of reward

achievements that vary in the amount of effort they require and the level of reward experienced. For individuals with the most severe deficits in executive functioning and reward, the level of reward has to be particularly high in relation to the level of effort to make the activity worthwhile. Figure 4: Hypothetical balance of effort and reward for various tasks and pastimes. Although the behaviour that is typically associated with ODD may be effective for compen‐ sating for deficits in reward experience, there are other strategies that can also enhance reward. Figure 4 shows a range of tasks, strategies and achievements that vary in the amount of effort they require and the level of reward experienced. For individuals with the most severe deficits in executive functioning and reward, the level of reward has to be particularly high in relation to the level of effort to make the activity worthwhile. Although the behaviour that is typically associated with ODD may be effective for compensating for deficits in reward experience, there are other strategies that can also enhance reward. Figure 4 shows a range of tasks, strategies and achievements that vary in the amount of effort they require and the level of reward experienced. For individuals with the most severe deficits in executive functioning and reward, the level of reward has to be particularly high in relation to the level of effort to make the activity worthwhile.

Figure 4 Hypothetical balance of effort and reward for various tasks and pastimes.

experience, there are other strategies that can also enhance reward. Figure 4 shows a range of tasks, strategies and

(bullying)

ODD and intellectual disability may find that going to the toilet for defecation is not sufficiently rewarding to be worth the effort [29]. An individual may indulge in self-stimulation as this provides reward and is not mentally demanding. Eating is also easy and rewarding, which may explain the recognised association of ODD with obesity [30, 31]. Individuals with

therefore have no meaningful incentive for putting effort into foregoing the satisfaction of hitting a sibling.

ODD and intellectual disability may find that going to the toilet for defecation is not sufficiently rewarding to be worth the effort [29]. An individual may indulge in self-stimulation as this provides reward and is not mentally demanding. Eating is also easy and rewarding, which may explain the recognised association of ODD with obesity [30, 31]. Individuals with ODD are particularly susceptible to addictions to substances such as nicotine or illicit drugs [32, 33]. Conversely, resisting impulses requires substantial effort and is not particularly rewarding. An aggressive and irritable child may

6

6

Comment [AP4]: The arrow connecting Reward with Good mood has become displaced

Comment [AP4]: The arrow connecting Reward with Good mood has become displaced

Intellectual capacity and tenacity determine an individual's capability for achievement. Individuals with severe ADHD, Intellectual capacity and tenacity determine an individual's capability for achievement. Individuals with severe ADHD, **Figure 4.** Hypothetical balance of effort and reward for various tasks and pastimes.

Comment [AP4]: The arrow connecting Reward with Good mood has become displaced Comment [AP4]: The arrow connecting Reward with Good mood has become displaced Intellectual capacity and tenacity determine an individual's capability for achievement. Individuals with severe ADHD, ODD and intellectual disability may find that going to the toilet for defecation is not sufficiently rewarding to be worth the effort [30]. An individual may indulge in self-stimulation as this provides reward and is not mentally demanding. Eating is also easy and rewarding, which may explain the recognised association of ODD with obesity [31, 32]. Individuals with ODD are particularly susceptible to addictions to substances such as nicotine or illicit drugs [33, 34]. Conversely, resisting impulses requires substantial effort and is not particularly rewarding. An aggressive and irritable child may therefore have no meaningful incentive for putting effort into foregoing the satisfaction of hitting a sibling.

Having a higher level of intellectual ability opens the possibility for higher levels of achieve‐ ment. Within the broad categories of chores, schoolwork and social interactions, different activities will vary in their level of interest and difficulty for the individual, with some chores and schoolwork being experienced as less arduous and more rewarding than others. The level of effort required for social interaction is often underestimated. Children generally demand a high level of attention from their friends, and even though play and conversation are reward‐ ing, a child with ADHD may find the intensity of the mental effort unsustainable. The child may consequently withdraw to a less demanding pastime, perhaps playing alongside their friend. A child may find relaxation from a low-level, repetitive activity, which can lead to an incorrect diagnostic label of autism spectrum disorder. Alternatively, a child with ADHD may be more comfortable playing with a younger or less intellectually demanding child, or an older child who can make allowances or entertain.

Some individuals with reward deficit may be intensely competitive, striving for the high rewards that accompany high achievement. Those who are intellectually able may appear 'driven' to exceptional achievement, combating their general dissatisfaction by striving for higher levels of reward. Failure may lead to hostility and antagonism towards those who are more successful. In other words, after not managing exceptional achievement, their reward deficit may be addressed by the less exacting activity of bullying. Some children use compe‐ tition to maintain motivation during play by making every activity into a win–lose situation. Such children may be unable to tolerate losing. However, being competitive may be used adaptively to enhance the reward associated with routine tasks or chores, for example, a child trying to break their record for how quickly they can get dressed.

With the exception of addiction, the higher rewards depend for their value on social recogni‐ tion or an emotional response from one or more other people. Even exceptional achievement needs a social frame of reference in order to designate its value. The higher rewards associated with more positive achievements tend to require higher levels of effort and aptitude. By contrast, negative behaviour such as bullying has a high balance of reward for the mental effort and is therefore easier for those who are less able. However, the rewards that are associated with low levels of effort and achievement may be associated with low self-esteem. This could negate some of the reward experienced from activities such as bullying. Attributing blame to the victim may reduce this negative effect on the bully's self-esteem[19].

The above figure and paragraphs classify a range pastimes and achievements with a model that assigns to each a comparative level of effort and reward. This model predicts the strategies

6

6

Figure 3: Oppositional behaviour that compensates for lack of reward

Figure 3 Oppositional behaviour that compensates for lack of reward

level of effort to make the activity worthwhile.

level of effort to make the activity worthwhile.

to the level of effort to make the activity worthwhile.

**Figure 3.** Oppositional behaviour that compensates for lack of reward

312 ADHD - New Directions in Diagnosis and Treatment

Increasing effort

Increasing effort

Although the behaviour that is typically associated with ODD may be effective for compensating for deficits in reward experience, there are other strategies that can also enhance reward. Figure 4 shows a range of tasks, strategies and achievements that vary in the amount of effort they require and the level of reward experienced. For individuals with the most severe deficits in executive functioning and reward, the level of reward has to be particularly high in relation to the

Although the behaviour that is typically associated with ODD may be effective for compensating for deficits in reward experience, there are other strategies that can also enhance reward. Figure 4 shows a range of tasks, strategies and achievements that vary in the amount of effort they require and the level of reward experienced. For individuals with the most severe deficits in executive functioning and reward, the level of reward has to be particularly high in relation to the

Deliberately upsetting people (bullying)

Deliberately upsetting people (bullying)

Intellectual capacity and tenacity determine an individual's capability for achievement. Individuals with severe ADHD, ODD and intellectual disability may find that going to the toilet for defecation is not sufficiently rewarding to be worth the effort [29]. An individual may indulge in self-stimulation as this provides reward and is not mentally demanding. Eating is also easy and rewarding, which may explain the recognised association of ODD with obesity [30, 31]. Individuals with

therefore have no meaningful incentive for putting effort into foregoing the satisfaction of hitting a sibling.

Intellectual capacity and tenacity determine an individual's capability for achievement. Individuals with severe ADHD, ODD and intellectual disability may find that going to the toilet for defecation is not sufficiently rewarding to be worth the effort [29]. An individual may indulge in self-stimulation as this provides reward and is not mentally demanding. Eating is also easy and rewarding, which may explain the recognised association of ODD with obesity [30, 31]. Individuals with ODD are particularly susceptible to addictions to substances such as nicotine or illicit drugs [32, 33]. Conversely, resisting impulses requires substantial effort and is not particularly rewarding. An aggressive and irritable child may

Increasing reward

Increasing reward

**Figure 4.** Hypothetical balance of effort and reward for various tasks and pastimes.

Figure 4: Hypothetical balance of effort and reward for various tasks and pastimes.

Figure 4 Hypothetical balance of effort and reward for various tasks and pastimes.

Although the behaviour that is typically associated with ODD may be effective for compen‐ sating for deficits in reward experience, there are other strategies that can also enhance reward. Figure 4 shows a range of tasks, strategies and achievements that vary in the amount of effort they require and the level of reward experienced. For individuals with the most severe deficits in executive functioning and reward, the level of reward has to be particularly high in relation and behaviours that are likely to characterise deficient internal reward processes. It is impor‐ tant to recognise the function that such behaviours serve for the individual in generating the sense of satisfaction that they crave. An individual's prevailing mood gives a measure of the success of their strategies for achieving adequate reward within a manageable level of effort.

### **3. Management**

Management of ADHD may involve medication, non-pharmacological treatment or a combi‐ nation of both.

### **3.1. Non-pharmacological management of ADHD**

Non-pharmacological approaches to management usually focus on the areas of functioning which are causing the most problems. This may involve additional learning support or other assistance related to the executive functioning deficits, such as help with organisation. However, the main emphasis is usually on behaviour management strategies. The conven‐ tional behavioural strategies used in ADHD are not specific for this condition, but aim to take good parenting and good classroom management to a higher level. Therefore, strategies may be applied to the whole family or to the entire class or even the whole school. An additional but less well utilised modality of non-pharmacological management targets the emotional issues. We suggest a larger role for emotional self-regulation as a means of promoting and maintaining a positive mood and outlook in ADHD.

#### *3.1.1. Addressing the imbalance of the level of mental effort required for achievement*

#### *3.1.1.1. Additional learning support*

This is designed to address specific problems exacerbated by the executive functioning deficits, for example, additional support with reading, so that this skill becomes easier and accom‐ plished with a more manageable level of effort. Reading is a complex skill that involves several components. Each component requires attention. Therefore, the individual has to recognise the letters, relate them to their sounds and blend the sounds together to decipher the word. The words then have to be remembered so that the sentences can be derived. The sentences have to be understood and their meaning remembered long enough to make sense of the passage. The main reward of the task is in the interest from the information contained in the passage.

When a child is learning to read, the process is slow and laborious and the reward from the information may be lost unless the sentence is very simple. With practice, the child starts to recognise common words without having to sound out each one individually and reading becomes easier and more fluent. This allows more attention to be focussed on the meaning. The information is received at a faster rate and the balance of effort to reward improves. As reading becomes more rewarding, the child may start to read books for pleasure and thereby further practice and develop their skills.

If a child has ADHD, their attention span for concentrating will be less than other children. The learning process may be more laborious and the child may be inclined to give up easily. It may be harder for the child with ADHD to attend to the meaning while simultaneously deciphering the individual words, which reduces the interest of the task for the child. At this stage, additional one-to-one teaching may accelerate the rate at which the child develops reading fluency. As reading is a prerequisite for success in almost every area of schooling, good skills that enable a child to read without putting all their attention and effort into the process will be beneficial in all areas of academic learning.

#### *3.1.1.2. Modifying the tasks and expectations*

and behaviours that are likely to characterise deficient internal reward processes. It is impor‐ tant to recognise the function that such behaviours serve for the individual in generating the sense of satisfaction that they crave. An individual's prevailing mood gives a measure of the success of their strategies for achieving adequate reward within a manageable level of effort.

Management of ADHD may involve medication, non-pharmacological treatment or a combi‐

Non-pharmacological approaches to management usually focus on the areas of functioning which are causing the most problems. This may involve additional learning support or other assistance related to the executive functioning deficits, such as help with organisation. However, the main emphasis is usually on behaviour management strategies. The conven‐ tional behavioural strategies used in ADHD are not specific for this condition, but aim to take good parenting and good classroom management to a higher level. Therefore, strategies may be applied to the whole family or to the entire class or even the whole school. An additional but less well utilised modality of non-pharmacological management targets the emotional issues. We suggest a larger role for emotional self-regulation as a means of promoting and

This is designed to address specific problems exacerbated by the executive functioning deficits, for example, additional support with reading, so that this skill becomes easier and accom‐ plished with a more manageable level of effort. Reading is a complex skill that involves several components. Each component requires attention. Therefore, the individual has to recognise the letters, relate them to their sounds and blend the sounds together to decipher the word. The words then have to be remembered so that the sentences can be derived. The sentences have to be understood and their meaning remembered long enough to make sense of the passage. The main reward of the task is in the interest from the information contained in the

When a child is learning to read, the process is slow and laborious and the reward from the information may be lost unless the sentence is very simple. With practice, the child starts to recognise common words without having to sound out each one individually and reading becomes easier and more fluent. This allows more attention to be focussed on the meaning. The information is received at a faster rate and the balance of effort to reward improves. As reading becomes more rewarding, the child may start to read books for pleasure and thereby

**3. Management**

314 ADHD - New Directions in Diagnosis and Treatment

**3.1. Non-pharmacological management of ADHD**

maintaining a positive mood and outlook in ADHD.

*3.1.1.1. Additional learning support*

further practice and develop their skills.

passage.

*3.1.1. Addressing the imbalance of the level of mental effort required for achievement*

nation of both.

A child with ADHD is likely to need a higher level of parent or teacher attention and the tasks may need to be modified to make them achievable. Management often involves looking at the particular problems to find modifications that may make the required tasks more manageable within a child's limited attention span. Such strategies may include keeping tasks short and varied and moving on to a new topic before boredom sets in. Instructions need to be easily understood and repeated if necessary, perhaps with a written task list. A child with ADHD may need to be reminded to remain on task. Breaks may be factored in, such as sending the child out on an errand.

### *3.1.1.3. Teaching organisational strategies*

Organisational skills can also be taught. These can include strategies to keep track of home‐ work, including structuring the tasks, using checklists and long-term planning of tasks with their completion dates [20, 35].

#### *3.1.2. Addressing the imbalance in the level of reward experienced: increasing the external rewards with conventional behaviour management*

Behaviour management strategies are generally used by the parent or teacher and are designed to make favourable behaviour more rewarding and negative behaviour less rewarding for the child. These strategies usually involve a combination of rewarding desired behaviour and negative consequences for behaviour that is being discouraged. They depend on the individual being able to evaluate in advance the consequences of their behaviour. The particulars of the behavioural strategies have to be carefully thought out.

Conventional behaviour management has the drawbacks that because the rewards and consequences are external and often tied to particular tasks and situations, they may not carry over to other tasks and settings. Conventional behavioural strategies often use emotional rewards, with the parent or teacher praising the child and showing delight if the child has achieved or put considerable effort into the task. The child may respond by trying harder in order to gain the satisfaction of making another person happy. Therefore, it is frequently observed that a child will work better for a teacher who cares and takes more interest in him, but works less well following a change of teacher. The long-term aim of behaviour manage‐ ment is that the behavioural change should become generalised as the child matures [36].

A review evaluating psychological interventions has demonstrated sufficient evidence to consider behaviour management to be an established and effective intervention for ADHD, either when administered by the parent following training or when used in the classroom [36].

In order for behaviour management to be effective, a number of prerequisites must be met.

### **1. The child must be capable of carrying out the target behaviour.**

This means that the goals should be realistic. It is important that goals are not too difficult such that the child gives up. Targeting small, manageable tasks is often the more effective approach. In children with a lot of behaviour that is perceived as problematic, goals need to be prioritised. For example, if a child regularly refuses to do any homework, rewarding the child for concentrating for 5 minutes and writing a single sentence and gradually working up to completing their entire half hour of homework may be more successful than choosing homework completion as the initial goal.

### **2. The child must understand the rewards and consequences and be able to relate these to their behaviour.**

The child needs to have sufficient capacity to be able to comprehend that there will be consequences. The child also has to make an emotional connection with the consequences. It has been shown that children with ADHD may choose immediate small rewards over larger, delayed rewards [37]. The relevance of this to the clinical setting is that children with ADHD may appear to 'live for the moment'. The child may at be able to recite the consequences for a particular misdemeanour; but at the moment of making a decision, the consequences appear to have little relevance to the child. Afterwards, the child may show no interest in the reason for their punishment, experiencing it only as a frustration. It may not be that the child is intellectually incapable of understanding the connection between an activity and its conse‐ quence, but that what is important or relevant to the child is the present.

#### **3. The rewards and consequences need to be meaningful and appropriate.**

Rewards and consequences should be chosen carefully. A child might be rewarded with time to play on a computer; a meaningful punishment might be taking away the child's favourite toy or game. Rewards and punishments that are small and repeatable are often more effective than larger ones. For example, if a parent is very angry with a child, there may be a temptation to extend the duration of the punishment, perhaps taking away the favourite toy or banning the child from watching television for a week. If the child subsequently misbehaves during that week, the parent has lost one valuable option for punishment. Alternatively, if the punishment is milder, for example, the child is prevented from watching just one show, or loses their game for only five or ten minutes, the same punishment can be repeated as often as necessary. Prolonged punishment with restoration of the item made dependent on good behaviour may be even less effective. To a child with ADHD, a week may be such a long time that they consider the item lost forever; furthermore, it may be unrealistic to expect the child to behave well for a whole week. Withdrawal of attention from a child who has misbehaved can also be effective.

### **4. The strategies should be applied consistently.**

Effective behaviour management requires consistent effort from the parent or teacher. If there is any leeway a child may become skilful in picking the time when they can get away with breaking a rule.

### **5. The child must choose to co-operate.**

A review evaluating psychological interventions has demonstrated sufficient evidence to consider behaviour management to be an established and effective intervention for ADHD, either when administered by the parent following training or when used in the classroom [36].

In order for behaviour management to be effective, a number of prerequisites must be met.

This means that the goals should be realistic. It is important that goals are not too difficult such that the child gives up. Targeting small, manageable tasks is often the more effective approach. In children with a lot of behaviour that is perceived as problematic, goals need to be prioritised. For example, if a child regularly refuses to do any homework, rewarding the child for concentrating for 5 minutes and writing a single sentence and gradually working up to completing their entire half hour of homework may be more successful than choosing

**2. The child must understand the rewards and consequences and be able to relate these**

The child needs to have sufficient capacity to be able to comprehend that there will be consequences. The child also has to make an emotional connection with the consequences. It has been shown that children with ADHD may choose immediate small rewards over larger, delayed rewards [37]. The relevance of this to the clinical setting is that children with ADHD may appear to 'live for the moment'. The child may at be able to recite the consequences for a particular misdemeanour; but at the moment of making a decision, the consequences appear to have little relevance to the child. Afterwards, the child may show no interest in the reason for their punishment, experiencing it only as a frustration. It may not be that the child is intellectually incapable of understanding the connection between an activity and its conse‐

Rewards and consequences should be chosen carefully. A child might be rewarded with time to play on a computer; a meaningful punishment might be taking away the child's favourite toy or game. Rewards and punishments that are small and repeatable are often more effective than larger ones. For example, if a parent is very angry with a child, there may be a temptation to extend the duration of the punishment, perhaps taking away the favourite toy or banning the child from watching television for a week. If the child subsequently misbehaves during that week, the parent has lost one valuable option for punishment. Alternatively, if the punishment is milder, for example, the child is prevented from watching just one show, or loses their game for only five or ten minutes, the same punishment can be repeated as often as necessary. Prolonged punishment with restoration of the item made dependent on good behaviour may be even less effective. To a child with ADHD, a week may be such a long time that they consider the item lost forever; furthermore, it may be unrealistic to expect the child to behave well for a whole week. Withdrawal of attention from a child who has misbehaved

**1. The child must be capable of carrying out the target behaviour.**

quence, but that what is important or relevant to the child is the present.

**3. The rewards and consequences need to be meaningful and appropriate.**

homework completion as the initial goal.

316 ADHD - New Directions in Diagnosis and Treatment

**to their behaviour.**

can also be effective.

Co-operation is likely to depend on the child's own assessment of the balance of effort to reward. If the effort required is disproportionate due to the executive functioning deficits associated with ADHD, the child may insist on a reward that appears similarly dispropor‐ tionate. For example, a small reward, such as adding a sticker to a chart for every task completed, may work for a few days until the child realises that the stickers are not worth the effort. At that stage, in order for the behaviour management to continue to be effective, a higher reward may be negotiated. This cycle may continue until the child will not even consider doing any homework unless rewarded with a very substantial sum of money. Alternatively, the child may perceive that he or she will experience greater satisfaction through non-co-operation. Figure 4 categorises bullying – behaviour designed to upset or hurt another person – as being more rewarding than schoolwork. Therefore, if a child can derive an alternative to co-operation that causes pain, this may appear an attractive option. If the child perceives that the parent or teacher is emotionally committed to their co-operation and genuinely wants to see the child carry out the task, this may provide an opportunity for bullying. This might take the form of deliberately destroying their work, for example, by scribbling on the page. Observing the resultant surprise, anger or frustration may be immensely satisfying for the child. Another very common strategy for non-co-operation is arguing. This may be a delaying tactic and a parent may be baffled that their child may spend twenty minutes and considerable effort arguing over ten minutes of homework, which ultimately still has to be done. To the child arguing may serve several purposes. Firstly, time spent arguing may be considered time wellspent because the homework is not actually being done. Secondly, the child may be negotiating a better deal, such as a higher reward or a reward in advance of the task. Winning such a concession would also be rewarding in itself (Figure 4). Thirdly, the child may be bullying the parent, enjoying the effect of the argument on their parent's emotions, for example, observing an increasing level of frustration or anger. It is important for adults to understand the value that a child may place on observing an emotional response. Withdrawing from the child to calm down may minimise the reward the child experiences for their negative behaviour.

#### *3.1.3. Emotional self-regulation*

Emotional self-regulation with the aim of improving the mood fits in with the logic of the MERIM because reward deficit resulting in a less positive mood is considered an intrinsic part of the symptomatology of the majority of individuals with ADHD. Although strategies that can lead to a higher level of task completion have merit, an important additional outcome is the effect on mood. Therefore, for example, if a child completes homework under protest and with the sole aim of gaining a tangible external reward, perhaps perceived as a bribe, this might be considered an acceptable outcome as the work is done. However, if the attitude towards the work is poor, it is likely that the child will complete it to the lowest acceptable standard. Therefore, an important additional aim would be to teach the child to value their work and gain internal reward in the satisfaction of a job done well. In other words, the positive aspects of the task that has been undertaken would be used to enhance the mood. Emotional selfregulation could supplement conventional behaviour management based on rewards and punishment, but places less emphasis on targeting particular behaviour, instead focusing on generating a positive mood through achievement. The main aim of this approach is to enhance achievement by promoting the cycle of achievement leading to a feeling of satisfaction, a happier mood and a readiness to take on the next challenge to achieve. Although not directly addressing the reward mechanisms, we have also included in this section anger management strategies.

#### *3.1.3.1. Potentiating the internal reward mechanisms for a positive mood*

Individuals may use a number of strategies which regulate their emotions. These strat‐ egies are not simply learned in childhood and adolescence but continue to develop, usually in a positive way, over the course of adult life [38]. Self-regulation strategies may be helpful as a long-term intervention for generating and maintaining positive emotions. For exam‐ ple, an intervention study of meditation (Loving Kindness Meditation) found that 35% of participants continued to derive positive emotional benefit from meditation a year after ceasing therapy [39].

Unlike conventional behaviour management, emotional self-regulation aiming to promote positive emotions has a theoretical advantage that its techniques directly address the effects of the underlying reward deficit. Furthermore, it can be applied to all aspects of daily life, and once taught and adopted, it does not rely on any outside sources for reward as individuals evaluate and provide their own reinforcement for their positive behaviour, developing strategies for sustaining their mood and self-esteem. The long-term goal would be for the individual to become independent in using the techniques of emotional self-regulation. This might happen if the individual notices that these strategies are worthwhile because they make him or her feel better. Because the individual has the control, self-regulation in relation to mood promotes individual responsibility and independence.

#### **Positive rumination**

Rumination involves repetitive thoughts that can influence an individual's emotional state. Rumination is conventionally considered to be negative in both the content of the ruminant thoughts and the emotional outcome as it focuses on the causes and symptoms of distress without seeking any solution to the perceived problems [40]. Negative rumination not only exacerbates depression and anxiety but is also a risk factor for a range of mental health problems, including aggressive behaviour in boys [41]. However, we suggest that spending time reflecting on a positive achievement could increase the level of enjoyment or satisfaction obtained. We have termed this positive rumination. We suggest that positive rumination may be a strategy used by healthy individuals that helps them to sustain a positive, stable mood and amicable outlook. It is a cognitive process that would involve some mental effort and therefore may come less easily to individuals with ADHD. It also depends on a person being

able to recognise their emotions, which can be a problem in ADHD [42]. Therefore, positive rumination may need to be specifically taught and practised in order for a person with ADHD to be able to use it effectively and understand and recognise its value.

There is evidence that frequent small, positive emotional boosts are associated with enhanced physical and mental well-being [24]. Positive rumination might provide this, but to be a workable strategy it would depend on the individual taking time to consider the good points about a piece of work or an activity and then reflecting on the sense of satisfaction that is generated. For example, after doing a piece of work, even if the work is not perfect, some positive attributes may be identified. These could initially be pointed out by the parent or teacher, but ultimately the individual would be encouraged to identify for themselves the value in their work. Times of reflection may also be built into the daily routine, for example, at bedtime thinking of the positive and enjoyable experiences and achievements of the day. These might include some of the following pleasant activities that are often associated with positive emotions: being helpful, interactions with others, playing, learning, exercise and spiritual activities [24]. In positive rumination, the individual has to be able to pause and reflect and have awareness of their mood, together with mood changes following on from their positive reflection.

### **Positive re-appraisal**

the work is poor, it is likely that the child will complete it to the lowest acceptable standard. Therefore, an important additional aim would be to teach the child to value their work and gain internal reward in the satisfaction of a job done well. In other words, the positive aspects of the task that has been undertaken would be used to enhance the mood. Emotional selfregulation could supplement conventional behaviour management based on rewards and punishment, but places less emphasis on targeting particular behaviour, instead focusing on generating a positive mood through achievement. The main aim of this approach is to enhance achievement by promoting the cycle of achievement leading to a feeling of satisfaction, a happier mood and a readiness to take on the next challenge to achieve. Although not directly addressing the reward mechanisms, we have also included in this section anger management

Individuals may use a number of strategies which regulate their emotions. These strat‐ egies are not simply learned in childhood and adolescence but continue to develop, usually in a positive way, over the course of adult life [38]. Self-regulation strategies may be helpful as a long-term intervention for generating and maintaining positive emotions. For exam‐ ple, an intervention study of meditation (Loving Kindness Meditation) found that 35% of participants continued to derive positive emotional benefit from meditation a year after

Unlike conventional behaviour management, emotional self-regulation aiming to promote positive emotions has a theoretical advantage that its techniques directly address the effects of the underlying reward deficit. Furthermore, it can be applied to all aspects of daily life, and once taught and adopted, it does not rely on any outside sources for reward as individuals evaluate and provide their own reinforcement for their positive behaviour, developing strategies for sustaining their mood and self-esteem. The long-term goal would be for the individual to become independent in using the techniques of emotional self-regulation. This might happen if the individual notices that these strategies are worthwhile because they make him or her feel better. Because the individual has the control, self-regulation in relation to mood

Rumination involves repetitive thoughts that can influence an individual's emotional state. Rumination is conventionally considered to be negative in both the content of the ruminant thoughts and the emotional outcome as it focuses on the causes and symptoms of distress without seeking any solution to the perceived problems [40]. Negative rumination not only exacerbates depression and anxiety but is also a risk factor for a range of mental health problems, including aggressive behaviour in boys [41]. However, we suggest that spending time reflecting on a positive achievement could increase the level of enjoyment or satisfaction obtained. We have termed this positive rumination. We suggest that positive rumination may be a strategy used by healthy individuals that helps them to sustain a positive, stable mood and amicable outlook. It is a cognitive process that would involve some mental effort and therefore may come less easily to individuals with ADHD. It also depends on a person being

*3.1.3.1. Potentiating the internal reward mechanisms for a positive mood*

promotes individual responsibility and independence.

strategies.

318 ADHD - New Directions in Diagnosis and Treatment

ceasing therapy [39].

**Positive rumination**

In therapeutic settings, emotional self-regulation has tended to be directed towards dealing with negative emotions, for example, in anxiety, depression and anger [43]. However, a more recent approach to emotional regulation aims to generate and promote positive emotions [39]. Some strategies, such as negative rumination, avoidance and suppression are associated with psychopathology, while re-appraisal, problem solving and acceptance are considered protec‐ tive. [43]. Positive re-appraisal involves redefining an adverse event in terms of any possible positive aspects [38]. Initially, the parent or teacher would need to assist the child, perhaps with a response such as: 'Although you lost your temper, you only hit him once, you calmed down quickly and you've learned that you should avoid him in future'. With time, the child may learn to practise positive re-appraisal. If the child's mood and self-esteem can so be preserved in times of adversity, he or she may be less tempted to resort to bullying in order to feel better.

#### *3.1.3.2. Anger management*

The symptoms of ODD might indicate a valuable role for anger management techniques. Strategies that have been used successfully for anger management include emotion recogni‐ tion, problem solving, cognitive re-appraisal and relaxation with controlled breathing [44]. Recognition of emotion involves developing an awareness of symptoms associated with physiological arousal, such as feeling hot and having a pounding heart. Cognitive re-appraisal is designed to counteract an aggressive individual's tendency to respond with anger or blame if they have difficulty interpreting another person's actions [19]. The tendency to blame or to attribute hostility to another person in ambiguous situations may be used to justify aggression and can be associated with poor problem solving skills [45]. Therapy may emphasise thinking of non-personal reasons to explain another's behaviour instead of taking offense (for example: 'she must be having a bad day') and also looking for positives in a social situation. Learning to delay responding impulsively while feeling angry or thinking of alternative responses may also be valuable, perhaps by using 'self-instructions', which may be rehearsed and practised [45]. Strategies for managing the arousal include firstly avoiding or moving away from the stimulus and then calming the physiological changes. This may be achieved by controlled breathing, concentrating on taking a deep breath and self-instructions such as 'calm down' or 'relax' during expiration, also imagining reducing the body temperature and heartbeat [45]. Large muscle exercise and relaxation may be beneficial for hyperactive impulsive children [46].

Self-regulation with the aim of promoting good mood would appear to be a logical and promising new approach that is worthy of consideration. If these strategies can be used effectively by people with ADHD, they could lead to improvements in mood, functioning and self-esteem, which would not be linked to specific tasks and situations. The lack of study of emotional regulation in ADHD does not necessarily mean that such strategies are not being used therapeutically and effectively. However, efficacy still needs to be establish‐ ed with further research.

### **3.2. Pharmacological management of ADHD**

The aim of treatment of ADHD is to achieve normal functioning. Non-pharmacological interventions can be successful, but the individual may still have ongoing problems associated with the underlying deficits of ADHD. Therefore, they would still experience mental fatigue with tasks that require sustained concentration. The tendency to act quickly and impulsively without the opportunity for adequate decision-making can greatly reduce the efficacy of behavioural management strategies. This is because behaviour management depends on the child being in a position to make a rational decision based on the pre-determined consequen‐ ces. Furthermore, the low mood that is associated with reward deficit will tend to reduce the inclination to co-operate. Children who have significant functional impairment due to ADHD are sometimes identifiable as those who do not respond to the management strategies that work well for their siblings or peers. Drug treatment can improve the deficits in executive functioning and reward.

The medical formulations used most frequently in ADHD are based on the stimulants dexamphetamine and methylphenidate. These enhance the levels of neurotransmitters and address the underlying neurochemical deficits. They result in improvements in cognitive functioning which increase as the dose is increased [47]. They also improve the mood and behaviour, which may be an effect of enhancing the activity of the dopamine reward pathway. In clinical settings, the dose is established not by the child's weight but by titration for optimal therapeutic effect [48]. The non-stimulant atomoxetine is also an effective treatment for ADHD [49].

#### *3.2.1. Mechanism of action of the stimulants*

Methylphenidate and dexamphetamine increase the synaptic levels of dopamine and nora‐ drenalin in the prefrontal cortex and in sub-cortical structures including the striatum and nucleus accumbens (a part of the brain involved with appetite control). Dopamine and noradrenalin are neurotransmitters which are released into synaptic clefts and transmit impulses between nerve cells. Higher concentrations may assist with neurotransmission. The stimulants potentiate neurotransmission by three different mechanisms: enhancing neuro‐ transmitter release, blocking reuptake by binding with the transporters and by direct stimu‐ lation of the receptors [50]. The actions of the stimulants on the different neurotransmitter systems depend on the amount of neurotransmitter and the affinities of the neurotransmitter receptors and transporters in the different regions of the brain [51]. The striatum is rich in dopamine; and although the dopamine transporter has high affinity for dopamine, it will also bind with noradrenalin. Conversely, noradrenalin is the principal neurotransmitter in the prefrontal cortex where it is taken up by the noradrenalin transporter. Dopamine is also present in the prefrontal cortex but at low levels and is taken up by the noradrenalin transporter, to which it binds with low affinity Dexamphetamine and methylphenidate are both highly effective for reducing the reuptake of dopamine and noradrenalin, but dexamphetamine also enhances the release of stored dopamine and increases serotonin levels [52].

#### *3.2.2. Clinical effects of the stimulants*

'she must be having a bad day') and also looking for positives in a social situation. Learning to delay responding impulsively while feeling angry or thinking of alternative responses may also be valuable, perhaps by using 'self-instructions', which may be rehearsed and practised [45]. Strategies for managing the arousal include firstly avoiding or moving away from the stimulus and then calming the physiological changes. This may be achieved by controlled breathing, concentrating on taking a deep breath and self-instructions such as 'calm down' or 'relax' during expiration, also imagining reducing the body temperature and heartbeat [45]. Large muscle exercise and relaxation may be beneficial for hyperactive impulsive children [46].

Self-regulation with the aim of promoting good mood would appear to be a logical and promising new approach that is worthy of consideration. If these strategies can be used effectively by people with ADHD, they could lead to improvements in mood, functioning and self-esteem, which would not be linked to specific tasks and situations. The lack of study of emotional regulation in ADHD does not necessarily mean that such strategies are not being used therapeutically and effectively. However, efficacy still needs to be establish‐

The aim of treatment of ADHD is to achieve normal functioning. Non-pharmacological interventions can be successful, but the individual may still have ongoing problems associated with the underlying deficits of ADHD. Therefore, they would still experience mental fatigue with tasks that require sustained concentration. The tendency to act quickly and impulsively without the opportunity for adequate decision-making can greatly reduce the efficacy of behavioural management strategies. This is because behaviour management depends on the child being in a position to make a rational decision based on the pre-determined consequen‐ ces. Furthermore, the low mood that is associated with reward deficit will tend to reduce the inclination to co-operate. Children who have significant functional impairment due to ADHD are sometimes identifiable as those who do not respond to the management strategies that work well for their siblings or peers. Drug treatment can improve the deficits in executive

The medical formulations used most frequently in ADHD are based on the stimulants dexamphetamine and methylphenidate. These enhance the levels of neurotransmitters and address the underlying neurochemical deficits. They result in improvements in cognitive functioning which increase as the dose is increased [47]. They also improve the mood and behaviour, which may be an effect of enhancing the activity of the dopamine reward pathway. In clinical settings, the dose is established not by the child's weight but by titration for optimal therapeutic effect [48]. The non-stimulant atomoxetine is also an effective

Methylphenidate and dexamphetamine increase the synaptic levels of dopamine and nora‐ drenalin in the prefrontal cortex and in sub-cortical structures including the striatum and

ed with further research.

320 ADHD - New Directions in Diagnosis and Treatment

functioning and reward.

treatment for ADHD [49].

*3.2.1. Mechanism of action of the stimulants*

**3.2. Pharmacological management of ADHD**

The beneficial effect of stimulant medications for improving the functioning of children with ADHD was first recognised in the 1930s [53]. The stimulant medications dexamphetamine and methylphenidate have the effect of reducing the level of physical activity and enhancing the ability for sustained attention. They also suppress the appetite [54]. The efficacy of the stimulants for treating the symptoms of ADHD has been well established in placebo controlled trials [48, 55]. In the Multimodal Treatment study of ADHD (MTA Study), it was shown that for the core features of ADHD (inattention, hyperactivity and impulsivity), stimulant medi‐ cation was more effective than behaviour therapy [18]. Behaviour management was better for comorbid conditions including ODD. Children treated only with stimulant medication required higher doses for optimal improvement than those randomised to a combination of medication and behaviour therapy, suggesting an interaction between behavioural strategies and medication, with differential effects on the different symptom types. The stimulants have been shown to be effective in reducing the symptoms of ADHD in pre-schoolers [56], schoolaged children [18], adolescents [55] and adults [57].

Clinical trials treating children with ADHD plus ODD have shown symptomatic improvement on medication for both of these conditions, but children with clinically significant symptoms of ODD required higher doses [55, 58, 59]. This suggests that different types of symptoms respond to different doses of medication. Evidence of two distinct pharmacological effects, each with its own therapeutic window, comes from the work of Sprague and Sleator [60]. They treated children with ADHD on two doses of methylphenidate and found that on the lower dose there was more improvement in learning, suggesting that this dose was targeting executive functioning. The higher dose was associated with greater improvements in social behaviour, but was less good for learning and may therefore have been treating the difficult, negative and hostile behaviour associated with ODD. This suggests that the stimulant effects for improving the deficits in executive functioning and reward are pharmacologically distinct, with different therapeutic windows that do not precisely coincide, reward deficit requiring higher doses for optimal treatment.

The main ongoing concern about the therapeutic use of stimulant medication in ADHD is the risk of abuse and diversion. Although methylphenidate is similar to cocaine in its affinity for the dopamine receptor, the addictive effect is the euphoria and this depends on a rapid rate of binding of the drug with the receptor [61]. Methylphenidate, particularly when taken orally, binds much more slowly than cocaine, which explains its far lower abuse potential. Atomox‐ etine is also used for treating ADHD. It is not a stimulant; it selectively inhibits noradrenalin reuptake and has minimal dopaminergic effect. It therefore lacks the abuse potential of the stimulants. It is also longer acting than the stimulants, giving a more consistent effect over the course of the day. However, the time taken for the levels to stabilise makes accurate dose titration more difficult.

Aside from their abuse potential, the most significant side effect of stimulant medication is the effect on appetite and weight, with a secondary effect on growth [62, 63]. It is as if the stimulant resets the appetite at a lower level. This results in initial weight loss. If a child remains on stimulant medication, the appetite recovers and weight gain resumes. After a year of treatment, the weight is usually approximately the same as it was at the time that medication was started. Appetite suppression appears to correlate closely with the therapeutic effect and a dose that does not affect weight is likely to be too low to be effective. Because weight gain is important for providing the resources necessary for growth in height, there is slowing of the height velocity, which gradually normalises over two to three years. Adult height appears not to be significantly affected by stimulant treatment, but there is some evidence that puberty may progress more slowly, with a later growth spurt [64, 65]. Stimulant medication also increases the heart rate and blood pressure [66]. Stimulant medications can also cause insomnia, irritability and feelings of sadness [67].

#### *3.2.3. Practical issues of pharmacological treatment*

The above section indicates that the actions of the stimulants are complex, that they have different effects in different parts of the brain and that the optimal doses for different aspects of functioning may not coincide. The dose–response curves for cognitive functioning and for mood and behaviour might look like Figure 5. This figure illustrates that the dose can be titrated to maximise either effect, but not both together. Alternatively, the dose giving the best overall effect might fall somewhere between the two peaks. Even if one effect is targeted, the selected dose may still lead to some improvements in the other effect. For example, a child with severe symptoms of ODD may function best on a relatively high dose of medication. Although this dose may be higher than his optimal dose for executive functioning, he may still concentrate substantially better than he would if unmedicated. This is likely to be related to some im‐ provement in his executive functioning on the selected dose and also because his attitude towards cognitive tasks may be better when the deficits in his dopamine neurotransmission are addressed.

with different therapeutic windows that do not precisely coincide, reward deficit requiring

The main ongoing concern about the therapeutic use of stimulant medication in ADHD is the risk of abuse and diversion. Although methylphenidate is similar to cocaine in its affinity for the dopamine receptor, the addictive effect is the euphoria and this depends on a rapid rate of binding of the drug with the receptor [61]. Methylphenidate, particularly when taken orally, binds much more slowly than cocaine, which explains its far lower abuse potential. Atomox‐ etine is also used for treating ADHD. It is not a stimulant; it selectively inhibits noradrenalin reuptake and has minimal dopaminergic effect. It therefore lacks the abuse potential of the stimulants. It is also longer acting than the stimulants, giving a more consistent effect over the course of the day. However, the time taken for the levels to stabilise makes accurate dose

Aside from their abuse potential, the most significant side effect of stimulant medication is the effect on appetite and weight, with a secondary effect on growth [62, 63]. It is as if the stimulant resets the appetite at a lower level. This results in initial weight loss. If a child remains on stimulant medication, the appetite recovers and weight gain resumes. After a year of treatment, the weight is usually approximately the same as it was at the time that medication was started. Appetite suppression appears to correlate closely with the therapeutic effect and a dose that does not affect weight is likely to be too low to be effective. Because weight gain is important for providing the resources necessary for growth in height, there is slowing of the height velocity, which gradually normalises over two to three years. Adult height appears not to be significantly affected by stimulant treatment, but there is some evidence that puberty may progress more slowly, with a later growth spurt [64, 65]. Stimulant medication also increases the heart rate and blood pressure [66]. Stimulant medications can also cause insomnia,

The above section indicates that the actions of the stimulants are complex, that they have different effects in different parts of the brain and that the optimal doses for different aspects of functioning may not coincide. The dose–response curves for cognitive functioning and for mood and behaviour might look like Figure 5. This figure illustrates that the dose can be titrated to maximise either effect, but not both together. Alternatively, the dose giving the best overall effect might fall somewhere between the two peaks. Even if one effect is targeted, the selected dose may still lead to some improvements in the other effect. For example, a child with severe symptoms of ODD may function best on a relatively high dose of medication. Although this dose may be higher than his optimal dose for executive functioning, he may still concentrate substantially better than he would if unmedicated. This is likely to be related to some im‐ provement in his executive functioning on the selected dose and also because his attitude towards cognitive tasks may be better when the deficits in his dopamine neurotransmission

higher doses for optimal treatment.

322 ADHD - New Directions in Diagnosis and Treatment

titration more difficult.

irritability and feelings of sadness [67].

are addressed.

*3.2.3. Practical issues of pharmacological treatment*

**Figure 5.** Hypothetical dose–response curves for the improvements in executive functioning and behaviour on stimu‐ lant medication **Effect** functioning Mood and

Cognitive

behaviour

As children mature, they tend to improve in their behaviour [16]. They also outgrow their dose as they gain weight. Therefore, a dose initially selected for optimal improvement in the symptoms of ODD may, with time, gradually progress into a dose that is better for maximising the executive functioning deficits as the drug levels decline with the growth of the child. **Drug dose**

The most important aspect of pharmacological management is to find the dose that works best for the individual. Careful dose titration while monitoring the changes in cognitive functioning and behaviour on medication and adjusting the dose to target those symptoms that are most impairing can be very effective. This is usually done by starting at a low dose and gradually increasing the dose while observing the changes in functioning. Behavioural rating scales may assist with comparing effects of different doses of medication. It is important that the rating scale includes items relating to cognitive functioning and to mood and behaviour, for example [68]. Dose titration and its effects are illustrated in Figure 6. Because the reward mechanisms also affect appetite control, the improvement in mood and behaviour correlates with weight loss. However, the dopamine reward pathway is only one of a series of mechanisms that affect energy balance and these other systems become activated as the weight drops, increasing the appetite and limiting further weight loss. [69] As children mature, they tend to improve in their behaviour [15]. They also outgrow their dose as they gain weight. Therefore, a dose initially selected for optimal improvement in the symptoms of ODD may, with time, gradually progress into a dose that is better for maximising the executive functioning deficits as the drug levels decline with the growth of the child. The most important aspect of pharmacological management is to find the dose that works best for the individual. Careful dose titration while monitoring the changes in cognitive functioning and behaviour on medication and adjusting the dose to target those symptoms that are most impairing can be very effective. This is usually done by starting at a low dose and gradually increasing the dose while observing the changes in functioning. Behavioural rating scales may assist with comparing effects of different doses of medication. It is important that the rating scale includes items relating to cognitive functioning and to mood and behaviour, for example [68]. Dose titration and its effects are illustrated in Figure 6. Because the reward mechanisms also affect appetite control, the improvement in mood and behaviour correlates with weight loss. However, the dopamine reward pathway is only one of a series of mechanisms that affect energy balance and these other systems become activated as the weight drops, increasing the appetite and limiting further weight loss. [69] **Figure 6 Stimulant medication and the effects of dose titration** 

The stimulant medications dexamphetamine and methylphenidate are short-acting, with an effect that lasts around 3–4 hours. In children who have significant hyperactivity or oppositional symptoms, the effect is usually obvious within 30 minutes of taking the dose. In children who only have inattention, the effect may be more subtle. As the effect wears off there may be rebound, with irritability and worsening of symptoms. The therapeutic effect may be prolonged by using formulations that release medication slowly over several hours. These may also wear off more slowly, reducing the

13

**Figure 6.** Stimulant medication and the effects of dose titration

The stimulant medications dexamphetamine and methylphenidate are short-acting, with an effect that lasts around 3–4 hours. In children who have significant hyperactivity or opposi‐ tional symptoms, the effect is usually obvious within 30 minutes of taking the dose. In children who only have inattention, the effect may be more subtle. As the effect wears off there may be rebound, with irritability and worsening of symptoms. The therapeutic effect may be pro‐ longed by using formulations that release medication slowly over several hours. These may also wear off more slowly, reducing the rebound associated with rapidly falling levels. Because the stimulants can cause difficulty with settling to sleep at night, medication is often targeted to be effective earlier in the day while the child is at school, wearing off into the evening. Although the short duration of action of the stimulants can be inconvenient, it has the advantage that it allows a constant comparison of the child's functioning on and off medica‐ tion. It is important to monitor the therapeutic effect and make dose adjustments whenever necessary as the dose usually needs to be increased periodically as the child grows.

#### *3.2.4. Changes in treatment requirements with maturity*

As children mature, they usually develop more control over their behaviour and this may reduce their reliance on medication. For example, a young hyperactive child may generate so much stress in the family that he or she may need medication every day. As the child matures, the hyperactivity may start to settle and medication may only be needed for school. The school years are often the most difficult stage of life for the individual with ADHD. This is because schoolwork involves prolonged periods of concentration and many of the tasks may not be intrinsically interesting. Once a person is no longer studying, they may be able to cease medication.

Although executive functioning deficits generally persist into adult life, with maturity individuals often become better at developing strategies to help them to function. However, some have ongoing problems with irritability and anger. An understanding of the reward deficit associated with ADHD may encourage such people to practise emotional self-regulation strategies to help promote a better mood and more rewarding existence.

### **4. Directions for research**

The main novel approach to treatment suggested in this chapter is the recommendation for strategies designed to enhance the positive emotional experiences in everyday life for indi‐ viduals with ADHD. These would clearly need to be evaluated with randomised controlled studies that include a plausible comparison treatment. In young children, behaviour manage‐ ment strategies are generally taught to the parents who then implement them with the child. Therefore, groups of parents could be taught conventional behaviour management using external rewards and punishments or strategies designed to promote positive emotions in the child through their achievement. Outcomes would be assessed using standardised rating scales relating not only to achievement in terms of task completion but also any positive effects on mood. In older children and adults with ADHD, particularly those with anger or opposi‐ tional features, there would be value in comparing anger management strategies that are intended to give more control over negative emotions, with strategies designed to enhance the positive experience of reward. Outcomes could be evaluated with standardised rating scales, both self-reported and observer-reported.

### **5. Conclusions**

The stimulant medications dexamphetamine and methylphenidate are short-acting, with an effect that lasts around 3–4 hours. In children who have significant hyperactivity or opposi‐ tional symptoms, the effect is usually obvious within 30 minutes of taking the dose. In children who only have inattention, the effect may be more subtle. As the effect wears off there may be rebound, with irritability and worsening of symptoms. The therapeutic effect may be pro‐ longed by using formulations that release medication slowly over several hours. These may also wear off more slowly, reducing the rebound associated with rapidly falling levels. Because the stimulants can cause difficulty with settling to sleep at night, medication is often targeted to be effective earlier in the day while the child is at school, wearing off into the evening. Although the short duration of action of the stimulants can be inconvenient, it has the advantage that it allows a constant comparison of the child's functioning on and off medica‐ tion. It is important to monitor the therapeutic effect and make dose adjustments whenever

necessary as the dose usually needs to be increased periodically as the child grows.

As children mature, they usually develop more control over their behaviour and this may reduce their reliance on medication. For example, a young hyperactive child may generate so much stress in the family that he or she may need medication every day. As the child matures, the hyperactivity may start to settle and medication may only be needed for school. The school years are often the most difficult stage of life for the individual with ADHD. This is because schoolwork involves prolonged periods of concentration and many of the tasks may not be intrinsically interesting. Once a person is no longer studying, they may be able to cease

Although executive functioning deficits generally persist into adult life, with maturity individuals often become better at developing strategies to help them to function. However, some have ongoing problems with irritability and anger. An understanding of the reward deficit associated with ADHD may encourage such people to practise emotional self-regulation

The main novel approach to treatment suggested in this chapter is the recommendation for strategies designed to enhance the positive emotional experiences in everyday life for indi‐ viduals with ADHD. These would clearly need to be evaluated with randomised controlled studies that include a plausible comparison treatment. In young children, behaviour manage‐ ment strategies are generally taught to the parents who then implement them with the child. Therefore, groups of parents could be taught conventional behaviour management using external rewards and punishments or strategies designed to promote positive emotions in the child through their achievement. Outcomes would be assessed using standardised rating scales relating not only to achievement in terms of task completion but also any positive effects on mood. In older children and adults with ADHD, particularly those with anger or opposi‐

strategies to help promote a better mood and more rewarding existence.

*3.2.4. Changes in treatment requirements with maturity*

324 ADHD - New Directions in Diagnosis and Treatment

medication.

**4. Directions for research**

In this chapter we have described the MERIM, a new way of conceptualising ADHD that emphasises the importance of mood in the overall symptomatology. This naturally leads on to strategies specifically aiming to enhance a person's experience of reward in order to sustain a stable and amicable mood. Although medication can directly address the neurochemical deficits, self-regulation strategies may play a valuable role in enhancing reward, leading to long-term improvements in behavioural functioning.

### **Author details**

Alison Poulton

Address all correspondence to: alison.poulton@sydney.edu.au

The University of Sydney - Sydney Medical School Nepean, Penrith, Australia

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## **Repetitive Transcranial Magnetic Stimulation in ADHD**

Pavel Theiner, Libor Ustohal, Tomáš Skřont, Martin Bareš and Tomáš Kašpárek

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/61158

#### **Abstract**

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Although there are very effective treatment approaches for ADHD available, the clini‐ cal management has its limits and a search for new treatment modalities is useful. rTMS found its use in neurology and is widely applied in psychiatric research and al‐ though its effect seems mild, it can be specific to some extend. The text reviews cur‐ rent knowledge on the neurobiology of ADHD symptoms with regard to a possible rTMS treatment. The basics of the rTMS method are described. The use of rTMS is summarized both generally in psychiatric disorders and specifically in ADHD. The safety issues are discussed both in adults and children. The text also brings a case study where rTMS was applied in an adult patient with ADHD.

**Keywords:** ADHD, rTMS, neurobiology

### **1. Introduction**

#### **1.1. Limits of current treatments for ADHD**

Although the current treatment approaches in ADHD are highly supported by research and are very effective, they are not suitable for all patients in need for treatment. Medications used in clinical practice are generally well tolerated; however, they have some safety issues. Cardiovascular effects are the most important of them. Both stimulants and atomoxetine increase heart rate and blood pressure and for some patients it prevents their use. Treatment with stimulants belongs to the most effective within psychiatry. Almost all guidelines recommend stimulants as first-line treatment. However, 20–35% of children and adolescents in clinical trials may have an inadequate response to initial stimulant treatment either due to insufficient efficacy or non-adherence [1]. The response rate in atomoxetine is even lower, with 40% of patients without significant improvement [2]. In adults, the response rates for methyl‐

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

phenidate are around 50% [3]. The long-time studies in adults with ADHD show high rates of non-adherence to medications. Only about half of the patients remain in treatment after two years [4]. As for the psychosocial treatment, the evidence-based efficacy remains unclear, although psychosocial treatments can have some positive impact for children with ADHD beyond the impact of pharmacologic treatment alone. The quality of studies aimed at psycho‐ social interventions is insufficient, although it improves continuously [5].

Therefore, although specific pharmacotherapies for ADHD exist, they are not always available or suitable for all individuals. Moreover, as for the effect on specific symptom clusters, such as impulsivity, inconsistent data exist with both positive and negative effect of stimulants [6]. Even more, there are other issues, such as parents' non-acceptance of pharmacological treatment, that limit the benefit from pharmacological treatment. The need for novel treatment approaches is clear. Repetitive transcranial magnetic stimulation (rTMS), one of the most recent treatment approaches in psychiatry, allows selective neuromodulation of regions involved in the functional neuroanatomy of individual symptomatic profiles.

#### **1.2. Functional neuroanatomy of ADHD symptoms**

Although there exist unifying theories on the nature of symptom clusters in ADHD, the evidence on unequal expression of individual symptoms across clinical samples suggests that at least some symptom clusters are based on distinct neurobiology. This notion is demonstrat‐ ed by a multivariate analysis of the results of testing of a large sample of ADHD subjects using cognitive battery that focused on cognitive control, reward- and time-processing that showed that these domains form distinct components, and that 80 % of subjects who had a deficit were deficient on only one component [7]. Dysfunctions in these cognitive domains may manifest in distinct symptom profiles in ADHD, i.e. inattention, impulsivity, and hyperactivity. Below, we summarize their functional neuroanatomy to evaluate the potential targets for rTMS treatment.

#### *1.2.1. Impulsivity*

Impulsivity is a clinically important feature that accompanies many neuropsychiatric disor‐ ders, including ADHD, and constitutes a significant risk for their development, and compli‐ cates their course and treatment. In contrast to its frequent manifestation and significant impact, relatively little is known about its neurobiology, and, more importantly, there is no effective specific treatment available at present, except for behavioral modification. This situation may result from inadequate definition of impulsive behaviour with insufficient discrimination between phenomenologically similar, but neurobiologically different, process‐ es.

Indeed, impulsivity is a heterogeneous concept which manifests in many ways, such as personality traits, behavioral features and particular way of behavioural and cognitive task performance. Moreover, in clinical populations, there is rather variable phenomenology of behaviour that is generally labeled as impulsive and a considerable inconsistency of impul‐ sivity concepts in neuropsychiatric disorders exists. It is not clear if there is a single psycho‐ logical process linked to a distinct neurobiology or if discrete patterns of impulsive behaviour could be found with specific functional neuroanatomy in various clinical contexts.

phenidate are around 50% [3]. The long-time studies in adults with ADHD show high rates of non-adherence to medications. Only about half of the patients remain in treatment after two years [4]. As for the psychosocial treatment, the evidence-based efficacy remains unclear, although psychosocial treatments can have some positive impact for children with ADHD beyond the impact of pharmacologic treatment alone. The quality of studies aimed at psycho‐

Therefore, although specific pharmacotherapies for ADHD exist, they are not always available or suitable for all individuals. Moreover, as for the effect on specific symptom clusters, such as impulsivity, inconsistent data exist with both positive and negative effect of stimulants [6]. Even more, there are other issues, such as parents' non-acceptance of pharmacological treatment, that limit the benefit from pharmacological treatment. The need for novel treatment approaches is clear. Repetitive transcranial magnetic stimulation (rTMS), one of the most recent treatment approaches in psychiatry, allows selective neuromodulation of regions

Although there exist unifying theories on the nature of symptom clusters in ADHD, the evidence on unequal expression of individual symptoms across clinical samples suggests that at least some symptom clusters are based on distinct neurobiology. This notion is demonstrat‐ ed by a multivariate analysis of the results of testing of a large sample of ADHD subjects using cognitive battery that focused on cognitive control, reward- and time-processing that showed that these domains form distinct components, and that 80 % of subjects who had a deficit were deficient on only one component [7]. Dysfunctions in these cognitive domains may manifest in distinct symptom profiles in ADHD, i.e. inattention, impulsivity, and hyperactivity. Below, we summarize their functional neuroanatomy to evaluate the potential targets for rTMS

Impulsivity is a clinically important feature that accompanies many neuropsychiatric disor‐ ders, including ADHD, and constitutes a significant risk for their development, and compli‐ cates their course and treatment. In contrast to its frequent manifestation and significant impact, relatively little is known about its neurobiology, and, more importantly, there is no effective specific treatment available at present, except for behavioral modification. This situation may result from inadequate definition of impulsive behaviour with insufficient discrimination between phenomenologically similar, but neurobiologically different, process‐

Indeed, impulsivity is a heterogeneous concept which manifests in many ways, such as personality traits, behavioral features and particular way of behavioural and cognitive task performance. Moreover, in clinical populations, there is rather variable phenomenology of behaviour that is generally labeled as impulsive and a considerable inconsistency of impul‐ sivity concepts in neuropsychiatric disorders exists. It is not clear if there is a single psycho‐

social interventions is insufficient, although it improves continuously [5].

involved in the functional neuroanatomy of individual symptomatic profiles.

**1.2. Functional neuroanatomy of ADHD symptoms**

332 ADHD - New Directions in Diagnosis and Treatment

treatment.

es.

*1.2.1. Impulsivity*

Impulsive behaviour is the execution of an immediate urge to act, bypassing consideration of possible means and outcomes of available alternatives. In a closer look, there may be several sources of such behaviour. Moreover, behaviours like compulsions or hyperactivity may resemble impulsivity on the phenomenological level while they result from different neuro‐ biological and psychological processes [8]. Contemporary neuroscience opens new possibili‐ ties for objective analysis of neurophysiological sources of behavior. Moreover, it brings new ways of treatment that are guided by detailed knowledge of neurobiology of individual signs and symptoms.

Impulsivity may be expressed in personality traits, cognitive and emotional processes or behaviour control [9]. **Impulsive personality traits** include impulsivity proper, i.e. tendency to act rashly without evaluation of consequences (most frequently measured using the Barrat Impulsivity Scale); furthermore, it is reflected in the concept of *sensation seeking* (search of novel intense experiences without consideration of associated risks), *lack of perseverance*, *positive and negative urgency* (a tendency to act rashly during intense positive or negative affects) or high *reward sensitivity*.

**Cognitive manifestation of impulsivity** includes a concept of **behavioural disinhibition**, i.e. inability to suppress irrelevant or unfavourable behaviour ("stop impulsivity" – Go-No go task, Stop signal task), and a concept of **risky decision-making** and **reward processing** with preference of immediate, but in a long run, disadvantageous gains, and inability to postpone reward ("wait impulsivity" – various modifications of Delayed Discounting paradigm, Iowa Gambling task). Compulsion is a repetitive urge to act that leads to a stereotyped behavior; impulsivity, on the other hand, is not stereotypic.

The forms of impulsivity associated with ADHD involve the inadequate control of behaviour, poor sustained inhibition, the inability to delay a response or defer gratification, or the inability to inhibit dominant or prepotent responses. An equal or perhaps greater problem is the delay aversion – children and adults find waiting aversive, and therefore they act impulsively to terminate the delay more quickly. There is a reduction of symptoms of impulsivity with age, but adults still describe some symptoms of it. The clinical manifestations of impulsivity are described as "acts before thinking", "does not learn from mistakes", "says things without thinking" and "does not think about risks or effects of actions" [10, 11]. Impulsivity in individuals with ADHD is associated with greater emotional and behavioral impairments in all stages of life. The consequences of impulsivity often include poor academic and occupa‐ tional performance, problems in interpersonal relationships. Impulsivity is also associated with an elevated risk for substance abuse, cigarette smoking, driving problems or antisocial behaviors. [12]

#### *1.2.1.1. Functional neuroanatomy of impulsivity*

Functional neuroanatomy of symptoms is based on imaging of brain activity during execution of a specific behavioral paradigm. Therefore, there are no studies of impulsivity, hyperactivity, nor any other clinical symptom. Rather, the neuroanatomy is based on associations between a particular pattern of responses during behavioral paradigm that engage specific cognitive processes and clinical manifestation of an illness. Impulsivity is associated with changes in reward processing, behavioral inhibition, and, perhaps, time processing. Failures in any of these processes can manifest as impulsivity. Although it might be difficult sometimes to differentiate what process causes a specific pattern of behavioral responses, for the sake of clarity the functional neuroanatomy of reward, behavioral inhibition, and time processing will be elaborated individually. The evidence suggests that they represent distinct patterns of brain circuit dysfunctions, and, therefore, they may form distinct phenotypes of impulsivity (i.e. "stopping" – "inhibition-dependent" and "waiting" – "reward-dependent" impulsivity).

Test features that require **inhibition** of inappropriate behaviour activate right inferior frontal gyrus, orbitofrontal gyrus, anterior cingulate, motor and premotor regions (motor cortex M1, supplementary motor area, dorsal premotor cortex), striatum, thalamus, and nucleus subtha‐ lamicus. It seems that behavioural inhibition itself consists of several subprocesses: inhibition of interference, response delay, and response cancellation. All of them are linked to the activation of the right inferior frontal gyrus, supplementary motor cortex, and parietal cortex. Inhibition of interference activates to a greater degree premotor and parietal cortex; cancella‐ tion of response represents a late phase of response inhibition and is linked with higher activation of fronto-striatal circuits. Meta-analysis of fMRI studies revealed strong evidence for decreased activation of the right inferior frontal gyrus, right supplementary motor area (BA6) and anterior cingulate (BA 32), right fusiform gyrus (BA 19), left caudate head, and right thalamus during motor inhibition tasks (Go-NoGo or Stop signal tasks) in ADHD [13].

Impulsivity linked with inadequate **reward processing** that involves decision-making and reward evaluation activates medial prefrontal cortex, medial orbitofrontal cortex, anterior cingulate, hippocampus, insula, amygdala, and ventral striatum or nucleus accumbens [9, 14]. Subjects with ADHD show decreased activation within this network, with a replicated finding of hypoactivation of ventral striatum during reward anticipation [15]. Edel et al. [16] showed that there might be dissociation of the neuronal deficit during reward processing between ADHD subtypes: predominantly inattentive subtype was linked with hypoactivation of ventral striatum, combined subtype with hypoactivation of orbitofrontal cortex.

#### *1.2.2. Attention deficit*

Deficits of sustained attention belong to very common findings in ADHD. A meta-analysis of fMRI studies (that used Continuous performance, Odd-ball, or Mental rotation tasks) detected significant decrease of brain activity in the right dorsolateral prefrontal cortex (BA 8, 46), right inferior parietal cortex (BA 40), right precuneus (BA 7), right superior temporal gyrus (BA 42), left putamen, and right thalamus; on the other hand, increased activity in cerebellum was found too [13]. However, individual studies show also involvement of the left hemisphere dysfunctions – using fMRI during vigilance task in boys with ADHD found decreased activation of the left dorsolateral prefrontal cortex (middle frontal gyrus, BA 46, 9, 8), superior parietal cortex (postcentral gyrus, BA 6, 4, 2, 1, 7), and subcortical structures involved in frontostriatal loops [17]. DLPFC activation was related to the test performance, i.e. the reduced DLPFC activation corresponded to deficits in sustained attention. Findings of abnormal functional connectivity within fronto-striatal loop during Continuous performance task in children with ADHD [18] demonstrates that the abnormal pattern of activity affects whole networks – which might be advantageous for the TMS applications, where only selected parts of the network are accessible, and still the influence of a part of a network may affect interconnected areas as well.

Arnsten describes a comprehensible model of attention, with two systems. The "bottom-up" system represents stimuli from the environment processed in association areas (posterior parts of the brain – the occipital, parietal, and temporal lobes) and projected to the PFC according to their salience. The "top-down" system represents the actions of the PFC which chooses which stimuli will be enhanced (relevant) and which will be suppressed (distracting) according to their relevance for long-time goals processed by the PFC. The PFC uses its extensive projections back to the sensory association cortices. [19]

In addition to the disorders of attention, dysfunction of several other cognitive functions, such as working memory and executive functions can be found in ADHD [20], albeit only in a subgroup of patients [21]. They are linked to reduced DLPFC activity [22].

### *1.2.3. Time processing*

nor any other clinical symptom. Rather, the neuroanatomy is based on associations between a particular pattern of responses during behavioral paradigm that engage specific cognitive processes and clinical manifestation of an illness. Impulsivity is associated with changes in reward processing, behavioral inhibition, and, perhaps, time processing. Failures in any of these processes can manifest as impulsivity. Although it might be difficult sometimes to differentiate what process causes a specific pattern of behavioral responses, for the sake of clarity the functional neuroanatomy of reward, behavioral inhibition, and time processing will be elaborated individually. The evidence suggests that they represent distinct patterns of brain circuit dysfunctions, and, therefore, they may form distinct phenotypes of impulsivity (i.e. "stopping" – "inhibition-dependent" and "waiting" – "reward-dependent" impulsivity).

Test features that require **inhibition** of inappropriate behaviour activate right inferior frontal gyrus, orbitofrontal gyrus, anterior cingulate, motor and premotor regions (motor cortex M1, supplementary motor area, dorsal premotor cortex), striatum, thalamus, and nucleus subtha‐ lamicus. It seems that behavioural inhibition itself consists of several subprocesses: inhibition of interference, response delay, and response cancellation. All of them are linked to the activation of the right inferior frontal gyrus, supplementary motor cortex, and parietal cortex. Inhibition of interference activates to a greater degree premotor and parietal cortex; cancella‐ tion of response represents a late phase of response inhibition and is linked with higher activation of fronto-striatal circuits. Meta-analysis of fMRI studies revealed strong evidence for decreased activation of the right inferior frontal gyrus, right supplementary motor area (BA6) and anterior cingulate (BA 32), right fusiform gyrus (BA 19), left caudate head, and right thalamus during motor inhibition tasks (Go-NoGo or Stop signal tasks) in ADHD [13].

Impulsivity linked with inadequate **reward processing** that involves decision-making and reward evaluation activates medial prefrontal cortex, medial orbitofrontal cortex, anterior cingulate, hippocampus, insula, amygdala, and ventral striatum or nucleus accumbens [9, 14]. Subjects with ADHD show decreased activation within this network, with a replicated finding of hypoactivation of ventral striatum during reward anticipation [15]. Edel et al. [16] showed that there might be dissociation of the neuronal deficit during reward processing between ADHD subtypes: predominantly inattentive subtype was linked with hypoactivation

Deficits of sustained attention belong to very common findings in ADHD. A meta-analysis of fMRI studies (that used Continuous performance, Odd-ball, or Mental rotation tasks) detected significant decrease of brain activity in the right dorsolateral prefrontal cortex (BA 8, 46), right inferior parietal cortex (BA 40), right precuneus (BA 7), right superior temporal gyrus (BA 42), left putamen, and right thalamus; on the other hand, increased activity in cerebellum was found too [13]. However, individual studies show also involvement of the left hemisphere dysfunctions – using fMRI during vigilance task in boys with ADHD found decreased activation of the left dorsolateral prefrontal cortex (middle frontal gyrus, BA 46, 9, 8), superior parietal cortex (postcentral gyrus, BA 6, 4, 2, 1, 7), and subcortical structures involved in frontostriatal loops [17]. DLPFC activation was related to the test performance, i.e. the reduced

of ventral striatum, combined subtype with hypoactivation of orbitofrontal cortex.

*1.2.2. Attention deficit*

334 ADHD - New Directions in Diagnosis and Treatment

There exists growing evidence on impairment of various time-processing mechanisms in ADHD that form an independent domain of ADHD manifestation: perceptual timing, temporal foresight, and motor timing reflected in abnormalities of interval duration estimation and discrimination, delay discounting, and sensorimotor synchronization [23], i.e. processing of both interval estimation and fine-grained millisecond timing of brain events is affected. Since there is a relationship between time-processing deficits and measures of impulsivity and attention deficit [23], it seems that this neurocognitive abnormality may be another source of core behavioral manifestations of ADHD.

Functional neuroanatomy of time-processing deficits in ADHD converges on the pattern of reduced activation of bilateral inferior frontal gyrus, orbitofrontal cortex (in particular, in time foresight paradigms – delayed discounting task), SMA, precentral gyrus, insula, and cerebel‐ lum [24–27].

### *1.2.4. Emotion dysregulation*

Emotion dysregulation is an important component of ADHD and according to many it should be considered in diagnostic conceptualizations of ADHD [28, 29]. It was found to be linked to some ADHD variables such as greater ADHD functional impairment, lower quality of life, ADHD persistence, and higher ADHD severity in childhood [30]. Shaw et al. [31] describes emotion dysregulation as emotional expressions and experiences that are excessive in relation to social norms and context-inappropriate; rapid, poorly controlled shifts in emotion ("labili‐ ty"); and the anomalous allocation of attention to emotional stimuli. In the study of Vidal et al., adults with ADHD presented higher levels of emotional lability when compared to clinical control subjects and community subjects [30].

Similarly to attention, there are different systems that regulate emotions. The "bottom-up" system is represented by emotional responses of the amygdala and ventral striatum to external stimuli. Their projections to prefrontal cortex (PFC) draw attention to emotionally loaded processes and similarly to attention, this bottom-up system stresses salience of emotions and not their current relevance. Subcortical structures, the amygdala, and the ventral striatum play a key role in generation of emotions. These areas project to ventrolateral prefrontal cortex (VLPFC), which is not a centre for emotion regulation, rather it decides if regulation is necessary. The need for regulation is signalized to the dorsolateral PFC (DLPFC), either via the anterior middle cingulate cortex or directly. The DLPFC processes the information from VLPFC and relays it to other brain structures involved in emotomotor control [32], which represents the "top-down" regulation based on relevance of the emotion for tasks and goals currently processed by the DLPFC. This ability is included in the broader concept of "executive functions", i.e. the processes that are focused on attaining long-term goals through organizing and planning.

Emotion dysregulation in ADHD may arise from deficits at multiple levels. These range from abnormal early orienting to emotional stimuli, particularly with regard to negative stimuli and reward valuation through an inability to recruit top-down regulatory effort in response to emotional stimuli. Meantime, deficits in cognitive processes, including working memory and response inhibition, may contribute to emotion dysregulation, but they do not seem to be alone to explain its presence in ADHD [31]. In children with ADHD and emotional lability, deficits in emotion regulation were associated with altered amygdala–cortical intrinsic functional connectivity (iFC). The cortical structures involved were rostral anterior cingulate cortex (positive iFC in individuals with high emotional lability). Emotional lability scores were also negatively associated with iFC between bilateral amygdala and posterior insula/superior temporal gyrus [33].

#### *1.2.5. Motor symptoms and hyperactivity*

Hyperactivity is a non-specifically increased tendency to act. The question is if it is a conse‐ quence of inadequate motor inhibition or if there are other sources for hyperactivity. Although there are no functional imaging studies of hyperactivity per se, there are reports of motor system changes in ADHD. During simple motor tasks, reduced activity of primary motor (BA4) and sensor cortex in ADHD subjects was observed [34]. Moreover, abnormal co-operation of motor system was seen as well – McLeod et al. (2014) [35] described reductions in functional connectivity at rest between the primary motor cortex and the bilateral inferior frontal gyri, right supramarginal gyrus, angular gyri, insular cortices, amygdala, putamen, and pallidum. It seems that increased lateral prefrontal cortex activity is involved in compensation of inadequate motor system performance in ADHD subjects [36].

#### **1.3. Potential targets for rTMS treatment**

From the network point of view, there seems to be an involvement of at least three distinct circuits – lateral attentional network, medial reward-related network, and fronto-cerebellar time-processing network. At present, the state-of-the-art rTMS technology enables modulation of regions that lay close to the surface of the brain, i.e. lateral parts. Based on the above reviewed functional neuroanatomy, potential accessible candidate targets are represented by dorsolat‐ eral prefrontal cortex, ventrolateral prefrontal cortex, inferior frontal gyrus, dorsal parts of supplementary motor cortex, and cerebellum. Modulation of dorsolateral prefrontal cortex may lead to changes of attention, working memory, and executive functions, but through the top-down regulations it may exert effects on emotional dysregulation symptoms, and impul‐ sivity. Inferior frontal gyrus stimulation may lead to changes in behavioral inhibition and time estimation. Cerebellar stimulation may influence time processing, cognitive functioning, and, perhaps, even the affective symptoms of ADHD. rTMS of cerebellum is technically possible; however, the tolerability due to the neck muscle stimulation might limit its clinical use. Quite recently, rTMS approaches that use a double-cone or HAUT coils demonstrated their ability to modulate activity of medial cortical regions [37, 38]. This technological advancement would enable direct targeting of medial cortical nodes related to reward processing, which may bring increased efficacy in the treatment of impulsivity in ADHD.

### **2. Repetitive transcranial magnetic stimulation**

#### **2.1. General description and current use in psychiatry**

Similarly to attention, there are different systems that regulate emotions. The "bottom-up" system is represented by emotional responses of the amygdala and ventral striatum to external stimuli. Their projections to prefrontal cortex (PFC) draw attention to emotionally loaded processes and similarly to attention, this bottom-up system stresses salience of emotions and not their current relevance. Subcortical structures, the amygdala, and the ventral striatum play a key role in generation of emotions. These areas project to ventrolateral prefrontal cortex (VLPFC), which is not a centre for emotion regulation, rather it decides if regulation is necessary. The need for regulation is signalized to the dorsolateral PFC (DLPFC), either via the anterior middle cingulate cortex or directly. The DLPFC processes the information from VLPFC and relays it to other brain structures involved in emotomotor control [32], which represents the "top-down" regulation based on relevance of the emotion for tasks and goals currently processed by the DLPFC. This ability is included in the broader concept of "executive functions", i.e. the processes that are focused on attaining long-term goals through organizing

Emotion dysregulation in ADHD may arise from deficits at multiple levels. These range from abnormal early orienting to emotional stimuli, particularly with regard to negative stimuli and reward valuation through an inability to recruit top-down regulatory effort in response to emotional stimuli. Meantime, deficits in cognitive processes, including working memory and response inhibition, may contribute to emotion dysregulation, but they do not seem to be alone to explain its presence in ADHD [31]. In children with ADHD and emotional lability, deficits in emotion regulation were associated with altered amygdala–cortical intrinsic functional connectivity (iFC). The cortical structures involved were rostral anterior cingulate cortex (positive iFC in individuals with high emotional lability). Emotional lability scores were also negatively associated with iFC between bilateral amygdala and posterior insula/superior

Hyperactivity is a non-specifically increased tendency to act. The question is if it is a conse‐ quence of inadequate motor inhibition or if there are other sources for hyperactivity. Although there are no functional imaging studies of hyperactivity per se, there are reports of motor system changes in ADHD. During simple motor tasks, reduced activity of primary motor (BA4) and sensor cortex in ADHD subjects was observed [34]. Moreover, abnormal co-operation of motor system was seen as well – McLeod et al. (2014) [35] described reductions in functional connectivity at rest between the primary motor cortex and the bilateral inferior frontal gyri, right supramarginal gyrus, angular gyri, insular cortices, amygdala, putamen, and pallidum. It seems that increased lateral prefrontal cortex activity is involved in compensation of

From the network point of view, there seems to be an involvement of at least three distinct circuits – lateral attentional network, medial reward-related network, and fronto-cerebellar time-processing network. At present, the state-of-the-art rTMS technology enables modulation

and planning.

temporal gyrus [33].

*1.2.5. Motor symptoms and hyperactivity*

336 ADHD - New Directions in Diagnosis and Treatment

**1.3. Potential targets for rTMS treatment**

inadequate motor system performance in ADHD subjects [36].

Transcranial magnetic stimulation (TMS) is a diagnostic and therapeutical technique based on the principle of electromagnetic induction of electric current in the brain. It uses high-density magnetic field (approximately 2T lasting 0.1 ms) to induce electric field inside cortex, which is able to depolarize neurons [39]. Repetitive transcranial magnetic stimulation (rTMS) depolarizes neurons repetitively with either high (HF) or low frequency (LF) in order to change neuronal excitability for a longer period of time. The excitability can be lowered by using a low-frequency stimulation [40], and vice versa, high-frequency stimulation is able to render the neuron more sensible to stimuli, thus more excitable [41]. Findings from the neuroimaging studies that have localized dysfunctional parts of cortex in particular diseases can be trans‐ formed into new treatment approaches. However, recent findings suggest that the effect of rTMS is more complex and the excitatory/inhibitory paradigm is not fully satisfying as some works suggest mixed excitatory and inhibitory effects of either HF or LF-rTMS [42] and the excitatory effect of HF-rTMS on motor-evoked potentials might be caused by the decrease of gamma-amminobutyric acid-mediated inhibition [43]. The method is non-invasive and few side effects have been reported so far. The complete mechanism of changes remains unclear, but it is believed that rTMS affects gene expression [44], synaptic plasticity, dopamine release [45, 46], and release of endogenous opioids [47]. The ability of rTMS to affect not only the particular area it is aimed at but also the whole functional site is crucial as it is able to modulate function in more distant parts of brain [48, 49].

Each rTMS protocol is characterized by its focus of stimulation, frequency of stimuli, intensity, frequency of sessions, total number of pulses, train and intertrain time, a total time of session, and the shape of the coil. Taking this into account, many variables which can modify the effect of stimulation are present and researchers need to consider each of them when designing a protocol. The choice of the region of the brain cortex used for stimulation is based on lesion studies or imaging data that suggest an approximate localization of the studied cortical function, e.g. dorsolateral prefrontal cortex, supplementary motor area, etc. The choice of a particular place on subject's scalp to put on the coil is based on anatomy or imaging data of the particular subject. The intensity of each stimulation is usually standardized according to a percent of RMT (resting motor threshold), determined in each individual. 1 Hz stimulation is typically used for LF-rTMS, and 5–20 Hz stimulation in HF-rTMS. Multiple imaging techniques are used for online monitoring of rTMS effect in studies (EEG, PET, fMRI).

Another form of rTMS – the Theta-Burst stimulation (TBS) – consists of 3 pulses at 50 Hz repeated at 200 ms interval (hence 5 Hz frequency). This stimulation, when applied continu‐ ously (cTBS), is considered to mimic long-term depression effect on cortical excitability, while when applied intermittently (iTBS), long-term potentiation-like (LTP-like) effect is observed [50]. However, Gamboa showed that doubling the duration of the stimulation leads to conversion of its effect [51].

Largest body of evidence supporting the efficacy of rTMS was reached in trials with patients suffering of drug-resistant major depression and this success of rTMS led to approval of this technique in this indication by Food and Drug Administration in the USA in 2008. The method is also used in neuropsychiatry for the treatment of anxiety disorders [52], child autism [53, 54], Parkinson's disease [55], and positive symptoms of schizophrenia such as auditory hallucinations [56, 57]. And for number of other diseases, this technique is in various states of research (neuropathic pain, Tourette's syndrome, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, Alzheimer's disease, tinnitus, obsessive compulsive disorder, negative symptoms of schizophrenia, substance abuse, addiction, and craving) [55].

#### *2.1.1. Safety issues*

Although rTMS is believed to be a very safe technique, several side effects were described in previous studies. Of the major concern is the possibility of seizure induction, mostly during excitatory rTMS (HF), considered the most serious TMS-related acute side effect. However, the incidence of seizures was extremely rare (0.1–0.5%) and was mostly connected to receiving rTMS exceeding previous guideline recommendations, often in patients under a medication potentially lowering the seizure threshold. A short intertrain time is considered to be one of the potential triggers of seizures during rTMS [58]. Further research and analysis should be performed to identify protocol aspects and indication criteria lowering the risk of seizures.

As rTMS produces rather intensive noise (over 120 dB) [59], considerations about its effect on patient's hearing should be taken into account. The amplitude of rTMS sound depends on the coil design and the absolute stimulation intensity. Thus, sound intensity experienced by the patient during stimulation depends directly on the subject's motor threshold which is indi‐ vidually variable across the population [60]. According to safety guidelines [58], hearing protection is highly recommended as some subjects with no hearing protection experienced a hearing loss or threshold shifts in past studies [61, 62].

Headache is a relatively frequent adverse effect of rTMS, but this discomfort usually vanishes within minutes with either no need for medications or it responds to common analgesics. A scalp pain or discomfort is a common adverse effect of rTMS as well and an ideal method to decrease this discomfort is still in research (e.g. local application of lidocaine) [63, 64]. How‐ ever, the scalp pain and discomfort typically vanish straight after the application of pulses and eventually it seems there is a kind of accommodation as the first session is usually refered as the most painful.

Repetitive transcranial magnetic stimulation is contraindicated in patients with metallic (conductive, ferromagnetic, or other magnetic-sensitive) objects in or near the head (within 30 cm of the treatment coil), e.g. implanted electrodes, bullet fragments, aneurysm clips, stents and similar, or implanted stimulator devices in or near the head, e.g. deep brain stimulators and vagus nerve stimulators.

#### **2.2. Repetitive transcranial magnetic stimulation in the treatment of ADHD**

#### *2.2.1. Children and adolescents*

protocol. The choice of the region of the brain cortex used for stimulation is based on lesion studies or imaging data that suggest an approximate localization of the studied cortical function, e.g. dorsolateral prefrontal cortex, supplementary motor area, etc. The choice of a particular place on subject's scalp to put on the coil is based on anatomy or imaging data of the particular subject. The intensity of each stimulation is usually standardized according to a percent of RMT (resting motor threshold), determined in each individual. 1 Hz stimulation is typically used for LF-rTMS, and 5–20 Hz stimulation in HF-rTMS. Multiple imaging techniques are used for online monitoring of rTMS effect in studies (EEG, PET, fMRI).

Another form of rTMS – the Theta-Burst stimulation (TBS) – consists of 3 pulses at 50 Hz repeated at 200 ms interval (hence 5 Hz frequency). This stimulation, when applied continu‐ ously (cTBS), is considered to mimic long-term depression effect on cortical excitability, while when applied intermittently (iTBS), long-term potentiation-like (LTP-like) effect is observed [50]. However, Gamboa showed that doubling the duration of the stimulation leads to

Largest body of evidence supporting the efficacy of rTMS was reached in trials with patients suffering of drug-resistant major depression and this success of rTMS led to approval of this technique in this indication by Food and Drug Administration in the USA in 2008. The method is also used in neuropsychiatry for the treatment of anxiety disorders [52], child autism [53, 54], Parkinson's disease [55], and positive symptoms of schizophrenia such as auditory hallucinations [56, 57]. And for number of other diseases, this technique is in various states of research (neuropathic pain, Tourette's syndrome, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, Alzheimer's disease, tinnitus, obsessive compulsive disorder,

negative symptoms of schizophrenia, substance abuse, addiction, and craving) [55].

Although rTMS is believed to be a very safe technique, several side effects were described in previous studies. Of the major concern is the possibility of seizure induction, mostly during excitatory rTMS (HF), considered the most serious TMS-related acute side effect. However, the incidence of seizures was extremely rare (0.1–0.5%) and was mostly connected to receiving rTMS exceeding previous guideline recommendations, often in patients under a medication potentially lowering the seizure threshold. A short intertrain time is considered to be one of the potential triggers of seizures during rTMS [58]. Further research and analysis should be performed to identify protocol aspects and indication criteria lowering the risk of seizures.

As rTMS produces rather intensive noise (over 120 dB) [59], considerations about its effect on patient's hearing should be taken into account. The amplitude of rTMS sound depends on the coil design and the absolute stimulation intensity. Thus, sound intensity experienced by the patient during stimulation depends directly on the subject's motor threshold which is indi‐ vidually variable across the population [60]. According to safety guidelines [58], hearing protection is highly recommended as some subjects with no hearing protection experienced a

hearing loss or threshold shifts in past studies [61, 62].

conversion of its effect [51].

338 ADHD - New Directions in Diagnosis and Treatment

*2.1.1. Safety issues*

Several limitations exist for the use of any therapy in children regarding their developing brain. Every novel therapy in neuropsychiatry needs to be evaluated carefully in children, especially in the terms of long-term safety. According to the theory of "sensitive periods" (a time period within brain development when an intervention has a strong effect on the brain [65]) in childhood, neuromodulation methods might be able to affect the brain function in a more stable and effective way during these periods. Although there is no evidence of any serious side effects of rTMS in children, it has to be kept in mind that the risk of inducing maladaptive neuroplasticity during sensitive periods of development of the child brain is still present and there is great need to clearly describe the neurophysiology of the impact of rTMS on a developing brain [54].

Dorsolateral prefrontal cortex (DLPFC), and especially right DLPFC, is believed to be highly involved in the pathophysiology of ADHD – see above. Two studies reported an application of rTMS over DLPFC in children and adolescents with ADHD. Weaver and colleagues (2012) applied HF-rTMS (10 Hz, 100% of the observed motor threshold) over the right DLPFC in 9 young patients (4 of them between 15 and 17). Their sham-controlled crossover safety study revealed an overall improvement in ADHD symptoms, but no difference between the sham and the active rTMS sessions [66]. Isenberg et al. showed that LF-rTMS on the left DLPFC has similar effect in patients with depression as HF-rTMS on the right DLPFC [67]. Gomez et al. based their protocol on these findings and applied 1 Hz rTMS of 90% of the rest motor threshold over the left DLPFC in ten school-aged boys (ages 7–12) suffering from ADHD. Although this study was performed to establish tolerability and safety of this protocol in children, their preliminary results have been promising because of significant clinical improvement of ADHD symptoms (mainly inattentiveness in school and hyperactivity/impulsivity at home) as referred by teachers, parents, and partly confirmed by the attending physician [68].

Two other studies applied the rTMS in children with ADHD for different purposes. One of them successfully evaluated TMS-evoked N100 measuring by EEG as a suitable marker for online monitoring of rTMS effects in children with ADHD as they found significant reduction of the amplitude of TMS-evoked N100 in comparison to the sham stimulation [69]. Loo et al. (2006) used 10 Hz rTMS on two 16-years-old girls suffering from depression and ADHD and described improvement in depression but no change in ADHD symptoms [70]. Nevertheless, all these studies revealed no serious adverse effects in children with ADHD undergoing rTMS.

Considering the wide comorbidity of ADHD and Tourette's syndrome (60–80% according to hospital studies) [71], it is worth noticing some promising results of rTMS treatment. Two studies [72, 73] applied LF-rTMS of 100/110% of motor threshold over the supplementary motor area and showed significant improvement in tics; these improvements lasted for a minimum of 6 months [73]. However, three participants with ADHD reported no change in ADHD symptoms. Nevertheless, improving the tic symptoms can increase the compliance of ADHD patients and give the therapist possibility to better address the therapy of ADHD symptoms.

### *2.2.2. Adults*

As the recent findings have revealed, in over 50% of children with ADHD the symptoms persist to adulthood. Adult ADHD has become a large point of interest for research. Considering the fact that attention deficit symptoms tend to persist into adulthood more often than hyperac‐ tivity symptoms, a pilot study was performed using HF-rTMS on the right DLPFC. This stimulation resulted in improvements in attention but with small clinical significance [74]. One patient in a case study reported particular dysphoria, inability to respond emotionally, hypobulia, tension, and impaired attention after the same stimulation protocol [75]. Applying inhibitory protocol on the contralateral DLPFC might be worth trying as well.

On the other hand, two studies with inhibitory protocol with LF-rTMS over the supplementary motor area (SMA) reported significant clinical improvement in hyperactivity in two women with the hyperactive/impulsive subtype of ADHD [76, 77].

Some studies focused on other functions typically impaired in ADHD (e.g. attention, impul‐ sivity) trying to influence them by non-invasive brain stimulation in healthy population. The DLPFC was stimulated in studies measuring the effect of stimulation on sustained attention or impulsivity or inhibition. HF-rTMS over the left DLPFC led to better performance in the Conners Continuous Performance task [78]. Continuous Theta-burst stimulation over the DLPFC resulted in choosing larger delayed rewards rather than smaller immediate ones in the Delay Discounting test [79]. Similar results were reached after stimulation of the medial prefrontal cortex by HF-rTMS [80]. Interestingly, anodal transcranial direct current stimulation (tDCS) applied over either the left or the right DLPFC resulted in more careful driving on a driving simulator [81].

The performance in the Stop Signal task, which is also used for the diagnosis of impulsivity, was affected by anodal tDCS over the pre-SMA and participants performed greater number of correctly inhibited responses in comparison with the active stimulation over M1 [82].

### **2.3. Why are the results of studies so variable?**

online monitoring of rTMS effects in children with ADHD as they found significant reduction of the amplitude of TMS-evoked N100 in comparison to the sham stimulation [69]. Loo et al. (2006) used 10 Hz rTMS on two 16-years-old girls suffering from depression and ADHD and described improvement in depression but no change in ADHD symptoms [70]. Nevertheless, all these studies revealed no serious adverse effects in children with ADHD undergoing rTMS.

Considering the wide comorbidity of ADHD and Tourette's syndrome (60–80% according to hospital studies) [71], it is worth noticing some promising results of rTMS treatment. Two studies [72, 73] applied LF-rTMS of 100/110% of motor threshold over the supplementary motor area and showed significant improvement in tics; these improvements lasted for a minimum of 6 months [73]. However, three participants with ADHD reported no change in ADHD symptoms. Nevertheless, improving the tic symptoms can increase the compliance of ADHD patients and give the therapist possibility to better address the therapy of ADHD

As the recent findings have revealed, in over 50% of children with ADHD the symptoms persist to adulthood. Adult ADHD has become a large point of interest for research. Considering the fact that attention deficit symptoms tend to persist into adulthood more often than hyperac‐ tivity symptoms, a pilot study was performed using HF-rTMS on the right DLPFC. This stimulation resulted in improvements in attention but with small clinical significance [74]. One patient in a case study reported particular dysphoria, inability to respond emotionally, hypobulia, tension, and impaired attention after the same stimulation protocol [75]. Applying

On the other hand, two studies with inhibitory protocol with LF-rTMS over the supplementary motor area (SMA) reported significant clinical improvement in hyperactivity in two women

Some studies focused on other functions typically impaired in ADHD (e.g. attention, impul‐ sivity) trying to influence them by non-invasive brain stimulation in healthy population. The DLPFC was stimulated in studies measuring the effect of stimulation on sustained attention or impulsivity or inhibition. HF-rTMS over the left DLPFC led to better performance in the Conners Continuous Performance task [78]. Continuous Theta-burst stimulation over the DLPFC resulted in choosing larger delayed rewards rather than smaller immediate ones in the Delay Discounting test [79]. Similar results were reached after stimulation of the medial prefrontal cortex by HF-rTMS [80]. Interestingly, anodal transcranial direct current stimulation (tDCS) applied over either the left or the right DLPFC resulted in more careful driving on a

The performance in the Stop Signal task, which is also used for the diagnosis of impulsivity, was affected by anodal tDCS over the pre-SMA and participants performed greater number of correctly inhibited responses in comparison with the active stimulation over M1 [82].

inhibitory protocol on the contralateral DLPFC might be worth trying as well.

with the hyperactive/impulsive subtype of ADHD [76, 77].

symptoms.

340 ADHD - New Directions in Diagnosis and Treatment

*2.2.2. Adults*

driving simulator [81].

The differences between individual studies result from their methodology. There are great many parameters in rTMS that can be adjusted differently. The parameters are described above and studies use unequal designs. The reason for such differences is the practical absence of standard rTMS protocols for ADHD, the firm knowledge of the right technical setting is absent.

There is a possibility to use parameters that have been successful in the treatment of depressive disorder or negative symptoms of schizophrenia where the stimulation of the DLPFC is applied as well – high frequency, ideally 10Hz, above-threshold intensity (above 100% of the individual's resting motor threshold), higher number of treatment sessions (15 at least), higher number of pulses per session and totally during the treatment, and possibly the use of structural and functional brain imaging techniques for more accurate targeting of the best place of stimulation. This protocol has to be tested in trials (double-blind and placebo-controlled ideally) that could prove whether these parameters are really optimal for patients with ADHD. It is worth noting that in patients with obsessive-compulsive disorder this assumption was wrong and there is a search for a different target instead of the DLPFC. Even the protocols for much more studied disorders like depression or negative symptoms of schizophrenia differ, however, in different studies. In ADHD studies, the inter-individual variability is an important factor as extensive studies are lacking. The same protocol may lead to different outcomes in individual patients and in small sample studies the inter-individual variability can overweight the inter-group variability.

The measures of outcome can also differ in different studies. ADHD is defined by its diagnostic criteria and a lot of questionnaires are used to measure the changes in symptomatology. The functioning in individuals with ADHD varies considerably and the results in neuropsycho‐ logical tests correspond to this variability. Changes induced by rTMS may be small and only detectable in testing, but patients' expectations may be higher with such a "hi-tech treatment" so patients can subjectively overestimate or underestimate the results. More studies examining patients' subjective feelings as well as objective measures of attention and hyperactivity before and after rTMS are needed.

### **3. Case study**

An adult female patient 25-years-old with ADHD, a university student, was enrolled to the pilot study which examined the efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) in adult ADHD. Although she described having had the symptoms of ADHD before starting school education at the age of 6 years, she was never diagnosed by a psychiatrist and was never treated. She was assessed by only a school psychologist who communicated to her parents that she would not be able to study at university. She, however, did not give up, and this motivated her to work harder. She had good results at basic and secondary schools even though she suffered from inattention. The results at university were considerably poorer, but with a high level of motivation she was able to finish her bachelor's degree. Nonetheless, she had to consult a psychiatrist for the first time during the studies and she was diagnosed with adjustment disorder with prevailing depressive mood and suspected ADHD. She was medicated with paroxetine 20 mg daily and also with valproate 500 mg daily for emotional instability. Her mood improved with the medication, but she still had disturbing symptoms of inattention. A year later she found our experimental rTMS study and agreed willingly to participate.

Before the procedure, she was assessed by two psychiatrists experienced in diagnosing ADHD and the diagnosis was confirmed. Consecutively, she had a neuropsychological evaluation aimed at attention. She did not meet any contraindication for rTMS (epilepsy, pathological EEG, metal object in skull, cardiostimulator, or drug pump) and thus she could start rTMS. The high-frequency stimulation of the left dorsolateral prefrontal cortex (DLPFC) was used; this alternative had been previously used in another patient with ADHD (see [74]) and seemed effective and well-tolerated.

Before the initiation of stimulation, we first localized the spot whose stimulation triggered a motor-evoked potential (MEP) in the abductor pollicis brevis muscle. Then, we determined in a standard way the resting motor threshold (RMT) as the lowest stimulation intensity that is able to trigger a MEP of at least 50 µV in the above mentioned muscle five times out of ten consecutive trials [83]. The exact stimulation localization was determined according to the "5 cms rule" – that is, a localization 5 cm more rostral from the RTM spot. The patient had ten sessions during her treatment with high-frequency (10Hz) rTMS; the intensity was 110% of the RTM; and the pulse count was 1500 in a session with the stimulation train invariably 10 seconds long with an inter-train pause of 30 seconds. The treatment was well tolerated and no adverse effects were seen during the whole course of treatment. After treatment, she did not feel any subjective improvement in attention, but the control neuropsychological evaluation showed improvements in almost all tests focused on attention. A few weeks after rTMS, she was informed she was in the second trimester of pregnancy which meant she had been pregnant in the course of the rTMS treatment. In a year, she contacted us again and reported her pregnancy without complications as well as the delivery of a healthy child. She even managed to finish successfully her university studies.

This case study supports with evidence the hypothesis that rTMS may be an effective and safe treatment option for adult ADHD. It seems safe even in pregnant female subjects; the evidence is however insufficient.

### **4. Summary**

rTMS treatment of ADHD is in its infancy. The best treatment regimen, duration of acute treatment, neurostimulation target, and symptoms modulated by rTMS are to be determined. Although the method proved to be effective in several psychiatric indications (schizophrenia, major depression), the efficacy in ADHD needs to be studied in detail before any final conclusions. The neurobiology of ADHD is linked with dysfunctions of cortical regions that are accessible to rTMS modulation. The many regulatory functions of DLPFC enable TMS stimulation trials for many disorders. Majority of neurobiologic findings in ADHD involve this cortical area, thus giving sense to the use of rTMS in ADHD. Since frequent limitation of rTMS studies is only approximate localization of stimulation targets, when trying to target specific regions linked with ADHD, fMRI-guided neuronavigation may be of crucial impor‐ tance for the success of treatment regimens.

### **5. Abbreviations**

she was diagnosed with adjustment disorder with prevailing depressive mood and suspected ADHD. She was medicated with paroxetine 20 mg daily and also with valproate 500 mg daily for emotional instability. Her mood improved with the medication, but she still had disturbing symptoms of inattention. A year later she found our experimental rTMS study and agreed

Before the procedure, she was assessed by two psychiatrists experienced in diagnosing ADHD and the diagnosis was confirmed. Consecutively, she had a neuropsychological evaluation aimed at attention. She did not meet any contraindication for rTMS (epilepsy, pathological EEG, metal object in skull, cardiostimulator, or drug pump) and thus she could start rTMS. The high-frequency stimulation of the left dorsolateral prefrontal cortex (DLPFC) was used; this alternative had been previously used in another patient with ADHD (see [74]) and seemed

Before the initiation of stimulation, we first localized the spot whose stimulation triggered a motor-evoked potential (MEP) in the abductor pollicis brevis muscle. Then, we determined in a standard way the resting motor threshold (RMT) as the lowest stimulation intensity that is able to trigger a MEP of at least 50 µV in the above mentioned muscle five times out of ten consecutive trials [83]. The exact stimulation localization was determined according to the "5 cms rule" – that is, a localization 5 cm more rostral from the RTM spot. The patient had ten sessions during her treatment with high-frequency (10Hz) rTMS; the intensity was 110% of the RTM; and the pulse count was 1500 in a session with the stimulation train invariably 10 seconds long with an inter-train pause of 30 seconds. The treatment was well tolerated and no adverse effects were seen during the whole course of treatment. After treatment, she did not feel any subjective improvement in attention, but the control neuropsychological evaluation showed improvements in almost all tests focused on attention. A few weeks after rTMS, she was informed she was in the second trimester of pregnancy which meant she had been pregnant in the course of the rTMS treatment. In a year, she contacted us again and reported her pregnancy without complications as well as the delivery of a healthy child. She even

This case study supports with evidence the hypothesis that rTMS may be an effective and safe treatment option for adult ADHD. It seems safe even in pregnant female subjects; the evidence

rTMS treatment of ADHD is in its infancy. The best treatment regimen, duration of acute treatment, neurostimulation target, and symptoms modulated by rTMS are to be determined. Although the method proved to be effective in several psychiatric indications (schizophrenia, major depression), the efficacy in ADHD needs to be studied in detail before any final conclusions. The neurobiology of ADHD is linked with dysfunctions of cortical regions that are accessible to rTMS modulation. The many regulatory functions of DLPFC enable TMS stimulation trials for many disorders. Majority of neurobiologic findings in ADHD involve

willingly to participate.

342 ADHD - New Directions in Diagnosis and Treatment

effective and well-tolerated.

is however insufficient.

**4. Summary**

managed to finish successfully her university studies.

This chapter tries to provide with current knowledge about the neurobiology of ADHD for the purpose of explaining the role of a novel treatment approach in psychiatry – repetitive transcranial magnetic stimulation. The structures of brain have usually long and complicated names. We use some abbreviations to shorten the text. All abbreviations are written in full words as they occur for the first time. Here are some of the most common for your reference.

ADHD – attention-deficit hyperactivity disorder


### **Acknowledgements**

The work was supported by the Ministry of Health, Czech Republic – conceptual development of research organization (FNBr, 65269705), and by a research grant No. NT-13437, and by a research grant from the Grant Agency of the Ministry of Health, Czech Republic (AZV) No. 15-30062A.

### **Author details**

Pavel Theiner1\*, Libor Ustohal1 , Tomáš Skřont<sup>1</sup> , Martin Bareš2 and Tomáš Kašpárek1

\*Address all correspondence to: ptheiner@fnbrno.cz

1 Department of Psychiatry, University Hospital Brno and Faculty of Medicine, Masaryk University, Czech Republic

2 1st Department of Neurology, University Hospital of St. Anne and Faculty of Medicine, Masaryk University, Czech Republic

### **References**


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**Author details**

Pavel Theiner1\*, Libor Ustohal1

344 ADHD - New Directions in Diagnosis and Treatment

University, Czech Republic

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\*Address all correspondence to: ptheiner@fnbrno.cz

, Tomáš Skřont<sup>1</sup>

, Martin Bareš2

1 Department of Psychiatry, University Hospital Brno and Faculty of Medicine, Masaryk

2 1st Department of Neurology, University Hospital of St. Anne and Faculty of Medicine,

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