**5. Targets**

The proposed target areas for DBS in treatment-refractory addiction are several but welldocumented rationale for the choice of the target is required in order to investigate the effectiveness, safety and feasibility.

#### **5.1. Nucleus accumbens (Nacc)**

There is considerable preclinical evidence to support a role for the nucleus accumbens in mediating the motivational effects of conditioned stimuli associated with the drug leading to its anticipation. DBS in the NAcc has been successful in treating the behavioral component in addiction disorders and substance abuse [36, 37]. Ablative surgeries targeted at the NAcc have been used for several years (between 2000 and 2004) in China with mixed results, but a relapse rate of 50% and ethical concerns now limit the use of destructive procedures in the treatment of addiction [38–40]. The limited outcome and the consecutive side effects (poor concentration, poor short-term memory, aconuresis, changes in sexual desire and decreased interest to various degrees) are nevertheless expected considering the preclinical data investigating the role of the nucleus accumbens. However, there is no clear evidence for a specific alteration of the nucleus accumbens in addicted individuals. Despite the reserves considered earlier, few clinical studies are considering application of DBS in the accumbens of addicts and therefore as first indication with successful results as for example on one case of heroin addiction [41, 42]. Clinical data about the efficacy of NAcc stimulation exist in the literature in small case series. In two single case studies, two patients who underwent bilateral NAcc stimulation for heroin addiction experienced abstinence from opioids to the last follow-up, respectively, at 6 years and 6 months [42, 43]. A similar outcome was observed in other two separate cases of patients with chronic, severe alcoholism who were treated with DBS in the NAcc reporting abstinence at 1 year [24, 25, 44]. In a single case of NAcc DBS for obsessive compulsive disorder (OCD), quit smoking was reported [45], but a subsequent analysis of 10 patients who received DBS of the NAcc for OCD, TS, or anxiety found that only three patients achieved nicotine abstinence within 30 months [46]. These case reports show the potential for treatment of substance abuse disorders with DBS of the NAcc, but randomized and blinded studies are lacking. However, DBS of NAcc, as any other basal ganglia targets, can be associated with unpredictable limbic symptoms such as mania and depression [47]. A recent study showed that the DBS of different NAcc subregions had different effects on a natural reward such as the motivation for food intake. Specifically, the stimulation of the lateral shell decreased the motivation to food while the stimulation of the core was without effects [48]. According to some authors, there would be a different response of NAcc neurons to natural rewards with respect to secondary rewards to drug intake even if it was not possible to demonstrate a preferential localization of such neurons in the core or in the shell [49]. The NAcc shell is unlikely to be a good candidate for DBS, considering the empirical evidence for its detrimental effect on general motivation and impulse control [50]. In conclusion, the NAcc DBS seems to be able to exercise a significant control over drug abuse and behavioral components mostly in alcohol and oppiate addictions; therefore, alternative structures have been considered for DBS with limited preclinical empirical or theoretical support.

The side effects of hypothalamotomy consist of amnesia, vegetative crisis and reduction of libido and sexual desire [41]. The unconventional electrical stimulation of LH in rats while reducing the stimuli that induce the use of cocaine does not change the motivation for its intake [53]. Therefore, electrical stimulation of the posterior hypothalamus seems to have similar effects to the lesion producing a reduction of cocaine intake but preserving the processes of motivation [54]. The lack of effectiveness on motivation and possible severe adverse effects make lateral hypothalamus a target that cannot be used in addiction at the moment.

Deep Brain Stimulation in Treatment-Refractory Addiction

http://dx.doi.org/10.5772/intechopen.73694

5

Amygdala is involved in the process of evaluating the positivity or negativity of experience and in the formation of connections between experience and other signals becoming the center of emotional memory and learning [55]. In humans, the reduction of amygdala volume has been related to increase in desire for alcohol and cocaine intake and greater tendency to relapse [56], while in rats its functional block leads to increase in compulsivity of cocaine intake and seeking and reduction of its anxiety-producing effect [57, 58]. However, DBS of the amygdala does not find a clinical application in the treatment of addiction at present, even if

The lateral habenula (LHb) is a critical brain structure modulating aversive and rewarding behaviors through the GABAergic and glutaminergic efferent projections to the ventral tegmental area (VTA) by means of the fasciculus retroflexus (FR). The selective degeneration of this bundle in drug abuse led to a possible use of deep brain stimulation for the treatment of this condition. In rats, deep brain stimulation of LHb with low-frequency (10 Hz)-highfrequency alternate stimulation (100 Hz) attenuates cocaine self-administration, extinction training and reinstatement of cocaine seeking while conventional high-frequency stimulation did not have any effect and low-frequency stimulation increases cocaine self-administration [60]. The effect of unconventional LHb DBS on cocaine reinforcement may be due to reduction

Recent studies documented that deep brain stimulation of the dorsolateral caudate/putamen significantly attenuates cocaine seeking following chronic cocaine self-administration and withdrawal in rats [61] and also an increase of gray matter in both the ventral and the dorsal striatum in human addicts [62]. The application of DBS in the dorsal striatum may induce undesirable hypokinetic symptoms similar to Parkinson's disease symptoms due to

Cingulotomies have been performed for the drug-dependence treatment in order to interrupt obsessional thoughts about drug use. Significant complications have progressively been

of the cocaine-induced increase in glutaminergic input to the VTA.

the spread of current to the close motor regions.

**5.3. Amygdala**

it has been proposed by some authors [59].

**5.4. Lateral habenula (LHb)**

**5.5. Dorsal striatum**

**5.6. Prefrontal cortex (PFC)**

#### **5.2. Lateral hypothalamus (LH)**

The hypothalamic drive control of food-motivated behavior has been extended to drug reward [51]. The lateral portion of the hypothalamus (LH) may be a possible target in the treatment of addiction as it has been demonstrated at this level of important transcriptional modifications in subjects with compulsive drug intake and significant control of alcohol intake following radiofrequency stereotactic lesions of the ventromedial nucleus [52]. The side effects of hypothalamotomy consist of amnesia, vegetative crisis and reduction of libido and sexual desire [41]. The unconventional electrical stimulation of LH in rats while reducing the stimuli that induce the use of cocaine does not change the motivation for its intake [53]. Therefore, electrical stimulation of the posterior hypothalamus seems to have similar effects to the lesion producing a reduction of cocaine intake but preserving the processes of motivation [54]. The lack of effectiveness on motivation and possible severe adverse effects make lateral hypothalamus a target that cannot be used in addiction at the moment.
