**3.1 Cognitive behavioral therapy and mood disorders**

Psychotherapy processes appear to target maladaptive cognitive and emotional patterns by engaging their biological analogues that are responsive to a discrete mode of treatment [45]. One salient example involves re-appraisal technique under cognitive behavioral therapy (CBT) for depression, where patients are invited to re-interpret their negative perceptions of unpleasant occurrences in a more positive light. Mood ratings before and after re-thinking negative events revealed improved positive affect, mediated by elevated activity in dorsolateral and dorsomedial PFC coupled with decreased activity in the amygdala and orbitofrontal cortex [46]. To delineate CBT- induced mechanism of neuroplasticity in depression, FDG-PET scans before and after psychotherapy relative to paroxetine treatment were acquired from patients instructed to 'avoid ruminating on any one topic' during scanning [47]. Although efficacy of both treatments was comparable, differential activity patterns emerged in frontal and limbic regions, implying that medication and psychotherapy might achieve their therapeutic effects in different ways. Whilst CBT was associated with decreased metabolism in multiple frontal regions including the dorsolateral PFC together with increased activity in the hippocampus, parahippocampal gyrus, and dorsal cingulate gyrus, paroxetine- induced increased PFC metabolism, and decrease in hippocampal, parahippocampal, posterior cingulate and ventral subgenual cingulate activity. This modality-specific mechanism of neuroplasticity posits that CBT exerts 'top- down' changes in cognitive processing in favor of engaging ventral and limbic regions, which mediate attention to personally salient stimuli, whereas antidepressant drugs prompt 'bottom-up' disengagement of ventral, frontal and limbic regions. Although this model runs counter the

*Treatment-Induced Brain Plasticity in Psychiatric Disorders DOI: http://dx.doi.org/10.5772/intechopen.85448*

aforementioned emotion regulation model, divergent findings might result from using healthy subjects in the former study and patients with depression in the latter, invoking the notion that brain activation results from the interaction between underlying brain state and treatment modality [48].

In efforts to elucidate CBT- induced neural mechanism of anxiety disorders functional neuroimaging study examined pre-and-post CBT brain activity patterns in non-medicated patients with spider phobia and healthy subjects [49]. The former exhibited elevated activation in the parahippocampal gyrus and right dorsolateral PFC prior to the treatment, which was normalized with successful group CBT sessions focused on exposure therapy. Given that parahippocampal gyrus mediates contextual memory, authors suggested that after CBT less demand was placed on the dorsolateral PFC to construct a cognitive defense to the perceived threat. Moreover, a therapy- induced shift of activity to the ventral PFC was indexed, which might play a role in down-regulation of limbic activity and thereby dampening fear reaction. Collectively, these studies depict a neuroplastic model of cognitive behavioral therapy which posits altered engagement of dorsal prefrontal circuitry to down-regulate limbic and ventral prefrontal structures thereby improving affect in response to emotionally significant contexts.

### **3.2 Dialectic behavioral therapy and borderline personality disorder**

Given that psychotherapy is the gold standard treatment modality for borderline personality disorder [50], extensive research efforts focused on measuring brain changes induced by specific modes of therapy. To date, dialectic behavioral therapy is the most researched, refined and evidenced-based therapy informed by a deficit model in self-regulation, distress tolerance and interpersonal skills, deemed to arise from transaction between highly sensitive individuals and invalidating environments [51, 52]. DBT purports to render individuals more mindful and able to manage relationships effectively by incorporating the concept of dialectics and strategy of validation into approach focused on skills acquisition and behavioral shaping.

Consistent with the skills deficit model of BPD, neuroimaging evidence supports that acquisition of affective control strategies under DBT balances neural substrates of emotion regulation. One salient example indexed neural activity alterations under re-appraisal and reported dampened insula and ACC activity, together with an enhanced connectivity of the latter to medial and superior frontal gyrus, superior temporal gyrus, and inferior parietal cortices [53]. Notably, treatmentinduced increase in dorsal ACC activity during exposure to negative stimuli was associated with improvement self-reported BPD symptoms, suggesting a possible biomarker of improved affect regulation. In a similar study Winter et al. [54] set out to establish whether neural correlates of distraction might be amenable to a successful DBT. In this view, 31 BPD patients under constant medication were scanned before and after a 12- week residential DBT-based treatment while performing a distraction task. When compared to 15 BPD control patients under non-DBT-based treatment or no treatment at all, and 22 healthy participants, 16 DBT responders exhibited attenuated activity in the right inferior parietal lobe/supramarginal gyrus. Notably, this pattern of brain activity was correlated with improvement in self-reported borderline symptom severity (ZAN-BPD). Furthermore, treatment was associated with a reduction in the right perigenual ACC activity and increased activity in these regions during distraction in the context of aversive stimuli. These findings might reflect a shift from emotional to more cognitive processing in the context of aversive stimuli, thereby suggesting an improvement in emotional susceptibility under DBT.

Taken together aforementioned studies support that DBT processes target maladaptive emotional patterns by altering their biological analogues that are responsive to discrete cognitive strategies. DBT normalizes frontolimbic imbalances as part of the disturbed circuitry, which appear to mediate amelioration of BPD symptomatology. Caution must be exercised however, while interpreting results as medications may attenuate emotional responses in BPD patients [55], and giving combinations of drug subtypes makes it impossible to isolate the effect of a single agent.

### **3.3 IPT and depression**

IPT is a short-term treatment that typically consists of 12–16 one-hour weekly sessions focused on improving interpersonal relationships. Drawing directly on identifiable issues between patients and therapists, it purports to instil the ability to make the necessary adjustments in interpersonal situations that will help to reduce symptoms of depression. Several imaging studies have examined biomarkers of cerebral reorganization induced by IPT relative to pharmacotherapy. One of them compared the effects of the former and venlafaxine (37.5 mg daily) on regional CBF using 99mTc-HMPAO SPECT in 28 drug-naive or drug-free patients with MDD [56]. Whilst comparative clinical improvements were mediated by elevated activity in the right basal ganglia in both treatment groups, patients in the IPT group also exhibited an increase in the right posterior cingulate activity. However, drawing firm conclusion from these findings is hampered by methodological issues as four patients with a strong preference for venlafaxine could choose the treatment, while one preferred IPT. Moreover, subjects in the latter evidenced greater striatal perfusion, potentially reflecting design limitation. Brief duration of IPT and relatively low dose of venlafaxine give rise to the possibility that both treatments were suboptimal, thereby underscoring the engagement of limbic and paralimbic recruitment in psychotherapy-induced changes reported in parallel research [56].

A similar study on the effects of IPT and paroxetine relative to healthy controls [57] reported results analogous to CBT effects described by Goldapple et al. [47]. Whilst treatment response in both groups was associated with an increase in metabolism in limbic and paralimbic regions (the right insula and left inferior temporal lobe) relative to controls, unlike CBT the effects of IPT were mediated by a decrease in dorsal and ventral prefrontal cortical metabolism. A follow-up study was set out to correlate treatment-mediated changes in brain activity patterns with amelioration in mood symptoms measured by the Hamilton Depression Rating Scale and the tension/anxiety and fatigue clusters of the Profile of Mood States [58]. A cohort of 39 patients under either paroxetine or IPT for MDD exhibited post-treatment reductions in ventral and dorsal frontal lobe metabolism, which was associated with improvements in the anxiety/somatization and psychomotor retardation symptom clusters. Unlike previous findings of negative correlation between activity in the dorsolateral PFC and improvement on global depression scores under CBT, in the present study alterations in dorsolateral PFC activity positively correlated with improvement in cognitive disturbance. These suggest that each treatment modality engages dorsolateral PFC function differently to achieve a specific therapeutic effect. While CBT appears to engage this region to attenuate 'over-thinking' in depression, IPT might induce it to improve general cognitive abilities.

### **3.4 Psychoeducation and euthymic bipolar disorder**

Given that pharmacotherapy is often ineffective for treatment of residual depressive, dysthymic and dysphoric symptoms [59], researchers have shown *Treatment-Induced Brain Plasticity in Psychiatric Disorders DOI: http://dx.doi.org/10.5772/intechopen.85448*

interest in psychoeducation in targeting emotional and cognitive processes [60–63]. Psychoeducation is a treatment option for bipolar disorder focused on improving coping strategies to manage symptoms in everyday life, compliance with medication to prevent thymic relapses, quality of life and social functioning [64, 65]. Whilst wealth of research exists to support its efficacy in clinical symptoms improvement, less is known how therapeutic change is achieved on the level of neural functioning.

Favre and collaborates [66] set out to index neural processes before and after psychoeducation therapy in 16 euthymic bipolar patients (EBP) matched against 16 healthy subjects. Pre-treatment fMRI scans revealed reduced activity of cognitive control regions (bilateral inferior and left superior frontal gyri, right insula, right fusiform gyrus and bilateral occipital gyri) and elevated activity of emotion-related processing regions (bilateral hippocampus, parahippocampal gyri and the left middle temporal gyrus) in the treatment group. Thus, aberrant cognitive and emotion processing that characterize acute episodes in bipolar disorder appear to persist during euthymic phase. Post-treatment clinical improvement was mediated by increased activity of inferior frontal gyri and a pattern of decreased activity of right hippocampus and parahippocampal gyrus. These findings suggest that psychoeducation improves cognitive control by engaging prefrontal networks and normalizes generation of emotional responses by quieting activity within limbic networks.

### **3.5 Cognitive remediation therapy and schizophrenia**

Cognitive remediation therapy (CRT) is an evidence-based treatment for neuropsychological deficits in memory, attention, executive function, social cognition or metacognition across a host of neuropsychiatric disorders [67–69]. There is a growing literature focused on neurobiological changes that mediate cognitive recovery under this type of intervention in patients with schizophrenia [70–73], mood disorders [74], mild cognitive impairment [75] and in healthy adults [76]. Majority of studies examined the effects of cognitive remediation on brain functioning in patients with schizophrenia and have amounted to several systematic reviews and meta-analyses [76–78]. Findings lend support to the frontal hypoactivation mechanism of cognitive impairment and suggest that cognitive remediation improves these networks efficiency. Most commonly reported areas of post-treatment amelioration in efficiency involved prefrontal and thalamic regions. Meusel and collaborates [73] set out to describe functional correlates of cognitive remediation in patients with bipolar disorder or depression versus healthy controls. Thirty eight subjects completed 10 weeks of treatment and were scanned (fMRI) during an n-back working memory task and a recollection memory task to investigate the potential for change within these networks. PRE-POST improvements correlated with functional activation in lateral and medial prefrontal, superior temporal, and lateral parietal regions, suggesting neural correlates improved working memory under cognitive remediation.

## **4. Discussion**

The predominant paradigm of modern psychiatry posits that advances in neurosciences can unravel the mysteries of mental illness. Since the 1990s were declared the decade of the brain, imaging evidence has taught us a great deal about neural correlates of symptoms expression and recovery from an insult to the brain [79]. Despite remarkable neuroscientific advances, specific mechanisms behind major mental illnesses, thus far, have not been identified [80]. Moreover, whilst neurotransmitters are known to mediate synaptic pathways, research has not yet

been able to explain any psychiatric disorder in terms of chemical imbalances [81]. Various reasons exist as to why neuroscience is unlikely to provide a definite understanding of the disordered mind. First and foremost, what is preventing the scientific strategy to reduce psychiatry to neuroscience is the fact that diagnoses listed in the Diagnostic and Statistical Manual of Mental Disorders' are not diseases but merely syndromes without a precise endophenotype [82]. Moreover, the pathways from temperamental vulnerabilities to illness cannot be understood without taking into account psychosocial adversities [83]. In this view, associations between biomarkers of pathological and treatment processes are unlikely to be strong or linear. Pharmacotherapy, whilst useful in severe mental disorders, it is not in any way curative, and psychosocial interventions continue to play an important role in psychiatric treatment, evoking multiple risk factors and complex interactive pathways to the disordered mind [84].

Research efforts in tandem with more powerful imaging techniques will further unravel the intricacy of cerebral organization behind pathological and treatment processes. Nonetheless, the scientific strategy to reduce psychiatry to neurosciences is hindered by a discrepancy between a clinical phenomenon and its neural substrate, which is rooted in a conceptual mind and brain gap.
