Abnormal brain oscillations persist after recovery from bipolar depression.

When directly perturbed in healthy subjects, premotor cortical areas generate electrical oscillations in the beta range (20-40Hz). In schizophrenia, major depressive disorder and bipolar disorder (BD), these oscillations are markedly reduced, in terms of amplitude and frequency. However, it still remains unclear whether these abnormalities can be modulated over time, or if they can be still observed after treatment. Here, we employed transcranial magnetic stimulation (TMS) combined with EEG to assess the frontal oscillatory activity in eighteen BD patients before/after antidepressant treatments (sleep deprivation and light therapy), relative to nine healthy controls. In order to detect dominant frequencies, event related spectral perturbations (ERSP) were computed for each TMS/EEG session in all participants, using wavelet decomposition. The natural frequency at which the cortical circuit oscillates was calculated as the frequency value with the largest power across 300ms post-stimulus time interval. Severity of depression markedly decreased after treatment with 12 patients achieving response and nine patients achieving remission. TMS/EEG resulted in a significant activation of the beta/gamma band response (21-50Hz) in healthy controls. In patients, the main frequencies of premotor EEG responses to TMS did not significantly change before/after treatment and were always significantly lower than those of controls (11-27Hz) and comparable in patients achieving remission and in those not responding to treatment. These results suggest that the reduction of natural frequencies is a trait marker of BD, independent from the clinical status of the patients. The present findings shed light on the neurobiological underpinning of severe psychiatric disorders and demonstrate that TMS/EEG represents a unique tool to develop biomarkers in psychiatry.

Cognitive remediation and functional improvement in schizophrenia: Is it a matter of size?

BACKGROUND: Cognitive Remediation represents the best available tool to treat cognitive deficits in schizophrenia and evidence suggests an effect also on global functioning. However, the relationship between cognitive and functional improvement is not yet fully elucidated: do cognitive changes need to be of a definite size and/or encompass a certain number of domains in order to impact on daily functioning? This study aims to explore the role of cognitive improvement, evaluated both quantitatively and qualitatively through the use of Italian equivalent scores, on the daily functioning of patients. As secondary goal, the influence of demographic, clinical and neuropsychological variables on functional outcome was also systematically investigated. METHODS: One hundred subjects with a diagnosis of schizophrenia underwent 36 sessions of Cognitive Remediation and were evaluated at baseline and after the training with the Brief Assessment of Cognition in Schizophrenia and the Quality of Life Scale. RESULTS: A total of 70% of patients improved in at least one cognitive domain and over 50% obtained a normalized score. Among the clinical and neurocognitive factors examined, the only significant predictor of quality of life's improvement was the proportion of cognitive functions that reached an equivalent score of "normal". CONCLUSIONS: This study suggests that improvements in daily functioning depend on the achievement of a cognitive profile as much as possible "normal", harmonious and balanced, supporting the idea that a qualitative leap in cognition is needed in order to gain an advantage in real life activities.

Combined social cognitive and neurocognitive rehabilitation strategies in schizophrenia: neuropsychological and psychopathological influences on Theory of Mind improvement.

BACKGROUND: Neurocognitive and social cognitive impairments represent important treatment targets in schizophrenia, as they are significant predictors of functional outcome. Different rehabilitative interventions have recently been developed, addressing both cognitive and psychosocial domains. Although promising, results are still heterogeneous and predictors of treatment outcome are not yet identified. In this study we evaluated the efficacy of two newly developed social cognitive interventions, respectively based on the use of videotaped material and comic strips, combined with domain-specific Cognitive Remediation Therapy (CRT). We also analysed possible predictors of training outcome, including basal neurocognitive performance, the degree of cognitive improvement after CRT and psychopathological variables. METHOD: Seventy-five patients with schizophrenia treated with CRT, were randomly assigned to: social cognitive training (SCT) group, Theory of Mind Intervention (ToMI) group, and active control group (ACG). RESULTS: ANOVAs showed that SCT and ToMI groups improved significantly in ToM measures, whereas the ACG did not. We reported no influences of neuropsychological measures and improvement after CRT on changes in ToM. Both paranoid and non-paranoid subjects improved significantly after ToMI and SCT, without differences between groups, despite the better performance in basal ToM found among paranoid patients. In the ACG only non-paranoid patients showed an improvement in non-verbal ToM. CONCLUSION: Results showed that both ToMI and SCT are effective in improving ToM in schizophrenia with no influence of neuropsychological domains. Our data also suggest that paranoid symptoms may discriminate between different types of ToM difficulties in schizophrenia.

Combined neurocognitive and metacognitive rehabilitation in schizophrenia: Effects on bias against disconfirmatory evidence.

BACKGROUND: A Metacognitive Training for Schizophrenia patients (MCT) was developed to target the cognitive biases that characterize the illness. Results suggest positive MCT effects encompassing several aspects of psychopathology and subjective well-being. There are still open questions concerning the effect on different cognitive biases and the interplay between them and both psychopathology and neurocognition. Specifically, the bias against disconfirmatory evidence (BADE) has never been tested in previous trials on MCT. In this study we evaluated the feasibility of MCT combined with a cognitive remediation therapy (CACR) in schizophrenia and its effect on BADE. Moreover, we investigated the relationships between BADE and both neuropsychology and psychopathology, taking into account mutual influences on the degree of improvement. METHODS: Fifty-seven schizophrenia outpatients were randomly assigned to CACR + control group or MCT+CACR and assessed at baseline and after treatment for psychopathology, neurocognition and BADE. RESULTS: After MCT+CACR patients showed significantly greater improvements on BADE. Although BADE baseline performances correlated with several cognitive domains, no association was found between BADE improvement and neurocognitive nor psychopathological measures. CONCLUSIONS: This study enlightened for the first time the efficacy of MCT+CACR on BADE in schizophrenia, suggesting the importance to develop a more specific intervention tailored on individual needs of patients.

White matter microstructure in bipolar disorder is influenced by the serotonin transporter gene polymorphism 5-HTTLPR.

Bipolar disorder (BD) is associated with signs of widespread disruption of white matter (WM) integrity. A polymorphism in the promoter of the serotonin transporter (5-HTTLPR) influenced functional cortico-limbic connectivity in healthy subjects and course of illness in BD, with the short (s) allele being associated with lower functional connectivity, and with earlier onset of illness and poor response to treatment. We tested the effects of 5-HTTLPR on diffusion tensor imaging (DTI) measures of WM microstructure in 140 inpatients, affected by a major depressive episode in course of BD, of Italian descent. We used whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial, radial and mean diffusivity and fractional anisotropy. Compared with l/l homozygotes, 5-HTTLPR*s carriers showed significantly increased radial and mean diffusivity in several brain WM tracts, including corpus callosum, cingulum bundle, uncinate fasciculus, corona radiata, thalamic radiation, inferior and superior longitudinal fasciculus and inferior fronto-occipital fasciculus. An increase of mean and radial diffusivity, perpendicular to the main axis of the WM tract, is thought to signify increased space between fibers, thus suggesting demyelination or dysmyelination, or loss of bundle coherence. The effects of 5-HTTLPR on the anomalous emotional processing in BD might be mediated by changes of WM microstructure in key WM tracts contributing to the functional integrity of the brain.

Abnormal cortico-limbic connectivity during emotional processing correlates with symptom severity in schizophrenia.

BACKGROUND: Impaired emotional processing is a core feature of schizophrenia (SZ). Consistent findings suggested that abnormal emotional processing in SZ could be paralleled by a disrupted functional and structural integrity within the fronto-limbic circuitry. The effective connectivity of emotional circuitry in SZ has never been explored in terms of causal relationship between brain regions. We used functional magnetic resonance imaging and Dynamic Causal Modeling (DCM) to characterize effective connectivity during implicit processing of affective stimuli in SZ. METHODS: We performed DCM to model connectivity between amygdala (Amy), dorsolateral prefrontal cortex (DLPFC), ventral prefrontal cortex (VPFC), fusiform gyrus (FG) and visual cortex (VC) in 25 patients with SZ and 29 HC. Bayesian Model Selection and average were performed to determine the optimal structural model and its parameters. RESULTS: Analyses revealed that patients with SZ are characterized by a significant reduced top-down endogenous connectivity from DLPFC to Amy, an increased connectivity from Amy to VPFC and a decreased driving input to Amy of affective stimuli compared to HC. Furthermore, DLPFC to Amy connection in patients significantly influenced the severity of psychopathology as rated on Positive and Negative Syndrome Scale. CONCLUSIONS: Results suggest a functional disconnection in brain network that contributes to the symptomatic outcome of the disorder. Our findings support the study of effective connectivity within cortico-limbic structures as a marker of severity and treatment efficacy in SZ.

Fronto-limbic disconnection in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a severe, disabling and life-threatening illness. Disturbances in emotion and affective processing are core features of the disorder with affective instability being paralleled by mood-congruent biases in information processing that influence evaluative processes and social judgment. Several lines of evidence, coming from neuropsychological and imaging studies, suggest that disrupted neural connectivity could play a role in the mechanistic explanation of these cognitive and emotional symptoms. The aim of the present study is to investigate the effective connectivity in a sample of bipolar patients. METHODS: Dynamic causal modeling (DCM) technique was used to study 52 inpatients affected by bipolar disorders consecutively admitted to San Raffaele hospital in Milano and forty healthy subjects. A face-matching task was used as activation paradigm. RESULTS: Patients with BD showed a significantly reduced endogenous connectivity in the DLPFC to Amy connection. There was no significant group effect upon the endogenous connection from Amy to ACC, from ACC to Amy and from DLPFC to ACC. CONCLUSIONS: Both DLPFC and ACC are part of a network implicated in emotion regulation and share strong reciprocal connections with the amygdale. The pattern of abnormal or reduced connectivity between DLPFC and amygdala may reflect abnormal modulation of mood and emotion typical of bipolar patients.

Adverse childhood experiences influence white matter microstructure in patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is associated with adverse childhood experiences (ACE), which worsen the lifetime course of illness, and with signs of widespread disruption of white matter (WM) integrity in adult life. ACE are associated with changes in WM microstructure in healthy humans. METHOD: We tested the effects of ACE on diffusion-tensor imaging (DTI) measures of WM integrity in 80 in-patients affected by a major depressive episode in the course of BD. We used whole-brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial, radial and mean diffusivity, and fractional anisotropy. RESULTS: ACE hastened the onset of illness. We observed an inverse correlation between the severity of ACE and DTI measures of axial diffusivity in several WM fibre tracts contributing to the functional integrity of the brain and including the corona radiata, thalamic radiations, corpus callosum, cingulum bundle, superior longitudinal fasciculus, inferior fronto-occipital fasciculus and uncinate fasciculus. CONCLUSIONS: Axial diffusivity reflects the integrity of axons and myelin sheaths, and correlates with functional connectivity and with higher-order abilities such as reasoning and experience of emotions. In patients with BD axial diffusivity is increased by lithium treatment. ACE might contribute to BD pathophysiology by hampering structural connectivity in critical cortico-limbic networks.

A single nucleotide polymorphism in SLC1A1 gene is associated with age of onset of obsessive-compulsive disorder.

Different genetic polymorphisms in the SLC1A1 have been shown to be associated with obsessive-compulsive disorder. Rs301430 is a T/C functional polymorphism affecting the gene expression and extrasynaptic glutamate concentration.We observed that Rs301430 influence age at onset in obsessive-compulsive disorder.

Effect of glutamate transporter EAAT2 gene variants and gray matter deficits on working memory in schizophrenia.

Glutamate is the major excitatory neurotransmitter in the brain, with up to 40% of all synapses being glutamatergic. An altered glutamatergic transmission could play a critical role in working memory deficts observed in schizophrenia and could underline progressive changes such as grey matter loss throughout the brain. The aim of the study was to investigate if gray matter volume and working memory could be modulated by a genetic polymorphism related to glutamatergic function. Fifty schizophrenia patients underwent magnetic resonance and working memory testing outside of the scanner and were genotyped for rs4354668 EAAT2 polymorphism. Carriers of the G allele had lower gray matter volumes than T/T homozygote and worse working memory performance. Poor working memory performance was associated with gray matter reduction. Differences between the three genotypes are more relevant among patients showing poor performance at the 2-back task. Since glutamate abnormalities are known to be involved in excitotoxic processes, the decrease in cortical thickness observed in schizophrenia patients could be linked to an excess of extracellular glutamate. The differential effect of EAAT2 observed between good and poor performers suggests that the effect of EEAT2 on gray matter might reveal in the presence of a pathological process affecting gray matter.

Circadian clock gene Per3 variants influence the postpartum onset of bipolar disorder.

Postpartum depression can mark the onset of bipolar disorder. The coding region of Per3 gene contains a variable-number tandem-repeat polymorphism, which has been shown to influence bipolar disorder onset and to affect breast cancer risk. We showed a relationship between Per3 polymorphism and postpartum depressive onset in bipolar disorder.

Emotional reactivity in chronic schizophrenia: structural and functional brain correlates and the influence of adverse childhood experiences.

BACKGROUND: Despite behavioural signs of flattened affect, patients affected by schizophrenia show enhanced sensitivity to negative stimuli. The current literature concerning neural circuitry for emotions supports dysregulations of cortico-limbic networks, but gives contrasting results. Adverse childhood experiences (ACEs) could persistently influence emotional regulation and neural correlates of response to emotional stimuli in healthy humans. This study evaluated the effect of ACEs and chronic undifferentiated schizophrenia on neural responses to emotional stimuli (negative facial expression). METHOD: Brain blood-oxygen-level-dependent functional magnetic resonance imaging neural responses to a face-matching paradigm, and regional grey matter (GM) volumes were studied at 3.0 T in the amygdala, hippocampus, anterior cingulated cortex (ACC) and prefrontal cortex (PFC). The severity of ACEs was assessed. Participants included 20 consecutively admitted in-patients affected by chronic undifferentiated schizophrenia, and 20 unrelated healthy volunteers from the general population. RESULTS: Patients reported higher ACEs than controls. Worse ACEs proportionally led to decreasing responses in the amygdala and hippocampus, and to increasing responses in the PFC and ACC in all participants. Patients showed higher activations in the amygdala and hippocampus, and lower activations in the PFC and ACC. Higher ACEs were associated with higher GM volumes in the PFC and ACC, and schizophrenia was associated with GM reduction in all studied regions. CONCLUSIONS: Structural and functional brain correlates of emotional reactivity are influenced by both current chronic undifferentiated schizophrenia and the severity of past ACEs.

Computer-aided neurocognitive remediation in schizophrenia: durability of rehabilitation outcomes in a follow-up study.

Cognitive deficits in patients with schizophrenia constitute a limiting factor to the chances of rehabilitation of daily living abilities, like personal and relational autonomy and working ability. Cognitive Remediation Therapy (CRT) is a rehabilitative technique that aims at the recovery of single cognitive functions through the execution of massive exercises of impaired cognitive domains. This study aims to establish if the results achieved through an intensive deficit-specific neurocognitive treatment of three months duration, were maintained over time. The sample consists in 100 patients diagnosed with schizophrenia according to the criteria of DSM IV. Patients were assessed on cognitive and daily functioning at baseline, after 3 months of either CRT or placebo training added to their standard rehabilitation treatment, at 6 month and 12-month follow-up. Results showed significant changes that were maintained at follow-up for executive function, attention and psychomotor coordination. Moreover the significant improvement in daily functioning was maintained at 6 and 12-month follow-up. In conclusion improvements in cognitive functions and daily functioning achieved through the association of CRT and standard rehabilitation treatment persist over time after the conclusion of the training period.

Effect of catechol-O-methyltransferase Val(108/158)Met polymorphism on antidepressant efficacy of fluvoxamine.

RATIONALE: The catechol-O-methyltransferase (COMT) enzyme inactivates catecholamines, and the COMT Val(108/158)Met polymorphism (rs4680) influences the enzyme activity. Recent clinical studies found a significant effect of rs4680 on antidepressant response to fluoxetine and paroxetine, but several other studies were negative. No study considered drug plasma levels as possible nuisance covariate. OBJECTIVES: We studied the effect of rs4680 on response to fluvoxamine antidepressant monotherapy. PATIENTS AND METHODS: Forty-one consecutively admitted inpatients affected by a major depressive episode in course of major depressive disorder were administered fluvoxamine for 6 weeks. Changes in severity of depression were assessed with weekly Hamilton Depression ratings and analyzed with repeated measures ANOVA in the context of General Linear Model, with rs4680 and fluvoxamine plasma levels as factors. RESULTS: rs4680 significantly interacted with time in affecting antidepressant response to fluvoxamine, with outcome being inversely proportional to the enzyme activity: better effects in Met-carriers, worse effects in Val/Val homozygotes. The effect became significant at the fourth week of treatment, and influence final response rates. Fluvoxamine plasma levels had marginal effects on outcome. CONCLUSIONS: This is the first study that reports a positive effect of rs4680 on response to fluvoxamine, and the third independent report of its influence on response to selective 5-HT reuptake inhibitors (SSRIs). Our findings support the hypothesis that factors affecting catecholaminergic neurotransmission might contribute to shape the individual response to antidepressants irrespective of their primary molecular target.

A symptom-specific analysis of the effect of high-frequency left or low-frequency right transcranial magnetic stimulation over the dorsolateral prefrontal cortex in major depression.

BACKGROUND: We have investigated the efficacy of high-frequency left (HFL) versus low-frequency right (LFR) repetitive transcranial magnetic stimulation (rTMS) in depression, focusing on specific symptoms as possible predictors of outcome for these two different types of stimulation. METHOD: Seventy-four outpatients with a major depressive episode treated with an adequate antidepressant dosage for at least 4 weeks were included in our study and randomly assigned to two different groups: HFL or LFR rTMS. The Hamilton Rating Scale for Depression (HAM-D) items were pooled into 6 factors to evaluate specific symptoms as possible predictors of response. RESULTS: Twenty-one out of 32 patients (65.6%) and 24 out of 42 patients (57.1%) were responders in the HFL and LFR groups, respectively. No significant difference in response rate was observed. Considering the whole sample, we found an inverse correlation between activity and HAM-D score reduction and a significant positive relation between somatic anxiety and outcome. An inverse correlation between psychic anxiety and HAM-D score reduction emerged considering the HFL group. In the LFR group, there was a significant negative relationship between baseline activity and the outcome. CONCLUSION: These findings support the hypothesis that LFR rTMS could be as effective as HFL rTMS and more suitable for patients with a higher anxiety degree, particularly in bipolar patients.

Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-ß activity.

At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3-beta promoter single-nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of rs334558 on grey matter volumes (voxel-based morphometry) of 57 patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness. These results support the interest for GSK3-beta as a factor affecting neuropathology in major behavioural disorders, such as schizophrenia, and thus as a possible target for treatment.

Changes in medial prefrontal cortex neural responses parallel successful antidepressant combination of venlafaxine and light therapy.

Few pilot prospective studies performed BOLD fMRI before and after treatment in order to define the neural correlates of antidepressant response. To determine how antidepressant treatment influences the pattern of neural response to a task targeting the depressive biases in information processing (moral valence decision), eight depressed inpatients were treated with combined venlafaxine and light therapy for four weeks. Brain BOLD functional magnetic resonance imaging on a 3.0 Tesla scanner was performed before and after treatment. Treatment and moral value of the stimuli showed the most significant interaction in right medial frontal gyrus (BA 10), where also clinical status was found to be inversely correlated with response to negative stimuli after treatment. A significant interaction of treatment and valence of the stimuli was also detected in other areas that have been widely associated with the depressive illness.

'Theory' of mind impairment in patients affected by schizophrenia and in their parents.

"Theory of mind" (ToM) is the ability to judge the mental states of the self and others. It is currently considered as a part of the broader concept of social cognition, known to influence the social behaviour of patients affected by schizophrenia. Recently it has been hypothesized that the impairment of ToM is a trait that can be detected both in patients with schizophrenia and in non-psychotic relatives of patients, but it still not clear what the contribution of the familial patterns of cognitive impairment is. The aim of this study is to assess parental impairments of ToM performance considering the effects of the neurocognitive abilities known to be impaired in their first-degree relatives and to influence ToM in schizophrenic patients. Patients, their parents and control trios were assessed with the Wisconsin Card Sorting Test (WCST), the Symbol Coding Task and the ToM Picture Sequencing Task. The ANCOVA analysis on 47 trios including a schizophrenic offspring and 47 healthy trios showed a statistically significant poorer performance of patients and their parents in comparison to control trios at Symbol Coding Task and ToM task. Moreover a regression analysis showed that the neuropsychological abilities tested were significant predictors of ToM performance only in patients. Results confirm a ToM impairment among parents of patients with schizophrenia that is not directly correlated to other aspects of neurocognitive functioning.

Clock genes beyond the clock: CLOCK genotype biases neural correlates of moral valence decision in depressed patients.

Gene polymorphisms in the mammalian biological clock system influence individual rhythms. A single nucleotide polymorphism (SNP) in the 3' flanking region of CLOCK (3111 T/C; rs1801260) influenced diurnal preference in healthy humans and caused sleep phase delay and insomnia in patients affected by bipolar disorder. Genes of the biological clock are expressed in many brain structures other than in the 'master clock' suprachiasmatic nuclei. These areas, such as cingulate cortex, are involved in the control of many human behaviors. Clock genes could then bias 'nonclock' functions such as information processing and decision making. Thirty inpatients affected by a major depressive episode underwent blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI). The cognitive activation paradigm was based on a go/no-go task. Morally connoted words were presented. Genotyping of CLOCK was performed for each patients. We measured activity levels through actimetry during the day before the fMRI study. CLOCK 3111 T/C SNP was associated with activity levels in the second part of the day, neuropsychological performance and BOLD fMRI correlates (interaction of genotype and moral valence of the stimuli). Our results support the hypothesis that individual clock genotype may influence several variables linked with human behaviors in normal and psychopathological conditions.

Response to SSRIs and role of the hormonal therapy in post-menopausal depression.

The aim of this study is to prospectively evaluate the antidepressant response to SSRIs in depressed post-menopausal women with or without hormonal therapy (HT), and to analyze the possible influence of basal serum levels of gonadotropins and sexual hormones on the antidepressant response. 170 post-menopausal women with a depressive episode (DSM-IV criteria)--47 on HT and 123 not on HT--started the treatment with an SSRI. Depressive symptoms were assessed at baseline and 7 weeks thereafter by raters blind to treatment regimen. Response rates were 63.2% in the group without HT and 83.7% in the HT group (p=0.013). An inverse correlation emerged between the basal levels of LH and the improvement in HRSD scores (p=0.001) in the group without HT. In conclusion, HT appeared to improve the antidepressant response to SSRIs. Furthermore, in post-menopausal women, LH basal levels may be taken into account as possible predictor of response.