Successful antidepressant chronotherapeutics enhance fronto-limbic neural responses and connectivity in bipolar depression.

The identification of antidepressant response predictors in bipolar disorder (BD) may provide new potential enhancements in treatment selection. Repeated total sleep deprivation combined with light therapy (TSD+LT) can acutely reverse depressive symptoms and has been proposed as a model antidepressant treatment. This study aims at investigating the effect of TSD+LT on effective connectivity and neural response in cortico-limbic circuitries during implicit processing of fearful and angry faces in patients with BD. fMRI and Dynamic Causal Modeling (DCM) were combined to study the effect of chronotherapeutics on neural responses in healthy controls (HC, n = 35) and BD patients either responder (RBD, n = 26) or non responder (nRBD, n = 11) to 3 consecutive TSD+LT sessions. Twenty-four DCMs exploring connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), Amygdala (Amy), fusiform gyrus and visual cortex were constructed. After treatment, patients significantly increased their neural responses in DLPFC, ACC and insula. nRBD showed lower baseline and endpoint neural responses than RBD. The increased activity in ACC and in medial prefrontal cortex, associated with antidepressant treatment, was positively associated with the improvement of depressive symptomatology. Only RBD patients increased intrinsic connectivity from DLPFC to ACC and reduced the modulatory effect of the task on Amy-DLPFC connection. A successful antidepressant treatment was associated with an increased functional activity and connectivity within cortico-limbic networks, suggesting the possible role of these measures in providing possible biomarkers for treatment efficacy.

Neural correlates of anxiety sensitivity in panic disorder: A functional magnetic resonance imaging study.

Panic disorder has been associated with dysfunctional neuropsychological dimensions, including anxiety sensitivity. Brain-imaging studies of the neural correlates of emotional processing have identified a network of structures that constitute the neural circuitry for emotions. The anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC) and insula, which are part of this network, are also involved in the processing of threat-related stimuli. The aim of the study was to investigate if neural activity in response to emotional stimuli in the cortico-limbic network is associated to anxiety sensitivity in panic disorder. In a sample of 18 outpatients with panic disorder, we studied neural correlates of implicit emotional processing of facial affect expressions with a face-matching paradigm; correlational analyses were performed between brain activations and anxiety sensitivity. The correlational analyses performed showed a positive correlation between anxiety sensitivity and brain activity during emotional processing in regions encompassing the PFC, ACC and insula. Our data seem to confirm that anxiety sensitivity is an important component of panic disorder. Accordingly, the neural underpinnings of anxiety sensitivity could be an interesting focus for treatment and further research.

Right hemisphere neural activations in the recall of waking fantasies and of dreams.

The story-like organization of dreams is characterized by a pervasive bizarreness of events and actions that resembles psychotic thought, and largely exceeds that observed in normal waking fantasies. Little is known about the neural correlates of the confabulatory narrative construction of dreams. In this study, dreams, fantasies elicited by ambiguous pictorial stimuli, and non-imaginative first- and third-person narratives from healthy participants were recorded, and were then studied for brain blood oxygen level-dependent functional magnetic resonance imaging on a 3.0-Tesla scanner while listening to their own narrative reports and attempting a retrieval of the corresponding experience. In respect to non-bizarre reports of daytime activities, the script-driven recall of dreams and fantasies differentially activated a right hemisphere network including areas in the inferior frontal gyrus, and superior and middle temporal gyrus. Neural responses were significantly greater for fantasies than for dreams in all regions, and inversely proportional to the degree of bizarreness observed in narrative reports. The inferior frontal gyrus, superior and middle temporal gyrus have been implicated in the semantic activation, integration and selection needed to build a coherent story representation and to resolve semantic ambiguities; in deductive and inferential reasoning; in self- and other-perspective taking, theory of mind, moral and autobiographical reasoning. Their degree of activation could parallel the level of logical robustness or inconsistency experienced when integrating information and mental representations in the process of building fantasy and dream narratives.

Sterol Regulatory Element Binding Transcription Factor-1 Gene Variation and Medication Load Influence White Matter Structure in Schizophrenia.

BACKGROUND: Diffusion tensor imaging (DTI) studies have shown a widespread disruption of white matter (WM) microstructure in schizophrenia. Furthermore, higher fractional anisotropy (FA) has been consistently correlated with the severity of psychotic symptoms. Antipsychotic drugs (APDs) affect lipid homeostasis. Gene polymorphisms in sterol regulatory element binding transcription factor (SREBF)-1 and SREBF-2 have been associated with schizophrenia. METHODS: In a sample of 65 patients affected by chronic schizophrenia, we investigated the effect of ongoing APD medication, SREBF-1 rs11868035 polymorphism and SREBF-2 rs1052717 polymorphism on the WM microstructure, using tract-based spatial statistics with threshold-free cluster enhancement. RESULTS: We reported increased FA associated with the risk rs11868035 G/G genotype in several WM tracts, mainly located in the left hemisphere, and opposite effects of the APD medication load, with reduced FA and generally increased diffusivity. These opposite effects overlapped in the forceps minor, cingulum, uncinate fasciculus, the superior and inferior longitudinal fasciculi, the corticospinal tract, inferior fronto-occipital fasciculus and the anterior thalamic radiation. CONCLUSION: We suggest that changes of WM structure could be an as yet poorly explored biomarker of the effects of APDs, to be further investigated in prospective studies correlating long-term clinical effects with changes of DTI measures in specific WM tracts contributing to the functional integrity of the brain. © 2015 S. Karger AG, Basel.

Cognitive performances associate with measures of white matter integrity in bipolar disorder.

BACKGROUND: Neuropsychological deficits constitute enduring trait-like features in bipolar disorder (BD), and persist in euthymia. White matter (WM) abnormalities are one of the most consistently reported findings in neuroimaging studies of BD. We hypothesized that neuropsychological performances could correlate with WM integrity in a sample of bipolar patients in core WM tracts. METHODS: Seventy-eight patients affected by BD were evaluated for verbal memory, working memory, psychomotor coordination, executive functions, attention and information processing, and verbal fluency through the Brief Assessment of Cognition in Schizophrenia. White matter integrity was evaluated using DTI and tract-based spatial statistics with threshold free cluster enhancement (p>0.949). RESULTS: We observed that cognitive performances in attention and information processing, working memory, executive functions and psychomotor coordination were associated with DTI measures of WM integrity in several association fibres: inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, cingulum bundle, corpus callosum, and corona radiata. LIMITATION: The drug treatments administered during the course of the illness could have influenced DTI measures and neurocognitive function. Other limitations include issues such as generalizability due to the lack of a control group, possible undetected past comorbidities, population stratification, and the presence of a 28% of patients which previously experienced delusions. CONCLUSIONS: This is the first study to use a validated cognitive battery to investigate the principal cognitive domains in BD. Our data confirm the importance of WM integrity as a neurobiological underpinning of cognitive deficits.

Lithium and GSK-3ß promoter gene variants influence cortical gray matter volumes in bipolar disorder.

RATIONALE: Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase-3ß (GSK-3ß). The less active GSK-3ß promoter gene variants have been associated with less detrimental clinical features of BD. GSK-3ß gene variants and lithium can influence brain gray and white matter structure in psychiatric conditions, so we studied their combined effect in BD. OBJECTIVES: The aim of this study is to investigate the effects of ongoing long-term lithium treatment and GSK-3ß promoter rs334558 polymorphism on regional gray matter (GM) volumes of patients with BD. MATERIALS AND METHODS: GM volumes were estimated with 3.0 Tesla MRI in 150 patients affected by a major depressive episode in course of BD. Duration of lifetime lithium treatment was retrospectively assessed. Analyses were performed by searching for significant effects of lithium and rs334558 in the whole brain. RESULTS: The less active GSK-3ß rs334558*G gene promoter variant and the long-term administration of lithium were synergistically associated with increased GM volumes in the right frontal lobe, in a large cluster encompassing the boundaries of subgenual and orbitofrontal cortex (including Brodmann areas 25, 11, and 47). Effects of lithium on GM revealed in rs334558*G carriers only, consistent with previously reported clinical effects in these genotype groups, and were proportional to the duration of treatment. CONCLUSIONS: Lithium and rs334558 influenced GM volumes in areas critical for the generation and control of affect, which have been widely implicated in the process of BD pathophysiology. In the light of the protective effects of lithium on white matter integrity, our results suggest that the clinical effects of lithium associate with a neurotrophic effect on the whole brain, probably mediated by GSK-3ß inhibition.

The serotonin transporter genotype modulates the relationship between early stress and adult suicidality in bipolar disorder.

OBJECTIVE: Bipolar disorder (BD) is associated with a higher risk of suicide and with worse early life stress. A serotonin (5-hydroxytryptamine; 5-HT) transporter-linked polymorphic region (5-HTTLPR) has been shown to influence the relationship between stress and the risk of attempting suicide in the general population, but has not been investigated in BD. METHODS: We studied 136 inpatients (93 females, 43 males) with a major depressive episode in the course of BD. Early and recent stressful life events were scored on the Social Readjustment Rating Scale (SRRS). Regional gray matter (GM) volumes were analyzed, acquiring T1-weighted images on a 3.0 Tesla scanner. RESULTS: Homozygote l/l patients attempted suicide in a higher proportion than *s carriers. A separate-slopes logistic regression showed a significant effect of 5-HTTLPR on the relationship between stress, depression, and suicide among *s carriers, but not among l/l homozygotes, early stress associated with worse probability of attempting suicide and with earlier age at onset of BD. Exposure to early stress correlated with GM volumes in the right prefrontal cortex (Brodmann area 46) - again, in *s carriers only. CONCLUSIONS: 5-HTTLPR modulated the relationship between early life stress and the core features of bipolar illness. 5-HTTLPR*s carriers showed a higher sensitivity to the effects of stress; when exposed to low levels of early stress, they were protected against suicide in respect to l/l, but higher levels of stress progressively increased their risk of suicide and reduced the age at onset of illness.

Effect of early stress on hippocampal gray matter is influenced by a functional polymorphism in EAAT2 in bipolar disorder.

Current views on the pathogenesis of psychiatric disorders focus on the interplay between genetic and environmental factors, with individual variation in vulnerability and resilience to hazards being part of the multifactorial development of illness. The aim of the study is to investigate the effect of glutamate transporter polymorphism SLC1A2-181A>C and exposure to Adverse Childhood Experiences (ACE) on hippocampal gray matter volume of patients with bipolar disorder (BD). Patients exposed to higher levels of ACE reported lower gray matter volume. The effect of SLC1A2-181A>C revealed itself only among patients exposed to lower levels of ACE, with T/T homozygotes showing the lowest, and G/G the highest, gray matter volume. The greatest difference between high and low exposures to ACE was observed in carriers of the G allele. Since the mutant G allele has been associated with a reduced transcriptional activity and expression of the transporter protein, we could hypothesize that after exposure to highest levels of ACE G/G homozygotes are more vulnerable to stress reporting the highest brain damage as a consequence of an excess of free glutamate.

Adverse childhood experiences and gender influence treatment seeking behaviors in obsessive-compulsive disorder.

BACKGROUND: Exposure to adverse childhood experiences (ACE) increases the risk of adult physical and mental health disorders, including obsessive-compulsive disorder (OCD), and influences adult brain structure and function. ACE could influence the use of psychotropic drugs in adulthood, and treatment seeking behaviors. METHODS: We assessed the severity of ACE in a sample of 31 healthy controls and 66 patients with OCD who were consecutively referred for hospitalization and were either drug-naïve or drug-treated. In addition, we explored the possible clinical relevance of ACE with two additional analyses: (a) a discriminant function analysis with sex and ACE as factors, and (b) a logistic regression with use of medication as dependent variable and ACE as factor. RESULTS: Despite comparable age, years at school, age at onset of illness, duration of illness, and severity of illness (Y-BOCS), adult drug-naïve patients reported lower exposure to ACE and later contacts with mental health professionals than drug-treated. This effect was particularly evident in female patients compared to males. CONCLUSIONS: The interaction of gender with factors linked with the early familial environment biased access to psychiatric care and use of medication, independent of OCD-associated factors such as severity of symptoms or duration of illness. The need for medications of patients could be higher in families where OCD symptomatology is associated with ACE.

Neural correlates of delusion in bipolar depression.

Approximately one-half of all patients affected by bipolar disorder present psychotic features at least in one occasion. This factor worsens the personal and social burden of the disease. Several studies find an altered brain activity in mesolimbic and prefrontal regions in relation to aberrant attribution of salience to stimuli in delusional patients. The aim of the present study is to investigate gray matter (GM) structural correlates of the past history of delusions in a sample of bipolar patients. The sample includes 34 delusional and 39 non-delusional bipolar patients. Brain-imaging volumetric sequences were acquired on a 3.0 T scanner. Voxel based morphometry (VBM) was performed comparing delusional and non-delusional patients. VBM analysis found significant (p=0.001) differences in prefrontal areas and in the insula where delusional patients show lower GM volume compared to non-delusional patients. The main finding of the present study is a reduction of gray matter volume in the dorsolateral prefrontal cortex and in the insula of delusional patients. This result supports the hypothesis of abnormalities in salience and executive-control networks of delusional patients, which could be associated with an aberrant assignment of salience to the elements of one's own experience that is linked to delusion and psychotic symptoms.

Lithium and GSK3-ß promoter gene variants influence white matter microstructure in bipolar disorder.

Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-ß (GSK3-ß). The less active GSK3-ß promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-ß gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-ß promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-ß rs334558*C gene-promoter variants, and the long-term administration of the GSK3-ß inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-ß inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.

Widespread changes of white matter microstructure in obsessive-compulsive disorder: effect of drug status.

Diffusion tensor imaging (DTI) allows the study of white matter (WM) structure. Literature suggests that WM structure could be altered in obsessive-compulsive disorder (OCD) proportional to the severity of the disease. Heterogeneity of brain imaging methods, of the studied samples, and of drug treatments make localization, nature, and severity of the WM abnormalities unclear. We applied Tract-Based Spatial Statistics (TBSS) of DTI measures to compare fractional anisotropy (FA), mean, axial, and radial diffusivity of the WM skeleton in a group of 40 consecutively admitted inpatients affected by severe OCD (18 drug-naive, and 22 with an ongoing drug treatment) and 41 unrelated healthy volunteers from the general population. Data were analyzed accounting for the effects of multiple comparisons, and of age, sex, and education as nuisance covariates. Compared to controls, OCD patients showed a widespread reduction of FA with a concurrent increase of mean and radial diffusivity. In no brain areas patients had higher FA or lower diffusivity values than controls. These differences were observed in drug-treated patients compared to drug-naive patients and healthy controls, which in turn did not differ among themselves in any DTI measure. Reduced FA with increased mean and radial diffusivity suggests significant changes in myelination of WM tracts, without axonal loss. Drug treatments could modify the structure of cell membranes and myelin sheaths by influencing cellular lipogenesis, cholesterol homeostasis, autophagy, oligodendrocyte differentiation and remyelination. Changes of DTI measures in drug-treated OCD patients could reflect pathophysiological underpinnings of OCD, or a yet unexplored part of the mechanism of action of drugs.

Catechol-O-methyltransferase (COMT) genotype biases neural correlates of empathy and perceived personal distress in schizophrenia.

BACKGROUND: The catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism (rs4680) influences enzyme activity with valine (Val) allele associated with higher enzymatic activity. Several studies suggest that factors influencing dopaminergic transmission could control response to stressful situations. Empathy is an essential element of human behavior, requires the ability to adopt another person's perspective, and has been found to be dysfunctional in schizophrenia. METHODS: Twenty-eight schizophrenic patients underwent functional magnetic resonance imaging performing an empathy task. Perceived empathy has been evaluated with the Interpersonal Reactivity Index. RESULTS: An effect of COMT on perceived distress subscale has been shown, with methionine (Met)/Met subjects reporting lower rates of stress compared with Val/Val. Moreover, imaging results showed an effect of genotype on empathy processing in the anterior cingulate with Val/Val subjects showing the lowest activation. DISCUSSION: This is the first study of the effect of rs4680 on interpersonal distress and neural correlates of empathy in schizophrenia. We found a decrease in neural responses in areas that ensure a cognitive control of emotion that is paralleled by perceived distress in interpersonal situation; this functional pattern seems to be influenced by rs4680 COMT polymorphism.

The reality monitoring deficit as a common neuropsychological correlate of schizophrenic and affective psychosis.

UNLABELLED: For many decades, Neuropsychological functioning has been a key point in the study of psychotic disorders. The main aim of these studies is to give a description of the neurocognitive "profile" of schizophrenia, with only little attention being paid to the common and discriminating features of different psychotic disorders. Recent studies support the hypothesis that patients affected by psychiatric disorders with psychotic symptoms have specific abnormalities of reality testing of ongoing perception, which become evident with source monitoring task. Ninety-eight patients and 50 controls were studied. Patients were divided by diagnosis and previous history of psychotic features and were administered Source Monitoring Task to test reality testing of ongoing perception. Frequencies of correct and false attributions were recorded. To obtain measures of observer sensitivity and response biases, a signal detection analysis was performed. AIMS: Studying neuropsychological correlate of psychosis in euthymic mood disordered patients and patients with schizophrenia with or without delusions. RESULTS: Patients with psychotic features use more lax criteria in evaluating self-generated, but not perceived stimuli compared to patients without psychotic features. CONCLUSIONS: Our findings support the hypothesis of selective biases in reality monitoring as neuropsychological correlates of psychosis.

Different neural responses to a moral valence decision task in unipolar and bipolar depression.

Objectives. Patients affected by bipolar disorder (BP) and major depressive disorder (UP) share the susceptibility to experience depression and differ in their susceptibility to mania, but clinical studies suggest that the biological substrates of the two disorders could influence the apparently similar depressive phases. The few brain imaging studies available described different brain metabolic and neural correlates of UP and BP. Methods. We studied the BOLD neural response to a moral valence decision task targeting the depressive biases in information processing in 36 subjects (14 BP, 11 UP, and 11 controls). Results. Main differences between UP and controls and between UP and BP were detected in left ventrolateral prefrontal cortex (PFC, BA 47). Neural responses of BP patients differed from those of control subjects in multiple brain areas, including anterior cingulate cortex (ACC) and medial PFC, bilateral dorsolateral PFC, temporal cortex and insula, and parietal and occipital cortex. Conclusions. Our results are in agreement with hypotheses of dysfunctions in corticolimbic circuitries regulating affects and emotions in mood disorders and suggest that specific abnormalities, particularly in ventrolateral PFC, are not the same in UP and BP depression.

Neural responses to emotional stimuli in comorbid borderline personality disorder and bipolar depression.

Borderline personality disorder (BPD) is a severe clinical condition characterised by different maladaptive traits such as impulsivity and affective lability. Mood and emotion dysregulation are core features of affective disorders. Indeed patients affected by mood disorder (MD) have a significantly higher prevalence of comorbid BPD, resulting in more unstable mood and poorer response to medication. Blood oxygen level-dependent functional magnetic resonance imaging has been used to investigate the neural correlates of emotional face processing. Images for each subject were entered into an analysis of variance (ANOVA) dividing participants into three group (MD, MD+BPD, Controls). MD+BPD patients show lower activations in the dorsolateral prefrontal cortex and higher activations in the cingulate cortex and hippocampus. The present study identifies the neural basis of the interaction between BPD and MD. The lower rate of response to treatment in MD+BPD could be related to a more severe emotional dysregulation syndrome.

Caudate gray matter volume in obsessive-compulsive disorder is influenced by adverse childhood experiences and ongoing drug treatment.

BACKGROUND: Exposure to adverse childhood experiences (ACE) increases the risk of adult physical and mental health disorders, including obsessive-compulsive disorder (OCD), and influences adult cortical neural responses and gray matter (GM) volumes. Robust neuroimaging findings associated OCD with corticostriatal dysfunction and with abnormal morphology and metabolism of cortical areas and basal ganglia. METHODS: We explored the GM correlates of ACE in 40 patients with OCD (15 drug-naive and 25 drug-treated patients) with magnetic resonance imaging voxel-based morphometry at 3.0 T. Regional GM volumes were the dependent variable, and drug treatment (naive vs treated) and breadth of exposure to ACE (high vs low) were the factors of interest. Sex, duration of illness, and handedness were considered as nuisance covariates. Whole brain statistical threshold was P < 0.05 familywise error corrected for multiple comparisons. RESULTS: Patients with higher levels of exposure to ACE showed increased GM volume in the head of the left caudate nucleus. Ongoing drug treatment was associated with reduced GM volume in the same area. Earlier age at onset of OCD, need for medication treatment, and mixed handedness were correlated with higher levels of ACE. CONCLUSIONS: Exposure to ACE increased, and ongoing drug treatment decreased, caudate GM in OCD. Increased volume and metabolism of the caudate nucleus have been consistently associated with OCD. Our findings suggest a detrimental effect of ACE on the brain underpinnings of OCD, with an opposite effect of medications.

Gene-gene interaction of glycogen synthase kinase 3-ß and serotonin transporter on human antidepressant response to sleep deprivation.

BACKGROUND: Glycogen synthase kinase 3-ß (GSK3-ß) is involved in the control of cell behavior and in the mechanism of action of lithium and serotonergic antidepressants, and in humans a promoter variant (rs334558*C) was associated with reduced activity and better antidepressant response. The short form of a polymorphism in the promoter in the serotonin transporter (5-HTTLPR) has been consistently associated with worse antidepressant response. In animals the knockout of GSK3-ß counteracts the depressive-like behavioral effects of 5-HT inhibition. METHODS: With a translational approach, we studied the effect of 5-HTTLPR and rs334558 on antidepressant response to sleep deprivation in a unique sample of 122 patients affected by a major depressive episode in course of bipolar disorder. Mood was self rated on Visual Analog Scales, and severity of depression was rated on Montgomery-Asberg rating scale. RESULTS: We observed a triple interaction of 5-HTTLPR, rs334558 and treatment on severity of depression. While among rs334558 T/T homozygotes the best antidepressant response was associated with 5-HTTLPR l/l homozygosity, among the rs334558 C carriers the 5-HTTLPR s/s showed the best response to treatment. CONCLUSIONS: A gene promoter polymorphism which reduces the activity of GSK3-ß counteracts the detrimental influence of the short form of the 5-HT promoter on antidepressant response. A key component of Wnt pathway, and upstream of the mTOR signaling cascade, GSK3-ß influences synaptic plasticity and cell resilience. Gene-gene interactions between components of the monoaminergic signal transduction pathways and of plasticity related pathways can shape the individual antidepressant response.

Tract-specific white matter structural disruption in patients with bipolar disorder.

OBJECTIVES: A growing body of evidence suggests that, independent of localized brain lesions, mood disorders can be associated with dysfunction of brain networks involved in the modulation of emotional and cognitive behavior. We used diffusion tensor (DT) tractography to quantify the presence and extent of structural injury to the connections between the amygdala and other brain regions, which included the subgenual, the supragenual and posterior cingulate, the parahippocampal, the orbitofrontal and dorsolateral prefrontal cortices, as well as the insula. METHODS: Using a 3.0 Tesla scanner, conventional and DT magnetic resonance imaging sequences of the brain were acquired from 15 adult patients with major depressive disorder (MDD), 15 with bipolar disorder (BD), and 21 age-matched healthy controls. Using FSL software, diffusivity changes of the white matter (WM) fiber bundles belonging to the emotional network were measured. RESULTS: Compared to controls and MDD patients, BD patients had significantly decreased average fractional anisotropy, increased average mean diffusivity, and increased average axial and radial diffusivity values in the majority of the WM fiber bundles connecting structures of the anterior limbic network (p-values ranging from 0.002 to 0.040). Medication load did not influence the results with the exception of lithium, which was associated with normal diffusivity values in tracts connecting the amygdala with the subgenual cingulate cortex. CONCLUSIONS: We detected specific WM abnormalities, suggestive of disrupted integrity of fiber bundles in the brains of patients with BD. These abnormalities might contribute to understanding both mood dysregulation and cognitive disturbances in BD, and might provide an objective marker to monitor treatment efficacy in this condition.

Opposite effects of suicidality and lithium on gray matter volumes in bipolar depression.

BACKGROUND: Mood disorders are associated with the highest increase of attempted and completed suicide. Suicidality in major depressive disorder and in schizophrenia has been associated with reduced gray matter volumes in orbitofrontal cortex. Lithium reduces the suicide risk of patients with bipolar disorder (BD) to the same levels of the general population, and can increase GM volumes. We studied the effect of a positive history of attempted suicide and ongoing lithium treatment on regional GM volumes of patients affected by bipolar depression. METHODS: With a correlational design, we studied 57 currently depressed inpatients with bipolar disorder: 19 with and 38 without a positive history of suicide attempts, 39 unmedicated and 18 with ongoing lithium treatment. Total and regional gray matter volumes were assessed using voxel-based morphometry. RESULTS: Total GM volume is inversely correlated with depression severity. A positive history of suicide attempts was associated with higher stress in early life. Suicide attempters showed reduced GM volumes in several brain areas including dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, superior temporal cortex, parieto-occipital cortex, and basal ganglia. Long term lithium treatment was associated with increased GM volumes in the same areas where suicide was associated with decreased GM. CONCLUSIONS: Reduced GM volumes in critical cortical areas of suicidal patients could be a biological correlate of an impaired ability to associate choices and outcomes and to plan goal-directed behaviors based on a lifetime historical perspective, which, coupled with mood-congruent depressive cognitive distortions, could lead to more hopelessness and suicide. Lithium could exert its specific therapeutic effect on suicide by acting in the same areas.