Dysfunctional family environment in affected versus unaffected offspring of parents with bipolar disorder.

OBJECTIVE: Children of parents with bipolar disorder (BD) are at heightened risk for developing mood and other psychiatric disorders. We proposed to evaluate the environment of families with at least one parent with BD type I (BDF) with affected offspring (aBDF) and unaffected offspring (uBDF) compared with control families without a history of DSM-IV Axis I disorder (CF). METHOD: We used the Family Environment Scale (FES) to evaluate 47 BDF (aBDF + uBDF) and 30 CF. Parents were assessed through the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Diagnosis of the offspring was determined through the Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Version (K-SADS-PL) interview. RESULTS: There were statistically significant differences between aBDF, uBDF and CF in cohesion (p = 0.003), intellectual-cultural orientation (p = 0.01), active-recreational orientation (p = 0.007), conflict (p = 0.001), control (p = 0.01), moral-religious emphasis (p = 0.01) and organization (p = 0.001). The aBDF showed higher levels of control (p = 0.02) when compared to the uBDF. CONCLUSIONS: Families with a BD parent presented more dysfunctional interactions among members. Moreover, the presence of BD or other psychiatric disorders in the offspring of parents with BD is associated with higher levels of control. These results highlight the relevance of psychosocial interventions to improve resilience and family interactions.

A longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment.

In order to assess the association between therapeutic response to lithium treatment and fronto-limbic brain structures' volumes in bipolar I patients (BPI) 24 BPI and 11 healthy comparisons underwent MRI scans at baseline and 4 weeks later. The BPIs received lithium during the 4 week period with a goal of achieving therapeutic blood levels of >0.5 mEq/L (mean level 0.67 mEq/L). Mood symptoms were rated with the Hamilton Depression and the Young Mania Rating Scales at baseline and after 4 weeks, and response was defined as >50% decrease on either scale. Hippocampus, amygdala, prefrontal (PFC), dorsolateral prefrontal (DLPFC), and anterior cingulate cortex (ACC) volumes were obtained by Freesurfer image analysis suite. According to baseline symptoms and treatment response, patients were assigned to three groups: euthymics (n=6), responders (n=12) and non-responders (n=6). Taken over both time periods, non-responders had smaller right amygdala than healthy comparisons and euthymic BPI (p=0.035 and p=0.003, respectively). When baseline and after treatment volumes were compared, there was a significant enlargement in left PFC and left DLPFC in BPI who responded to treatment (p=0.002 and p=0.006, respectively). Left hippocampus and right ACC volumes decreased in non-responders (p=0.02 and p=0.0001, respectively). According to the findings decreased left hippocampus and right ACC volumes may be markers of non-response to lithium amongst BPI. Smaller right amygdala may reflect symptomatic remission and be a marker of treatment non-response. Increases in left PFC and left DLPFC as a result of lithium treatment may relate to lithium's neurotrophic effects.

Is impulsivity a common trait in bipolar and unipolar disorders?

OBJECTIVES: Impulsivity is increased in bipolar and unipolar disorders during episodes and is associated with substance abuse disorders and suicide risk. Impulsivity between episodes predisposes to relapses and poor therapeutic compliance. However, there is little information about impulsivity during euthymia in mood disorders. We sought to investigate trait impulsivity in euthymic bipolar and unipolar disorder patients, comparing them to healthy individuals and unaffected relatives of bipolar disorder patients. METHODS: Impulsivity was evaluated by the Barratt Impulsiveness Scale (BIS-11A) in 54 bipolar disorder patients, 25 unipolar disorder patients, 136 healthy volunteers, and 14 unaffected relatives. The BIS-11A mean scores for all four groups were compared through the Games-Howell test for all possible pairwise combinations. Additionally, we compared impulsivity in bipolar and unipolar disorder patients with and without a history of suicide attempt and substance abuse disorder. RESULTS: Bipolar and unipolar disorder patients scored significantly higher than the healthy controls and unaffected relatives on all measures of the BIS-11A except for attentional impulsivity. On the attentional impulsivity measures there were no differences among the unaffected relatives and the bipolar and unipolar disorder groups, but all three of these groups scored higher than the healthy participant group. There was no difference in impulsivity between bipolar and unipolar disorder subjects with and without suicide attempt. However, impulsivity was higher among bipolar and unipolar disorder subjects with past substance use disorder compared to patients without such a history. CONCLUSIONS: Questionnaire-measured impulsivity appears to be relatively independent of mood state in bipolar and unipolar disorder patients; it remains elevated in euthymia and is higher in individuals with past substance abuse. Elevated attentional and lower non-planning impulsivity in unaffected relatives of bipolar disorder patients distinguished them from healthy participants, suggesting that increased attentional impulsivity may predispose to development of affective disorders, while reduced attentional impulsivity may be protective.

Negative expressed emotion best discriminates families with bipolar disorder children.

BACKGROUND: Children and adolescents with bipolar disorder (BD) live in family environments with high levels of expressed emotion (EE), conflict, and tension; as well as low maternal warmth and cohesion. These family characteristics have been evaluated in research settings using different scales. Nonetheless, empirically supported assessment instruments are not always feasible to be used in clinical settings. Our aim was to identify the best characteristics that discriminate BD families from control by building a classifier with the main characteristics found from different scales. We also built a classifier based on the adjective check-list scale (ACL) because this scale would be the most feasible one to be used in clinical setting. METHODS: We evaluated 33 families of pediatric BD patients and 29 control families. Two self-report scales, ACL and the Family Environment Scale (FES), and a direct interview scale, the Psychosocial Schedule for School Age Children-Revised (PSS-R), were administered. RESULTS: BD families presented lower positive EE and higher negative EE, less cohesion, organization, greater conflict and control; lower rate of intact family, higher maternal and paternal tension compared to control families. Both classifiers demonstrated high accuracy. The offspring's EE toward the mother was the family characteristic that best discriminated BD from control families. LIMITATIONS: Small sample size and cross-sectional design. CONCLUSIONS: Families of BD children presented altered communication and functioning. The high accuracy of the ACL-based classifier highlights a feasible scale to be used in clinical settings. Further studies assessing prognosis associated with the patterns of communication in such families are needed.

Does anxiety increase impulsivity in patients with bipolar disorder or major depressive disorder?

The objective of this study was to examine whether anxiety increases impulsivity among patients with bipolar disorder (BPD) and major depressive disorder (MDD). Subjects comprised 205 BPD (mean age ± SD 36.6 ± 11.5 y; 29.3% males) and 105 with MDD (mean age ± SD 38 ± 13.1 y; 29.5% males) diagnosed using the DSM-IV-SCID. Impulsivity was assessed with the Barratt Impulsivity Scale and anxiety with the Hamilton Anxiety Rating Scale. Comorbid anxiety disorders were present in 58.9% of the BPD and 29.1% of MDD. BPD were significantly more impulsive than MDD (p < 0.001), and both BPD and MDD subjects showed significantly higher impulsivity when anxiety was present either as a comorbidity (p = 0.010) or as a symptom (p = 0.011). Impulsivity rose more rapidly with increasing anxiety symptoms in MDD than in BPD. The presence of anxiety, either as a comorbid disorder or as current anxiety symptoms, is associated with higher impulsivity in subjects with either BPD or MDD.

Association between prior alcohol use disorders and decreased prefrontal gray matter volumes in bipolar I disorder patients.

Up to 50% of bipolar disorder (BD) patients present a lifetime diagnosis of alcohol use disorders (AUD). BD patients with comorbid AUD, even when in remission from the AUD, have a poorer outcome and functional impairment than patients with BD alone. The neurobiological abnormalities that potentially characterize this severe subgroup of BD patients are unknown. Our goal was to investigate gray matter (GM) volume abnormalities in BD I patients with comorbid AUD. Twenty-one BD-AUD patients, 21 BD-nonAUD BD patients, and 25 healthy controls (HC), matched by age, gender, and handedness were studied. The BD-AUD patients were in remission from AUD on average for 6.8 years. 3D SPGR MRIs (TR=25 ms, TE=5 ms, slice thickness=1.5 mm) were acquired from all subjects using a 1.5 T GE Signa Imaging System. We used an optimized voxel-based morphometry protocol to compare GM volumes among the groups. BD-AUD patients presented smaller GM volumes in the left medial frontal and the right anterior cingulate gyri compared to BD-nonAUD patients. BDnon-AUD patients did not present GM volume differences compared to HC. These findings provide evidence for an effect of comorbid AUD on regional brain structure of BD I patients and warrant further research on neurobiological aspects of this prevalent and severe comorbidity.

Falta de integridad de la sustancia blanca en la depresión bipolar como posible marcador estructural de la enfermedad / Disruption of white matter integrity in bipolar depression as a possible structural marker of illness

Fundamento. La resonancia magnética (RM) mediante tensor de difusión permite el estudio de la integridad de los tractos de sustancia blanca (SB). Los estudios publicados sugieren que en el trastorno bipolar podría estar alterada su integridad. La heterogeneidad de los métodos de diagnóstico por imagen cerebral, de las muestras estudiadas y de los tratamientos farmacológicos no contribuye a dilucidar la localización, la naturaleza y la gravedad de las anomalías de la SB. Métodos. Aplicamos el programa informático FSL con la herramienta tract-based spatial statistics (TASS) a los parámetros de RM mediante tensor de difusión para comparar la anisotropía fraccional (AF) y la difusividad media y radial de la estructura de SB en un grupo de 40 pacientes ingresados consecutivamente, afectados por un episodio depresivo mayor, sin características psicóticas, con un diagnóstico de trastorno bipolar de tipo I, y 21 individuos voluntarios, sanos, no emparentados, de la población general. Resultados. Comparado con los individuos de control, en los pacientes se identificó una menor AF en la rodilla del cuerpo calloso y en la parte anterior y supraposterior derecha de la corona radiada y mayores valores de difusividad radial en los tractos de SB del esplenio, rodilla y cuerpo del cuerpo calloso, parte mediodorsal derecha del haz del cíngulo, parte anterior izquierda y superior y posterior bilateral de la corona radiada, fascículo longitudinal superior bilateral y radiación talámica posterior derecha. En los pacientes no se detectaron áreas cerebrales con mayores valores de AF o menores valores de difusividad que en los individuos de control. Conclusiones. La disminución de la AF con un aumento de la difusividad media y radial sugiere una desmielinización y/o dismielinización significativa sin una pérdida axónica. Comparando nuestros hallazgos con otras observaciones de muestras homogéneas de pacientes eutímicos y maníacos, se puede formular la hipótesis de que los cambios en los parámetros de la integridad de la SB podrían ser comparables a las fases de la enfermedad en el trastorno bipolar (AU)

Background. Diffusion tensor imaging allows the study of integrity of white matter (WM) tracts. Literature suggests that WM integrity could be altered in bipolar disorder. Heterogeneity of brain imaging methods, the studied samples, and drug treatments make localization, nature, and severity of the WM abnormalities unclear. Methods. We applied tract-based spatial statistics of diffusion tensor imaging measures to compare fractional anisotropy (FA), mean, and radial diffusivity of the WM skeleton in a group of 40 consecutively admitted inpatients affected by a major depressive episode without psychotic features with a diagnosis of bipolar disorder type I and 21 unrelated healthy volunteers from the general population. Results. Compared with control subjects, patients showed lower FA in the genu of the corpus callosum and in anterior and right superior-posterior corona radiata and higher values of radial diffusivity in WM tracts of splenium, genu and body of corpus callosum, right mid-dorsal part of the cingulum bundle, left anterior and bilateral superior and posterior corona radiata, bilateral superior longitudinal fasciculus, and right posterior thalamic radiation. Patients had no brain areas with higher FA or lower diffusivity values than control subjects. Conclusions. Reduced FA with increased mean and radial diffusivity suggests significant demyelination and/or dysmyelination without axonal loss. Comparing our findings with other observations in homogeneous samples of euthymic and manic patients, it can be hypothesized that changes in measures of WM integrity might parallel illness phases of bipolar illness (AU)

Disruption of white matter integrity in bipolar depression as a possible structural marker of illness.

BACKGROUND: Diffusion tensor imaging allows the study of integrity of white matter (WM) tracts. Literature suggests that WM integrity could be altered in bipolar disorder. Heterogeneity of brain imaging methods, the studied samples, and drug treatments make localization, nature, and severity of the WM abnormalities unclear. METHODS: We applied tract-based spatial statistics of diffusion tensor imaging measures to compare fractional anisotropy (FA), mean, and radial diffusivity of the WM skeleton in a group of 40 consecutively admitted inpatients affected by a major depressive episode without psychotic features with a diagnosis of bipolar disorder type I and 21 unrelated healthy volunteers from the general population. RESULTS: Compared with control subjects, patients showed lower FA in the genu of the corpus callosum and in anterior and right superior-posterior corona radiata and higher values of radial diffusivity in WM tracts of splenium, genu and body of corpus callosum, right mid-dorsal part of the cingulum bundle, left anterior and bilateral superior and posterior corona radiata, bilateral superior longitudinal fasciculus, and right posterior thalamic radiation. Patients had no brain areas with higher FA or lower diffusivity values than control subjects. CONCLUSIONS: Reduced FA with increased mean and radial diffusivity suggests significant demyelination and/or dysmyelination without axonal loss. Comparing our findings with other observations in homogeneous samples of euthymic and manic patients, it can be hypothesized that changes in measures of WM integrity might parallel illness phases of bipolar illness.

Lower N-acetyl-aspartate levels in prefrontal cortices in pediatric bipolar disorder: a ¹H magnetic resonance spectroscopy study.

OBJECTIVE: The few studies applying single-voxel ¹H spectroscopy in children and adolescents with bipolar disorder (BD) have reported low N-acetyl-aspartate (NAA) levels in the dorsolateral prefrontal cortex (DLPFC), and high myo-inositol / phosphocreatine plus creatine (PCr+Cr) ratios in the anterior cingulate. The aim of this study was to evaluate NAA, glycerophosphocholine plus phosphocholine (GPC+PC) and PCr+Cr in various frontal cortical areas in children and adolescents with BD. We hypothesized that NAA levels within the prefrontal cortex are lower in BD patients than in healthy controls, indicating neurodevelopmental alterations in the former. METHOD: We studied 43 pediatric patients with DSM-IV BD (19 female, mean age 13.2 ± 2.9 years) and 38 healthy controls (19 female, mean age 13.9 ± 2.7 years). We conducted multivoxel in vivo ¹H spectroscopy measurements at 1.5 Tesla using a long echo time of 272 ms to obtain bilateral metabolite levels from the medial prefrontal cortex (MPFC), DLPFC (white and gray matter), cingulate (anterior and posterior), and occipital lobes. We used the nonparametric Mann-Whitney U test to compare neurochemical levels between groups. RESULTS: In pediatric BD patients, NAA and GPC+PC levels in the bilateral MPFC, and PCr+Cr levels in the left MPFC were lower than those seen in the controls. In the left DLPFC white matter, levels of NAA and PCr+Cr were also lower in BD patients than in controls. CONCLUSIONS: Lower NAA and PCr+Cr levels in the PFC of children and adolescents with BD may be indicative of abnormal dendritic arborization and neuropil, suggesting neurodevelopmental abnormalities.

Structural equation modeling and principal component analysis of gray matter volumes in major depressive and bipolar disorders: differences in latent volumetric structure.

Abnormalities of the cortico-striatal-thalamic-cortical (CSTC) and the limbic-cortico-striatal-thalamic-cortical (LCSTC) circuits have been hypothesized in mood disorders. We performed principal component analysis (PCA) to identify latent volumetric systems on regional brain volumes and correlated these patterns with clinical characteristics; further, we performed exploratory structural equation modeling (SEM) to test a priori hypotheses about the organization among the structures comprising the CSTC and LCSTC circuits, and to investigate differences among subjects with bipolar disorder (BD), major depressive disorder (MDD), and healthy controls (HC). Participants included 45 BD and 31 MDD patients, and 72 HC. Regional MR brain volumes were used to calculate patterns of volumetric covariance. The identified latent volumetric systems were related to the depression severity and the duration of illness. BD differed from HC on the estimated parameters describing the paths of cortico-striatal, thalamo-striatal and intrastriatal loops of the CSTC circuit, and the paths between anterior and posterior cingulate cortex (PCC), and hippocampus to amygdala of the LCSTC circuit. MDD differed from HC on the paths between putamen and thalamus, and PCC to hippocampus. This study provides evidence to suggest different organizational patterns among structures within the CSTC and LCSTC circuits for BD, MDD, and HC, which may point to structural abnormalities underlying mood disorders.

Reduced medial prefrontal N-acetyl-aspartate levels in pediatric major depressive disorder: a multi-voxel in vivo(1)H spectroscopy study.

There is increasing evidence of a reciprocal fronto-limbic network in the pathogenesis of mood disorders. Prior in vivo proton ((1)H) spectroscopy studies provide evidence of abnormal neurochemical levels in the cingulate and dorsolateral prefrontal cortex (DLPFC) of adult subjects with major depressive disorder (MDD). We examined whether similar abnormalities occur in children and adolescents with MDD. We collected two-dimensional multi-voxel in vivo (1)H spectroscopy data at 1.5 Tesla to quantify levels of N-acetyl-aspartate (NAA), glycerolphosphocholine plus phosphocholine (GPC+PC), and phosphocreatine plus creatine (PCr+Cr) in the DLPFC, medial prefrontal cortex (MPFC), and anterior cingulate (AC) of children and adolescents aged 8-17 years with MDD (n=16) compared with healthy control subjects (n=38). Analysis of covariance with age and gender as covariates was performed. MDD subjects showed significantly lower levels of NAA in the right MPFC and right AC than controls. MDD subjects also had significantly lower levels of GPC+PC in the right AC than control subjects. There were no significant differences in other metabolites in the studied regions. Pediatric patients with MDD exhibit neurochemical alterations in prefrontal cortex regions that are important in the monitoring and regulation of emotional states.

Morphology of the subgenual prefrontal cortex in pediatric bipolar disorder.

OBJECTIVES: The subgenual prefrontal cortex (SGPFC) is an important brain region involved in emotional regulation and reward mechanisms. Volumetric abnormalities in this region have been identified in adults with bipolar disorder but thus far not in pediatric cases. We examined the volume of this brain region in subjects with pediatric bipolar disorder (PBD) and compared them to healthy controls. METHODS: Fifty one children and adolescents (mean age ± SD; 13.2 ± 2.9 y) with DSM-IV PBD and 41 (mean age ± SD; 13.7 ± 2.7 y) healthy comparison subjects (HC) underwent 1.5 T structural magnetic resonance imaging (MRI) brain scans. We traced the SGPFC manually and compared SGPFC gray matter volumes using analysis of covariance with age, gender, and intracranial volume as covariates. We also examined the relationship of family history of affective disorders and medication status to SGPFC volumes. RESULTS: SGPFC volumes were not significantly different in PBD and HC subjects. However, exploratory analysis showed PBD subjects who had one or more first degree relatives with mood disorders (n = 33) had significantly smaller left hemisphere SGPFC compared to HC (p = 0.03 Sidak corrected). Current usage of a mood stabilizer was significantly associated with larger right SGPFC volume in PBD (F = 4.82, df = 1/41, p = 0.03). CONCLUSION: Subjects with PBD and a close family history of mood disorders may have smaller left SGPFC volumes than HC. Mood stabilizing medication may also impact SGPFC size and could have masked more subtle abnormalities overall.

Anterior genu corpus callosum and impulsivity in suicidal patients with bipolar disorder.

Suicidality is a life-threatening symptom in patients with bipolar disorder (BD). Impulsivity and mood instability are associated with suicidality in mood disorders. Evidence suggests that gray and white matter abnormalities are linked with impulsivity in mood disorders, but little is known about the association between corpus callosum (CC) and impulsivity in BD. We examined the relationship between CC areas, impulsivity and suicidality in BD patients. We studied 10 female BD patients with a history of suicide attempt (mean+/-SD age 36.2+/-10.1 years), 10 female BD patients without suicide attempt history (44.2+/-12.5 years) and 27 female healthy subjects (36.9+/-13.8 years). Impulsivity was evaluated by the Barratt Impulsivity Scale (BIS). We traced MR images to measure the areas of the CC genu, anterior body, posterior body, isthmus and splenium. The genu was divided into anterior, middle and posterior regions. The suicidal and non-suicidal BD patients had significantly higher BIS total, attention and non-planning scores than the healthy subjects (ps<0.01), and the suicidal BD patients had significantly higher BIS motor scores than the non-suicidal BD and healthy subjects (ps<0.01). There were no significant differences among the three groups on any regional CC areas, although the suicidal BD patients had the smallest areas. The suicidal BD patients showed a significant inverse correlation between anterior genu area and the BIS total (r=-0.75, p=0.04), motor (r=-0.79, p=0.02) and non-planning scores (r=-0.79, p=0.02). These correlations were not found in the non-suicidal BD patients or healthy subjects. The results suggest that the anterior medial frontal region may be involved in the pathophysiology of impulsive and suicidal behaviors in BD.

Bipolar disorder comorbid with alcoholism: a 1H magnetic resonance spectroscopy study.

Alcoholism is highly prevalent among bipolar disorder (BD) patients, and its presence is associated with a worse outcome and refractoriness to treatment of the mood disorder. The neurobiological underpinnings that characterize this comorbidity are unknown. We sought to investigate the neurochemical profile of the dorsolateral prefrontal cortex (DLPFC) of BD patients with comorbid alcoholism. A short-TE, single-voxel (1)H spectroscopy acquisition at 1.5T from the left DLFPC of 22 alcoholic BD patients, 26 non-alcoholic BD patients and 54 healthy comparison subjects (HC) were obtained. Absolute levels of N-acetyl aspartate, phosphocreatine plus creatine, choline-containing compounds, myo-inositol, glutamate plus glutamine (Glu+Gln) and glutamate were obtained using the water signal as an internal reference. Analysis of co-variance was used to compare metabolite levels among the three groups. In the primary comparison, non-alcoholic BD patients had higher glutamate concentrations compared to alcoholic BD patients. In secondary comparisons integrating interactions between gender and alcoholism, non-alcoholic BD patients presented significantly higher glutamate plus glutamine (Glu+Gln) than alcoholic BD patients and HC. These results appeared to be driven by differences in male subjects. Alcoholic BD patients with additional drug use disorders presented significantly lower myo-inositol than BD patients with alcoholism alone. The co-occurrence of BD and alcoholism may be characterized by neurochemical abnormalities related to the glutamatergic system and to the inositol second messenger system and/or in glial pathology. These abnormalities may be the neurochemical correlate of an increased risk to develop alcoholism in BD, or of a persistently worse clinical and functional status in BD patients in remission from alcoholism, supporting the clinical recommendation that efforts should be made to prevent or early diagnose and treat alcoholism in BD patients.

Normal metabolite levels in the left dorsolateral prefrontal cortex of unmedicated major depressive disorder patients: a single voxel (1)H spectroscopy study.

Few proton magnetic resonance spectroscopy ((1)H spectroscopy) studies have investigated the dorsolateral prefrontal cortex (DLPFC), a key region in the pathophysiology of major depressive disorder (MDD). We used (1)H spectroscopy to verify whether MDD patients differ from healthy controls (HC) in metabolite levels in this brain area. Thirty-seven unmedicated DSM-IV MDD patients were compared with 40 HC. Subjects underwent a short echo-time (1)H spectroscopy examination at 1.5 T, with an 8-cm(3) single voxel placed in the left DLPFC. Reliable absolute metabolite levels of N-acetyl aspartate (NAA), phosphocreatine plus creatine (PCr+Cr), choline-containing compounds (GPC+PC), myo-inositol, glutamate plus glutamine (Glu+Gln), and glutamate were obtained using the unsuppressed water signal as an internal reference. Metabolite levels in the left DLPFC did not statistically differ between MDD patients and HC. We found an interaction between gender and diagnosis on PCr+Cr levels. Male MDD patients presented lower levels of PCr+Cr than male HC, and female MDD patients presented higher levels of PCr+Cr than female HC. Moreover, length of illness was inversely correlated with NAA levels. These findings suggest that there is not an effect of diagnosis on the left DLPFC neurochemistry. Possible effects of gender on PCr+Cr levels of MDD patients need to be further investigated.

Altered hippocampal morphology in unmedicated patients with major depressive illness.

Despite converging evidence that major depressive illness is associated with both memory impairment and hippocampal pathology, findings vary widely across studies and it is not known whether these changes are regionally specific. In the present study we acquired brain MRIs (magnetic resonance images) from 31 unmedicated patients with MDD (major depressive disorder; mean age 39.2+/-11.9 years; 77% female) and 31 demographically comparable controls. Three-dimensional parametric mesh models were created to examine localized alterations of hippocampal morphology. Although global volumes did not differ between groups, statistical mapping results revealed that in MDD patients, more severe depressive symptoms were associated with greater left hippocampal atrophy, particularly in CA1 (cornu ammonis 1) subfields and the subiculum. However, previous treatment with atypical antipsychotics was associated with a trend towards larger left hippocampal volume. Our findings suggest effects of illness severity on hippocampal size, as well as a possible effect of past history of atypical antipsychotic treatment, which may reflect prolonged neuroprotective effects. This possibility awaits confirmation in longitudinal studies.

Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder.

OBJECTIVE: Impulsivity is associated with the clinical outcome and likelihood of risky behaviors among bipolar disorder (BD) patients. Our previous study showed an inverse relationship between impulsivity and orbitofrontal cortex (OFC) volume in healthy subjects. We hypothesized that BD patients would show an inverse relationship between impulsivity and volumes of the OFC, anterior cingulate cortex (ACC), medial prefrontal cortex, and amygdala, which have been implicated in the pathophysiology of BD. METHODS: Sixty-three BD patients were studied (mean +/- SD age = 38.2 +/- 11.5 years; 79% female). The Barratt Impulsiveness Scale (BIS), version 11A, was used to assess trait impulsivity. Images were processed using SPM2 and an optimized voxel-based morphometry protocol. We examined the correlations between BIS scores and the gray matter (GM) and white matter (WM) volumes of the prespecified regions. RESULTS: Left rostral ACC GM volume was inversely correlated with the BIS total score (t = 3.95, p(corrected) = 0.003) and the BIS motor score (t = 5.22, p(corrected) < 0.001). In contrast to our hypothesis, OFC volumes were not significantly associated with impulsivity in BD. No WM volume of any structure was significantly correlated with impulsivity. No statistical association between any clinical variable and the rostral ACC GM volumes reached significance. CONCLUSIONS: Based on our previous findings and the current results, impulsivity may have a different neural representation in BD and healthy subjects, and the ACC may be involved in the pathophysiology of abnormal impulsivity regulation in BD patients.

An MRI-based approach for the measurement of the dorsolateral prefrontal cortex in humans.

The dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of mental disorders. Previous region-of-interest MRI studies that attempted to delineate this region adopted various landmarks and measurement techniques, with inconsistent results. We developed a new region-of-interest measurement method to obtain morphometric data of this region from structural MRI scans, taking into account knowledge from cytoarchitectonic postmortem studies and the large inter-individual variability of this region. MRI scans of 10 subjects were obtained, and DLPFC tracing was performed in the coronal plane by two independent raters using the semi-automated software Brains2. The intra-class correlation coefficients between two independent raters were 0.94 for the left DLPFC and 0.93 for the right DLPFC. The mean +/- S.D. DLPFC volumes were 9.23 +/- 2.35 ml for the left hemisphere and 8.20 +/- 2.08 ml for the right hemisphere. Our proposed method has high inter-rater reliability and is easy to implement, permitting the standardized measurement of this region for clinical research applications

Orbitofrontal cortex gray matter volumes in bipolar disorder patients: a region-of-interest MRI study.

OBJECTIVES: Functional and postmortem studies suggest that the orbitofrontal cortex (OFC) is involved in the pathophysiology of bipolar disorder (BD). This anatomical magnetic resonance imaging (MRI) study examined whether BD patients have smaller OFC gray matter volumes compared to healthy comparison subjects (HC). METHODS: Twenty-eight BD patients were compared to 28 age- and gender-matched HC. Subjects underwent a 1.5T MRI with 3D spoiled gradient recalled acquisition. Total OFC and medial and lateral subdivisions were manually traced by a blinded examiner. Images were segmented and gray matter volumes were calculated using an automated method. RESULTS: Analysis of covariance, with intracranial volume as covariate, showed that BD patients and HC did not differ in gray matter volumes of total OFC or its subdivisions. However, total OFC gray matter volume was significantly smaller in depressed patients (n = 10) compared to euthymic patients (n = 18). Moreover, total OFC gray matter volumes were inversely correlated with depressive symptom intensity, as assessed by the Hamilton Depression Rating Scale. OFC gray matter volumes were not related to lithium treatment, age at disease onset, number of episodes, or family history of mood disorders. CONCLUSIONS: Our results suggest that abnormal OFC gray matter volumes are not a pervasive characteristic of BD, but may be associated with specific clinical features of the disorder.

Neuronal correlates of brain-derived neurotrophic factor Val66Met polymorphism and morphometric abnormalities in bipolar disorder.

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been proposed as a possible candidate for involvement in the pathophysiology of bipolar disorder (BD). To determine whether an association exists between the BDNF Val66Met genotype and morphometric abnormalities of the brain regions involved in memory and learning in BD and healthy subjects. Forty-two BD patients and 42 healthy subjects were studied. Interactions between BDNF Val66Met genotype and diagnosis in gray (GM) volumes were analyzed using an optimized voxel-based morphometry technique. Declarative memory function was assessed with the California Verbal Learning Test II. Left and right anterior cingulate GM volumes showed a significant interaction between genotype and diagnosis such that anterior cingulate GM volumes were significantly smaller in the Val/Met BD patients compared with the Val/Val BD patients (left P=0.01, right P=0.01). Within-group comparisons revealed that the Val/Met carriers showed smaller GM volumes of the dorsolateral prefrontal cortex compared with the Val/Val subjects within the BD patient (P=0.01) and healthy groups (left P=0.03, right P=0.03). The Val/Met healthy subjects had smaller GM volumes of the left hippocampus compared with the Val/Val healthy subjects (P<0.01). There was a significant main effect of diagnosis on memory function (P=0.04), but no interaction between diagnosis and genotype was found (P=0.48). The findings support an association between the BDNF Val66Met genotype and differential gray matter content in brain structures, and suggest that the variation in this gene may play a more prominent role in brain structure differences in subjects affected with BD.