Dissociable brain structural changes associated with predisposition, resilience, and disease expression in bipolar disorder.

Genetic factors are important in the etiology of bipolar disorder (BD). However, first-degree relatives of BD patients are at risk for a number of psychiatric conditions, most commonly major depressive disorder (MDD), although the majority remain well. The purpose of the present study was to identify potential brain structural correlates for risk and resilience to mood disorders in patients with BD, type I (BD-I) and their relatives. Structural magnetic resonance imaging scans were acquired from 30 patients with BD-I, 50 of their first-degree relatives (28 had no Axis I disorder, while 14 had MDD) and 52 controls. We used voxel-based morphometry, implemented in SPM5 to identify group differences in regional gray matter volume. From the identified clusters, potential differences were further examined based on diagnostic status (BD-I patients, MDD relatives, healthy relatives, controls). Whole-brain voxel-based analysis identified group differences in the left hemisphere in the insula, cerebellum, and substantia nigra. Increased left insula volume was associated with genetic preposition to BD-I independent of clinical phenotype. In contrast, increased left substantia nigra volume was observed in those with the clinical phenotype of BD-I. Changes uniquely associated with the absence of a clinical diagnosis in BD relatives were observed in the left cerebellum. Our data suggest that in BD, genetic and phenotype-related influences on brain structure are dissociable; if replicated, these findings may help with early identification of high-risk individuals who are more likely to transition to syndromal states.

Corpus callosum size and shape alterations in individuals with bipolar disorder and their first-degree relatives.

Reductions in the size of the corpus callosum (CC) have been described in patients with bipolar disorder (BD), although the contribution of genetic factors to these changes is unclear. We previously showed a global thinning of the CC in BD patients, and found those with a family history of affective disorders had a larger CC than those without. In this study, we compared callosal size and shape in 180 individuals: 70 with BD, 45 of their first-degree relatives, and 75 healthy controls. The callosum was extracted from a mid-sagittal slice from T1-weighted magnetic resonance images, and its total area, length and curvature were compared across groups. A non-parametric permutation method was used to examine for alterations in width of the callosum along 39 points. Validating our previous findings, a significant global reduction in callosal thickness was seen in BD patients, with a disproportionate thinning in the anterior body. First-degree relatives did not differ in callosal size or shape from controls. In BD patients, duration of illness and age were associated with thinning in the anterior body; BD patients on lithium treatment showed a thicker anterior mid-body than those on other psychotropics. Global and regional thinning of the callosum is seen in BD but not in their first-degree relatives. This suggests that CC abnormalities are linked to disease expression in BD and may not represent a marker of familial predisposition.

No gender differences in brain activation during the N-back task: an fMRI study in healthy individuals.

Gender differences have been well established in verbal and spatial abilities but few studies have examined if these differences also extend into the domain of working memory in terms of behavioural differences and brain activation. The conclusions that can be drawn from these studies are not clear cut but suggest that even though gender differences might not be apparent from behavioural measures, the underlying neural substrate associated with working memory might be different in men and women. Previous research suggests activation in a network of frontal and parietal regions during working memory tasks. This study aimed to investigate gender differences in patterns of brain activation during a verbal version of the N-back working memory task, which incorporates the effects of increased demands on working memory. A total of 50 healthy subjects, aged 18 to 58 years, that were equally split by gender were recruited matched for age, levels of education and ethnicity. All subjects underwent functional magnetic resonance imaging. We found that men and women performed equally well in terms of accuracy and response times, while using similar brain regions to the same degree. Our observations indicate that verbal working memory is not affected by gender at the behavioural or neural level, and support the findings of a recent meta-analysis by Hyde ([ 2005]: Sex Roles 53:717-725) that gender differences are generally smaller than intra-gender differences in many cognitive domains.

No differential effect of age on brain matter volume and cognition in bipolar patients and healthy individuals.

BACKGROUND: Bipolar disorder (BD) is associated with brain structural and cognitive abnormalities. There is a paucity of evidence regarding the evolution of these deficits over time. This study examined the relationship between age and brain morphology and cognition in patients with BD type I. METHODS: Brain structural magnetic resonance imaging data were acquired using a 1.5T scanner from 71 BD patients and 82 age- and gender-matched controls and analysed using Statistical Parametric Mapping. In addition, participants were evaluated using the Wechsler Adult Intelligence Scale, Revised; the Wechsler Memory Scale, third edition; the Hayling Sentence Completion Task, a measure of response inhibition; and the Wisconsin Card Sorting Test, which reflects rule discovery and perseveration. RESULTS: We found a significant effect of age but not of diagnosis and no age-by-diagnosis interaction in global gray and white matter and cerebrospinal fluid volumes. There was no differential effect of age on the two diagnostic groups with respect to cognitive task performance. CONCLUSIONS: Our findings do not support differential age-related changes in brain structure and cognition in patients with bipolar disorder compared to healthy individuals. Cross-sectional studies are, however, limited and longitudinal data will be required to further explore this issue.

The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study.

The functional catechol-O-methyltransferase (COMT Val108/158Met) polymorphism has been shown to have an impact on tasks of executive function, memory and attention and recently, tasks with an affective component. As oestrogen reduces COMT activity, we focused on the interaction between gender and COMT genotype on brain activations during an affective processing task. We used functional MRI (fMRI) to record brain activations from 74 healthy subjects who engaged in a facial affect recognition task; subjects viewed and identified fearful compared to neutral faces. There was no main effect of the COMT polymorphism, gender or genotypexgender interaction on task performance. We found a significant effect of gender on brain activations in the left amygdala and right temporal pole, where females demonstrated increased activations over males. Within these regions, Val/Val carriers showed greater signal magnitude compared to Met/Met carriers, particularly in females. The COMT Val108/158Met polymorphism impacts on gender-related patterns of activation in limbic and paralimbic regions but the functional significance of any oestrogen-related COMT inhibition appears modest.

Pilot investigation of the changes in cortical activation during facial affect recognition with lamotrigine monotherapy in bipolar disorder.

BACKGROUND: Bipolar disorder is associated with dysfunction in prefrontal and limbic areas implicated in emotional processing. AIMS: To explore whether lamotrigine monotherapy may exert its action by improving the function of the neural network involved in emotional processing. METHOD: We used functional magnetic resonance imaging to examine changes in brain activation during a sad facial affect recognition task in 12 stable patients with bipolar disorder when medication-free compared with healthy controls and after 12 weeks of lamotrigine monotherapy. RESULTS: At baseline, compared with controls, patients with bipolar disorder showed overactivity in temporal regions and underactivity in the dorsal medial and right ventrolateral prefrontal cortex, and the dorsal cingulate gyrus. Following lamotrigine monotherapy, patients demonstrated reduced temporal and increased prefrontal activation. CONCLUSIONS: This preliminary evidence suggests that lamotrigine may enhance the function of the neural circuitry involved in affect recognition.

Structural brain correlates of response inhibition in Bipolar Disorder I.

Deficits in response inhibition are a prominent feature of Bipolar Disorder, type I (BDI). The purpose of this study was to examine the relationship between inhibitory control and cerebral structure as it may inform our understanding of the pathophysiology of BDI. Inhibitory control was measured in remitted patients with BDI (n = 44) and healthy controls (n = 44), using the interference score from the Stroop Colour Word Task and the scaled total error score from the Hayling Sentence Completion Test. Structural magnetic resonance imaging brain scans were also obtained for all participants. For both measures, better performance in controls correlated positively with gray matter volume in the dorsal and ventral prefrontal cortical (PFC) regions with parietal involvement additionally seen for the interference score. In contrast, better inhibitory control in BDI patients correlated positively with gray matter volume in the right parietal cortical regions, namely the cuneus for the scaled total error score and the inferior parietal lobule for the interference score. The observed lack of correlation between PFC grey matter and measures of inhibitory control in BDI patients is suggestive of PFC dysfunction; the correlation between response inhibition and parietal grey matter volume may be indicative of a compensatory involvement of the parietal cortices in BDI.

Changes in brain activation during working memory and facial recognition tasks in patients with bipolar disorder with Lamotrigine monotherapy.

Verbal working memory and emotional self-regulation are impaired in Bipolar Disorder (BD). Our aim was to investigate the effect of Lamotrigine (LTG), which is effective in the clinical management of BD, on the neural circuits subserving working memory and emotional processing. Functional Magnetic Resonance Imaging data from 12 stable BD patients was used to detect LTG-induced changes as the differences in brain activity between drug-free and post-LTG monotherapy conditions during a verbal working memory (N-back sequential letter task) and an angry facial affect recognition task. For both tasks, LGT monotherapy compared to baseline was associated with increased activation mostly within the prefrontal cortex and cingulate gyrus, in regions normally engaged in verbal working memory and emotional processing. Therefore, LTG monotherapy in BD patients may enhance cortical function within neural circuits involved in memory and emotional self-regulation.

Functional neuroimaging studies in mood disorders.

BACKGROUND: Our understanding of the neural circuitry involved in mood disorders is rapidly expanding through the ever-increasing application of functional brain imaging techniques. OBJECTIVES: A selective review of functional neuroimaging studies in patients with primary mood disorders was undertaken in order to identify points of commonality and controversy in the existing literature. METHODS: Articles published between 1980 and July 2005 were identified using a range of keywords from relevant on-line databases and key journals. RESULTS: Increased activity within limbic regions has been consistently associated with depressive states and may also be present in manic states too. Dorsal and ventral prefrontal regions appear compromised as suggested by emerging evidence of cortical inefficiency within prefrontal regions or reductions in their connectivity with limbic areas. Most of the functional changes observed are at least partly reversible following clinical remission although deficits in prefrontal regions may be state-related. CONCLUSIONS: Despite the use of disparate functional imaging modalities, there is a convergence of findings, and the results described do not appear to differ between unipolar and bipolar depression. However, further data are required in order to fully determine the functional changes occurring during manic states. Future work will also need to elucidate the effects of medication, the utility of specific cognitive tasks, and blood oxygenation level-dependent interactions within these affective states.

Maudsley Bipolar Disorder Project: insights sobre o papel do córtex pré-frontal em pacientes com transtorno de humor bipolar tipo I / The Maudsley Bipolar Disorder Project: insights into the role of the prefrontal cortex in bipolar disorder I

OBJETIVO: O projeto Maudsley Bipolar Disorder foi criado para investigar características cognitivas e estruturais/funcionais do cérebro em pacientes com Transtorno de Humor Bipolar Tipo I (THB-I). MÉTODOS: Quarenta e três pacientes com THB-I foram selecionados em uma unidade de atendimento secundário, em um momento de remissão da doença, para participarem do estudo. Os pacientes foram pareados a controles sadios de acordo com idade, sexo, raça e nível de escolaridade. Cada participante foi submetido a uma extensa revisão clínica, com avaliação cognitiva e exame de ressonância magnética (RM) para a obtenção de dados estruturais e funcionais do cérebro. RESULTADOS: Quando comparados aos controles, os pacientes demonstraram um sutil e difuso comprometimento com redução mais marcante no nível das funções executivas. Os pacientes também apresentaram decrementos volumétricos no córtex pré-frontal ventral (CPFV) bilateralmente e córtex pré-frontal dorsal (CPFD) esquerdo. O volume da amígdala estava bilateralmente aumentado. A ressonância magnética funcional (RMf) mostrou anormalidades sutis no CPFD, com marcados decrementos de atividade tanto no CPFD como no CPFV durante tarefas que dependiam da interação funcional dessas regiões. CONCLUSÕES: Os resultados sugerem que ocorrem traços de déficits em funções executivas em pacientes com THB-I, assim como alteração de estrutura e funcionamento do córtex pré-frontal.

Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder.

BACKGROUND: Trait functional abnormalities in BD patients have only been reported in the ventral prefrontal cortex (VPFC). We examined whether deficits in VPFC-related inhibitory processes, but not dorsal prefrontal (DPFC) based executive functions, represent an endophenotypic marker for bipolar disorder I (BDI). METHODS: We used the Wisconsin Card Sorting Test (WCST), commonly associated with DPFC function, and the Hayling Sentence Completion Task (HSCT) which engages the VPFC. Performance on these tests of 43 healthy participants was compared to that of 10 remitted BDI patients and 15 of their unaffected offspring. RESULTS: Compared to healthy participants, patients and their offspring made more errors in the HSCT but offspring achieved more categories and made fewer perseverative errors in the WCST. CONCLUSIONS: Impaired response inhibition, predominantly a VPFC related function, may reflect familial predisposition to BDI while deficits in rule attainment, a DPFC based function, may be associated only with the clinical phenotype.

New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings.

Bipolar affective disorder (BD) is a severe mental illness, characterized by episodes of mania and depression. With the development of Magnetic Resonance Imaging (MRI), neuroimaging methods are now allowing investigation of the neurocircuitry involved in this disorder. This in turn has aided further neuropathological exploration of the brain. Structural MRI and Magnetic Resonance Spectroscopy studies suggest that brain abnormalities in BD are mostly regional, as global measures (cerebral, white and gray matter and ventricular volumes) do not seem to be affected in the majority of patients. The prefrontal and anterior cingulate cortices, and amygdalae are consistently implicated in BD, whilst the evidence for hippocampal involvement is less convincing. Functional studies have found that the activity of the dorsal prefrontal cortex and the anterior cingulate are closely associated with mood symptoms. Activity in the ventral and orbital prefrontal cortex appears reduced both during episodes and in remission. In contrast, amygdala activity shows a persistent increase. We suggest that abnormal interaction between the amygdala and the ventral/orbitofrontal cortex may be a central feature of the pathophysiology of BD.