Katie Mahon

A role for white matter abnormalities in the pathophysiology of bipolar disorder.

Bipolar disorder is a chronically disabling psychiatric disorder characterized by manic states that is often interspersed with periods of depression whose neurobiology remains largely unknown. There is, however, increasing evidence that white matter (WM) abnormalities may play an important role in the neurobiology of the disorder. In this review we critically evaluate evidence for WM abnormalities in bipolar disorder obtained from neuroimaging, neuropathological, and genetic research. Increased rates of white matter hyperintensities, regional volumetric abnormalities, abnormal water diffusion along prefrontal-subcortical tracts, fewer oligodendrocytes in prefrontal WM, and alterations in the expression of myelin- and oligodendrocyte-related genes are among the most consistent findings. Abnormalities converge in the prefrontal WM and, in particular, tracts that connect prefrontal regions and subcortical gray matter structures known to be involved in emotion. Taken together, the evidence supports and clarifies a model of BD that involves disconnectivity in regions implicated in emotion generation and regulation.

Empirical evidence for discrete neurocognitive subgroups in bipolar disorder: clinical implications.

BACKGROUND Recent data suggest trait-like neurocognitive impairments in bipolar disorder (BPD), with deficits about 1 s.d. below average, less severe than deficits noted in schizophrenia. The frequency of significant impairment in BPD is approximately 60%, with 40% of patients characterized as cognitively spared. This contrasts with a more homogeneous presentation in schizophrenia. It is not understood why some BPD patients develop deficits while others do not. METHOD A total of 136 patients with BPD completed the MATRICS Consensus Cognitive Battery and data were entered into hierarchical cluster analyses to: (1) determine the optimal number of clusters (subgroups) that fit the sample; and (2) assign subjects to a specific cluster based on individual profiles. We then compared subgroups on several clinical factors and real-world community functioning. RESULTS Three distinct neurocognitive subgroups were found: (1) an intact group with performance comparable with healthy controls on all domains but with superior social cognition; (2) a selective impairment group with moderate deficits on processing speed, attention, verbal learning and social cognition and normal functioning in other domains; and (3) a global impairment group with severe deficits across all cognitive domains comparable with deficits in schizophrenia. CONCLUSIONS These results suggest the presence of multiple cognitive subgroups in BPD with unique profiles and begin to address the relationships between these subgroups, several clinical factors and functional outcome. Next steps will include using these data to help guide future efforts to target these disabling symptoms with treatment.

A Voxel-Based Diffusion Tensor Imaging Study of White Matter in Bipolar Disorder

There is evidence from post-mortem and magnetic resonance imaging studies that hyperintensities, oligodendroglial abnormalities, and gross white matter volumetric alterations are involved in the pathophysiology of bipolar disorder. There is also functional imaging evidence for a defect in frontal cortico–subcortical pathways in bipolar disorder, but the white matter comprising these pathways has not been well investigated. Few studies have investigated white matter integrity in patients with bipolar disorder compared to healthy volunteers and the majority of studies have used manual region-of-interest approaches. In this study, we compared fractional anisotropy (FA) values between 30 patients with bipolar disorder and 38 healthy volunteers in the brain white matter using a voxelwise analysis following intersubject registration to Talairach space. Compared to healthy volunteers, patients demonstrated significantly (p<0.001; cluster size ⩾50) higher FA within the right and left frontal white matter and lower FA within the left cerebellar white matter. Examination of individual eigenvalues indicated that group differences in both axial diffusivity and radial diffusivity contributed to abnormal FA within these regions. Tractography was performed in template space on averaged diffusion tensor imaging data from all individuals. Extraction of bundles passing through the clusters that differed significantly between groups suggested that white matter abnormalities along the pontine crossing tract, corticospinal/corticopontine tracts, and thalamic radiation fibers may be involved in the pathogenesis of bipolar disorder. Our findings are consistent with models of bipolar disorder that implicate dysregulation of cortico-subcortical and cerebellar regions in the disorder and may have relevance for phenomenology.

White Matter Abnormalities in Pediatric Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a prevalent and often severely disabling illness with onset generally in childhood or adolescence. Although white matter deficits have been implicated in the neurobiology of OCD, few studies have been conducted in pediatric patients when the brain is still developing and have examined their functional correlates. In this study, 23 pediatric OCD patients and 23 healthy volunteers, between the ages of 9 and 17 years, matched for sex, age, handedness, and IQ, received a diffusion tensor imaging exam on a 3T GE system and a brief neuropsychological battery tapping executive functions. Patient symptom severity was assessed using the Childrens Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Patients with OCD exhibited significantly greater fractional anisotropy compared to matched controls in the left dorsal cingulum bundle, splenium of the corpus callosum, right corticospinal tract, and left inferior fronto-occipital fasciculus. There were no regions of significantly lower fractional anisotropy in patients compared to controls. Higher fractional anisotropy in the splenium was significantly correlated with greater obsession severity on the CY-BOCS in the subgroup of psychotropic drug-naïve patients. Among patients, there was a significant association between greater fractional anisotropy in the dorsal cingulum bundle and better performance on measures of response inhibition and cognitive control. The overall findings suggest a pattern of greater directional coherence of white matter tracts in OCD very early in the course of illness, which may serve a compensatory mechanism, at least for response inhibition functions typically subserved by the cingulum bundle.

Impulsivity in bipolar disorder: relationships with neurocognitive dysfunction and substance use history.

Impulsivity is a core feature in bipolar disorder. Although mood symptoms exacerbate impulsivity, self‐reports of impulsivity are elevated, even during euthymia. Neurocognitive processes linked to impulsivity (e.g., attention, inhibition) are also impaired in patients with bipolar disorder, and a high frequency of comorbidities associated with impulsivity, such as substance use disorders, further highlights the clinical relevance of this dimension of the illness. Our objective was to assess the relationship between impulsivity and cognition in bipolar disorder.

Abnormal temporal lobe white matter as a biomarker for genetic risk of bipolar disorder.

BACKGROUND Brain white matter (WM) abnormalities have been hypothesized to play an important role in the neurobiology of bipolar disorder (BD). The nature of these abnormalities is not well-characterized, however, and it is unknown whether they occur after disease onset or represent potential markers of genetic risk. METHODS We examined WM integrity (assessed via fractional anisotropy [FA]) with diffusion tensor imaging in patients with BD (n=26), unaffected siblings of patients with BD (n=15), and healthy volunteers (n=27) to identify WM biomarkers of genetic risk. RESULTS The FA differed significantly (p<.05; corrected) among the three groups within the right temporal WM. Unaffected siblings had FA values that were intermediate to and significantly different from those of healthy volunteers and patients with BD (healthy control subjects>unaffected siblings>BD). Moreover, FA values in this region correlated negatively and significantly with trait impulsivity in unaffected siblings. Probabilistic tractography indicated that the regional abnormality lies along the inferior fronto-occipital fasciculus, a large intrahemispheric association pathway. CONCLUSIONS Our results suggest that lower WM integrity in the right temporal lobe might be a biomarker for genetic risk of BD. It is conceivable that the attenuated nature of these WM abnormalities present in unaffected siblings allows for some preservation of adaptive emotional regulation, whereas more pronounced alterations observed in patients is related to the marked emotional dysregulation characteristic of BD.

Oxytocin and social cognition in affective and psychotic disorders

Impairments in social cognition are now recognized as core illness features in psychotic and affective disorders. Despite the significant disability caused by social cognitive abnormalities, treatments for this symptom dimension are lacking. Here, we describe the evidence demonstrating abnormalities in social cognition in schizophrenia, major depressive disorder, and bipolar disorder, as well as the neurobiology of social cognition including the role of oxytocin. We then review clinical trials of oxytocin administration in psychotic and affective disorders and the impact of this agent on social cognition. To date, several studies have demonstrated that oxytocin may improve social cognition in schizophrenia; too few studies have been conducted in affective disorders to determine the effect of oxytocin on social cognition in these disorders. Future work is needed to clarify which aspects of social cognition may be improved with oxytocin treatment in psychotic and affective disorders.

The association between childhood trauma and facial emotion recognition in adults with bipolar disorder

Many patients with bipolar disorder (BD) have difficulties in facial emotion recognition, which may also be impaired in maltreated children and in subjects who have a positive history of childhood traumatic experiences. Childhood trauma is reported with a high prevalence in BD and it is considered a risk factor for the disorder. As the relationship between facial emotion recognition and childhood trauma in BD has not yet been directly investigated, in this study we examined whether the presence of a childhood trauma in affectively stable BD patients was associated with poorer performance in emotion recognition. Seventy-five BD I and II participants completed the Childhood Trauma Questionnaire retrospectively assessing five types of childhood trauma (emotional, physical and sexual abuse, and emotional and physical neglect) and the Emotion Recognition Task evaluating the ability to correctly identify six basic facial emotions (happiness, sadness, anger, disgust, fear and surprise). Our results suggest that the presence of childhood trauma in participants with BD is associated with a more severe clinical presentation (earlier onset, longer duration of illness, and higher depressive symptom ratings) and that BD patients with a positive childhood history of emotional neglect perform worse than those without such a history in recognizing anger.

Affective temperaments and neurocognitive functioning in bipolar disorder

BACKGROUND There is evidence that patients with bipolar disorder (BD) score higher on affective temperament ratings compared to healthy controls (HCs). Moreover, unaffected relatives demonstrate similar patterns as BD patients suggesting that such temperaments are related to the genetic risk for BD and may serve as endophenotypes for the disorder. It is unknown whether affective temperaments are associated with other core features of BD, such as impairments in neurocognition. This study examined the relationship between affective temperaments and neurocognition in patients with BD and in HCs. METHODS Temperaments were evaluated using the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego, Auto-questionnaire version (TEMPS-A) in 64 patients with BD and 109 HCs. Neurocognitive functioning was evaluated using the MATRICS Consensus Cognitive Battery (MCCB). Correlational analyses between temperaments and cognition were conducted in BD and HC subjects. RESULTS Data suggest that affective temperaments and neurocognition are correlated. In BD higher ratings of cyclothymia and irritability were associated with better processing speed, working memory, reasoning and problem-solving. In the HC group, increased irritability was related to worse performance on measures of attention and social cognition. LIMITATIONS Lack of functional outcome measures to evaluate the impact of temperaments and cognition on psychosocial functioning. It would be useful to test these findings on unaffected relatives of BD patients. CONCLUSIONS Cyclothymic and irritable temperaments are correlated with specific aspects of neurocognition in BD. This study is among the few exploring the dimensional relationship between temperaments and cognition in BD, and provides preliminary evidence for future studies investigating the neural and genetic mechanisms underlying the association between these variables.

The relationship between sleep quality and neurocognition in bipolar disorder

BACKGROUNDS Sleep and circadian rhythm disruptions are prominent, trait-like features of bipolar disorder (BD) which precede the onset of mood episodes. Neurocognitive impairments also characterize BD not only during acute phases of the illness but also during remission. Although the relationship between these two debilitating aspects of the illness might seem intuitive, very little is known about their relationship. We examined the association between sleep dysfunction and neurocognition in BD. METHODS In a sample of 117 BD patients (mean age=45.0±10.7; 59.0% (n=69) male), neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Sleep quality data were collected using the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI). Partial Pearson correlations tested for a relationship between sleep and neurocognition. Path analyses were conducted to examine the hypothesized direct influence of sleep disruption on neurocognition. RESULTS Higher levels of sleep disruptions were associated with a more severe clinical presentation and poorer performance in social cognition, visual learning and working memory. Social cognition and working memory were directly (negatively) predicted by sleep disruptions. LIMITATIONS The study was limited by a relatively small sample size and the lack of behavioral and biological objectives measure of activity/rest cycles. CONCLUSIONS Our study suggests that in patients with BD, sleep disruptions have a detrimental effect on general level of psychopathology and contribute directly to impaired cognitive functioning in the domains of social cognition and working memory. More research using objective measurement of sleep should be pursued to support these data and to further investigate the causal relationship between these disabling aspects of the illness.