Prefrontal Cortex In Bipolar Disorder Research Articles

Decreased Functional Connectivity of Vermis-Ventral Prefrontal Cortex in Bipolar Disorder.

Objectives: To investigate changes in functional connectivity between the vermis and cerebral regions in the resting state among subjects with bipolar disorder (BD).Methods: Thirty participants with BD and 28 healthy controls (HC) underwent the resting state functional magnetic resonance imaging (fMRI). Resting-state functional connectivity (rsFC) of the anterior and posterior vermis was examined. For each participant, rsFC maps of the anterior and posterior vermis were computed and compared across the two groups.Results: rsFC between the whole vermis and ventral prefrontal cortex (VPFC) was significantly lower in the BD groups compared to the HC group, and rsFC between the anterior vermis and the middle cingulate cortex was likewise significantly decreased in the BD group.Limitations: 83.3% of the BD participants were taking medication at the time of the study. Our findings may in part be attributed to treatment differences because we did not examine the effects of medication on rsFC. Further, the mixed BD subtypes in our current study may have confounding effects influencing the results.Conclusions: These rsFC differences of vermis-VPFC between groups may contribute to the BD mood regulation.

Involvement of the nuclear factor-\u03baB transcriptional complex in prefrontal cortex immune activation in bipolar disorder

Bipolar disorder and schizophrenia have multiple clinical and genetic features in common, including shared risk associated with overlapping susceptibility loci in immune-related genes. Higher activity of the nuclear factor-κB (NF-κB) transcription factor complex, which regulates the transcription of multiple immune markers, has been reported to contribute to immune activation in the prefrontal cortex in schizophrenia. These findings suggest the hypothesis that elevated NF-κB activity is present in the prefrontal cortex in bipolar disorder in a manner similar to that seen in schizophrenia. Therefore, we quantified levels of NF-κB-related mRNAs in the prefrontal cortex of 35 matched pairs of bipolar disorder and unaffected comparison subjects using quantitative PCR. We found that transcript levels were higher in the prefrontal cortex of bipolar disorder subjects for several NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs, and were lower for an NF-κB inhibitor. Transcript levels for NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs levels were also highly correlated with each other. This pattern of elevated transcript levels for NF-κB-related markers in bipolar disorder is similar to that previously reported in schizophrenia, suggesting that cortical immune activation is a shared pathophysiological feature between the two disorders.

Sex difference in glia gene expression in the dorsolateral prefrontal cortex in bipolar disorder: Relation to psychotic features

BackgroundSuicide, psychotic features and gender influence the epidemiology and clinical prognosis of bipolar disorder (BD). Differences in glial function between the genders might contribute to these clinical variables. Here we studied expression of glial genes in human post-mortem prefrontal cortex of BD and control subjects in relation to suicide, psychotic features and sex. MethodsReal time PCR was used to detect transcriptional alterations of 16 glia-related genes in two brain areas, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC), from 30 patients with BD subdivided by suicide and psychotic features, and from 34 well-matched control cases. ResultsWe found no evidence of immune activation in BD. Instead, we found three microglial genes to be downregulated in the DLPFC of non-suicidal individuals with BD, i.e. CD68, triggering receptor expressed on myeloid cells 2 (TREM2) and purinergic receptor 12 (P2RY12). A remarkable sex difference was observed in the DLPFC of patients with BD: 14 glia-related genes were expressed at significantly higher levels in males, including all three glial cell types. A subset analysis showed that the sex differences were closely associated with the presence of psychotic features. ConclusionsNo evidence of immune activation was found in these two brain regions in BD. The sex-specific differences in glial gene expression in BD, found particularly in patients with psychotic features, may be associated with the potential co-existence of mania and psychotic features and could potentially contribute to the gender-biased characteristics in BD.

Cortical thickness and subcortical volumes alterations in euthymic bipolar I patients treated with different mood stabilizers.

Reported structural abnormalities of patients with bipolar disorder (BD) are inconsistent and the use of psychotropic medication is one of the sources of heterogeneity. A fairly small number of morphometric studies have involved comparison of BD on different mood stabilizers. Here in this study, we aimed to investigate the cortical thickness and subcortical volumes in euthymic BD patients on lithium and valproate and healthy controls (HC), and to elucidate the relationship between the use of medication and brain structure variations. We acquired structural magnetic resonance imaging data from 35 BD patients (19/valproate;16/lithium) and 30 HC subjects. Cortical thickness was compared in multiple locations across the continuous cortical surface, and subcortical volumes were compared on a structure-by-structure basis. Group analyses revealed widespread thinning of the prefrontal cortex in BD. Compared with BD on valproate, BD on lithium showed significant increased cortical thickness of the left rostral middle frontal cortex and right superior frontal cortex, while cortical thickness was not significantly different between BD on lithium and HC in the bilateral rostral middle frontal cortex. Moreover, no significant difference was observed in subcortical volume. Limitations of this study comprise the possible effect of other psychotropic drugs, small sample size and the cross-sectional design. Therefore, the results suggest medication-related neurobiological difference between BD patients on different mood stabilizers, but no casual role can be proposed. Our findings provided new evidence about the effects of psychotropic medication upon neuroanatomy in BD, and could help to explain the inconsistency of existing studies as well as contribute to the extraction of reliable neuroimaging biomarkers in BD.

Dissociable patterns of abnormal frontal cortical activation during anticipation of an uncertain reward or loss in bipolar versus major depression

Recent research has found abnormalities in reward-related neural activation in bipolar disorder (BD), during both manic and euthymic phases. However, reward-related neural activation in currently depressed individuals with BD and that in currently depressed individuals with major depressive disorder (MDD) have yet to be directly compared. Here, we studied these groups, examining the neural activation elicited during a guessing task in fronto-striatal regions identified by previous studies. We evaluated neural activation during a reward task using fMRI in two groups of depressed individuals, one with bipolar I disorder (BD-I) (n = 23) and one with MDD (n = 40), with similar levels of illness severity, and a group of healthy individuals (n = 37). Reward expectancy-related activation in the anterior cingulate cortex was observed in the healthy individuals, but was significantly reduced in depressed patients (BD-I and MDD together). Anticipation-related activation was increased in the left ventrolateral prefrontal cortex in the BD-I depressed group compared with the other two groups. There were no significant differences in prediction error-related activation in the ventral striatum across the three groups. The findings extend previous research which has identified dysfunction within the ventrolateral prefrontal cortex in BD, and show that abnormally elevated activity in this region during anticipation of either reward or loss may distinguish depressed individuals with BD-I from those with MDD. Altered activation of the anterior cingulate cortex during reward expectancy characterizes both types of depression. These findings have important implications for identifying both common and distinct properties of the neural circuitry underlying BD-I and MDD.

Increased density of AKAP5-expressing neurons in the anterior cingulate cortex of subjects with bipolar disorder

Brain anatomical abnormalities as well as cognitive and emotional processing deficits have been reported for the prefrontal cortex in bipolar disorder, which are in part attributable to cellular and laminar abnormalities in postsynaptic protein expression. A kinase anchoring protein (AKAP) 5/79 plays a key role in postsynaptic signalling of excitatory synapses. We aimed to reveal if the cellular expression of AKAP5/79 protein is altered in the anterior cingulate cortex and the dorsolateral prefrontal cortex in bipolar disorder. Ten subjects with bipolar disorder and ten control cases were investigated by use of immunohistochemical and morphometric techniques. Compared with controls in subjects with bipolar disorder, the numerical density of AKAP5-expressing neurons was significantly increased in the left (p = 0.002) and right (p = 0.008) anterior cingulate cortex. Layer-specific counting revealed that left side layers II (p = 0.000), III (p = 0.001) and V (p = 0.005) as well as right side layers III (p = 0.007), IV (p = 0.007) and V (p = 0.004) had significantly increased AKAP5-positive cell densities in bipolar disorder. In contrast, no statistically significant differences were found for the dorsolateral prefrontal cortex. However, we observed a more intense intraneuronal immunostaining in both prefrontal areas in bipolar disorder patients. Elevated cell numbers and increased intracellular expression of AKAP, together with the altered expression patterns of most intracellular interaction partners of this protein in bipolar disorder as known from the literature, might point to disease-related abnormalities of the AKAP-associated signalosome in prefrontal cortex neurons.

N-methyl-D-aspartate receptor expression in parvalbumin-containing inhibitory neurons in the prefrontal cortex in bipolar disorder.

Inhibitory neural circuits and the glutamatergic regulation of these circuits in the cerebral cortex appear to be disturbed in bipolar disorder. In this study, we addressed the hypothesis that, in the prefrontal cortex (PFC), disturbances of glutamatergic regulation of the class of inhibitory neurons that contain the calcium buffer parvalbumin (PV) via N-methyl-D-aspartate (NMDA) receptor may contribute to the pathophysiology of bipolar disorder. We used double in situ hybridization with a sulfur-35-labeled riboprobe for the NR2A subunit of the NMDA receptor and a digoxigenin-labeled riboprobe for PV in a cohort of 18 subjects with bipolar disorder and 18 demographically matched normal control subjects. We observed no differences in the relative density and laminar distribution of the PV-expressing neurons between subjects with bipolar disorder and matched normal control subjects. Furthermore, the density of the PV neurons that co-expressed NR2A messenger RNA (mRNA) or the cellular expression of NR2A mRNA in the PV neurons that exhibited a detectable level of this transcript was unaltered in subjects with bipolar disorder. These findings suggest that, in the PFC, glutamatergic regulation of PV-containing inhibitory neurons via NR2A-containing NMDA receptors does not appear to be altered in bipolar disorder. However, the possibility that other subsets of gamma-aminobutyric acid (GABA) neurons or other glutamate receptor subtypes are affected cannot be excluded.

Altered prefrontal lobe oxygenation in bipolar disorder: a study by near-infrared spectroscopy

Previous studies have reported prefrontal cortex (PFC) pathophysiology in bipolar disorder. We examined the hemodynamics of the PFC during resting and cognitive tasks in 29 patients with bipolar disorder and 27 healthy controls, matched for age, verbal abilities and education. The cognitive test battery consisted of letter and category fluency (LF and CF), Sets A and B of the Raven's Colored Progressive Matrices (RCPM-A and RCPM-B) and the letter cancellation test (LCT). The tissue oxygenation index (TOI), the ratio of oxygenated hemoglobin (HbO2) concentration to total hemoglobin concentration, was measured in the bilateral PFC by spatially resolved near-infrared spectroscopy. Changes in HbO2 concentration were also measured. The bipolar group showed slight but significant impairment in performance for the non-verbal tasks (RCPM-A, RCPM-B and LCT), with no significant between-group differences for the two verbal tasks (LF and CF). A group x task x hemisphere analysis of variance (ANOVA) on the TOI revealed an abnormal pattern of prefrontal oxygenation across different types of cognitive processing in the bipolar group. Post hoc analyses following a group x task x hemisphere ANOVA on HbO2 concentration revealed that the bipolar group showed a greater increase in HbO2 concentration in the LCT and in RCPM-B, relative to controls. Both indices of cortical activation (TOI and HbO2 concentration) indicated a discrepancy in the PFC function between verbal versus non-verbal processing, indicating task-specific abnormalities in the hemodynamic control of the PFC in bipolar disorder.

Proneness to hypomania predicts EEG coherence between left motor cortex and left prefrontal cortex

Previous research has demonstrated that hypomania is associated with approach motivation and activity in the left prefrontal cortex (PFC). Other research has linked left motor cortex excitability to approach motivation, suggesting the existence of connections between the motor cortex and PFC. The present research extends this work using unilateral hand contractions to manipulate contralateral cortical activity, and examining the relationship between motor cortex and PFC inter-electrode EEG coherence and hypomania. Within the right-hand contraction condition, hypomania related to greater connectivity between the left motor cortex and left PFC, relative to connectivity between the left motor cortex and right PFC. No relationships were found within the left-hand condition. The present research provides additional support for the role of the left PFC in bipolar disorder, as well as an important extension of research linking motor cortex excitability to emotion and approach motivation.

Decrease in creatine kinase messenger RNA expression in the hippocampus and dorsolateral prefrontal cortex in bipolar disorder

Bipolar disorder (BPD) affects more than 2 million adults in the USA and ranks among the top 10 causes of worldwide disabilities. Despite its prevalence, very little is known about the etiology of BPD. Recent evidence suggests that cellular energy metabolism is disturbed in BPD. Mitochondrial function is altered, and levels of high-energy phosphates, such as phosphocreatine (PCr), are reduced in the brain. This evidence has led to the hypothesis that deficiencies in energy metabolism could account for some of the pathophysiology observed in BPD. To further explore this hypothesis, we examined levels of creatine kinase (CK) mRNA, the enzyme involved in synthesis and metabolism of PCr, in the hippocampus (HIP) and dorsolateral prefrontal cortex (DLPFC) of control, BPD and schizophrenia subjects. Tissue was obtained from the Harvard Brain Tissue Resource Center. Real-time quantitative polymerase chain reaction (HIP, DLPFC) and gene expression microarrays (HIP) were employed to compare the brain and mitochondrial 1 isoforms of CK. Both CK isoforms were downregulated in BPD. Furthermore, mRNA transcripts for oligodendrocyte-specific proteins were downregulated in the DLPFC, whereas the mRNA for the neuron-specific protein microtubule-associated protein 2 was downregulated in the HIP. Although some of the downregulation of CK might be explained by cell loss, a more general mechanism seems to be responsible. The downregulation of CK transcripts, if translated into protein levels, could explain the reduction of high-energy phosphates previously observed in BPD.

Age, Rapid-Cycling, and Pharmacotherapy Effects on Ventral Prefrontal Cortex in Bipolar Disorder: A Cross-Sectional Study

Neuroimaging data suggest that deficits in ventral prefrontal cortex (VPFC) function in bipolar disorder (BD) progress during adolescence and young adulthood. However, the developmental trajectory of VPFC morphological abnormalities in BD is unknown. This study investigated potential age-dependent volume abnormalities in VPFC in BD. Thirty-seven individuals diagnosed with BD I (14 adolescents, 10 young adults and 13 older adults) and 56 healthy comparison subjects (HC) participated in imaging. Gray and white matter volumes of VPFC were measured using high-resolution structural magnetic resonance imaging (MRI). We used a mixed model, repeated measures analysis to examine VPFC volumes across age groups while co-varying for total brain volume. Potential effects of illness features including rapid-cycling and medication were explored. VPFC volumes declined with age (p < .001). The diagnosis-by-age group interaction was significant (p = .01). Relative to HC subjects, VPFC gray and white matter volumes were significantly smaller in BD patients only in young adulthood (p = .04). In participants with BD, VPFC volumes were significantly smaller in participants with rapid-cycling than participants without rapid-cycling (p = .02). Conversely, current use of medication was associated with larger VPFC gray matter volumes (p = .005), independent of age. These preliminary findings suggest the presence of a more rapid initial decline in VPFC volumes with age in adolescents and young adults with BD than HC. These findings also suggest that the rapid-cycling subtype of BD is associated with larger VPFC volume deficits than the non-rapid-cycling subtype, and that pharmacotherapy may have trophic or protective effects on VPFC volumes in BD patients.

An MRI study of subgenual prefrontal cortex in patients with familial and non-familial bipolar I disorder

Background: Over the past few years there has been an interest in the use of magnetic resonance imaging (MRI) to study specific brain regions in bipolar disorder. The present study compared the grey matter volume in the subgenual prefrontal cortex in patients with familial and non-familial bipolar disorder and normal control subjects. Methods: MRI brain scans were performed on 12 patients with bipolar I disorder including six patients with a positive family history of bipolar disorder as well as eight control subjects. Results: There was a significant reduction in the grey matter volume in the right subgenual prefrontal cortex, but not in the left subgenual prefrontal cortex. A family history×sex interaction with right prefrontal cortex volume was also observed as a trend. For females, a positive family history was associated with reduced right prefrontal cortex volumes; for males, a positive family history was associated with increased right prefrontal cortex volumes. Limitations: Small sample size, reduced statistical power. Conclusion: These data add to the emerging literature on structural changes in the subgenual prefrontal cortex in bipolar disorder, especially in patients with a positive family history.

Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder

Background: Bipolar disorder (BPD) is a mental illness in which depression and mania typically alternate, and both phases can present with psychotic features. The symptomatology of BPD, therefore, resembles major depressive disorder (MDD) and schizophrenia (SCHZ), posing diagnostic dilemmas. Distinct alterations in cellular architecture of the dorsolateral prefrontal cortex distinguish SCHZ and MDD, whereas the cellular neuropathology of BPD has not been studied. Methods: Dorsolateral prefrontal area 9 was analyzed using a three-dimensional morphometric method in postmortem brains from 10 BPD patients and 11 matched nonpsychiatric control subjects. Results: Area 9 in BPD was characterized by reduced neuronal density in layer III (16%–22%) and reduced pyramidal cell density in layers III and V (17%–30%). A 19% reduction in glial density was found in sublayer IIIc coupled with enlargement and changes in shape of glial nuclei spanning multiple layers. Conclusions: The morphologic signature of BPD, i.e., decreased neuronal and glial density in association with glial hypertrophy, is distinct from previously described elevations in neuronal density in SCHZ, instead resembling the reductions in cell density found in MDD. Thus, the neuropathologic distinctions between BPD and SCHZ are indicative of separate mental illnesses, each with a unique morphologic disturbance of specific neural circuits.

406. Prefrontal cell pathology distinguishes bipolar disorder from schizophrenia

Bipolar disorder (BPD) is a mental illness in which depression and psychosis are present in an alternating course, and therefore the symptomatology of the disease resembles both major depressive disorder (MDD) and schizophrenia (SCHZ). Neuroimaging evidence has implicated the prefrontal cortex as a site of common morphological and metabolic abnormalities in all three disorders. Recent morphometric studies have demonstrated changes in prefrontal cell architecture in SCHZ (Selemon et al., 1995; 1998; Rajkowska et al., 1998) and MDD (Rajkowska et al., 1999). In contrast, cellular neuropathology in BPD has not been described. In this postmortem study, we analyzed area 9 of the dorsolateral prefrontal cortex in 10 subjects with BPD and 11 matched nonpsychiatric controls using a 3-D morphometric method. In comparison to nonpsychiatric controls, the prefrontal cortex in BPD was characterized by significant, lamina-specific reductions in the density of neurons with predominantly pyramidal shape, reductions in the density of glial cells, enlargement of glial nuclei and changes in their shape. These findings imply that the morphologic signature of BPD, i.e. glial hypertrophy in association with decreased neuronal and glial density, is distinct from our previously described elevations in neuronal density in SCHZ and more closely resembles the reductions in cell density found in MDD. Both SCHZ and BPD cortices, however, exhibit atrophy of neuronal cytoplasm in cortical layer III. Thus, the prefrontal cortex in BPD manifests a unique pattern of neuropathology that may reflect underlying neurochemical imbalances specific to this mental illness and distinct from SCHZ.

Left-lateralized reduction of volume and glucose metabolism in the subgenual prefrontal cortex in bipolar disorder

Left-lateralized reduction of volume and glucose metabolism in the subgenual prefrontal cortex in bipolar disorder