Disturbed cortico-amygdalar functional connectivity as pathophysiological correlate of working memory deficits in bipolar affective disorder.

Patients suffering from bipolar affective disorder show deficits in working memory functions. In a previous functional magnetic resonance imaging study, we observed an abnormal hyperactivity of the amygdala in bipolar patients during articulatory rehearsal in verbal working memory. In the present study, we investigated the dynamic neurofunctional interactions between the right amygdala and the brain systems that underlie verbal working memory in both bipolar patients and healthy controls. In total, 18 euthymic bipolar patients and 18 healthy controls performed a modified version of the Sternberg item-recognition (working memory) task. We used the psychophysiological interaction approach in order to assess functional connectivity between the right amygdala and the brain regions involved in verbal working memory. In healthy subjects, we found significant negative functional interactions between the right amygdala and multiple cortical brain areas involved in verbal working memory. In comparison with the healthy control subjects, bipolar patients exhibited significantly reduced functional interactions of the right amygdala particularly with the right-hemispheric, i.e., ipsilateral, cortical regions supporting verbal working memory. Together with our previous finding of amygdala hyperactivity in bipolar patients during verbal rehearsal, the present results suggest that a disturbed right-hemispheric "cognitive-emotional" interaction between the amygdala and cortical brain regions underlying working memory may be responsible for amygdala hyperactivation and affects verbal working memory (deficits) in bipolar patients.

Disturbed anterior prefrontal control of the mesolimbic reward system and increased impulsivity in bipolar disorder.

Bipolar disorder (BD) is characterized by recurrent mood episodes ranging from severe depression to acute full-blown mania. Both states of this severe psychiatric disorder have been associated with alterations of reward processing in the brain. Here, we present results of a functional magnetic resonance imaging (fMRI) study on the neural correlates and functional interactions underlying reward gain processing and reward dismissal in favor of a long-term goal in bipolar patients. Sixteen medicated patients diagnosed with bipolar I disorder, euthymic to mildly depressed, and sixteen matched healthy controls performed the 'desire-reason dilemma' (DRD) paradigm demanding rejection of priorly conditioned reward stimuli to successfully pursue a superordinate goal. Both groups exhibited significant activations in reward-related brain regions, particularly in the mesolimbic reward system. However, bipolar patients showed reduced neural responses of the ventral striatum (vStr) when exploiting a reward stimulus, and exhibited a decreased suppression of the reward-related activation of the mesolimbic reward system while having to reject immediate reward in favor of the long-term goal. Further, functional interaction between the anteroventral prefrontal cortex and the vStr in the 'DRD' was significantly impaired in the bipolar group. These findings provide evidence for a reduced responsivity of the vStr to reward stimuli in BD, possibly related to clinical features like anhedonia. The disturbed top-down control of mesolimbic reward signals by prefrontal brain regions in BD can be interpreted in terms of a disease-related enhanced impulsivity, a trait marker of BD.

Correlation between amygdala volume and age in bipolar disorder - a systematic review and meta-analysis of structural MRI studies.

The amygdala has gained special interest regarding the neuropathology of bipolar disorder (BD). Structural magnetic resonance imaging (MRI) studies with patients suffering from BD have yielded quite inconsistent results with respect to amygdala volume. We performed a meta-analysis of structural MRI studies that investigated right and left amygdala volume in pediatric and adult patients with BD. The aim was to assess the heterogeneous findings and to investigate whether a correlation between amygdala volume and the patient's age exists. Studies were searched for in "Pub Med" (last search June 2007), and data for right and left amygdala volume in cm(3) were extracted and combined in a meta-analysis. Thirteen studies with 389 scans of patients and 488 scans of healthy control subjects (HC) were included. The impact of age on the difference in amygdala volume between patients and HC was assessed by meta-regression. The amygdala volume was bilaterally reduced in the overall sample of patients with BD and the pediatric subsample. The results of the adult studies were less homogeneous, and on average, no significant difference between adult patients and HC was found. A meta-regression analysis revealed a positive correlation between mean age and amygdala volume in patients with BD. We speculate that amygdala volume is reduced at the onset of the disease and increases with age.

Cortical neurochemistry in euthymic patients with bipolar I disorder.

OBJECTIVE: Prefrontal and anterior cingulate cortical regions are assumed to be involved in the pathophysiology of mood regulation. Reduced prefrontal and anterior cingulate function indicated by decreased N-acetyl-aspartate (NAA) levels in patients with bipolar disorder has been reported inconsistently. A positive correlation between lithium serum level and NAA concentrations has been found previously. The aim of this study was to re-investigate prefrontal and anterior cingulate neurochemistry in a sample of euthymic patients with bipolar I disorder. METHODS: NAA, choline (Cho), creatine (Cr) and myo-inositol (Ins) in left dorsolateral prefrontal cortex and left anterior cingulate cortex were measured in 33 euthymic patients with bipolar I disorder and 29 healthy comparison subjects by using proton magnetic resonance spectroscopy ([(1)H]MRS). RESULTS: Metabolic ratios did not differ between patients with bipolar I disorder and comparison subjects in prefrontal and anterior cingulate cortex neither in the total sample nor in the pairwise matched sub-sample. We could not observe an association between lithium level and NAA ratios. Lithium treated patients demonstrated unchanged NAA or myo-inositol ratios compared to alternatively treated patients. CONCLUSION: In contrast to prior findings, we could not observe any metabolic alterations in euthymic patients with bipolar disorder.

5-HTTLPR genotype influences amygdala volume.

BACKGROUND: Functional imaging studies in healthy individuals revealed an association between 5-HTTLPR genotype and neuronal activity in the amygdala. The aim of this study was firstly to investigate a possible overall impact of the 5-HTTLPR on amygdala volume in patients with bipolar disorder and healthy individuals and secondly to test a diagnosis specific influence of the 5-HTTLPR on amygdala volume. METHODS: We performed a region of interest analysis of amygdala volume in 37 patients with bipolar I disorder and 37 healthy control subjects. The 5-HTTLPR genotype of each proband was determined and the subjects were separated according to 5-HTTLPR genotype and for statistical analyses the groups SS and SL were combined and compared with the group LL. RESULTS: This study shows that carriers of the short allele (SL or SS) of the 5-HTTLPR polymorphism exhibit a relatively increased volume of the right amygdala compared to homozygous L-allele carriers irrespective of diagnosis status. However, further analyses with the factors genotype and diagnosis were not able to reproduce this result. CONCLUSIONS: The present findings are consistent with the view that the 5-HTTLPR polymorphism might modulate neuronal size or number in the amygdala. It would be worthwhile investigating the relationship between serotonin transporter function and amygdala function and volume in further studies.

Dopamine transporter genotype influences N-acetyl-aspartate in the left putamen.

INTRODUCTION: Dopaminergic activity in the brain is modulated by the dopamine transporter (DAT). Several lines of evidence suggest that a variable number of tandem repeats (VNTR) polymorphism of the DAT1 gene (SLC6A3) influences its gene expression. The aim of this study was to determine whether the DAT1VNTR polymorphism alters the metabolic ratios NAA/Cho, NAA/Cr, Cho/Cr and Ins/Cr in the left dorsolateral prefrontal cortex, anterior cingulate cortex, and putamen in healthy subjects and psychiatric patients irrespective of clinical diagnosis. MATERIAL AND METHODS: Sixty-four individuals (30 patients with bipolar disorder, 18 patients with obsessive-compulsive disorder, and 16 healthy subjects) participated in the study. The 3'-UTR VNTR polymorphism of DAT1 (SLC6A3) gene was genotyped in all individuals. (1)H-MRS was performed in the above-mentioned brain regions. RESULTS: The individuals with the homozygous DAT1 10-repeat genotype presented significantly higher ratios of NAA/Cho and NAA/Cr in the left putamen compared to the group of individuals with the 9/9-repeat or 9/10-repeat genotype. CONCLUSION: The VNTR polymorphism of the DAT1-gene modulates NAA/Cho and NAA/Cr in the left putamen independent of psychiatric diagnosis status. These results suggest an association of DAT1 VNTR polymorphism, dopaminergic activity, and neuronal function in putamen.

SNAP-25 genotype influences NAA/Cho in left hippocampus.

The SNAP-25 gene is an integral part of the vesicle docking and fusion machinery that controls neurotransmitter release. Several post mortem studies revealed a reduction of SNAP-25 protein in the hippocampus of patients with schizophrenia and bipolar disorder (BD). Thirty-eight patients with schizophrenia, BD or obsessive-compulsive disorder and 17 healthy controls participated in the study. Proton magnetic resonance spectroscopy in left hippocampus was performed in each individual. Three single nucleotide polymorphisms (SNP) of the SNAP-25 gene were genotyped. Individuals with the homozygous CC genotype of the DdeI SNP presented a significantly higher ratio of N-acetyl-aspartate (NAA)/choline-containing compounds (Cho) in the left hippocampus compared to the group of individuals with the homozygous TT genotype. The SNAP-25 genotype may modulate synaptic plasticity and neurogenesis in the left hippocampus, and altered NAA/Cho ratio may be an indicator for this genetic modulation of neuronal function in the hippocampus.

No change to grey and white matter volumes in bipolar I disorder patients.

BACKGROUND: Structural brain imaging is assumed to be a key method to elucidate the underlying neuropathology of bipolar disorder. However, magnetic resonance imaging studies using region of interest analysis and voxel-based morphometry (VBM) revealed quite inconsistent findings. Hence, there is no clear evidence so far for core regions of cortical or subcortical structural abnormalities in bipolar disorder. The aim of this study was to investigate grey and white matter volumes in a large sample of patients with bipolar I disorder. METHODS: Thirty-five patients with bipolar I disorder and 32 healthy controls matched with respect to gender, handedness and education participated in the study. MRI scanning was performed and an optimized VBM analysis was conducted. RESULTS: We could not observe any significant differences of grey or white matter volumes between patients with bipolar disorder and healthy control subjects. Additional analyses did not reveal significant correlations between grey or white matter volume with number of manic or depressive episodes, duration of illness, existence of psychotic symptoms, and treatment with lithium or antipsychotics. CONCLUSIONS: With this VBM study we were not able to identify core regions of structural abnormalities in bipolar disorder.