Cerebellar morphological differences and associations with extrinsic factors in bipolar disorder type I.

BACKGROUND: The neural underpinnings of bipolar disorder (BD) remain poorly understood. The cerebellum is ideally positioned to modulate emotional regulation circuitry yet has been understudied in BD. Literature suggests differences in cerebellar activity and metabolism in BD, however findings on structural differences remain contradictory. Potential reasons include combining BD subtypes, small sample sizes, and potential moderators such as genetics, adverse childhood experiences (ACEs), and pharmacotherapy. METHODS: We collected 3 T MRI scans from participants with (N = 131) and without (N = 81) BD type I, as well as blood and questionnaires. We assessed differences in cerebellar volumes and explored potentially influential factors. RESULTS: The cerebellar cortex was smaller bilaterally in participants with BD. Polygenic propensity score did not predict any cerebellar volumes, suggesting that non-genetic factors may have greater influence on the cerebellar volume difference we observed in BD. Proportionate cerebellar white matter volumes appeared larger with more ACEs, but this may result from reduced ICV. Time from onset and symptom burden were not associated with cerebellar volumes. Finally, taking sedatives was associated with larger cerebellar white matter and non-significantly larger cortical volume. LIMITATIONS: This study was cross-sectional, limiting interpretation of possible mechanisms. Most of our participants were White, which could limit the generalizability. Additionally, we did not account for potential polypharmacy interactions. CONCLUSIONS: These findings suggest that external factors, such as sedatives and childhood experiences, may influence cerebellum structure in BD and may mask underlying differences. Accounting for such variables may be critical for consistent findings in future studies.

Functional connectivity of the cerebellar vermis in bipolar disorder and associations with mood.

Purpose: Studies of the neural underpinnings of bipolar type I disorder have focused on the emotional control network. However, there is also growing evidence for cerebellar involvement, including abnormal structure, function, and metabolism. Here, we sought to assess functional connectivity of the cerebellar vermis with the cerebrum in bipolar disorder and to assess whether connectivity might depend on mood. Methods: This cross-sectional study enrolled 128 participants with bipolar type I disorder and 83 control comparison participants who completed a 3 T magnetic resonance imaging (MRI) study, which included anatomical as well as resting state Blood Oxygenation Level Dependent (BOLD) imaging. Functional connectivity of the cerebellar vermis to all other brain regions was assessed. Based on quality control metrics of the fMRI data, 109 participants with bipolar disorder and 79 controls were included in the statistical analysis comparing connectivity of the vermis. In addition, the data was explored for the potential impacts of mood, symptom burden, and medication in those with bipolar disorder. Results: Functional connectivity between the cerebellar vermis and the cerebrum was found to be aberrant in bipolar disorder. The connectivity of the vermis was found to be greater in bipolar disorder to regions involved in motor control and emotion (trending), while reduced connectivity was observed to a region associated with language production. In the participants with bipolar disorder, past depression symptom burden affected connectivity; however, no effects of medication were observed. Functional connectivity between the cerebellar vermis and all other regions revealed an inverse association with current mood ratings. Conclusion: Together the findings may suggest that the cerebellum plays a compensatory role in bipolar disorder. The proximity of the cerebellar vermis to the skull may make this region a potential target for treatment with transcranial magnetic stimulation.

Functional Connectivity of the Cerebellar Vermis in Bipolar Disorder and Associations with Mood.

Purpose: Studies of the neural underpinnings of bipolar type I disorder have focused on the emotional control network. However, there is also growing evidence for cerebellar involvement, including abnormal structure, function, and metabolism. Here, we sought to assess functional connectivity of the cerebellum with the cerebrum in bipolar disorder and to assess whether any effects might depend on mood. Methods: This cross-sectional study enrolled 128 participants with bipolar type I disorder and 83 control comparison participants who completed a 3T MRI scan, which included anatomical imaging as well as resting state BOLD imaging. Functional connectivity of the cerebellar vermis to all other brain regions was assessed. Based on quality control metrics of the fMRI data, 109 participants with bipolar disorder and 79 controls were used to in the statistical analysis comparing connectivity of the vermis as well as associations with mood. Potential impacts of medications were also explored. Results: Functional connectivity of the cerebellar vermis in bipolar disorder was found to differ significantly between brain regions known to be involved in the control of emotion, motor function, and language. While connections with emotion and motor control areas were significantly stronger in bipolar disorder, connection to a region associated language production was significantly weaker. In the participants with bipolar disorder, ratings of depression and mania were inversely associated with vermis functional connectivity. No effect of medications on these connections were observed. Conclusion: Together the findings suggest cerebellum may play a compensatory role in bipolar disorder and when it can no longer fulfill this role, depression and mania develop. The proximity of the cerebellar vermis to the skull may make this region a potential target for treatment with transcranial magnetic stimulation.

Distinct patterns of altered quantitative T1ρ and functional BOLD response associated with history of suicide attempts in bipolar disorder.

Despite the high risk for suicide, relatively few studies have explored the relationship between suicide and brain imaging measures in bipolar disorder. In addition, fewer studies have explored the possibility that altered brain metabolism may be associated with suicide attempt. To begin to fill in these gaps, we evaluated functional (task based fMRI) and metabolic (quantitative T1ρ) differences associated with suicide attempt in participants with bipolar disorder. Thirty-nine participants with bipolar disorder underwent fMRI during a flashing checkerboard task and 27 also underwent quantitative T1ρ. The relationship between neuroimaging and history of suicide attempt was tested using multiple regression while adjusting for age, sex, and current mood state. Differences between two measures of suicide attempt (binary: yes/no and continuous: number of attempts) were quantified using the corrected Akaike Information Criterion. Participants who had attempted suicide had greater fMRI task-related activation in visual areas and the cerebellum. The number of suicide attempts was associated with a difference in BOLD response in the amygdala, prefrontal cortex, and cerebellum. Increased quantitative T1ρ was associated with number of suicide attempts in limbic, basal ganglia, and prefrontal cortex regions. This study is a secondary analysis with a modest sample size. Differences between measures of suicide history may be due to differences in statistical power. History of suicide was associated with limbic, prefrontal, and cerebellar alterations. Results comparing those with and without suicide attempts differed from results using number of suicide attempts, suggesting that these variables have different neurobiological underpinnings.

Proton Exchange Magnetic Resonance Imaging: Current and Future Applications in Psychiatric Research.

Proton exchange provides a powerful contrast mechanism for magnetic resonance imaging (MRI). MRI techniques sensitive to proton exchange provide new opportunities to map, with high spatial and temporal resolution, compounds important for brain metabolism and function. Two such techniques, chemical exchange saturation transfer (CEST) and T1 relaxation in the rotating frame (T1ρ), are emerging as promising tools in the study of neurological and psychiatric illnesses to study brain metabolism. This review describes proton exchange for non-experts, highlights the current status of proton-exchange MRI, and presents advantages and drawbacks of these techniques compared to more traditional methods of imaging brain metabolism, including positron emission tomography (PET) and MR spectroscopy (MRS). Finally, this review highlights new frontiers for the use of CEST and T1ρ in brain research.

Inflammatory and vascular correlates of mood change over 8 weeks.

BACKGROUND: Mood disorders have been associated with a variety of cardiovascular disease risk factors, including inflammation and large artery stiffness, particularly while depressed although longitudinal studies have been limited. METHODS: With measurements at baseline and 8 weeks, the researchers prospectively assessed mood, levels of inflammatory markers (hsCRP and TNF-α), serum lipids, and large artery stiffness in a cohort of 26 participants with a diagnosis of a mood disorder, enriched for current depression. Depressive symptoms were measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline and 8 weeks. Associations between depressive symptoms and other measures were assessed using linear mixed models, unadjusted and adjusted for age and BMI. RESULTS: The mean age of the participants (n=26) was 41.6 (standard deviation [SD] 12.8) years, and 81% were female. During the study, there was a mean (SD) MADRS score improvement of 9.5 (9.4) from baseline to eight weeks. Reductions in the primary outcome TNF-α with improvement in depression fell short of significance (P=0.076). In secondary analyses, there was a statistically significant association between improved cholesterol ratio (P=0.038) and triglycerides (P=0.042) with depression improvement. There was no statistically significant change in large artery stiffness during the study. CONCLUSION: Improved depressive symptoms were associated with improved cholesterol ratios even after adjustment, suggesting possible mechanism by which acute mood states may influence cardiovascular disease risk. Future longitudinal studies with extended and intensive follow-up investigating cardiovascular disease risk related to acute changes and persistence of mood symptoms is warranted.

Impact of Mood on Endothelial Function and Arterial Stiffness in Bipolar Disorder.

BACKGROUND: Previous research in bipolar disorder demonstrates greater than expected vascular dysfunction later in the course of illness, proportionate to the cumulative burden of mood symptoms. However, little is known about the effect of acute mood states on vascular function. Here we examine the relation between vascular function and mood state in individuals with bipolar disorder. METHOD: This prospective study followed 40 individuals with bipolar disorder for up to 6 months. Participants were assessed for mood state and vascular function at baseline, 2 weeks, and 6 months. Mood state was determined using clinician-administered Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale. Vascular function was assessed by flow-mediated dilation (FMD) of the brachial artery, forearm vascular resistance (FVR), and arterial stiffness. RESULTS: Participants had a mean age of 30.1 years and 75% were male. Primary outcome measures FMD and nitroglycerine-mediated dilation were not found to have statistically significant associations with depressive or manic symptoms. In unadjusted models, higher manic symptoms were significantly associated with increased FVR nitroprusside-mediated dilation and diastolic blood pressure. In adjusted models, higher depressive symptoms were significantly associated with increases in augmentation index adjusted for heart rate of 75 bpm, and higher manic symptoms remained associated with increases in diastolic blood pressure. CONCLUSION: FMD may have limited sensitivity as a biomarker for measuring short-term effects of mood state. Longer-term prospective studies are needed to clarify the temporal relation between chronic mood symptoms and vascular function in bipolar disorder.