Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen’s d =−0.293; P = 1.71 × 10−21), left fusiform gyrus (d =−0.288; P = 8.25 × 10−21) and left rostral middle frontal cortex (d =−0.276; P =2.99 × 10−19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case–control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=−0.232; P=3.50 × 10−7) and thalamus (d=−0.148; P=4.27 × 10−3) and enlarged lateral ventricles (d=−0.260; P=3.93 × 10−5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Objective An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta‐analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. Method Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. Results Impairments were found for all 11 test‐measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26–0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test‐measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. Conclusion This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta‐analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

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BackgroundPsychological traumatic events, such as war or road traffic accidents, are widespread. A small but significant proportion of survivors develop post-traumatic stress disorder (PTSD). Distressing, sensory-based involuntary memories of trauma (henceforth ‘flashbacks’) are the hallmark symptom of PTSD. Understanding the development of flashbacks may aid their prevention. This work is the first to combine the trauma film paradigm (as an experimental analogue for flashback development) with neuroimaging to investigate the neural basis of flashback aetiology. We investigated the hypothesis that involuntary recall of trauma (flashback) is determined during the original event encoding.MethodA total of 22 healthy volunteers viewed a traumatic film whilst undergoing functional magnetic resonance imaging (fMRI). They kept a 1-week diary to record flashbacks to specific film scenes. Using a novel prospective fMRI design, we compared brain activation for those film scenes that subsequently induced flashbacks with both non-traumatic control scenes and scenes with traumatic content that did not elicit flashbacks (‘potentials’).ResultsEncoding of scenes that later caused flashbacks was associated with widespread increases in activation, including in the amygdala, striatum, rostral anterior cingulate cortex, thalamus and ventral occipital cortex. The left inferior frontal gyrus and bilateral middle temporal gyrus also exhibited increased activation but only relative to ‘potentials’. Thus, these latter regions appeared to distinguish between traumatic content that subsequently flashed back and comparable content that did not.ConclusionsResults provide the first prospective evidence that the brain behaves differently whilst experiencing emotional events that will subsequently become involuntary memories – flashbacks. Understanding the neural basis of analogue flashback memory formation may aid the development of treatment interventions for this PTSD feature.

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ObjectivesCognitive impairment is known to occur in bipolar disorder (BD), even in euthymic patients, with largest effect sizes often seen in Verbal Learning and Memory Tasks (VLT). However, comparisons between BD Type-I and Type-II have produced inconsistent results partly due to low sample sizes.MethodsThis study compared the performance of 183 BDI with 96 BDII out-patients on an adapted version of the Rey Verbal Learning Task. Gender, age, years of education, mood scores and age at onset were all used as covariates. Current medication and a variety of illness variables were also investigated for potential effects on VLT performance.ResultsBDI patients were significantly impaired relative to BDII patients on all five VLT outcome measures after controlling for the other variables [Effect Sizes=.13–.17]. The impairments seem to be unrelated to drug treatment and largely unrelated to illness variables, although age of onset affected performance on three outcome measures and number of episodes of mood elevation affected performance on one.LimitationsThis study used historical healthy controls. Analysis of potential drug effects was limited by insufficient participants not being drug free. Cross-sectional nature of the study limited the analysis of the potential effect of illness variables.ConclusionsThis study replicates earlier findings of increased verbal learning impairment in BDI patients relative to BDII in a substantially larger sample. Such performance cannot be wholly explained by medication effects or illness variables. Thus, the cognitive impairment is likely to reflect a phenotypic difference between bipolar sub-types.

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