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Patients with bipolar disorder (BD) show alterations in both gray matter volume (GMV) and white matter (WM) integrity compared with healthy controls (HC). However, it remains unclear whether the phenotypically distinct BD subtypes (BD-I and BD-II) also exhibit brain structural differences. This study investigated GMV and WM differences between HC, BD-I, and BD-II, along with clinical and genetic associations. N = 73 BD-I, n = 63 BD-II patients and n = 136 matched HC were included. Using voxel-based morphometry and tract-based spatial statistics, main effects of group in GMV and fractional anisotropy (FA) were analyzed. Associations between clinical and genetic features and GMV or FA were calculated using regression models. For FA but not GMV, we found significant differences between groups. BD-I patients showed lower FA compared with BD-II patients (p tfce-FWE  = 0.006), primarily in the anterior corpus callosum. Compared with HC, BD-I patients exhibited lower FA in widespread clusters (p tfce-FWE  < 0.001), including almost all major projection, association, and commissural fiber tracts. BD-II patients also demonstrated lower FA compared with HC, although less pronounced (p tfce-FWE  = 0.049). The results remained unchanged after controlling for clinical and genetic features, for which no independent associations with FA or GMV emerged. Our findings suggest that, at a neurobiological level, BD subtypes may reflect distinct degrees of disease expression, with increasing WM microstructure disruption from BD-II to BD-I. This differential magnitude of microstructural alterations was not clearly linked to clinical and genetic variables. These findings should be considered when discussing the classification of BD subtypes within the spectrum of affective disorders., (© 2024. The Author(s).)

Background: Functional magnetic resonance imaging studies on emotion processing in patients with bipolar disorder (BD) show hyperactivity of limbic-striatal brain areas and hypoactivity in inferior frontal areas compared to healthy participants. However, heterogeneous results in patients with different disease states and different valences of emotional stimuli have been identified., Methods: To integrate previous results and elucidate the impact of disease state and stimulus valence, we conducted a systematic literature search for journal articles in the Web of Science Core Collection including MEDLINE databases and employed a coordinate-based-meta-analysis of functional-MRI studies comparing emotion processing in BD-patients with healthy participants using seed-based d mapping (SDM) to test for between-subjects-effects. We included 31 studies published before 11/2022 with a total of N = 766 BD-patients and N = 836 controls., Results: Patients with BD showed hyperactivated regions involved in salience processing of emotional stimuli (e.g., the bilateral insula) and hypoactivation of regions associated with emotion regulation (e.g., inferior frontal gyrus) during emotion processing, compared to healthy participants. A more detailed descriptive analysis revealed a hypoactive (anterior) insula in manic BD-patients specifically for negative in comparison to positive emotion processing., Discussion: This meta-analysis corroborates the overall tenor of existing literature that patients with BD show an increased emotional reactivity (hyperactivity of salience-processing regions) together with a lower (cognitive) control (hypoactivity of brain areas associated with emotion regulation) over emotional states. Our analysis suggests reduced interoceptive processing of negative stimuli in mania, pointing out the need for longitudinal within-subject analyses of emotion processing., (© 2023 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Objectives: To elucidate the relationship between the course of bipolar disorder (BD) and structural brain changes across the life span, we conducted a systematic review of longitudinal imaging studies in adolescent and adult BD patients., Methods: Eleven studies with 329 BD patients and 277 controls met our PICOS criteria (participants, intervention, comparison, outcome and study design): BD diagnosis based on DSM criteria, natural course of disease, comparison of grey matter changes in BD individuals over ≥1-year interval between scans., Results: The selected studies yielded heterogeneous findings, partly due to varying patient characteristics, data acquisition and statistical models. Mood episodes were associated with greater grey matter loss in frontal brain regions over time. Brain volume decreased or remained stable in adolescent patients, whereas it increased in healthy adolescents. Adult BD patients showed increased cortical thinning and brain structural decline. In particular, disease onset in adolescence was associated with amygdala volume reduction, which was not reported in adult BD., Conclusions: The evidence collected suggests that the progression of BD impairs adolescent brain development and accelerates structural brain decline across the lifespan. Age-specific changes in amygdala volume in adolescent BD suggest that reduced amygdala volume is a correlate of early onset BD. Clarifying the role of BD in brain development across the lifespan promises a deeper understanding of the progression of BD patients through different developmental episodes., (© 2023 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Repeated hospitalizations are a characteristic of severe disease courses in patients with affective disorders (PAD). To elucidate how a hospitalization during a nine-year follow-up in PAD affects brain structure, a longitudinal case-control study (mean [SD] follow-up period 8.98 [2.20] years) was conducted using structural neuroimaging. We investigated PAD (N = 38) and healthy controls (N = 37) at two sites (University of Münster, Germany, Trinity College Dublin, Ireland). PAD were divided into two groups based on the experience of in-patient psychiatric treatment during follow-up. Since the Dublin-patients were outpatients at baseline, the re-hospitalization analysis was limited to the Münster site (N = 52). Voxel-based morphometry was employed to examine hippocampus, insula, dorsolateral prefrontal cortex and whole-brain gray matter in two models: (1) group (patients/controls)×time (baseline/follow-up) interaction; (2) group (hospitalized patients/not-hospitalized patients/controls)×time interaction. Patients lost significantly more whole-brain gray matter volume of superior temporal gyrus and temporal pole compared to HC (p FWE  = 0.008). Patients hospitalized during follow-up lost significantly more insular volume than healthy controls (p FWE  = 0.025) and more volume in their hippocampus compared to not-hospitalized patients (p FWE  = 0.023), while patients without re-hospitalization did not differ from controls. These effects of hospitalization remained stable in a smaller sample excluding patients with bipolar disorder. PAD show gray matter volume decline in temporo-limbic regions over nine years. A hospitalization during follow-up comes with intensified gray matter volume decline in the insula and hippocampus. Since hospitalizations are a correlate of severity, this finding corroborates and extends the hypothesis that a severe course of disease has detrimental long-term effects on temporo-limbic brain structure in PAD., (© 2023. The Author(s).)

Background: Motivational dysregulation represents a core vulnerability factor for bipolar disorder. Whether this also comprises aberrant learning of stimulus-reinforcer contingencies is less clear., Methods: To answer this question, we compared healthy first-degree relatives of individuals with bipolar disorder (n = 42) known to convey an increased risk of developing a bipolar spectrum disorder and healthy individuals (n = 97). Further, we investigated the effects of the behavioral activation system (BAS) on reinforcement learning across the entire sample. All participants were assessed with a probabilistic learning task that distinguishes learning from positive and negative feedback. Main outcome measures included choice frequencies and learning rate parameters generated by computational reinforcement learning algorithms., Results: First-degree relatives choose more rewarding stimuli more consistently and showed marginally reduced learning rates from unexpected negative feedback. Further, first-degree relatives had lower BAS scores than controls, which were negatively associated with learning rates from unexpected negative feedback., Limitations: However as probands also reported other mental disorders such as Attention-Deficit/Hyperactivity Disorder and substance abuse among their first-degree relatives, we cannot know, whether these findings are specific to the risk for bipolar disorder., Conclusion: The behavior of first-degree relatives of individuals with bipolar disorder, who also display increased BAS sensitivity, is less influenced by unexpected negative feedback. This reduced learning from unexpected negative feedback biases subsequent choices towards stimuli with higher probabilities for a reward. In sum, our results confirm the role of aberrant reinforcement learning in the pathophysiology of bipolar disorder., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: The human brain is organized into large-scale networks that dynamically interact with each other. Extensive evidence has shown characteristic changes in certain large-scale networks during transitions from internally directed to externally directed attention. The aim of the present study was to compare these context-dependent network interactions during emotion regulation and to examine potential alterations in remitted unipolar and bipolar disorder patients., Methods: We employed a multi-region generalized psychophysiological interactions analysis to quantify connectivity changes during distraction vs reappraisal pair-wise across 90 regions placed throughout the four networks of interest (default-mode, frontoparietal, salience, and dorsal attention networks). Using network contingency analysis and permutation testing, we estimated the likelihood that the number of significant condition-dependent connectivity changes in every pair of networks exceeds the number expected by chance. We first examined the pattern of functional connectivity in 42 healthy subjects (sample I) and then compared these connectivity patterns across healthy individuals (n=23) and remitted bipolar (n=21) and unipolar disorder patients (n=21) in an independent sample II., Results: In sample I, distraction compared to reappraisal was characterized by reduced connectivity within the default-mode network and between the default-mode and two cognitive control networks and increased connectivity among the cognitive control networks. In sample II, both patient groups exhibited abnormally increased default-mode intra- and inter-network connectivity during distraction compared to reappraisal., Conclusions: The present study highlights the role of large-scale network interactions in emotion regulation and provides preliminary evidence of default-mode inter- and intra-network connectivity impairments in remitted bipolar and unipolar patients during emotion regulation., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Previous research suggests that bipolar disorder (BD) is characterized by deficits in cognitive control (CC). Impaired CC has been found in high-risk samples and is associated with the maintenance of BD symptoms. It remains unclear, however, whether BD is characterized by a general deficit in CC or by a deficit that is specifically related to the processing of emotional material., Methods: The sample consisted of 42 remitted bipolar patients and 39 healthy controls (HC). We examined whether BD individuals display impaired CC when confronted with negative as well as positive material using an arithmetic inhibition task that required inhibition of pictorial stimulus material., Results: Whereas both groups showed difficulties in exerting CC over negative material, only BD individuals exhibited deficient CC over positive material., Limitations: Even though we intended the negative and positive pictures in the arithmetic inhibition task to be similarly arousing, participants in the current study rated the negative compared to the positive pictures as more arousing., Conclusions: BD is associated with impaired CC when processing emotional - especially positive - stimuli even when patients are in remission. Possible implications of this deficit especially for emotion regulation are discussed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Heightened impulsivity has been suggested as a possible risk factor for bipolar disorder (BD). However, studies on high-risk populations are scarce and have mainly focused on individuals with a genetic risk. The present study investigated two high-risk samples for BD with regard to several aspects of the impulsivity construct., Methods: Unaffected relatives of BD patients (genetically defined high-risk group, N=29) and participants scoring high on the Hypomanic Personality Scale (psychometrically defined high-risk sample, N=25) were being compared to respective control groups (N=27 and N=25) using a multi-method approach. Participants were accessed on the Barratt Impulsiveness Scale-11 (BIS-11, trait impulsivity), the Stop Signal Task (response inhibition), and the Cambridge Gambling Task (impulsive behavior in decision-making processes)., Results: Both high-risk groups reported heightened impulsivity on the BIS-11, as well as impulsive decision-making, whereas no significant group differences in response inhibition were observed., Limitations: Limitations were the lack in specificity of the results for BD and the cross-sectional study design, which does not allow conclusions about the influence of impulsivity on the development of or resilience for BD in risk groups., Conclusions: Our findings support the assumption that increased trait impulsivity and impulsive decision-making are a vulnerability marker for and an endophenotype of BD., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Deficient emotion regulation has been proposed as a crucial pathological mechanism in bipolar disorder (BD). We therefore investigated emotion regulation impairments in BD, the related neural underpinnings and their etiological relevance for the disorder. Twenty-two euthymic patients with bipolar-I disorder and 17 unaffected first-degree relatives of BD-I patients, as well as two groups of healthy gender-, age- and education-matched controls (N=22/17, respectively) were included. Participants underwent functional magnetic resonance imaging while applying two different emotion regulation techniques, reappraisal and distraction, when presented with emotional images. BD patients and relatives showed impaired downregulation of amygdala activity during reappraisal, but not during distraction, when compared with controls. This deficit was correlated with the habitual use of reappraisal. The negative connectivity of amygdala and orbitofrontal cortex (OFC) observed during reappraisal in controls was reversed in BD patients and relatives. There were no significant differences between BD patients and relatives. As being observed in BD patients and unaffected relatives, deficits in emotion regulation through reappraisal may represent heritable neurobiological abnormalities underlying BD. The neural mechanisms include impaired control of amygdala reactivity to emotional stimuli and dysfunctional connectivity of the amygdala to regulatory control regions in the OFC. These are, thus, important aspects of the neurobiological basis of increased vulnerability for BD.

Objective: Emotion regulation deficits are a key characteristic of bipolar disorder (BD). In the present study, we asked if deficits in emotion regulation are also a vulnerability marker for BD. To this end, we investigated a healthy group of participants at high-risk for developing BD, defined on the basis of a hypomanic personality trait. We examined the neural correlates of two emotion regulation strategies, reappraisal and distraction., Method: Twenty-two individuals with higher risk for BD and twenty-four controls were investigated in a functional magnetic resonance imaging paradigm. Participants were presented with negative, positive and neutral pictures and were either required to passively view the images, to down-regulate the emotional response by reappraising the pictures' content, or to perform a distracting arithmetic task., Results: High-risk individuals showed increased emotional reactivity to negative stimuli, indicated by heightened amygdala activation during passive viewing. High-risk participants were also less successful in down-regulating amygdala activity using reappraisal of negative stimuli. During distraction from positive stimuli, high-risk individuals showed heightened task-related activity in the inferior parietal cortex, suggesting increased distractibility by task-irrelevant positive background stimuli. There were no differences in habitual emotion regulation as assessed by a self-report questionnaire., Limitations: Generalizability of the present results is limited by the age- and education-homogenous sample and the small sample size., Conclusions: This is the first study to report neural correlates of increased emotional reactivity and deficient emotion regulation in healthy individuals at risk for BD. These findings suggest inefficient emotion regulation through reappraisal and distraction in individuals with high hypomanic personality who are supposed to be at higher risk to develop bipolar disorder., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Bipolar disorder (BD) is a severe, chronic disease with a heritability of 60-80%. BD is frequently misdiagnosed due to phenomenological overlap with other psychopathologies, an important issue that calls for the identification of biological and psychological vulnerability and disease markers. Altered structural and functional connectivity, mainly between limbic and prefrontal brain areas, have been proposed to underlie emotional and motivational dysregulation in BD and might represent relevant vulnerability and disease markers. In the present laboratory review we discuss functional and structural neuroimaging findings on emotional and motivational dysregulation from our research group in BD patients and healthy individuals at risk to develop BD. As a main result of our studies, we observed altered orbitofrontal and limbic activity and reduced connectivity between dorsal prefrontal and limbic brain regions, as well as reduced integrity of fiber tracts connecting prefrontal and subcortical brain structures in BD patients and high-risk individuals. Our results provide novel insights into pathophysiological mechanisms of bipolar disorder. The current laboratory review provides a specific view of our group on altered brain connectivity and underlying psychological processes in bipolar disorder based on our own work, integrating relevant findings from others. Thereby we attempt to advance neuropsychobiological models of BD.

Objective: Neuropsychological deficits and emotion dysregulation are present in symptomatic and euthymic patients with bipolar disorder. However, there is little evidence on how cognitive functioning is influenced by emotion, what the neural correlates of emotional distraction effects are, and whether such deficits are a consequence or a precursor of the disorder. The authors used functional MRI (fMRI) to investigate these questions., Method: fMRI was used first to localize the neural network specific to a certain cognitive task (mental arithmetic) and then to test the effect of emotional distractors on this network. Euthymic patients with bipolar I disorder (N=22), two populations at high risk for developing the disorder (unaffected first-degree relatives of individuals with bipolar disorder [N=17]), and healthy participants with hypomanic personality traits [N=22]) were tested, along with three age-, gender-, and education-matched healthy comparison groups (N=22, N=17, N=24, respectively)., Results: There were no differences in performance or activation in the task network for mental arithmetic. However, while all participants exhibited slower responses when emotional distractors were present, this response slowing was greatly enlarged in bipolar patients. Similarly, task-related activation was generally increased under emotional distraction; however, bipolar patients exhibited a further increase in right parietal activation that correlated positively with the response slowing effect., Conclusions: The results suggest that emotional dysregulation leads to exacerbated neuropsychological deficits in bipolar patients, as evidenced by behavioral slowing and task-related hyperactivation. The lack of such a deficit in high-risk populations suggests that it occurs only after disease onset, rather than representing a vulnerability marker.