Association Between the Fronto-Limbic Network and Cognitive and Emotional Functioning in Individuals With Bipolar Disorder: A Systematic Review and Meta-analysis.

Importance: Individuals with bipolar disorder (BD) experience cognitive and emotional dysfunctions. Various brain circuits are implicated in BD but have not been investigated in a meta-analysis of functional magnetic resonance imaging (fMRI) studies. Objective: To investigate the brain functioning of individuals with BD compared with healthy control individuals in the domains of emotion processing, reward processing, and working memory. Data Sources: All fMRI experiments on BD published before March 2020, as identified in a literature search of PubMed, Embase, Web of Science, Cochrane Library, PsycInfo, Emcare, Academic Search Premier, and ScienceDirect. The literature search was conducted on February 21, 2017, and March 2, 2020, and data were analyzed from January 2021 to January 2022. Study Selection: fMRI experiments comparing adult individuals with BD and healthy control individuals were selected if they reported whole-brain results, including a task assessing at least 1 of the domains. In total, 2320 studies were screened, and 253 full-text articles were evaluated. Data Extraction and Synthesis: A total of 49 studies were included after selection procedure. Coordinates reporting significant activation differences between individuals with BD and healthy control individuals were extracted. Differences in brain region activity were tested using the activation likelihood estimation method. Main Outcomes and Measures: A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to stimuli in 3 cognitive domains between individuals with BD and healthy control individuals were different. Results: The study population included 999 individuals with BD (551 [55.2%] female) and 1027 healthy control individuals (532 [51.8%] female). Compared with healthy control individuals, individuals with BD showed amygdala and hippocampal hyperactivity and hypoactivation in the inferior frontal gyrus during emotion processing (20 studies; 324 individuals with BD and 369 healthy control individuals), hyperactivation in the orbitofrontal cortex during reward processing (9 studies; 195 individuals with BD and 213 healthy control individuals), and hyperactivation in the ventromedial prefrontal cortex and subgenual anterior cingulate cortex during working memory (20 studies; 530 individuals with BD and 417 healthy control individuals). Limbic hyperactivation was only found during euthymia in the emotion and reward processing domains; abnormalities in frontal cortex activity were also found in individuals with BD with mania and depression. Conclusions and Relevance: This systematic review and meta-analysis revealed evidence for activity disturbances in key brain areas involved in cognitive and emotion processing in individuals with BD. Most of the regions are part of the fronto-limbic network. The results suggest that aberrations in the fronto-limbic network, present in both euthymic and symptomatic individuals, may be underlying cognitive and emotional dysfunctions in BD.

Effects of the COVID-19 pandemic in a preexisting longitudinal study of patients with recently diagnosed bipolar disorder: Indications for increases in manic symptoms.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic interfered in the daily lives of people and is assumed to adversely affect mental health. However, the effects on mood (in)stability of bipolar disorder (BD) patients and the comparison to pre-COVID-19 symptom severity levels are unknown. METHOD: Between April and September, 2020, symptoms and well-being were assessed in the Bipolar Netherlands Cohort (BINCO) study of recently diagnosed patients with BD I and II. The questionnaire contained questions regarding manic and depressive symptoms (YMRS and ASRM, QIDS), worry (PSWQ), stress (PSS), loneliness, sleep, fear for COVID-19, positive coping, and substance use. As manic, depressive and stress symptoms levels were assessed pre-COVID-19, their trajectories during the lockdown restrictions were estimated using mixed models. RESULTS: Of the 70 invited BD patients, 36 (51%) responded at least once (mean age of 36.7 years, 54% female, and 31% BD type 1) to the COVID-19 assessments. There was a significant increase (X2 = 17.06; p = .004) in (hypo)manic symptoms from baseline during the first COVID-19 wave, with a decrease thereafter. Fear of COVID-19 (X2 = 18.01; p = .003) and positive coping (X2  = 12.44; p = .03) were the highest at the start of the pandemic and decreased thereafter. Other scales including depression and stress symptoms did not vary significantly over time. CONCLUSION: We found a meaningful increase in manic symptomatology from pre-COVID-19 into the initial phases of the pandemic in BD patients. These symptoms decreased along with fear of COVID-19 and positive coping during the following months when lockdown measures were eased.

Anger and cluster B personality traits and the conversion from unipolar depression to bipolar disorder.

INTRODUCTION: Feelings of anger and irritability are prominent symptoms of bipolar disorder (BD) that may occur during hypomanic, depressive and, especially, during mixed mood states. We aimed to determine whether such constructs are associated with the conversion to BD in subjects with a history of unipolar depression. METHODS: Data were derived from the depressed participants of Netherlands Study of Depression and Anxiety with 9 years of follow-up. Hypomania was ascertained using the Composite International Diagnostic Interview at 2, 4, 6, and 9 years follow-up. Cross-sectionally, we studied the association between prevalent hypomania and anger related constructs with the "Spielberger Trait Anger subscale," the "Anger Attacks" questionnaire, the cluster B personality traits part of the "Personality Disorder Questionnaire," and "aggression reactivity." Prospectively, we studied whether aggression reactivity predicted incident hypomania using Cox regression analyses. RESULTS: Cross-sectionally, the bipolar conversion group (n = 77) had significantly higher scores of trait anger and aggression reactivity, as well as a higher prevalence on "anger attacks," "antisocial traits," and "borderline traits" compared to current (n = 349) as well as remitted (n = 1159) depressive patients. In prospective analyses in 1744 participants, aggression reactivity predicted incident hypomania (n = 28), with a multivariate-adjusted hazard ratio of 1.4 (95% confidence interval: 1.02-1.93; p = .037). CONCLUSION: Anger is a risk factor for conversion from unipolar depression to BD. In addition, patients who converted to BD showed on average more anger, agitation and irritability than people with a history of unipolar depression who had not converted.

Emotion avoidance and fear bradycardia in patients with borderline personality disorder and healthy controls.

BACKGROUND AND OBJECTIVES: Exaggerated emotional reactivity is supposed to be essential in the etiology of borderline personality disorder (BPD). More specifically, models of defensive behavior would predict reduced freezing behavior -indicated by fear bradycardia-in response to threat. This study examined automatic fear bradycardia responses in BPD versus healthy controls and the role of emotion dysregulation, more specifically tendencies to avoid emotions. METHODS: Patients with BPD (n = 23) and healthy controls (n = 18) completed questionnaires and then watched neutral, pleasant and unpleasant pictures while heart rate was assessed. RESULTS: Emotion avoidance interacted with group: it was associated with distinct autonomic responses in healthy controls but not in BPD patients. Controls with lower emotion avoidance tendencies showed bradycardia in response to unpleasant pictures, while controls with higher emotion avoidance tendencies did not. BPD patients showed no bradycardia, irrespective of their emotion avoidance tendencies. LIMITATIONS: This study is limited by a small sample size. Comorbidity or medication intake were not controlled for. CONCLUSIONS: The results may suggest impaired automatic defense responses in BPD. Further understanding of the regulation of distress and defense responses might improve BPD treatment.

Mental Imagery Affects Subsequent Automatic Defense Responses.

Automatic defense responses promote survival and appropriate action under threat. They have also been associated with the development of threat-related psychiatric syndromes. Targeting such automatic responses during threat may be useful in populations with frequent threat exposure. Here, two experiments explored whether mental imagery as a pre-trauma manipulation could influence fear bradycardia (a core characteristic of freezing) during subsequent analog trauma (affective picture viewing). Image-based interventions have proven successful in the treatment of threat-related disorders and are easily applicable. In Experiment 1, 43 healthy participants were randomly assigned to an imagery script condition. Participants executed a passive viewing task with blocks of neutral, pleasant, and unpleasant pictures after listening to an auditory script that was either related (with a positive or a negative outcome) or unrelated to the unpleasant pictures from the passive viewing task. Heart rate was assessed during script listening and during passive viewing. Imagining negative related scripts resulted in greater bradycardia (neutral-unpleasant contrast) than imagining positive scripts, especially unrelated. This effect was replicated in Experiment 2 (n = 51), again in the neutral-unpleasant contrast. An extra no-script condition showed that bradycardia was not induced by the negative-related script, but rather that a positive script attenuated bradycardia. These preliminary results might indicate reduced vigilance after unrelated positive events. Future research should replicate these findings using a larger sample. Either way, the findings show that highly automatic defense behavior can be influenced by relatively simple mental imagery manipulations.