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Background: Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments. Aim: This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders. Methods: In this randomized, double-blinded, placebo-controlled trial, cognitively impaired patients with remitted BD or MDD received 1 weekly recombinant human EPO (40,000 IU/mL) or saline infusion for a 12-week period. Assessments were conducted at baseline, after 2 weeks of treatment (week 3), immediately after treatment (week 13) and at 6-months follow-up. Participants underwent functional MRI during performance on a n-back working memory (WM) task at baseline and week 3, and for a subgroup 6 weeks post-treatment (week 18). The primary outcome was a cognitive composite score at week 13, whereas secondary outcomes comprised sustained attention and functioning. WM-related dPFC activity was a tertiary outcome. Results: Data were analysed for 101 of the 103 included patients (EPO, n = 58; saline, n = 43). There were no effects of EPO over saline on any cognitive or functional outcomes or on WM-related dPFC activity. Conclusions: The absence of treatment-related changes in cognition and neural activity was unexpected and contrasts with multiple previous preclinical and clinical studies. It is possible that the lack of effects resulted from a recent change in the manufacturing process for EPO. Nevertheless, the findings support the validity of dPFC target engagement as a biomarker model for pro-cognitive effects, according to which treatments that do not improve cognition should not modulate dPFC activity. Trial registrations: EudraCT no.: 2016–004023-24; ClinicalTrials.gov identifier: NCT03315897. [ABSTRACT FROM AUTHOR]

Background: Electroconvulsive therapy (ECT) is an efficient and rapid-acting treatment indicated for severe depressive disorders. While ECT is commonly accompanied by transient memory decline, the brain mechanisms underlying these side effects remain unclear. Aims: In this exploratory functional magnetic resonance (fMRI) study, we aimed to compare effects of ECT versus pharmacological treatment on neural response during episodic memory encoding in patients with affective disorders. Methods: This study included 32 ECT-treated patients (major depressive disorder (MDD), n = 23; bipolar depression, n = 9) and 40 partially remitted patients in pharmacological treatment (MDD, n = 24; bipolar disorder, n = 16). Participants underwent neuropsychological assessment, a strategic picture encoding fMRI scan paradigm, and mood rating. The ECT group was assessed before ECT (pre-ECT) and 3 days after their eighth ECT session (post-ECT). Results: Groups were comparable on age, gender, and educational years (p s ⩾ 0.05). Within-group analyses revealed a selective reduction in verbal learning and episodic memory pre- to post-ECT (p = 0.012) but no decline in global cognitive performance (p = 0.3). Functional magnetic resonance imaging analyses adjusted for mood symptoms revealed greater activity in ECT-treated patients than pharmacologically treated No-ECT patients across left precentral gyrus (PCG), right dorsomedial prefrontal cortex (dmPFC), and left middle frontal gyrus (MFG). In ECT-treated patients, greater decline in verbal learning and memory performance from pre- to post-ECT correlated with higher PCG response (r = −0.46, p = 0.008), but not with dmPFC or MFG activity (p s ⩾ 0.1), post-ECT. Conclusions: Episodic memory decline was related to greater neural activity in the left PCG, but unrelated to increased dmPFC and MFG activity, immediately after ECT. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) is commonly associated with cognitive impairments, that directly contribute to patients' functional disability. However, there is no effective treatment targeting cognition in BD. A key reason for the lack of pro‐cognitive interventions is the limited insight into the brain correlates of cognitive impairments in these patients. This is the first study investigating the resting‐state neural underpinnings of cognitive impairments in different neurocognitive subgroups of patients with BD. Method: Patients with BD in full or partial remission and healthy controls (final sample of n = 144 and n = 50, respectively) underwent neuropsychological assessment and resting‐state functional magnetic resonance imaging. We classified the patients into cognitively impaired (n = 83) and cognitively normal (n = 61) subgroups using hierarchical cluster analysis of the four cognitive domains. We used independent component analysis (ICA) to investigate the differences between the neurocognitive subgroups and healthy controls in resting‐state functional connectivity (rsFC) in the default mode network (DMN), executive central network (ECN), and frontoparietal network (FPN). Results: Cognitively impaired patients displayed greater positive rsFC within the DMN and less negative rsFC within the ECN than healthy controls. Across cognitively impaired patients, lower positive connectivity within DMN and lower negative rsFC within ECN correlated with worse global cognitive performance. Conclusion: Cognitive impairments in BD seem to be associated with a hyper‐connectivity within the DMN, which may explain the failure to suppress task‐irrelevant DMN activity during the cognitive performance, and blunted anticorrelation in the ECN. Thus, aberrant connectivity within the DMN and ECN may serve as brain targets for pro‐cognitive interventions. [ABSTRACT FROM AUTHOR]

Background: Persistent cognitive deficits are prevalent in patients with bipolar disorder (BD) and unipolar disorder (UD), but treatments effectively targeting cognition in these mood disorders are lacking. This is partly due to poor insight into the neuronal underpinnings of cognitive deficits., Methods: The aim of this functional magnetic resonance imaging (fMRI) study was to investigate the neuronal underpinnings of working memory (WM)-related deficits in somatically healthy, remitted patients with BD or UD ( n = 66) with cognitive and functional impairments compared to 38 healthy controls (HC). The participants underwent neuropsychological testing and fMRI, while performing a visuospatial and a verbal N -back WM paradigm., Results: Relative to HC, patients exhibited hypo -activity across dorsolateral prefrontal cortex as well as frontal and parietal nodes of the cognitive control network (CCN) and hyper -activity in left orbitofrontal cortex within the default mode network (DMN) during both visuospatial and verbal WM performance. Verbal WM-related response in the left posterior superior frontal gyrus (SFG) within CCN was lower in patients and correlated positively with out-of-scanner executive function performance across all participants., Conclusions: Our findings suggest that cognitive impairments across BD and UD are associated with insufficient recruitment of task-relevant regions in the CCN and down-regulation of task-irrelevant orbitofrontal activity within the DMN during task performance. Specifically, a lower recruitment of the left posterior SFG within CCN during verbal WM was associated with lower cognitive performance.

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression but is associated with cognitive side effects. Side effects on executive function and memory may persist for months. Patients with a low cognitive reserve and/or poor cognition before ECT seem to be at greater risk of cognitive side effects than patients with a high cognitive reserve. However, better understanding of the nature and predictors of these side effects is needed. We recommend implementing a cognition assessment tool to monitor cognition during ECT. This may improve patient information and provide a basis for more personalised treatments.