Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Bipolar-ADHD comorbidity: screening for differences in neurocognition and virtual reality-based cognitive performance.

OBJECTIVES: Identification of comorbid attention-deficit/hyperactivity disorder (ADHD) in patients with bipolar disorder (BD) is complicated by overlapping cognitive symptoms and methodological challenges. This cross-sectional study investigated whether virtual reality (VR)-based cognitive assessment that mimics daily life cognitive challenges can aid in the detection of sustained attention impairment in BD individuals with comorbid ADHD (BD + ADHD). METHODS: Forty-nine fully or partially remitted outpatients with BD, of whom 14 (24%) had BD + ADHD, were assessed with the Cognition Assessment in Virtual Reality (CAVIR) test, including a sustained attention test that involves distractions, and the Screen for Cognitive Impairment in Psychiatry (SCIP). Patients were also rated for mood symptoms and functioning and completed questionnaires assessing subjective cognition and quality of life. Patients' cognitive impairment on the SCIP was estimated with reference to n = 100 demographically comparable healthy control participants. RESULTS: BD + ADHD participants exhibited more pronounced performance deficits on the CAVIR sustained attention test (t(48) = 2.15, p = .037, d = .66). Notably, deficits on this test were proportional to self-reported daily life concentration difficulties in BD + ADHD individuals. Exploratory analyses revealed that BD + ADHD participants also displayed greater impairment on the SCIP working memory- and delayed verbal learning subtests and greater subjective cognitive complaints than BD patients without this comorbidity (p-levels < .001), but only the difference in subjective cognition survived correction for multiple comparisons (F(1,47) = 14.13, p = .005, np2 = 0.24). CONCLUSION: Screening for deficits in sustained attention with an ecologically valid VR test involving distracting stimuli may be useful for identifying BD + ADHD individuals.

Effect of immersive virtual reality-based cognitive remediation in patients with mood or psychosis spectrum disorders: study protocol for a randomized, controlled, double-blinded trial.

BACKGROUND: Cognitive impairments are prevalent across mood disorders and psychosis spectrum disorders, but there is a lack of real-life-like cognitive training programmes. Fully immersive virtual reality has the potential to ensure motivating and engaging cognitive training directly relevant to patients' daily lives. We will examine the effect of a 4-week, intensive virtual reality-based cognitive remediation programme involving daily life challenges on cognition and daily life functioning in patients with mood disorders or psychosis spectrum disorders and explore the neuronal underpinnings of potential treatment efficacy. METHODS: The trial has a randomized, controlled, double-blinded, parallel-group design. We will include 66 symptomatically stable outpatients with mood disorders or psychosis spectrum disorders aged 18-55 years with objective and subjective cognitive impairment. Assessments encompassing a virtual reality test of daily life cognitive skills, neuropsychological testing, measures of daily life functioning, symptom ratings, questionnaires on subjective cognitive complaints, and quality of life are carried out at baseline, after the end of 4 weeks of treatment and at a 3-month follow-up after treatment completion. Functional magnetic resonance imaging scans are performed at baseline and at the end of treatment. The primary outcome is a broad cognitive composite score comprising five subtasks on a novel ecologically valid virtual reality test of daily life cognitive functions. Two complete data sets for 54 patients will provide a power of 80% to detect a clinically relevant between-group difference in the primary outcome. Behavioural data will be analysed using linear mixed models in SPSS, while MRI data will be analysed with the FMRIB Expert Analysis Tool (FEAT). Treatment-related changes in neural activity from baseline to end of treatment will be investigated for the dorsal prefrontal cortex and hippocampus as the regions of interest. DISCUSSION: The results will provide insight into whether virtual reality-based cognitive remediation has beneficial effects on cognition and functioning in symptomatically stable patients with mood disorders or psychosis spectrum disorders, which can aid future treatment development. TRIAL REGISTRATION: ClinicalTrials.gov NCT06038955. Registered on September 15, 2023.

Effect of erythropoietin on cognitive side-effects of electroconvulsive therapy in depression: A randomized, double-blind, placebo-controlled trial.

Electroconvulsive therapy (ECT) is one of the most effective and rapid-acting treatment for severe depression but is associated with cognitive side-effects. Identification of add-on treatments that counteract these side-effects would be very helpful. This randomized, double-blinded, placebo-controlled, parallel-group study investigated the effects of four add-on erythropoietin (EPO; 40,000 IU/ml) or saline (placebo) infusions over 2.5 weeks of ECT (eight ECT sessions) in severely depressed patients with unipolar or bipolar depression. Neuropsychological assessments were conducted pre-ECT, three days after the eighth ECT (week 4), and at a 3-month follow-up. Further, functional magnetic resonance imaging (fMRI) was conducted after the eighth ECT. The primary outcome was change from pre- to post-ECT in a 'speed of complex cognitive processing' composite. Secondary outcomes were verbal and autobiographical memory. Of sixty randomized patients, one dropped out before baseline. Data were thus analysed for 59 patients (EPO, n = 33; saline, n = 26), of whom 28 had fMRI data. No ECT-related decline occurred in the primary global cognition measure (ps≥0.1), and no effect of EPO versus saline was observed on this outcome (ps≥0.3). However post-ECT, EPO-treated patients exhibited faster autobiographical memory recall than saline-treated patients (p = 0.02), which was accompanied by lower memory-related parietal cortex activity. The absence of global cognition changes with ECT and EPO, coupled with the specific impact of EPO on autobiographical memory recall speed and memory-related parietal cortex activity, suggests that assessing autobiographical memory may provide increased sensitivity in evaluating and potentially preventing cognitive side-effects of ECT. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT03339596, EudraCT no.: 2016-002326-36.

Aberrant resting-state functional connectivity underlies cognitive and functional impairments in remitted patients with bipolar disorder.

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.

Association between brain serotonin 4 receptor binding and reactivity to emotional faces in depressed and healthy individuals.

Brain serotonergic (5-HT) signaling is posited to modulate neural responses to emotional stimuli. Dysfunction in 5-HT signaling is implicated in major depressive disorder (MDD), a disorder associated with significant disturbances in emotion processing. In MDD, recent evidence points to altered 5-HT4 receptor (5-HT4R) levels, a promising target for antidepressant treatment. However, how these alterations influence neural processing of emotions in MDD remains poorly understood. This is the first study to examine the association between 5-HT4R binding and neural responses to emotions in patients with MDD and healthy controls. The study included one hundred and thirty-eight participants, comprising 88 outpatients with MDD from the NeuroPharm clinical trial (ClinicalTrials.gov identifier: NCT02869035) and 50 healthy controls. Participants underwent an [11C]SB207145 positron emission tomography (PET) scan to quantify 5-HT4R binding (BPND) and a functional magnetic resonance imaging (fMRI) scan during which they performed an emotional face matching task. We examined the association between regional 5-HT4R binding and corticolimbic responses to emotional faces using a linear latent variable model, including whether this association was moderated by depression status. We observed a positive correlation between 5-HT4R BPND and the corticolimbic response to emotional faces across participants (r = 0.20, p = 0.03). This association did not differ between groups (parameter estimate difference = 0.002, 95% CI = -0.008: 0.013, p = 0.72). Thus, in the largest PET/fMRI study of associations between serotonergic signaling and brain function, we found a positive association between 5-HT4R binding and neural responses to emotions that appear unaltered in MDD. Future clinical trials with novel pharmacological agents targeting 5-HT4R are needed to confirm whether they ameliorate emotion processing biases in MDD.

Cerebrospinal fluid erythropoietin, oxidative stress, and cognitive functions in patients with bipolar disorder and healthy control participants: A longitudinal case-control study.

Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients' cognitive outcomes.

Association of neurocognitive function with psychiatric hospitalization and socio-demographic conditions in individuals with bipolar and major depressive disorders.

Background: Neurocognitive impairments are associated with poor clinical and employment outcomes in individuals with affective disorders. However, little is known about their associations with long-term clinical outcomes such as psychiatric hospitalizations, and with socio-demographic indicators other than employment. In the largest longitudinal study of neurocognition in affective disorders to date, we investigate the role of neurocognitive impairments on psychiatric hospitalizations and socio-demographic conditions. Methods: The study included 518 individuals with bipolar or major depressive disorder. Neurocognitive assessments covered executive function and verbal memory domains. Longitudinal data on psychiatric hospitalization and socio-demographic conditions (employment, cohabitation, and marital status) for up to 11 years were obtained using National population-based registers. The primary and secondary outcomes were psychiatric hospitalizations (n = 398) and worsening of socio-demographic conditions (n = 518), in the follow-up period since study inclusion, respectively. Cox regression models were used to examine the association of neurocognition with future psychiatric hospitalizations and the worsening of socio-demographic conditions. Findings: Clinically significant impairment in verbal memory (z-score ≤ -1; defined by the ISBD Cognition Task Force), but not in executive function, was associated with a higher risk of future hospitalization, when adjusted for age, sex, hospitalization in the year preceding inclusion, depression severity, diagnosis, and type of clinical trial (HR = 1.84, 95% CI:1.05-3.25, p = 0.034; n = 398). The results remained significant even after accounting for illness duration. Neurocognitive impairments were not associated with the worsening of socio-demographic conditions (p ≥ 0.17; n = 518). Interpretation: Promoting neurocognitive function, especially verbal memory, may mitigate the risk of future psychiatric hospitalization in individuals with affective disorders. Funding: Lundbeckfonden (R279-2018-1145).

The relationship between sleep disturbance and cognitive impairment in mood disorders: A systematic review.

BACKGROUND: Cognitive impairment experienced by people with bipolar disorders (BD) or major depressive disorder (MDD) is associated with impaired psychosocial function and poorer quality of life. Sleep disturbance is another core symptom of mood disorders which may be associated with, and perhaps worsen, cognitive impairments. The aim of this systematic review was to critically assess the relationship between sleep disturbance and cognitive impairment in mood disorders. METHODS: In this systematic review, relevant studies were identified using electronic database searches of PsychINFO, MEDLINE, Embase and Web of Science. FINDINGS: Fourteen studies were included; eight investigated people with BD, five investigated people with MDD, and one included both people with MDD and people with BD. One study was an intervention for sleep disturbance and the remaining thirteen studies used either a longitudinal or cross-sectional observational design. Ten studies reported a significant association between subjectively measured sleep disturbance and cognitive impairment in people with MDD or BD after adjusting for demographic and clinical covariates, whereas no such association was found in healthy participants. Two studies reported a significant association between objectively measured (actigraphy or polysomnography) sleep abnormalities and cognitive impairment in mood disorders. One study of cognitive behavioural therapy for insomnia modified for BD (CBTI-BD) found an association between improvements in sleep and cognitive performance in BD. INTERPRETATION: There is preliminary evidence to suggest a significant association between sleep disturbance and cognitive impairment in mood disorders. These findings highlight the need for further research of sleep disturbances and cognitive impairment in people with mood disorders.

Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. METHODS: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist. RESULTS: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. CONCLUSIONS: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.

Neural underpinnings of emotion regulation subgroups in remitted patients with recently diagnosed bipolar disorder.

Neuroimaging studies of bipolar disorder (BD) generally involve comparison with healthy controls (HC), which may mask neurobiological variability within the disorder. This study aims to assess the neural underpinnings of potential subgroups of BD patients based on functional activity in the emotion regulation network and its relation to illness characteristics and relapse risk. Eighty-seven remitted patients with recently diagnosed BD and 66 HC underwent functional magnetic resonance imaging (fMRI) while performing an emotion regulation task. Patients were re-assessed with clinical interviews after 16 (±5) months. Data-driven hierarchical cluster analysis was employed to investigate 'neuronal subgroups' of patients based on their neuronal activity in a pre-defined emotion regulation network. Relations between neuronal subgroups and illness characteristics and relapse rates were examined. Patients were allocated into two subgroups. Subgroup 1 (n=62, 75%) was characterized by exaggerated bilateral amygdala reactivity but normal prefrontal and temporo-parietal activation. Subgroup 2 (n= 22, 25%) showed widespread hypo-activity within all emotion regulation regions. Both subgroups were less successful at down-regulating their emotions than HC (F(2,146)=5.33, p=.006, ηp2=.07). Patients in subgroup 2 had a history of more and longer mixed episodes (ps≤.01). Importantly, heightened amygdala activity across all patients was associated with increased risk of relapse during a 16-month follow-up period (ß=3.36, 95% CI [1.49;550.35], N=60, p=.03). The identified neuronal subgroups of patients with either amygdala hyper-activity or broad network hypo-activity during emotion regulation points to neurobiological heterogeneity among remitted patients with BD. Heightened amygdala reactivity may be a neuronal target for personalized treatments to prevent relapse.

Impaired allocentric spatial memory in patients with affective disorders.

BACKGROUND: Memory disturbances are frequent in unipolar depression (UD) and bipolar disorder (BD) and may comprise important predisposing and maintaining factors. Previous studies have demonstrated hippocampal abnormalities in UD and BD but there is a lack of studies specifically assessing hippocampus-dependent memory. METHODS: We used a virtual task to assess hippocampus-dependent (allocentric) vs non-hipppocampal (egocentric) spatial memory in remitted and partially remitted patients with UD or BD (N = 22) and a healthy control group (N = 32). Participants also completed a range of standard neuropsychological and functional assessments. RESULTS: Participants in the UD/BD group showed selective impairments on high-load hippocampal (allocentric) memory compared to egocentric memory and this effect was independent of residual mood symptoms. Across both samples, both allocentric and egocentric spatial memory correlated with more general measures of memory and other aspects of cognition measured on standard neuropsychological tests but only high-load allocentric memory showed a significant relationship with functional capacity. CONCLUSION: Results show a selective impairment in high-load allocentric spatial memory compared to egocentric memory in the patient group, suggesting impaired hippocampal functioning in patients with remitted UD/BD.

Randomised controlled cognition trials in remitted patients with mood disorders published between 2015 and 2021: A systematic review by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Cognitive impairments are an emerging treatment target in mood disorders, but currently there are no evidence-based pro-cognitive treatments indicated for patients in remission. With this systematic review of randomised controlled trials (RCTs), the International Society for Bipolar Disorders (ISBD) Targeting Cognition Task force provides an update of the most promising treatments and methodological recommendations. METHODS: The review included RCTs of candidate pro-cognitive interventions in fully or partially remitted patients with major depressive disorder or bipolar disorder. We followed the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE and Cochrane Library from January 2015, when two prior systematic reviews were conducted, until February 2021. Two independent authors reviewed the studies with the Revised Cochrane Collaboration's Risk of Bias tool for Randomised trials. RESULTS: We identified 16 RCTs (N = 859) investigating cognitive remediation (CR; k = 6; N = 311), direct current or repetitive magnetic stimulation (k = 3; N = 127), or pharmacological interventions (k = 7; N = 421). CR showed most consistent cognitive benefits, with two trials showing improvements on primary outcomes. Neuromodulatory interventions revealed no clear efficacy. Among pharmacological interventions, modafinil and lurasidone showed early positive results. Sources of bias included small samples, lack of pre-screening for objective cognitive impairment, no primary outcome and no information on allocation sequence masking. CONCLUSIONS: Evidence for pro-cognitive treatments in mood disorders is emerging. Recommendations are to increase sample sizes, pre-screen for impairment in targeted domain(s), select one primary outcome, aid transfer to real-world functioning, investigate multimodal interventions and include neuroimaging.

Cognition in older adults with bipolar disorder: An ISBD task force systematic review and meta-analysis based on a comprehensive neuropsychological assessment.

OBJECTIVES: We aim to characterize the cognitive performance in euthymic older adults with bipolar disorder (OABD) through a comprehensive neuropsychological assessment to obtain a detailed neuropsychological profile. METHODS: We conducted a systematic search in MEDLINE/Pubmed, Cochrane, and PsycInfo databases. Original studies assessing cognitive function in OABD (age ≥50 years ) containing, at a minimum, the domains of attention/processing speed, memory, and executive functions were included. A random-effects meta-analysis was conducted to summarize differences between patients and matched controls in each cognitive domain. We also conducted meta-regressions to estimate the impact of clinical and socio-demographic variables on these differences. RESULTS: Eight articles, providing data for 328 euthymic OABD patients and 302 healthy controls, were included in the meta-analysis. OABD showed worse performance in comparison with healthy controls, with large significant effect sizes (Hedge's g from -0.77 to -0.89; p < 0.001) in verbal learning and verbal and visual delayed memory. They also displayed statistically significant deficits, with moderate effect size, in processing speed, working memory, immediate memory, cognitive flexibility, verbal fluency, psychomotor function, executive functions, attention, inhibition, and recognition (Hedge's g from -0.52 to -0.76; p < 0.001), but not in language and visuoconstruction domains. None of the examined variables were associated with these deficits. CONCLUSIONS: Cognitive dysfunction is present in OABD, with important deficits in almost all cognitive domains, especially in the memory domain. Our results highlight the importance of including a routine complete neuropsychological assessment in OABD and also considering therapeutic strategies in OABD.

Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis.

IMPORTANCE: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome. OBJECTIVE: To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome. DATA SOURCES: Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists. STUDY SELECTION: Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected. DATA EXTRACTION & SYNTHESIS: Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model. MAIN OUTCOMES & MEASURES: The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome. RESULTS: The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I2 = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I2 = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals. CONCLUSIONS & RELEVANCE: A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena. STUDY REGISTRATION: PROSPERO (CRD42021256965).

Neuronal underpinnings of cognitive impairment in bipolar disorder: A large data-driven functional magnetic resonance imaging study.

OBJECTIVES: Cognitive impairment occurs in approximately 50% of remitted patients with bipolar disorder (BD). However, there exists no treatment with replicated and robust efficacy on cognition in BD. This is partially due to limited insight into the neuronal underpinnings of cognitive impairment in these patients. This is the first study to investigate neuronal underpinnings of cognitive impairment in a large functional magnetic resonance imaging (fMRI) dataset comparing neural activity patterns between distinct neurocognitive subgroups of partially or fully remitted patients with BD. METHODS: Patients (n = 153) and healthy controls (HC) (n = 52) underwent neuropsychological assessment and fMRI, during which they performed a verbal N-back working memory (WM) task. Based on hierarchical cluster analysis of neuropsychological test performance, patients were grouped into one of two neurocognitive subgroups (cognitively impaired, n = 91; cognitively normal compared to HC, n = 62) that were compared on WM-related neural activity. RESULTS: Cognitively impaired patients displayed WM-related hypo-activity in left dorsolateral prefrontal cortex and frontal and parietal regions within a cognitive control network (CCN) as well as hyper-activity in the default mode network (DMN) compared to cognitively normal patients. In contrast, cognitively normal patients only exhibited hypo-activity within a small cluster in the superior frontal gyrus relative to HC. CONCLUSIONS: Cognitive impairment in BD seems to originate from a failure to recruit key regions in the CCN and to suppress task-irrelevant DMN activity during cognitive performance. These results highlight modulation of aberrant dorsal prefrontal and DMN activity as a putative target for pro-cognitive treatment in BD.

Action-based cognitive remediation in bipolar disorder improved verbal memory but had no effect on the neural response during episodic memory encoding.

Verbal memory and executive function impairments are common in remitted patients with bipolar disorder (BD). We recently found that Action-Based Cognitive Remediation (ABCR) may improve executive function and verbal memory in BD. Here, we investigated neuronal changes associated with ABCR treatment-related memory improvement in a longitudinal functional MRI (fMRI) study. Forty-five patients with remitted BD (ABCR: n = 26, control treatment: n = 19) completed a picture-encoding task during fMRI and tests of verbal memory and executive function outside the scanner before and after two weeks of ABCR/control treatment. The cognitive assessment was performed again following ten weeks of treatment. Thirty-four healthy controls underwent the same test protocol once for baseline comparisons. Patients showed a moderate improvement in a domain composite of verbal learning and memory both after two weeks and ten weeks of ABCR treatment, which correlated with improved executive function. At baseline, patients showed encoding-related hypoactivity in dorsal prefrontal cortex compared to healthy controls. However, treatment was not associated with significant task-related neuronal activity changes. Improved verbal learning and memory may have occurred through strengthened strategic processing targeted by ABCR. However, picture-encoding paradigms may be suboptimal to capture the neural correlates of this improvement, possibly by failing to engage strategic encoding processes.

Cognitive Adverse Effects of Electroconvulsive Therapy: A Discrepancy Between Subjective and Objective Measures?

OBJECTIVES: The character and duration of cognitive adverse effects of electroconvulsive therapy (ECT) are unclear. This study investigated (1) the sensitivity of a short cognitive test battery to cognitive adverse effects of ECT, (2) the relation between subjective and objective cognitive adverse effects, and (3) patient characteristics associated with more subjective than objective adverse effects. METHODS: Forty-one patients with unipolar or bipolar depression referred to ECT underwent assessments at baseline, 5 to 7 days post-ECT, and 3 months post-ECT. Patients rated their fear of various aspects of ECT on a visual analog scale. At each assessment, patients were evaluated for depressive symptoms, completed the Screen for Cognitive Impairment in Psychiatry (SCIP) and Trail Making Test-Part B (TMT-B), and rated their cognitive difficulties. RESULTS: Patients feared cognitive adverse effects and lack of treatment efficacy more than other aspects of ECT. The SCIP and TMT-B revealed transient decline in objective cognition after ECT, which was reversed after 3 months. Patients presented with more subjective than objective cognitive difficulties at baseline and more subjective than objective cognitive adverse effects of ECT. This discrepancy was significantly reduced at follow-up. Younger age and poorer objective cognition pretreatment were associated with more subjective than objective cognitive adverse effects 5 to 7 days after ECT. CONCLUSIONS: The SCIP and TMT-B are sensitive to cognitive adverse effects of ECT. Patients show more subjective than objective cognitive adverse effects of ECT. These insights can be used clinically to inform patients of treatment choice and expected cognitive consequences.

Cerebral Metabolic Rate of Glucose and Cognitive Tests in Long COVID Patients.

BACKGROUND: Common long-term sequelae after COVID-19 include fatigue and cognitive impairment. Although symptoms interfere with daily living, the underlying pathology is largely unknown. Previous studies report relative hypometabolism in frontal, limbic and cerebellar regions suggesting focal brain involvement. We aimed to determine whether absolute hypometabolism was present and correlated to same day standardized neurocognitive testing. METHODS: Fourteen patients included from a long COVID clinic had cognitive testing and quantitative dynamic [18F]FDG PET of the brain on the same day to correlate cognitive function to metabolic glucose rate. RESULTS: We found no hypometabolism in frontal, limbic and cerebellar regions in cognitively impaired relative to cognitive intact patients. In contrast, the cognitive impaired patients showed higher cerebellar metabolism (p = 0.03), which correlated with more severe deficits in working memory and executive function (p = 0.03). CONCLUSIONS: Hypermetabolism in the cerebellum may reflect inefficient brain processing and play a role in cognitive impairments after COVID-19.