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.

Effect of Action-Based Cognitive Remediation on cognitive impairment in patients with remitted bipolar disorder: A randomized controlled trial.

OBJECTIVES: Cognitive impairment affects many patients with bipolar disorder (BD), and treatments with replicated pro-cognitive effects are lacking. This study aimed to assess the effect of Action-Based Cognitive Remediation (ABCR) vs control treatment on cognitive impairment in patients with BD. METHODS: Patients with remitted BD with objective cognitive impairment were randomized to 10 weeks of ABCR vs control treatment, and assessed at baseline, after 2 weeks of treatment, at treatment completion and at 6 months follow-up. The primary outcome was a cognitive composite score. Secondary outcomes were executive function and observer-rated functional capacity. Tertiary measures included additional neuropsychological tests, performance-based functional capacity and quality of life. Data were analysed with linear mixed effects models. RESULTS: In total, 64 participants were randomized; given three dropouts before the baseline assessments, data were analysed for 61 participants (ABCR: n = 32, control: n = 29). There was no effect on ABCR vs control on the primary cognitive composite score (P-values ≥.60). At treatment completion, there was a large effect of ABCR vs control on the secondary executive function measure (treatment effect= -0.16, 95% CI [-0.27, -0.05], P ≤ .01, d = 0.65), and on subjective cognitive functioning (treatment effect = -5.38, 95% CI [-8.13, -2.67], P ≤ .001, d = 0.80), which disappeared at follow-up. There was no treatment-effect on functioning, and no association between cognitive and functional change. CONCLUSIONS: There was no effect of ABCR on the cognitive composite score. However, there was an effect on executive function and subjective cognitive functioning suggesting that ABCR may be relevant for patients with executive dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03295305.

Neural Response After a Single ECT Session During Retrieval of Emotional Self-Referent Words in Depression: A Randomized, Sham-Controlled fMRI Study.

Background: Negative neurocognitive bias is a core feature of depression that is reversed by antidepressant drug treatment. However, it is unclear whether modulation of neurocognitive bias is a common mechanism of distinct biological treatments. This randomized controlled functional magnetic resonance imaging study explored the effects of a single electroconvulsive therapy session on self-referent emotional processing. Methods: Twenty-nine patients with treatment-resistant major depressive disorder were randomized to one active or sham electroconvulsive therapy session at the beginning of their electroconvulsive therapy course in a double-blind, between-groups design. The following day, patients were given a self-referential emotional word categorization test and a free recall test. This was followed by an incidental word recognition task during whole-brain functional magnetic resonance imaging at 3T. Mood was assessed at baseline, on the functional magnetic resonance imaging day, and after 6 electroconvulsive therapy sessions. Data were complete and analyzed for 25 patients (electroconvulsive therapy: n = 14, sham: n = 11). The functional magnetic resonance imaging data were analyzed using the FMRIB Software Library randomize algorithm, and the Threshold-Free Cluster Enhancement method was used to identify significant clusters (corrected at P < .05). Results: A single electroconvulsive therapy session had no effect on hippocampal activity during retrieval of emotional words. However, electroconvulsive therapy reduced the retrieval-specific neural response for positive words in the left frontopolar cortex. This effect occurred in the absence of differences between groups in behavioral performance or mood symptoms. Conclusions: The observed effect of electroconvulsive therapy on prefrontal response may reflect early facilitation of memory for positive self-referent information, which could contribute to improvements in depressive symptoms including feelings of self-worth with repeated treatments.

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.

Neuronal and cognitive predictors of improved executive function following action-based cognitive remediation in patients with bipolar disorder.

Cognitive impairments in bipolar disorder (BD) are prevalent but effective treatments with replicated and lasting pro-cognitive effects are lacking. Treatment development is hampered by a lack of neurocircuitry biomarkers to predict treatment efficacy. Action-Based Cognitive Remediation (ABCR) improves executive function in BD and this was accompanied by increased dorsal prefrontal cortex (dPFC) response during working memory (WM) after two weeks of treatment. This study investigated whether pre-treatment WM-related dPFC response, executive dysfunction and/or subjective cognitive difficulties predicted ABCR treatment response on executive functions. Forty-five patients with fully or partially remitted BD (ABCR: n = 25, control treatment: n = 20) in our ABCR trial completed a spatial N-back WM task during functional magnetic resonance imaging (fMRI) at baseline. Patients also completed neuropsychological tests and rated their cognitive functions before and after 10 weeks of ABCR or control treatment. Multiple linear regression analyses were conducted to assess whether pre-treatment dPFC response, objective executive impairment and/or subjective cognitive difficulties predicted greater ABCR-related improvements of executive function. We found that treatment-related improvement in executive function was predicted by more WM-related dPFC hypo-activity at baseline (p = 0.03) in linear regression analyses adjusted for age, gender and education. In contrast, there was only a non-significant trend towards more executive dysfunction at baseline predicting greater ABCR-related executive improvement (p = 0.08). Subjective cognitive difficulties at baseline showed no association with treatment effects (p = 0.16). In conclusion, pre-treatment dPFC hypo-activity during WM performance predicts greater effects of ABCR treatment on executive function and may represent a neurocircuitry biomarker for treatment efficacy in this cognitive domain.

Cognition Assessment in Virtual Reality: Validity and feasibility of a novel virtual reality test for real-life cognitive functions in mood disorders and psychosis spectrum disorders.

There is a pressing need for measures of real-life cognitive functioning in patients with mood or psychotic disorders in clinical settings and treatment trials targeting cognition. We developed the first immersive virtual reality cognition assessment tool, the Cognition Assessment in Virtual Reality (CAVIR), which assesses verbal memory, processing speed, attention, working memory and planning skills in an interactive virtual reality kitchen scenario. This study investigates the sensitivity and validity of the CAVIR for cognitive impairments in mood and psychotic disorders and its association with functioning and neuropsychological performance. Symptomatically stable patients with mood disorders (MD; n = 40) or psychosis spectrum disorders (PSD; n = 41) and healthy control participants (HC; n = 40) completed the CAVIR and standard neuropsychological tests and were rated for clinical symptoms and daily functioning. We found that the CAVIR was sensitive to cognitive impairments across MD and PSD with large effect sizes (MD: F(73) = 11.61, p < .01, ηp2 = 0.14; PSD: F(72) = 18.24, p < .001, ηp2 = 0.19). There was a moderate to strong positive correlation between performance on the CAVIR and on neuropsychological tests (r(121) = 0.58, p < .001), which prevailed after adjustment for age, years of education and verbal IQ (B = 0.67, p < .001). Lower CAVIR scores correlated moderately with more observer-rated and performance-based functional disability (r(121) = -0.30, p < .01 and r(68) = 0.44, p < .001, respectively), also after adjustment for age, years of education and verbal IQ (B = 0.03, p < .001). In conclusion, the CAVIR is a sensitive and valid instrument for measuring real-life cognitive impairments in mood and psychotic disorders. After further psychometric assessments, the CAVIR can be implemented in clinical settings and trials targeting cognition.

Norms for the Screen for Cognitive Impairment in Psychiatry and cognitive trajectories in bipolar disorder.

BACKGROUND: The International Society for Bipolar Disorders Targeting Cognition Task Force recommends screening for and monitoring of cognitive impairments in patients with bipolar disorder (BD) with the Screen for Cognitive Impairment in Psychiatry (SCIP). The study aimed to provide the first demographically adjusted norms and change norms for the SCIP and to compare the cognitive trajectory over one year in remitted BD patients with normative cognitive change. METHODS: Patients with fully or partially remitted BD and healthy controls (HC) were assessed with the SCIP at baseline and at a one-year follow-up. Regression-based models were used to determine demographically adjusted norms and change norms. Using the change models, predicted follow-up scores were calculated for BD and HC, and independent t-tests were used to compare deviations of the observed from the predicted follow-up scores for BD vs. HC to assess differences in cognitive trajectories. RESULTS: Baseline data were collected for n=273 HC and n=218 BD, and follow-up data for n=139 HC and n=74 BD. Baseline norm models included age, sex and years of education, while change models included baseline SCIP scores and age. Patients with follow-up data showed selective impairments within verbal learning and recall at baseline. They followed the normative cognitive trajectories for all cognitive domains but verbal learning. LIMITATIONS: Cognition was assessed with a screening tool. CONCLUSIONS: We recommend implementing demographically adjusted norms and change norms for the SCIP in clinical and research settings. Change norms seem sensitive to subtle and selective cognitive decline over one year in remitted BD.

Change in prefrontal activity and executive functions after action-based cognitive remediation in bipolar disorder: a randomized controlled trial.

Cognitive impairment is prevalent in bipolar disorder (BD) but treatments with pro-cognitive effects are lacking. Insight concerning the neurocircuitry of cognitive improvement could provide a biomarker for pro-cognitive effects to advance treatment development. The dorsal prefrontal cortex (dPFC) is a promising region for such treatment target engagement. The aim of this functional magnetic resonance imaging (fMRI) study was to examine the effects of action-based cognitive remediation (ABCR) on early change in the dPFC blood-oxygen-level-dependent response in patients with BD in remission, and whether the observed neural change predicted improved executive functions following 10 weeks of treatment. Forty-five participants with remitted BD (ABCR: n = 26, control treatment: n = 19) completed a spatial n-back working memory task during fMRI and executive function tasks outside the scanner before and after two weeks of ABCR/control treatment, and an additional assessment of executive function at treatment completion. Thirty-four healthy controls underwent a single fMRI and executive function assessment for baseline comparisons. We found an early reversal of pretreatment hypo-activity in the dorsolateral prefrontal cortex (dlPFC) following ABCR vs. control during both high-load (2-back > 1-back) working memory (WM) (F(1,43) = 5.69, p = 0.02, η2 = 0.12) and general WM (2-back > 0-back) (F(1,43) = 5.61, p = 0.02, η2 = 0.12). This dlPFC activity increase predicted improved executive functions at treatment completion (high-load WM: B = -0.45, p = 0.01, general WM: B = -0.41, p < 0.01), independent of changes in subsyndromal symptoms. In conclusion, early dPFC increase may provide a neurocircuitry-based biomarker for pro-cognitive effects. Future cognition trials should include fMRI assessments to confirm the validity of this putative biomarker model across disorders with cognitive impairment.

Correction to: Effect of action-based cognitive remediation on cognition and neural activity in bipolar disorder: study protocol for a randomized controlled trial.

Following publication of the original article [1], the authors notified us that a comment in the Peripheral and neural biomarkers and genotype section was incorrectly phrased during editing. "4 weeks of treatment (four active ABCR sessions twice a week or control group sessions twice a week)" should have actually been described as "4 weeks of treatment (4 active, twice a week, ABCR sessions or 2 weekly control group sessions)".

Effect of action-based cognitive remediation on cognition and neural activity in bipolar disorder: study protocol for a randomized controlled trial.

BACKGROUND: Cognitive impairment is present in bipolar disorder (BD) during the acute and remitted phases and hampers functional recovery. However, there is currently no clinically available treatment with direct and lasting effects on cognitive impairment in BD. We will examine the effect of a novel form of cognitive remediation, action-based cognitive remediation (ABCR), on cognitive impairment in patients with BD, and explore the neural substrates of potential treatment efficacy on cognition. METHODS/DESIGN: The trial has a randomized, controlled, parallel-group design. In total, 58 patients with BD in full or partial remission aged 18-55 years with objective cognitive impairment will be recruited. Participants are randomized to 10 weeks of ABCR or a control group. Assessments encompassing neuropsychological testing and mood ratings, and questionnaires on subjective cognitive complaints, psychosocial functioning, and quality of life are carried out at baseline, after 2 weeks of treatment, after the end of treatment, and at a six-month-follow-up after treatment completion. Functional magnetic resonance imaging scans are performed at baseline and 2 weeks into treatment. The primary outcome is a cognitive composite score spanning verbal memory, attention, and executive function. Two complete data sets for 52 patients will provide a power of 80% to detect a clinically relevant between-group difference on the primary outcome. Behavioral data will be analyzed using mixed models in SPSS while MRI data will be analyzed with the FMRIB Expert Analysis Tool (FEAT). Early treatment-related changes in neural activity from baseline to week 2 will be investigated for the dorsal prefrontal cortex and hippocampus as the regions of interest and with an exploratory whole-brain analysis. DISCUSSION: The results will provide insight into whether ABCR has beneficial effects on cognition and functioning in remitted patients with BD. The results will also provide insight into early changes in neural activity associated with improvement of cognition, which can aid future treatment development. TRIAL REGISTRATION: Clinicaltrials.gov , NCT03295305 . Registered on 26 September 2017.

Does a single session of electroconvulsive therapy alter the neural response to emotional faces in depression? A randomised sham-controlled functional magnetic resonance imaging study.

Negative neurocognitive bias is a core feature of major depressive disorder that is reversed by pharmacological and psychological treatments. This double-blind functional magnetic resonance imaging study investigated for the first time whether electroconvulsive therapy modulates negative neurocognitive bias in major depressive disorder. Patients with major depressive disorder were randomised to one active ( n=15) or sham electroconvulsive therapy ( n=12). The following day they underwent whole-brain functional magnetic resonance imaging at 3T while viewing emotional faces and performed facial expression recognition and dot-probe tasks. A single electroconvulsive therapy session had no effect on amygdala response to emotional faces. Whole-brain analysis revealed no effects of electroconvulsive therapy versus sham therapy after family-wise error correction at the cluster level, using a cluster-forming threshold of Z>3.1 ( p<0.001) to secure family-wise error <5%. Groups showed no differences in behavioural measures, mood and medication. Exploratory cluster-corrected whole-brain analysis ( Z>2.3; p<0.01) revealed electroconvulsive therapy-induced changes in parahippocampal and superior frontal responses to fearful versus happy faces as well as in fear-specific functional connectivity between amygdala and occipito-temporal regions. Across all patients, greater fear-specific amygdala - occipital coupling correlated with lower fear vigilance. Despite no statistically significant shift in neural response to faces after a single electroconvulsive therapy session, the observed trend changes after a single electroconvulsive therapy session point to an early shift in emotional processing that may contribute to antidepressant effects of electroconvulsive therapy.

Study Protocol on Ecological Momentary Assessment of Health-Related Quality of Life Using a Smartphone Application.

Health-Related Quality of Life (HRQoL) is a construct of increasing importance in modern healthcare, and has typically been assessed using retrospective instruments. While such measures have been shown to have predictive utility for clinical outcomes, several cognitive biases associated with human recall and current mood state may undermine their validity and reliability. Retrospective tools can be further criticized for their lack of ecology, as individuals are usually assessed in less natural settings such as hospitals and health centers, and may be obliged to spend time and money traveling to receive assessment. Ecological momentary assessment (EMA) is an alternative, as mobile assessment using mobile health (mHealth) technology has the potential to minimize biases and overcome many of these limitations. Employing an EMA methodology, we will use a smartphone application to collect data on real-time HRQoL, with an adapted version of the widely used WHOQOL-BREF questionnaire. We aim to recruit a total of 450 healthy participants. Participants will be prompted by the application to report their real-time HRQoL over 2 weeks together with information on mood and current activities. At the end of 2 weeks, they will complete a retrospective assessment of their HRQoL and they will provide information about their sleep quality and perceived stress. The psychometric properties of real-time HRQoL will be assessed, including analysis of the factorial structure, reliability and validity of the measure, and compared with retrospective HRQoL responses for the same 2-week testing period. Further, we aim to identify factors associated with real-time HRQoL (e.g., mood, activities), the feasibility of the application, and within- and between-person variability in real-time HRQoL. We expect real-time HRQoL to have adequate validity and reliability, and positive responses on the feasibility of using a smartphone application for routine HRQoL assessment. The direct comparison of real-time and retrospective measures in this study will provide important novel insight into the efficacy of mHealth applications for HRQoL assessment. If shown to be valid, reliable and feasible for the collection of HRQoL data, mHealth applications may have future potential for facilitating clinical assessment, patient-physician communication, and monitoring individual HRQoL over course of treatment.