Effects of erythropoietin on cognitive impairment and prefrontal cortex activity across affective disorders: A randomized, double-blinded, placebo-controlled trial.

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.

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.

Whole genome sequencing in clinical practice.

Whole genome sequencing (WGS) is becoming the preferred method for molecular genetic diagnosis of rare and unknown diseases and for identification of actionable cancer drivers. Compared to other molecular genetic methods, WGS captures most genomic variation and eliminates the need for sequential genetic testing. Whereas, the laboratory requirements are similar to conventional molecular genetics, the amount of data is large and WGS requires a comprehensive computational and storage infrastructure in order to facilitate data processing within a clinically relevant timeframe. The output of a single WGS analyses is roughly 5 MIO variants and data interpretation involves specialized staff collaborating with the clinical specialists in order to provide standard of care reports. Although the field is continuously refining the standards for variant classification, there are still unresolved issues associated with the clinical application. The review provides an overview of WGS in clinical practice - describing the technology and current applications as well as challenges connected with data processing, interpretation and clinical reporting.

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.

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.

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.

Cognitive training with fully immersive virtual reality in patients with neurological and psychiatric disorders: A systematic review of randomized controlled trials.

Cognitive impairment occurs across several neuropsychiatric diseases and impede everyday functioning and quality of life. Fully immersive Virtual Reality (VR) aid motivation and engagement and therefore has a potential to help overcome the obstacles in the field of cognitive rehabilitation. The aim of this systematic review is to investigate whether VR can be a useful intervention in cognitive rehabilitation transdiagnostically. We identified nine studies with randomized controlled trials following the PRISMA guidelines in databases Pubmed, Embase and PsychInfo. The trials were all evaluated through Cochrane Collaboration's Risk of Bias. The studies were conducted in patients with mild cognitive impairment (k=4), schizophrenia (k=3), ADHD (k=1), or stroke (k=1) and involved 6-12 weeks of training. Overall, results showed improvement in some domains of cognition, primarily executive function and attention. The studies were pilot studies with 6-34 participants per treatment group. Risk of bias was either high (k=3) or moderate (some concerns) (k=6). Key reasons were suboptimal statistical analyses and lack of clarification on randomization and blinding of participants and assessors. In conclusion, this review found promising evidence for VR cognitive rehabilitation for neuropsychiatric illnesses. However, larger and methodologically stronger studies are warranted to establish the full potential of VR.

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.

The Internet-Based Cognitive Assessment Tool: System Design and Feasibility Study.

BACKGROUND: Persistent cognitive impairment is prevalent in unipolar and bipolar disorders and is associated with decreased quality of life and psychosocial dysfunction. The screen for cognitive impairment in psychiatry (SCIP) test is a validated paper-and-pencil instrument for the assessment of cognition in affective disorders. However, there is no digital cognitive screening tool for the brief and accurate assessment of cognitive impairments in this patient group. OBJECTIVE: In this paper, we present the design process and feasibility study of the internet-based cognitive assessment tool (ICAT) that is designed based on the cognitive tasks of the SCIP. The aims of this feasibility study were to perform the following tasks among healthy individuals: (1) evaluate the usability of the ICAT, (2) investigate the feasibility of the ICAT as a patient-administered cognitive assessment tool, and (3) examine the performance of automatic speech recognition (ASR) for the assessment of verbal recall. METHODS: The ICAT was developed in a user-centered design process. The cognitive measures of the ICAT were immediate and delayed recall, working memory, and psychomotor speed. Usability and feasibility studies were conducted separately with 2 groups of healthy individuals (N=21 and N=19, respectively). ICAT tests were available in the English and Danish languages. The participants were asked to fill in the post study system usability questionnaire (PSSUQ) upon completing the ICAT test. Verbal recall in the ICAT was assessed using ASR, and the performance evaluation criterion was word error rate (WER). A Pearson 2-tailed correlation analysis significant at the .05 level was applied to investigate the association between the SCIP and ICAT scores. RESULTS: The overall psychometric factors of PSSUQ for both studies gave scores above 4 (out of 5). The analysis of the feasibility study revealed a moderate to strong correlation between the total scores of the SCIP and ICAT (r=0.63; P=.009). There were also moderate to strong correlations between the SCIP and ICAT subtests for immediate verbal recall (r=0.67; P=.002) and psychomotor speed (r=0.71; P=.001). The associations between the respective subtests for working memory, executive function, and delayed recall, however, were not statistically significant. The corresponding WER for English and Danish responses were 17.8% and 6.3%, respectively. CONCLUSIONS: The ICAT is the first digital screening instrument modified from the SCIP using Web-based technology and ASR. There was good accuracy of the ASR for verbal memory assessment. The moderate correlation between the ICAT and SCIP scores suggests that the ICAT is a valid tool for assessing cognition, although this should be confirmed in a larger study with greater statistical power. Taken together, the ICAT seems to be a valid Web-based cognitive assessment tool that, after some minor modifications and further validation, may be used to screen for cognitive impairment in clinical settings.