Assessment of the neuronal underpinnings of cognitive impairment in bipolar disorder with a picture encoding paradigm and methodological lessons learnt.

BACKGROUND: Mood disorders are often associated with persistent cognitive impairments. However, pro-cognitive treatments are essentially lacking. This is partially because of poor insight into the neurocircuitry abnormalities underlying these deficits and their change with illness progression. AIMS: This functional magnetic resonance imaging (fMRI) study investigates the neuronal underpinnings of cognitive impairments and neuronal change after mood episodes in remitted patients with bipolar disorder (BD) using a hippocampus-based picture encoding paradigm. METHODS: Remitted patients with BD (n=153) and healthy controls (n=52) were assessed with neuropsychological tests and underwent fMRI while performing a strategic picture encoding task. A subgroup of patients (n=43) were rescanned after 16 months. We conducted data-driven hierarchical cluster analysis of patients' neuropsychological data and compared encoding-related neuronal activity between the resulting neurocognitive subgroups. For patients with follow-up data, effects of mood episodes were assessed by comparing encoding-related neuronal activity change in BD patients with and without episode(s). RESULTS: Two neurocognitive subgroups were revealed: 91 patients displayed cognitive impairments while 62 patients were cognitively normal. No neuronal activity differences were observed between neurocognitive subgroups within the dorsal cognitive control network or hippocampus. However, exploratory whole-brain analysis revealed lower activity within a small region of middle temporal gyrus in impaired patients, which significantly correlated with poorer neuropsychological performance. No changes were observed in encoding-related neuronal activity or picture recall accuracy with the occurrence of mood episode(s) during the follow-up period. CONCLUSION: Memory encoding fMRI paradigms may not capture the neuronal underpinnings of cognitive impairment or effects of mood episodes.

Characteristics influencing expected cognitive performance during hypoglycaemia in type 2 diabetes.

BACKGROUND: Acute hypoglycaemia is associated with cognitive impairment in patients with type 2 diabetes. However, there is limited understanding of the relationship between patients' expected cognitive difficulties and their objectively-measured deficits during non-severe hypoglycaemia. OBJECTIVE: This report investigates demographic and clinical factors associated with the discrepancy between expected (i.e., self-evaluated) and measurable (i.e., neuropsychological) cognitive functions in patients with type 2 diabetes during acute non-severe hypoglycaemia. METHODS: We performed an analysis of factors associated with the relationship between expected and measurable cognitive performance for data collected from a cohort of patients with type 2 diabetes (N = 25). Patients attended two experimental visits during which we performed hyper-insulinaemic glucose clamping; (i) non-severe hypoglycaemic clamp (plasma glucose (PG): 3.1 ±â€¯0.3 mmol/L) and (ii) normoglycaemic clamp (PG: 5.8 ±â€¯0.3 mmol/L), as part of a double-blinded cross-over study. During hypoglycaemia, patients' expected cognitive performance was assessed with a visual analogue scale after which objective cognitive functions were assessed with a neuropsychological test battery. We computed a global 'cognitive discrepancy' composite variable with score values on a scale between -10 and +10 using a novel statistical formula that creates a discrepancy score between subjective and objective cognition. Positive values reflect more expected than objectively-measured difficulties, while negative values reflect disproportionately more objectively-measured than expected cognitive difficulties. We used paired samples t-tests to compare degree of cognitive discrepancy between conditions of hypo- and normoglycaemia, while multiple regression analysis was performed to identify factors associated with the degree and direction of the cognitive discrepancy. The significance level for the analyses was p ≤ 0.05 (two-tailed). RESULTS: Patients generally underestimated their cognitive abilities (M = 1.6, SD = 3.3) during hypoglycaemia compared to normoglycaemia (M = -1.0, SD = 3.5) (p = 0.2), t(23) = 2.9, p < 0.01. Underestimation of cognitive capacity during hypoglycaemia was more pronounced for patients with younger age (ß = 0.5, p = 0.02), higher verbal IQ (ß = 0.5, p = 0.03), and more hypoglycaemia-related shakiness (ß = 0.4, p = 0.03). LIMITATIONS: The modest sample size limits the generalizability of the findings. CONCLUSIONS: Patients with type 2 diabetes underestimated their cognitive abilities during non-severe hypoglycaemic states, especially those with younger age, higher IQ, and more hypoglycaemia-related shakiness. These patients may thus have excessive preoccupations with their cognitive difficulties in relation to cognitively challenging daily life situations.

Relation between functional and cognitive impairments in remitted patients with bipolar disorder and suggestions for trials targeting cognition: An exploratory study.

BACKGROUND: Trials targeting cognition in bipolar disorder (BD) are advised to include a measure of functional capacity as key secondary or co-primary outcome to assess whether treatment efficacy on cognition translates into enhanced functional capacity. However, it is unclear which measure of functional capacity shows the strongest association with objectively-measured cognition and may thus be best suited for inclusion in cognition trials. METHODS: Participants (N = 58) with BD in partial or full remission with objective cognitive impairment and healthy controls (N = 37) were assessed with mood ratings and were given a comprehensive battery of neuropsychological tests and a questionnaire assessing subjective cognitive function, respectively. They were also assessed with performance-based, interview-based and self-reported measures of functional capacity. Associations between objective and subjective cognition and measures of functional capacity were assessed with correlation analyses. For significant correlations, multiple regression analyses were conducted to assess if the associations remained significant after adjustment for clinical and demographic variables. RESULTS: Objectively-measured cognition was directly associated with performance-based functional capacity (ß = 0.37, p < 0.01) also after adjustment for clinical and demographic variables, but not with self-reported or interview-based functional capacity (ps ≥0 .20). In contrast, subjective cognitive complaints were associated with self-reported (ß = 0.59, p < 0.01) and interview-based functional capacity (ß = 0.47, p < 0.01), but not performance-based functional capacity (ps ≥ 0.28). LIMITATIONS: The cross-sectional design and modest sample size. CONCLUSIONS: A performance-based measure of functional capacity seems most feasible for inclusion as a secondary outcome in cognition trials to capture improved functional capacity following treatment-related improvements in cognition.

Clinical characteristics associated with the discrepancy between subjective and objective cognitive impairment in depression.

BACKGROUND: Patients with unipolar disorder (UD) commonly experience cognitive dysfunction during symptomatic and remitted phases. However, it is not necessarily the patients with the greatest subjective complaints, who display the largest objectively-measured deficits on neuropsychological tests. OBJECTIVE: This report investigated the demographic and clinical factors associated with the discrepancy between subjective and objective measures of cognition in two separate depressed patient populations in Denmark and New Zealand, respectively, using a new methodology. METHODS: Data from 137 depressed patients and 103 healthy controls including neuropsychological test scores, self-reported cognitive difficulties, and ratings of mood were pooled from two studies conducted in Copenhagen, Denmark, and Christchurch, New Zealand, respectively. Cognitive discrepancy scores were calculated using a novel methodology, with positive values indicating disproportionately more subjective than objective difficulties (i.e., "sensitivity") and negative values indicating more objective than subjective impairments (i.e., "stoicism"). RESULTS: In the Danish partially remitted patient sample, greater 'sensitivity' was associated with more subsyndromal depression severity (standardized Beta (std. ß )= 0.4, p < 0.01)), illness duration (std. ß = 0.4, p < 0.01), and younger age (std. ß = 0.6, p < 0.001). This association was replicated in the New Zealand sample of more symptomatic patients (p-values ≤ 0.05). LIMITATIONS: The cross-sectional design hampered causal inferences. We had obtained different measures of objective and subjective cognition from the two studies. CONCLUSIONS: Patients with more depressive symptoms and younger age overreported cognitive impairments across all illness states. The use of an objective cognition screener thus seems particularly relevant for these patients to assess whether subjective complaints are accompanied by measurable cognitive deficits.

Systematic review of randomized controlled trials of candidate treatments for cognitive impairment in depression and methodological challenges in the field.

Cognitive impairment is a core feature of Major Depressive Disorder (MDD) but treatments targeting cognition are lacking. Numerous pre-clinical and clinical studies have investigated potential cognition treatments, but overall the evidence is conflicting. We conducted a systematic search following the PRISMA guidelines on PubMed and PsychInfo to evaluate the extant evidence and methodological challenges in randomized controlled trials (RCTs) of biological, psychological and behavioural candidate treatments targeting cognition in MDD. Inclusion criteria were RCTs with a placebo control assessing potential pro-cognitive effects of candidate treatments in MDD. Two independent authors reviewed the studies and assessed their risk of bias with the Cochrane Collaboration׳s Risk of Bias tool. Twenty-eight eligible studies (24 biological and four psychological or behavioural studies) were identified. Cognition was the primary treatment target in ten (36%) trials and an additional treatment outcome together with mood symptoms in 18 (64%) trials. The risk of bias was high or unclear in 93% of trials due to potential selective outcome reporting or 'pseudospecificity' (unspecific cognitive improvement due to reduced depression severity), and/or insufficient details on how the allocation sequence was generated or how blinding was maintained. Several promising treatments were identified, including vortioxetine, erythropoietin, transcranial direct current stimulation and cognitive remediation. However, several common methodological challenges may impede advances in the field. In particular, future trials should select one cognitive composite score as primary outcome, screen for cognitive impairment before inclusion of participants and address 'pseudospecificity' issues. Together, these strategies may improve the success of future cognition trials in MDD.

Predictors of the discrepancy between objective and subjective cognition in bipolar disorder: a novel methodology.

OBJECTIVE: The poor relationship between subjective and objective cognitive impairment in bipolar disorder (BD) is well-established. However, beyond simple correlation, this has not been explored further using a methodology that quantifies the degree and direction of the discrepancy. This study aimed to develop such a methodology to explore clinical characteristics predictive of subjective-objective discrepancy in a large BD patient cohort. METHODS: Data from 109 remitted BD patients and 110 healthy controls were pooled from previous studies, including neuropsychological test scores, self-reported cognitive difficulties, and ratings of mood, stress, socio-occupational capacity, and quality of life. Cognitive symptom 'sensitivity' scores were calculated using a novel methodology, with positive scores reflecting disproportionately more subjective complaints than objective impairment and negative values reflecting disproportionately more objective than subjective impairment ('stoicism'). RESULTS: More subsyndromal depressive and manic symptoms, hospitalizations, BD type II, and being male positively predicted 'sensitivity', while higher verbal IQ predicted more 'stoicism'. 'Sensitive' patients were characterized by greater socio-occupational difficulties, more perceived stress, and lower quality of life. CONCLUSION: Objective neuropsychological assessment seems especially warranted in patients with (residual) mood symptoms, BD type II, chronic illness, and/or high IQ for correct identification of cognitive deficits before commencement of treatments targeting cognition.