Digit Symbol Substitution Task Research Articles

Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial

RationaleTreatment with a highly purified oral solution of cannabidiol (CBD), derived from the plant Cannabis sativa L., demonstrated some evidence of central nervous system (CNS)-related adverse events in patients enrolled in phase 3 trials for treatment of childhood-onset epilepsy. Cannabidiol was categorized as a Schedule 1 substance by the United States Drug Enforcement Administration; therefore, it was important to test CBD for human abuse potential. MethodsThis was a single-dose, randomized, double-blind, double-dummy, placebo- and active-controlled crossover trial. The abuse potential of single oral doses of plant-derived pharmaceutical formulations of highly purified CBD (Epidiolex®; 750 mg, 1500 mg, and 4500 mg) was compared with that of single oral doses of alprazolam (2 mg), dronabinol (10 mg and 30 mg), and placebo in healthy recreational polydrug users. The primary endpoint to assess abuse potential was the maximum effect (Emax) on Drug-Liking visual analog scale (VAS). Other measurements included Emax on Overall Drug-Liking VAS, Take Drug Again VAS, positive and negative effects, other subjective effects, and Drug Similarity VAS. Cognitive and psychomotor functions were assessed using the Divided Attention Test, the Hopkins Verbal Learning Test—Revised, and the Digit–Symbol Substitution Task. Pharmacokinetic parameters were determined for CBD and its major metabolites. Standard safety measures and adverse events were assessed. Principal resultsOf 95 eligible subjects, 43 qualified for the treatment phase, received at least 1 dose of investigational medicinal product, and were included in safety assessments; 35 subjects were included in the pharmacodynamic analysis. Subjects receiving alprazolam and dronabinol had significantly higher Drug-Liking Emax (P < 0.0001) compared with those receiving placebo, confirming study validity. Compared with placebo, Drug-Liking was not significantly different for subjects taking 750-mg CBD (P = 0.51). Drug-Liking Emax values for 1500-mg and 4500-mg CBD were significantly different from placebo (P = 0.04 and 0.002, respectively); however, the mean differences were <10 points on VAS compared with >18-point differences between positive controls and placebo. Alprazolam and dronabinol had significantly higher Drug-Liking, Overall-Liking, and Take Drug Again VAS Emax values compared with all doses of CBD (P ≤ 0.004). In contrast to alprazolam, CBD administration had no observable effect on cognitive/psychomotor tests. Pharmacokinetic parameters for CBD in this trial were consistent with previous studies. The majority of adverse events reported during the trial were of mild or moderate severity; no serious adverse events or deaths were reported. ConclusionAdministration of a therapeutic dose of CBD (750 mg) showed significantly low abuse potential in a highly sensitive population of polydrug users. Although high and supratherapeutic doses of CBD (1500 mg and 4500 mg, respectively) had detectable subjective effects compared with placebo; the effects were significantly lower than those observed with alprazolam and dronabinol.

Eye movements - an early marker of cognitive dysfunctions.

Cognitive impairments or dysfunctions are one of the major issues of aging population and medical conditions like brain damage, stroke etc. Assessment of cognitive functioning is usually done by medical practitioners using various standard psychological tests which require expert interventions. In the present study we have tried to use eye tracking as a possible option for assessment of cognitive functions while executing a digitized digit symbol substitution task. The standard task has been modified so that more detail insights of one's cognitive state can be obtained without any manual intervention. Results show that it is possible to get more information like attention, perception etc. It also gives insight about the performance of an individual and can be used for analyzing the executive functions like processing speed, memory etc.

Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function.

Neurodegenerative disorders are associated with impaired cognitive function and worse physical health outcomes. This study aims to test whether polygenic risk for Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), or frontotemporal dementia (FTD) is associated with cognitive function and physical health in the UK Biobank, a cohort of healthy individuals. Group-based analyses were then performed to compare the top and bottom 10% for the three neurodegenerative polygenic risk scores; these groups were compared on the cognitive and physical health variables. Higher polygenic risk for AD, ALS, and FTD was associated with lower cognitive performance. Higher polygenic risk for FTD was also associated with increased forced expiratory volume in 1s and peak expiratory flow. A significant group difference was observed on the symbol digit substitution task between individuals with high polygenic risk for FTD and high polygenic risk for ALS. The results suggest some overlap between polygenic risk for neurodegenerative disorders, cognitive function and physical health.

Cognitive performance in adolescents with Delayed Sleep-Wake Phase Disorder: Treatment effects and a comparison with good sleepers

The present study aimed to investigate whether Australian adolescents with Delayed Sleep-Wake Phase Disorder have impaired cognitive performance and whether chronobiological treatment for Delayed Sleep-Wake Phase Disorder improves adolescents' sleep, daytime functioning and cognitive performance. Adolescents with Delayed Sleep-Wake Phase Disorder (mean = 15.68 ± 2.1 y, 62% f) reported significantly later sleep timing (d = 1.03–1.45), less total sleep time (d = 0.82) and greater daytime sleepiness (d = 2.66), fatigue (d = 0.63) and impairment (d = 2.41), compared to good sleeping adolescents (mean = 15.9 ± 2.4 y, 75% f). However, there were no significant between-group differences (all p > 0.05) in performance on the Operation Span (ηp2 = 0.043), Digit Span (forwards: ηp2 = 0.002, backwards: ηp2 = 0.003), Letter Number Sequencing (ηp2 < 0.001) (working memory) and Digit-Symbol Substitution Tasks (ηp2 = 0.010) (processing speed). Adolescents with Delayed Sleep-Wake Phase Disorder went on to receive 3 weeks of light therapy. At 3 months post-treatment, adolescents with Delayed Sleep-Wake Phase Disorder reported significantly advanced sleep timing (d = 0.56–0.65), greater total sleep time (d = 0.52) and improved daytime sleepiness (d = 1.33), fatigue (d = 0.84) and impairment (d = 0.78). Performance on the Operation Span (d = 0.46), Letter Number Sequencing (d = 0.45) and Digit-Symbol Substitution tasks (d = 0.57) also significantly improved.

Cognitive function and unsafe driving acts during an on-road test among community-dwelling older adults with cognitive impairments.

To examine the relationship between cognitive function and unsafe driving acts among community-dwelling older adults with cognitive impairments. Participants (n = 160) were older residents of Obu, Japan, aged ≥65 years with cognitive impairments. They regularly drove and were assessed for the number of unsafe driving acts without adequate verification during an on-road test. We also evaluated cognitive function (attention, executive function and processing speed). Other examined variables included demographics, driving characteristics and visual condition. Participants were classified into two groups according to the number of unsafe driving acts as follows: high group (≥4 unsafe driving acts) and low group (≤3 unsafe driving acts). The high group participants were older in age (P < 0.001) and obtained a lower score on the symbol digit substitution task (P = 0.002) than the low group. The number of unsafe driving acts showed modest significant positive correlations with age (r = 0.396, P < 0.001). The symbol digit substitution task score was significantly associated with the number of unsafe driving acts (β = -0.196, P < 0.05) after adjusting for age group. Processing speed was associated with unsafe driving acts that became worse with increasing age. Future study will be required to longitudinally examine the influence of processing speed on traffic accidents for those with cognitive impairments. Geriatr Gerontol Int 2018; 18: 847-852.

Associations of Nocturnal Blood Pressure With Cognition by Self-Identified Race in Middle-Aged and Older Adults: The GENOA (Genetic Epidemiology Network of Arteriopathy) Study.

BackgroundWhether the association of blood pressure (BP) during sleep (nocturnal BP) with cognition differs by race is unknown.Methods and ResultsParticipants in the GENOA (Genetic Epidemiology Network of Arteriopathy) Study underwent ambulatory BP measurements, brain magnetic resonance imaging, and cognitive function testing (the Rey Auditory Verbal Learning Test, the Digit Symbol Substitution Task, and the Trail Making Test Part B) between 2000 and 2007. We examined multivariable linear regression models of the nocturnal BP‐cognition association. Among 755 participants (mean age, 63 years; 64% women; 42% self‐identified black race; 76% taking antihypertensive medication), mean nocturnal systolic BP (SBP)/diastolic BP was 126/69 mm Hg, daytime SBP/diastolic BP level was 139/82 mm Hg, and mean reduction in SBP from day to night (dipping) was 9%. Among the entire sample, a race interaction was observed in Digit Symbol Substitution Task and Trail Making Test Part B (both P<0.15). Race‐stratified analyses showed that a 1‐SD increase in nocturnal SBP levels was associated with poorer Digit Symbol Substitution Task and log‐transformed Trail Making Test Part B scores (unstandardized regression coefficient [95% confidence interval]: −1.98 [−3.28 to −0.69] and 0.06 [0.004–0.12]; both P<0.05) in black but not white individuals. Additional adjustments for white matter hyperintensity volumes or brain atrophy, measured via brain magnetic resonance imaging, did not change the results. Results were similar when nocturnal SBP dipping was assessed as the exposure, yet daytime SBP levels yielded no association with cognition.ConclusionsNocturnal SBP measurements may be useful in assessing the potential risk for lower cognitive function in middle‐aged and older adults, particularly in black individuals.

Can an app help identify psychomotor function impairments during drinking occasions in the real world? A mixed-method pilot study

ABSTRACTBackground: Being able to measure the acute effects of alcohol consumption on psychomotor functions in natural settings could be useful in injury prevention interventions. This study examined the feasibility and acceptability of collecting app-based measures of information processing, working memory, and gait stability during times of typical alcohol consumption among young adults. Methods: Ten young adults (aged 21–26) with hazardous drinking completed a baseline assessment and ecological momentary assessments (EMA) on 4 consecutive Fridays and Saturdays, every hour from 8 pm to 12 am. EMA assessed alcohol consumption and perceived intoxication, followed by a digit symbol substitution task (DSST), a visuospatial working memory task (VSWMT), and a 5-step tandem gait task (TGT). Exit interviews probed user experiences. Multilevel models explored relationships between estimated blood alcohol concentration (eBAC; mg/dL) and DSST and VSWMT performance. Results: Participants completed 32% of EMA. Higher rates of noninitiation occurred later in the evening and over time. In multilevel models, higher eBAC was associated with lower DSST scores. Eight out of 10 individuals had at least 1 drinking occasion when they did not perceive any intoxication. Lower DSST scores would identify impairment in 45% of these occasions. Exit interviews indicated that adding real-time feedback on task performance could increase awareness of alcohol effects. Conclusions: Collecting app-based psychomotor performance data from young adults during drinking occasions is feasible and acceptable, but strategies to reduce barriers to task initiation are needed. Mobile DSST is sensitive to eBAC levels and could identify occasions when an individual may not perceive impairments.

ELEVATED COGNITIVE COMPLEXITY AND APOLIPOPROTEIN E GENOTYPE IN YOUNG ADULTS

Behavioural and imaging studies of young adult carriers of the APOE ε4 allele (ε4+), the strongest genetic risk factor for sporadic Alzheimer's disease (AD), have demonstrated inconsistent performance differences when compared to non-ε4 carriers (ε4-). Differential responses to cognitive complexity or load may underlie the differences observed. Therefore, we examined whether an intensive time-pressured battery of cognitive tests would result in genotype performance differences. Young adults (25 ε4+ and 24 ε4-, aged 18–28 years) were administered an intensive time-pressured 30-minute battery of cognitive assessments, comprising arithmetic, WAIS digit span, prospective memory card-sort, colour stroop, and digit-symbol substitution tasks. Additional measures included NART-IQ, a Trait Anxiety Inventory, and the GRIT test of subjective effort. One-way ANOVAs (covarying for additional factors e.g. NART-IQ, trait anxiety) assessed differences in time-challenged cognitive performance. No genotype differences were seen in performance accuracy. ε4+ demonstrated slower performance across cognitive tasks with a reaction time component, including the arithmetic addition, subtraction, and switching tasks (p<.05). ε4- reported significantly greater subjective effort throughout. Differences in NART-IQ and anxiety scores may contribute: the ε4+ carriers exhibited higher IQ and trait anxiety scores than their ε4- peers. This study presents preliminary data exploring effects of cognitive challenge induced by a time-pressured battery of tasks. There was some evidence that genotype differences were associated with different strategies, with ε4+ taking more time, and ε4+ applying more effort, under a time-pressured paradigm. Future work will explore whether genotype differences reflect different responses to time intensive vs cognitive complexity manipulations, and whether any genotype differences are associated with structural or functional brain activation patterns.

0208 CIRCADIAN MISALIGNMENT IMPACTS ON HUMAN COGNITIVE PERFORMANCE

Shift work increases the risk for disorders of sleep and human error. Overnight operations pose a challenge because our circadian biology promotes nocturnal sleep and daytime vigilance and performance, which may underlie cognitive vulnerability at night. Here we investigated if daily circadian misalignment, typical for night shift work, adversely impacts cognition across diverse cognitive domains. Thirteen healthy young individuals (27.8 ± 9.5 y; 7 men) underwent two 8-day protocols including either 4 days of circadian alignment (day shifts) or misalignment (night shifts; 12-h inverted behavioral/environmental cycles). Cognitive testing included tasks of sustained attention (Psychomotor Vigilance Task; PVT), cognitive throughput (Addition Task; ADD), information processing (Digit Symbol Substitution Task; DSST) visual-spatial performance (Unstable Tracking-Task; TKT) and declarative memory (Probed Recall Memory; PRM), all of which are sensitive to increased sleep pressure and circadian phase. Circadian misalignment over successive days increased cognitive vulnerability by ~10–20% on sustained attention, cognitive throughput, information processing and visual-motor performance, as compared circadian alignment. Attention, as indexed by PVT performance, was acutely impaired during the first 2 days of misalignment with subsequent improvement after 3 days (interaction of “circadian alignment/misalignment”, “day” and “time since awakening”, p=0.006). Conversely, learning, as indexed by changes in ADD, DSST and TKT performance, significantly improved across multiple days of circadian alignment, while no improvement occurred under misalignment (interaction of “circadian alignment/misalignment” and “day”, p<0.05). Lastly, we investigated if the effects of circadian misalignment on performance were also mediated by prior sleep-wake history. Accordingly, lower sleep efficiency in the sleep episode before cognitive testing significantly impaired performance (interaction of “sleep efficiency”, “circadian alignment/misalignment” and “night”; p<0.05). Our data indicate that daily circadian misalignment may explain cognitive vulnerabilities experienced by night workers, and provide a biological framework for the development of countermeasures against adverse cognitive effects in this vulnerable population. National Heart, Lung, and Blood Institute (NHLBI) Grant R01 HL094806, Clinical Translational Science Award UL1RR025758, and Brigham and Women’s Hospital from the National Center for Research Resources.

Association of Social Frailty With Both Cognitive and Physical Deficits Among Older People

ObjectivesOur objective was to investigate the association between social frailty and cognitive and physical function among older adults. DesignThis was a cross-sectional study. SettingWe examined community-dwelling adults in Japan. ParticipantsParticipants comprised 4425 older Japanese people from the National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes. MeasurementsSocial frailty was defined by using responses to 5 questions (going out less frequently, rarely visiting friends, feeling unhelpful to friends or family, living alone, and not talking with someone every day). Participants showing none of these components were considered nonfrail; those showing 1 component were considered prefrail; and those showing 2 or more components were considered frail. To screen for cognitive deficits, we assessed memory, attention, executive function, and processing speed. Having 2 or more tests with age-adjusted scores of at least 1.5 standard deviations below the reference threshold was sufficient to be characterized as cognitively deficient. To screen for physical function deficits, we assessed walking speed (<1.0 m/s cut-off) and grip strength (<26 kg for men; <18 kg for women cut-off). Scoring below the cut-off point on 1 or more tests was sufficient to be characterized as physically deficient. ResultsThe prevalence of social frailty was the following: nonfrailty, 64.1% (N = 2835); social prefrailty, 24.8% (N = 1097); social frailty, 11.1% (N = 493; P for trend < .001). All cognitive function tests (word list memory, Trail Making Test parts A and B, and the symbol digit-substitution task) significantly varied between social frailty groups; physical function (gait speed and grip strength) also varied between social frailty groups (all Ps for trend <.001). Referred to social nonfrailty, social frailty was independently associated with each cognitive deficit (odds ratio = 1.61, 95% confidence interval 1.13–2.30) and deficits in physical function (odds ratio = 1.99, 95% confidence interval 1.57–2.52) after adjusting for covariates. ConclusionsThis study revealed that social frailty is associated with both cognitive and physical function among Japanese older adults. And social frailty status was also negatively associated with physical function. Further studies are needed to elucidate if a casual association exists between social frailty and cognitive and physical function.

Low doses of mirtazapine or quetiapine for transient insomnia: A randomised, double-blind, cross-over, placebo-controlled trial.

Low doses of the antidepressant mirtazapine or the neuroleptic quetiapine are often prescribed off-label for insomnia. However, studies on the effects on sleep and hangover effects the following day are scarce. In this randomised, double-blind, cross-over, placebo-controlled trial, the influence of 7.5 mg mirtazapine and 50 mg quetiapine on both normal sleep and sleep disturbed by acoustic stress (traffic noise) as a model for transient insomnia was assessed. Additionally, hangover effects on next-day alertness and cognitive functioning were examined. A total of 19 healthy men without sleep complaints completed three treatment sessions, each session consisting of three consecutive nights in one of the mirtazapine, quetiapine or placebo conditions. Sleep was assessed using polysomnography and the Leeds Sleep Evaluation Questionnaire. Daytime sleepiness and cognitive functioning were assessed using the Leeds Sleep Evaluation Questionnaire, Karolinska Sleepiness Scale, Digit Symbol Substitution Task, Psychomotor Vigilance Task and an addition task. Under acoustic stress, both mirtazapine and quetiapine increased total sleep time by half an hour and reduced the number of awakenings by 35-40% compared to placebo. While quetiapine specifically increased the duration of non-rapid eye movement sleep, stage N2, mirtazapine mainly increased deep sleep stage N3. Subjects reported that both mirtazapine and quetiapine eased getting to sleep and improved sleep quality. Both drugs caused daytime sleepiness and lessened sustained attention. These findings support the use of low doses of mirtazapine and quetiapine for the treatment of insomnia. Further prospective studies on the long-term effects regarding effectiveness and adverse effects are needed.

The impact of meal timing on performance, sleepiness, gastric upset, and hunger during simulated night shift.

This study examined the impact of eating during simulated night shift on performance and subjective complaints. Subjects were randomized to eating at night (n=5; 23.2 ± 5.5 y) or not eating at night (n=5; 26.2 ± 6.4 y). All participants were given one sleep opportunity of 8 h (22:00 h-06:00 h) before transitioning to the night shift protocol. During the four days of simulated night shift participants were awake from 16:00 h-10:00 h with a daytime sleep of 6 h (10:00 h-16:00 h). In the simulated night shift protocol, meals were provided at ≈0700 h, 1900 h and 0130 h (eating at night); or ≈0700 h, 0930 h, 1410 h and 1900 h (not eating at night). Subjects completed sleepiness, hunger and gastric complaint scales, a Digit Symbol Substitution Task and a 10-min Psychomotor Vigilance Task. Increased sleepiness and performance impairment was evident in both conditions at 0400 h (p<0.05). Performance impairment at 0400 h was exacerbated when eating at night. Not eating at night was associated with elevated hunger and a small but significant elevation in stomach upset across the night (p<0.026). Eating at night was associated with elevated bloating on night one, which decreased across the protocol. Restricting food intake may limit performance impairments at night. Dietary recommendations to improve night-shift performance must also consider worker comfort.

Predictors of Cognitive Decline in Older Adult Type 2 Diabetes from the Veterans Affairs Diabetes Trial.

Cognitive decline disproportionately affects older adult type 2 diabetes. We tested whether randomized intensive (INT) glucose-lowering reduces the rate(s) of cognitive decline in adults with advanced type 2 diabetes (mean: age, 60 years; diabetes duration, 11 years) from the Veterans Affairs Diabetes Trial. A battery of neuropsychological tests [digit span, digit symbol substitution (DSym), and Trails-making Test-Part B (TMT-B)] was administered at baseline in ~1700 participants and repeated at year 5. Thirty-seven risk factors were evaluated as predictors of cognitive decline in multivariable regression analyses. The mean age-adjusted DSym or TMT-B declined significantly in all study participants (P < 0.001). Randomized INT glucose-lowering did not significantly alter the rate of cognitive decline. The final model of risk factors associated with 5-year decline in age-adjusted TMT-B included as significant predictors: longer baseline diabetes duration (beta = -0.028; P = 0.0057), lower baseline diastolic blood pressure (BP; beta = 0.028; P = 0.002), and baseline calcium channel blocker medication use (beta = -0.639; P < 0.001). Higher baseline pulse pressure was significantly associated with decline in age-adjusted TMT-B suggesting a role for both higher systolic and lower diastolic BPs. Baseline thiazide diuretic use (beta = -0.549; P = 0.015) was an additional significant predictor of 5-year decline in age-adjusted digit symbol score. Post-baseline systolic BP-lowering was significantly associated (P < 0.001) with decline in TMT-B performance. There was a significant inverse association between post-baseline plasma triglyceride-lowering (P = 0.045) and decline in digit symbol substitution task performance. A 5-year period of randomized INT glucose-lowering did not significantly reduce the rate of cognitive decline in older-aged adults with type 2 diabetes. Systolic and diastolic BPs as well as plasma triglycerides appeared as modifiable risk factors of the rate of cognitive decline in older adult type 2 diabetes.

Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder

Previous data have demonstrated that administration of inflammatory cytokines or their inducers leads to altered basal ganglia function associated with reduced psychomotor speed. Decreased psychomotor speed, referred to clinically as psychomotor retardation, is a cardinal symptom of major depressive disorder (MDD) and has been associated with poor antidepressant treatment response. We therefore examined the association between plasma inflammatory markers and psychomotor speed in ninety-three un-medicated patients with MDD. Psychomotor speed was assessed by a range of neuropsychological tests from purely motor tasks (e.g. movement latency and finger tapping) to those that involved motor activity with increasing cognitive demand and cortical participation (e.g. Trails A and Digit Symbol Substitution Task (DSST)). Linear regression analyses were performed to determine the relationship of inflammatory markers and psychomotor task performance controlling for age, race, sex, education, body mass index, and severity of depression. MDD patients exhibited decreased psychomotor speed on all tasks relative to normative standards. Increased IL-6 was associated with decreased performance on simple and choice movement time tasks, whereas MCP-1 was associated with decreased performance on the finger tapping task and DSST. IL-10 was associated with increased performance on the DSST. In an exploratory principle component analysis including all psychomotor tasks, IL-6 was associated with the psychomotor speed factor. Taken together, the data indicate that a peripheral inflammatory profile including increased IL-6 and MCP-1 is consistently associated with psychomotor speed in MDD. These data are consistent with data demonstrating that inflammation can affect basal ganglia function, and indicate that psychomotor speed may be a viable outcome variable for anti-inflammatory therapies in depression and other neuropsychiatric disorders with increased inflammation.

Dopamine pathway gene variants may modulate cognitive performance in the DHS - Mind Study.

BackgroundThere is an established association between type 2 diabetes and accelerated cognitive decline. The exact mechanism linking type 2 diabetes and reduced cognitive function is less clear. The monoamine system, which is extensively involved in cognition, can be altered by type 2 diabetes status. Thus, this study hypothesized that sequence variants in genes linked to dopamine metabolism and associated pathways are associated with cognitive function as assessed by the Digit Symbol Substitution Task, the Modified Mini‐Mental State Examination, the Stroop Task, the Rey Auditory‐Verbal Learning Task, and the Controlled Oral Word Association Task for Phonemic and Semantic Fluency in the Diabetes Heart Study, a type 2 diabetes‐enriched familial cohort (n = 893).MethodsTo determine the effects of candidate variants on cognitive performance, genetic association analyses were performed on the well‐documented variable number tandem repeat located in the 3' untranslated region of the dopamine transporter, as well as on single‐nucleotide polymorphisms covering genes in the dopaminergic pathway, the insulin signaling pathway, and the convergence of both. Next, polymorphisms in loci of interest with strong evidence for involvement in dopamine processing were extracted from genetic datasets available in a subset of the cohort (n = 572) derived from Affymetrix® Genome‐Wide Human SNP Array 5.0 and 1000 Genomes imputation from this array.ResultsThe candidate gene analysis revealed one variant from the DOPA decarboxylase gene, rs10499695, to be associated with poorer performance on a subset of Rey Auditory‐Verbal Learning Task measuring retroactive interference (P = 0.001, β = −0.45). Secondary analysis of genome‐wide and imputed data uncovered another DOPA decarboxylase variant, rs62445903, also associated with retroactive interference (P = 7.21 × 10−7, β = 0.3). These data suggest a role for dopaminergic genes, specifically a gene involved in regulation of dopamine synthesis, in cognitive performance in type 2 diabetes.

A 30-Minute, but Not a 10-Minute Nighttime Nap is Associated with Sleep Inertia.

To assess sleep inertia following 10-min and 30-min naps during a simulated night shift. Thirty-one healthy adults (aged 21-35 y; 18 females) participated in a 3-day laboratory study that included one baseline (BL) sleep (22:00-07:00) and one experimental night involving randomization to either: total sleep deprivation (NO-NAP), a 10-min nap (10-NAP) or a 30-min nap (30-NAP). Nap opportunities ended at 04:00. A 3-min psychomotor vigilance task (PVT-B), digit-symbol substitution task (DSST), fatigue scale, sleepiness scale, and self-rated performance scale were undertaken pre-nap (03:00) and at 2, 17, 32, and 47 min post-nap. The 30-NAP (14.7 ± 5.7 min) had more slow wave sleep than the 10-NAP (0.8 ± 1.5 min; P < 0.001) condition. In the NO-NAP condition, PVT-B performance was worse than pre-nap (4.6 ± 0.3 1/sec) at 47 min post-nap (4.1 ± 0.4 1/sec; P < 0.001). There was no change across time in the 10-NAP condition. In the 30-NAP condition, performance immediately deteriorated from pre-nap (4.3 ± 0.3 1/sec) and was still worse at 47 min post-nap (4.0 ± 0.5 1/sec; P < 0.015). DSST performance deteriorated in the NO-NAP (worse than pre-nap from 17 to 47 min; P < 0.008), did not change in the 10-NAP, and was impaired 2 min post-nap in the 30-NAP condition (P = 0.028). All conditions self-rated performance as better than pre-nap for all post-nap test points (P < 0.001). This study is the first to show that a 10-min (but not a 30-min) nighttime nap had minimal sleep inertia and helped to mitigate short-term performance impairment during a simulated night shift. Self-rated performance did not reflect objective performance following a nap.

Cognitive Slowing in Gulf War Illness Predicts Executive Network Hyperconnectivity: Study in a Population-Representative Sample.

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.

Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression.

Inflammation and altered glutamate metabolism are two pathways implicated in the pathophysiology of depression. Interestingly, these pathways may be linked given that administration of inflammatory cytokines such as interferon-α to otherwise non-depressed controls increased glutamate in the basal ganglia and dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy (MRS). Whether increased inflammation is associated with increased glutamate among patients with major depression is unknown. Accordingly, we conducted a cross-sectional study of 50 medication-free, depressed outpatients using single-voxel MRS, to measure absolute glutamate concentrations in basal ganglia and dACC. Multivoxel chemical shift imaging (CSI) was used to explore creatine-normalized measures of other metabolites in basal ganglia. Plasma and cerebrospinal fluid (CSF) inflammatory markers were assessed along with anhedonia and psychomotor speed. Increased log plasma C-reactive protein (CRP) was significantly associated with increased log left basal ganglia glutamate controlling for age, sex, race, body mass index, smoking status and depression severity. In turn, log left basal ganglia glutamate was associated with anhedonia and psychomotor slowing measured by the finger-tapping test, simple reaction time task and the Digit Symbol Substitution Task. Plasma CRP was not associated with dACC glutamate. Plasma and CSF CRP were also associated with CSI measures of basal ganglia glutamate and the glial marker myoinositol. These data indicate that increased inflammation in major depression may lead to increased glutamate in the basal ganglia in association with glial dysfunction and suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation as measured by CRP.

Sleepiness and Cognitive Performance among Younger and Older Adolescents across a 28-Hour Forced Desynchrony Protocol.

Quantify the homeostatic and circadian effects on sleepiness and performance of adolescents. Examine age-related changes in homeostatic and circadian regulation of sleepiness and performance by comparing younger and older adolescent groups. Three-week laboratory study including 12 cycles of a 28-h forced desynchrony protocol. Controlled laboratory environment with individual sleep and performance testing rooms and shared common areas. Twenty-seven healthy adolescents including 16 females. Ages ranged from 9.6-15.2 years and participants were split into younger (n = 14 ages 9-12) and older (n = 13 ages 13-15) groups based on median age split of 13.0 years. N/A. Testing occurred every 2 h during scheduled wake periods. Measures included sleep latency during repeated nap opportunities and scores from a computerized neurobehavioral assessment battery including a 10-min psychomotor vigilance task, a digit symbol substitution task, and the Karolinska Sleepiness Scale. Significant main effects of circadian and homeostatic factors were observed, as well as several circadian and homeostatic interaction effects. Age group did not have a significant main effect on sleep and performance data. A significant interaction of circadian phase and age group was found for sleep latency, with younger adolescents showing greater circadian modulation than older teens during the circadian night. Adolescents demonstrated a similar pattern of response to forced desynchrony as reported for adults. Sleepiness and performance were affected by homeostatic and circadian factors, and age group did not interact with homoeostatic and circadian factors for subjective sleepiness and most performance metrics. Younger adolescents had a shorter latency to sleep onset than older during the circadian bin spanning 4 to 8 h after the onset of melatonin secretion.

Increased inflammation is associated with increased glutamate in the basal ganglia of depressed patients

Previous work by our group has demonstrated that administration of the inflammatory cytokine interferon (IFN)-alpha increases glutamate in the left basal ganglia and dorsal anterior cingulate cortex (dACC). IFN-alpha-induced increases in glutamate were in turn associated with depressive symptoms. We therefore assessed the impact of inflammatory status on CNS glutamate in patients with major depression. Proton magnetic resonance spectroscopy (MRS) was used to estimate absolute glutamate concentrations in the left basal ganglia and dACC of 44 medication-free depressed patients, and inflammation was assessed by measures of plasma c-reactive protein (CRP). Increased CRP was associated with increased left basal glutamate in both a linear and stepwise fashion (r = 0.43, p = 0.004 and F(2,43) = 4.42, p = 0.012 respectively). In turn, basal ganglia glutamate was positively correlated with scores of anhedonia and measures of simple reaction time and negatively correlated with scores on the Digit Symbol Substitution Task and the finger tapping test (all p<0.05). CRP was not associated with glutamate concentrations in the dACC. These data provide the first evidence that increased inflammation in major depression is associated with increased glutamate in the basal ganglia which in turn is associated with alterations in motivation and psychomotor activity. These data also suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation.