Comparisons of electrophysiological markers of impaired executive attention after traumatic brain injury and in healthy aging.

Executive attention impairments are a persistent and debilitating consequence of traumatic brain injury (TBI). To make headway towards treating and predicting outcomes following heterogeneous TBI, cognitive impairment specific pathophysiology first needs to be characterized. In a prospective observational study, we measured EEG during the attention network test aimed at detecting alerting, orienting, executive attention and processing speed. The sample (N = 110) of subjects aged 18-86 included those with and without traumatic brain injury: n = 27, complicated mild TBI; n = 5, moderate TBI; n = 10, severe TBI; n = 63, non-brain-injured controls. Subjects with TBI had impairments in processing speed and executive attention. Electrophysiological markers of executive attention processing in the midline frontal regions reveal that, as a group, those with TBI and elderly non-brain-injured controls have reduced responses. We also note that those with TBI and elderly controls have responses that are similar for both low and high-demand trials. In subjects with moderate-severe TBI, reductions in frontal cortical activation and performance profiles are both similar to that of controls who are ∼4 to 7 years older. Our specific observations of frontal response reductions in subjects with TBI and in older adults is consistent with the suggested role of the anterior forebrain mesocircuit as underlying cognitive impairments. Our results provide novel correlative data linking specific pathophysiological mechanisms underlying domain-specific cognitive deficits following TBI and with normal aging. Collectively, our findings provide biomarkers that may serve to track therapeutic interventions and guide development of targeted therapeutics following brain injuries.

Shared functional connections within and between cortical networks predict cognitive abilities in adult males and females.

A thorough understanding of sex-independent and sex-specific neurobiological features that underlie cognitive abilities in healthy individuals is essential for the study of neurological illnesses in which males and females differentially experience and exhibit cognitive impairment. Here, we evaluate sex-independent and sex-specific relationships between functional connectivity and individual cognitive abilities in 392 healthy young adults (196 males) from the Human Connectome Project. First, we establish that sex-independent models comparably predict crystallised abilities in males and females, but only successfully predict fluid abilities in males. Second, we demonstrate sex-specific models comparably predict crystallised abilities within and between sexes, and generally fail to predict fluid abilities in either sex. Third, we reveal that largely overlapping connections between visual, dorsal attention, ventral attention, and temporal parietal networks are associated with better performance on crystallised and fluid cognitive tests in males and females, while connections within visual, somatomotor, and temporal parietal networks are associated with poorer performance. Together, our findings suggest that shared neurobiological features of the functional connectome underlie crystallised and fluid abilities across the sexes.

Estimated Regional White Matter Hyperintensity Burden, Resting State Functional Connectivity, and Cognitive Functions in Older Adults.

OBJECTIVE: White matter hyperintensities (WMH) are linked to deficits in cognitive functioning, including cognitive control and memory; however, the structural, and functional mechanisms are largely unknown. We investigated the relationship between estimated regional disruptions to white matter fiber tracts from WMH, resting state functional connectivity (RSFC), and cognitive functions in older adults. DESIGN: Cross-sectional study. SETTING: Community. PARTICIPANTS: Fifty-eight cognitively-healthy older adults. MEASUREMENTS: Tasks of cognitive control and memory, structural MRI, and resting state fMRI. We estimated the disruption to white matter fiber tracts from WMH and its impact on gray matter regions in the cortical and subcortical frontoparietal network, default mode network, and ventral attention network by overlaying each subject's WMH mask on a normative tractogram dataset. We calculated RSFC between nodes in those same networks. We evaluated the interaction of regional WMH burden and RSFC in predicting cognitive control and memory. RESULTS: The interaction of estimated regional WMH burden and RSFC in cortico-striatal regions of the default mode network and frontoparietal network was associated with delayed recall. Models predicting working memory, cognitive inhibition, and set-shifting were not significant. CONCLUSION: Findings highlight the role of network-level structural and functional alterations in resting state networks that are related to WMH and impact memory in older adults.

The Structural and Functional Neuroanatomy of Post-Stroke Depression and Executive Dysfunction: A Review of Neuroimaging Findings and Implications for Treatment.

Post-stroke depression and executive dysfunction co-occur and are highly debilitating. Few treatments alleviate both depression and executive dysfunction after stroke. Understanding the brain network changes underlying post-stroke depression with executive dysfunction can inform the development of targeted and efficacious treatment. In this review, we synthesize neuroimaging findings in post-stroke depression and post-stroke executive dysfunction and highlight the network commonalities that may underlie this comorbidity. Structural and functional alterations in the cognitive control network, salience network, and default mode network are associated with depression and executive dysfunction after stroke. Specifically, post-stroke depression and executive dysfunction are both linked to changes in intrinsic functional connectivity within resting state networks, functional over-connectivity between the default mode and salience/cognitive control networks, and reduced cross-hemispheric frontoparietal functional connectivity. Cognitive training and noninvasive brain stimulation targeted at these brain network abnormalities and specific clinical phenotypes may help advance treatment for post-stroke depression with executive dysfunction.

Strategies to Promote Cognitive Health in Aging: Recent Evidence and Innovations.

PURPOSE OF REVIEW: We review recent work on applications of non-pharmacologic strategies to promote cognitive health in older adulthood and discuss potential network mechanisms, limitations, and considerations for improving intervention uptake and efficacy. RECENT FINDINGS: In healthy older adults and patients with mild cognitive impairment, cognitive training produces global and domain-specific cognitive gains, though effect sizes tend to be modest and transfer is variable. Non-invasive brain stimulation has shown moderate success in enhancing cognitive function, though the optimum approach, parameters, and cortical targets require further investigation. Physical activity improves cognitive functions in late life, with emerging trials highlighting key intervention components that may maximize treatment outcomes. Multimodal interventions may be superior to single-component interventions in conferring cognitive gains, although interpretation is limited by modest sample sizes and variability in training components and parameters. Across modalities, individual differences in patient characteristics predict therapeutic response. These interventions may advance cognitive health by modulating functional networks that support core cognitive abilities including the default mode, executive control, and salience networks. Effectiveness of cognitive enhancement strategies may be increased with clinician-led coaching, booster sessions, gamification, integration of multiple intervention modalities, and concrete applications to everyday functioning. Future trials involving rigorous comparisons of training components, parameters, and delivery formats will be essential in establishing the precise approaches needed to maximize cognitive outcomes. Novel studies using patient-level clinical and neuroimaging features to predict individual differences in training gains may inform the development of personalized intervention prescriptions to optimize cognitive health in late life.

Feasibility and acceptability of the multicontext approach for individuals with acquired brain injury in acute inpatient rehabilitation: A single case series.

The Multicontext (MC) approach, a metacognitive intervention designed to improve awareness, strategy use, and executive functioning, may be beneficial for individuals with acquired brain injury (ABI) undergoing acute inpatient rehabilitation. The goal of this study was to provide evidence of feasibility and acceptability of the MC approach and to explore clinical outcomes. A case series of eight individuals with acquired brain injury and at least mild executive functioning impairment were recruited from an acute inpatient rehabilitation unit. The MC approach - involving guided questioning and patient self-generation of strategies practiced across everyday functional cognitive tasks - was implemented within routine occupational therapy. Occupational therapists implemented the MC approach with high adherence to the treatment protocol. Therapists' perceived challenges were the time constraints of inpatient rehabilitation as well as client factors. Participants rated the MC approach as highly satisfying and engaging. They described subjective improvements in their ability to use executive functioning strategies. The MC approach was associated with improvement in awareness, strategy use, and executive functioning at the conclusion of treatment. The MC approach may be a beneficial intervention for individuals with acquired brain injury and executive dysfunction undergoing acute inpatient rehabilitation. Further evaluation with larger samples in controlled trials is warranted.Trial registration: ClinicalTrials.gov identifier: NCT04363645..

Online awareness of performance on a functional cognitive assessment in individuals with stroke: A case-control study.

Unawareness is a significant barrier to cognitive rehabilitation following acquired brain injury. Little is known about online awareness of cognitively-based instrumental activities of daily living (C-IADL) after stroke, particularly C-IADLs that emphasize executive functions. Our goal was to evaluate in stroke patients (1) online awareness during and immediately after a C-IADL task that emphasizes executive functions and (2) the association between awareness and performance on the C-IADL task. Seventy-seven stroke patients on an acute inpatient rehabilitation unit and 77 control participants completed the 10-item Weekly Calendar Planning Activity (WCPA-10), a standardized C-IADL task that requires working memory, planning, shifting, and inhibition. Trained examiners observed the use of a self-checking strategy and self-recognition of errors during the task. Immediately after the task, participants estimated their accuracy, and rated their own performance, which was compared with objective accuracy. Relative to the control group, stroke patients overestimated their accuracy, less often recognized errors, and less frequently used a self-checking strategy. Overestimation was associated with worse overall performance on the WCPA-10. Findings suggest that poor online awareness of C-IADL performance is common in stroke patients undergoing acute inpatient rehabilitation. Increasing awareness through metacognitive interventions should be a core focus of early post-stroke cognitive rehabilitation.

Distinct functional and structural connections predict crystallised and fluid cognition in healthy adults.

White matter pathways between neurons facilitate neuronal coactivation patterns in the brain. Insight into how these structural and functional connections underlie complex cognitive functions provides an important foundation with which to delineate disease-related changes in cognitive functioning. Here, we integrate neuroimaging, connectomics, and machine learning approaches to explore how functional and structural brain connectivity relate to cognition. Specifically, we evaluate the extent to which functional and structural connectivity predict individual crystallised and fluid cognitive abilities in 415 unrelated healthy young adults (202 females) from the Human Connectome Project. We report three main findings. First, we demonstrate functional connectivity is more predictive of cognitive scores than structural connectivity, and, furthermore, integrating the two modalities does not increase explained variance. Second, we show the quality of cognitive prediction from connectome measures is influenced by the choice of grey matter parcellation, and, possibly, how that parcellation is derived. Third, we find that distinct functional and structural connections predict crystallised and fluid abilities. Taken together, our results suggest that functional and structural connectivity have unique relationships with crystallised and fluid cognition and, furthermore, studying both modalities provides a more comprehensive insight into the neural correlates of cognition.

Changes in the Activity Measure for Post-Acute Care Domains in Persons With Stroke During the First Year After Discharge From Inpatient Rehabilitation.

OBJECTIVE: To describe functional changes after inpatient stroke rehabilitation using the Activity Measure for Post-Acute Care (AM-PAC), an assessment measure sensitive to change and with a low risk of ceiling effect. DESIGN: Retrospective, longitudinal cohort study. SETTING: Inpatient rehabilitation unit of an urban academic medical center. PARTICIPANTS: Among 433 patients with stroke admitted from 2012-2016, a total of 269 (62%) were included in our database and 89 of 269 patients (33.1%) discharged from inpatient stroke rehabilitation had complete data. Patients with and without complete data were very similar. The group had a mean age of 68.0±14.2 years, National Institutes of Health Stroke Score of 8.0±8.0, and rehabilitation length of stay of 14.7±7.4 days, with 84% having an ischemic stroke and 22.5% having a recurrent stroke. INTERVENTION: None. MAIN OUTCOME MEASURES: Changes in function across the first year after discharge (DC) were measured in a variety of ways. Continuous mean scores for the basic mobility (BM), daily activity (DA), and applied cognitive domains of the AM-PAC were calculated at and compared between inpatient DC and 6 (6M) and 12 months (12M) post DC. Categorical changes among individuals were classified as "improved," "unchanged," or "declined" between the 3 time points based on the minimal detectable change, (estimated) minimal clinically important difference, and a change ≥1 AM-PAC functional stage (FS). RESULTS: For the continuous analyses, the Friedman test was significant for all domains (P≤.002), with Wilcoxon signed-rank test significant for all domains from DC to 6M (all P<.001) but with no change in BM and DA between 6M and 12M (P>.60) and a decline in applied cognition (P=.002). Despite group improvements from DC to 6M, for categorical changes at an individual level 10%-20% declined and 50%-70% were unchanged. Despite insignificant group differences from 6M-12M, 15%-25% improved and 20%-30% declined in the BM and DA domains. CONCLUSIONS: Despite group gains from DC to 6M and an apparent "plateau" after 6M post stroke, there was substantial heterogeneity at an individual level. Our results underscore the need to consider individual-level outcomes when evaluating progress or outcomes in stroke rehabilitation.

Subgroups Defined by the Montreal Cognitive Assessment Differ in Functional Gain During Acute Inpatient Stroke Rehabilitation.

OBJECTIVE: To validate subgroups of cognitive impairment on the Montreal Cognitive Assessment (MoCA)-defined as normal (score of 25-30), mildly impaired (score of 20-24), and moderately impaired (score less than 19)-by determining whether they differ in rehabilitation gain during inpatient stroke rehabilitation. DESIGN: Observational study. Linear regression models were conducted and predictors included MoCA subgroups and relevant baseline demographic and clinical covariates. Separate models included the cognitive subscale of the FIM instrument as a predictor. SETTING: Inpatient rehabilitation facility of an urban, academic medical center. PARTICIPANTS: Inpatients (N=334) with mild-moderate strokes who were administered the MoCA on admission. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The mean relative functional gain (mRFG) and mean relative functional efficiency (mRFE, which adjusts for length of stay) on the FIM total. RESULTS: MoCA subgroups significantly predicted mRFG and mRFE after accounting for age, sex, education, stroke severity, and recurrent vs first stroke. The normal group exhibited greater mRFG and mRFE than the mildly impaired group, while the moderately impaired group had significantly worse mRFG and mRFE than the mildly impaired group. The moderately impaired group had a significantly smaller proportion of individuals who made a clinically meaningful change on the total-FIM than the mildly impaired and normal groups. MoCA subgroups better accounted for mRFG and mRFE than a standard-of-care cognitive assessment (cognitive-FIM). CONCLUSIONS: Use of MoCA-defined subgroups can assist providers in predicting functional gain in survivors of stroke being treated in inpatient rehabilitation.

The diagnostic accuracy of the Montreal Cognitive Assessment in inpatient stroke rehabilitation.

The Montreal Cognitive Assessment (MoCA) is a commonly used screening measure for cognitive impairment; however, the diagnostic accuracy and optimal cutoff points in inpatients with mild stroke severity is unknown. We examined the diagnostic accuracy of the MoCA in an acute inpatient stroke rehabilitation unit (N = 95). The criterion neuropsychological assessment was the 30-minute National Institute of Neurological Disorders and Stroke-Canadian Stroke Network battery, modified to include the Symbol-Digit Modalities Test and Trail Making Test A & B. The MoCA had moderately strong diagnostic accuracy in receiver operating curve analyses, with areas under the curve ranging from .80 to .89 depending on the threshold for defining cognitive impairment. Sensitivity ranged from .72 to .87, and was generally greater than specificity, which ranged from .60 to .81. The optimal cutoff on the MoCA for detecting mild or greater cognitive impairment was <25/30. The optimal cutoff using more conservative definitions of cognitive impairment ranged from <23-24/30. Exploratory analyses of MoCA subgroups ("normal," "mildly impaired," and "functionally impaired") differed in the frequency and magnitude of impairment on the criterion neuropsychological assessment. These findings inform the clinical use of the MoCA in individuals with mild stroke in an inpatient rehabilitation setting.

Neuropsychological assessment without upper limb involvement: a systematic review of oral versions of the Trail Making Test and Symbol-Digit Modalities Test.

The Trail Making Test (TMT) and written version of the Symbol Digit Modalities Test (SDMT) assess attention, processing speed, and executive functions but their utility is limited in populations with upper limb dysfunction. Oral versions of the TMT and SDMT exist, but a systematic review of their psychometric properties and clinical utility has not been conducted, which was the goal of this study. Searches were conducted in PubMed and PsycINFO, test manuals, and the reference lists of included articles. Four measures were identified: the SDMT-oral, oral TMT-A, oral TMT-B, and the Mental Alternation Test (MAT). Two investigators independently reviewed abstracts to identify peer-reviewed articles that reported on these measures in adult populations. From each article, one investigator extracted information on reliability, validity, responsiveness, minimum detectable change, normative data, and demographic influences. A second investigator verified the accuracy of the data in a random selection of 10% of papers. The quality of the evidence for each psychometric property was rated on a 4-point scale (unknown, poor, adequate, excellent). Results showed excellent evidence for the SDMT-oral, adequate evidence for the oral TMT-B and MAT, and adequate to poor evidence for the oral TMT-A. These findings inform the clinical assessment of attention, processing speed, and executive functions in individuals with upper limb disability.

Perception of Communicative and Non-communicative Motion-Defined Gestures in Parkinson's Disease.

OBJECTIVES: Parkinson's disease (PD) is associated with deficits in social cognition and visual perception, but little is known about how the disease affects perception of socially complex biological motion, specifically motion-defined communicative and non-communicative gestures. We predicted that individuals with PD would perform more poorly than normal control (NC) participants in discriminating between communicative and non-communicative gestures, and in describing communicative gestures. We related the results to the participants' gender, as there are gender differences in social cognition in PD. METHODS: The study included 23 individuals with PD (10 men) and 24 NC participants (10 men) matched for age and education level. Participants viewed point-light human figures that conveyed communicative and non-communicative gestures and were asked to describe each gesture while discriminating between the two gesture types. RESULTS: PD as a group were less accurate than NC in describing non-communicative but not communicative gestures. Men with PD were impaired in describing and discriminating between communicative as well as non-communicative gestures. CONCLUSIONS: The present study demonstrated PD-related impairments in perceiving and inferring the meaning of biological motion gestures. Men with PD may have particular difficulty in understanding the communicative gestures of others in interpersonal exchanges.

Randomized Controlled Trial of a Home-Based Action Observation Intervention to Improve Walking in Parkinson Disease.

OBJECTIVE: To examine the feasibility and efficacy of a home-based gait observation intervention for improving walking in Parkinson disease (PD). DESIGN: Participants were randomly assigned to an intervention or control condition. A baseline walking assessment, a training period at home, and a posttraining assessment were conducted. SETTING: The laboratory and participants' home and community environments. PARTICIPANTS: Nondemented individuals with PD (N=23) experiencing walking difficulty. INTERVENTION: In the gait observation (intervention) condition, participants viewed videos of healthy and parkinsonian gait. In the landscape observation (control) condition, participants viewed videos of moving water. These tasks were completed daily for 8 days. MAIN OUTCOME MEASURES: Spatiotemporal walking variables were assessed using accelerometers in the laboratory (baseline and posttraining assessments) and continuously at home during the training period. Variables included daily activity, walking speed, stride length, stride frequency, leg swing time, and gait asymmetry. Questionnaires including the 39-item Parkinson Disease Questionnaire (PDQ-39) were administered to determine self-reported change in walking, as well as feasibility. RESULTS: At posttraining assessment, only the gait observation group reported significantly improved mobility (PDQ-39). No improvements were seen in accelerometer-derived walking data. Participants found the at-home training tasks and accelerometer feasible to use. CONCLUSIONS: Participants found procedures feasible and reported improved mobility, suggesting that observational training holds promise in the rehabilitation of walking in PD. Observational training alone, however, may not be sufficient to enhance walking in PD. A more challenging and adaptive task, and the use of explicit perceptual learning and practice of actions, may be required to effect change.

Pathophysiology, Assessment, and Management of Post-Stroke Cognitive Impairment, Depression, and Fatigue.

Post-stroke cognitive impairment, depression, and fatigue are common, persistent, and disabling. This review summarizes current knowledge on the pathophysiology, assessment, and management of these debilitating neuropsychiatric sequelae of stroke. We briefly review evolving knowledge on the neural mechanisms and risk factors for each condition. We describe patient-reported outcome measures and clinician rating techniques that can be used to assist in screening and comprehensive assessment. We then discuss behavioral and pharmacologic management strategies. Heterogeneity of stroke remains a challenge in management and new research is still needed to optimize and personalize treatments for stroke survivors.

Cognitive impairment and liver fibrosis in non-alcoholic fatty liver disease.

Background: Data regarding the prevalence and phenotype of cognitive impairment in non-alcoholic fatty liver disease (NAFLD) are limited. Objective: We assessed the prevalence and nature of cognitive deficits in people with NAFLD and assessed whether liver fibrosis, an important determinant of outcomes in NAFLD, is associated with worse cognitive performance. Methods: We performed a prospective cross-sectional study. Patients with NAFLD underwent liver fibrosis assessment with transient elastography and the following assessments: Cognitive Change Index, Eight-Item Informant Interview to Differentiate Aging and Dementia Questionnaire (AD8), Montreal Cognitive Assessment (MoCA), EncephalApp minimal hepatic encephalopathy test and a limited National Institutes of Health Toolbox battery (Flanker Inhibitory Control and Attention Test, Pattern Comparison Test and Auditory Verbal Learning Test). We used multiple linear regression models to examine the association between liver fibrosis and cognitive measures while adjusting for relevant covariates. Results: We included 69 participants with mean age 50.4 years (SD 14.4); 62% were women. The median liver stiffness was 5.0 kilopascals (IQR 4.0-6.9), and 25% had liver fibrosis (≥7.0 kilopascals). Cognitive deficits were common in people with NAFLD; 41% had subjective cognitive impairment, 13% had an AD8 >2, 32% had MoCA <26 and 12% had encephalopathy detected on the EncephalApp test. In adjusted models, people with liver fibrosis had modestly worse performance only on the Flanker Inhibitory Control and Attention Task (ß=-0.3; 95% CI -0.6 to -0.1). Conclusion: Cognitive deficits are common in people with NAFLD, among whom liver fibrosis was modestly associated with worse inhibitory control and attention.

Cognitive Symptoms of Post-COVID-19 Condition and Daily Functioning.

Importance: The frequent occurrence of cognitive symptoms in post-COVID-19 condition has been described, but the nature of these symptoms and their demographic and functional factors are not well characterized in generalizable populations. Objective: To investigate the prevalence of self-reported cognitive symptoms in post-COVID-19 condition, in comparison with individuals with prior acute SARS-CoV-2 infection who did not develop post-COVID-19 condition, and their association with other individual features, including depressive symptoms and functional status. Design, Setting, and Participants: Two waves of a 50-state nonprobability population-based internet survey conducted between December 22, 2022, and May 5, 2023. Participants included survey respondents aged 18 years and older. Exposure: Post-COVID-19 condition, defined as self-report of symptoms attributed to COVID-19 beyond 2 months after the initial month of illness. Main Outcomes and Measures: Seven items from the Neuro-QoL cognition battery assessing the frequency of cognitive symptoms in the past week and patient Health Questionnaire-9. Results: The 14 767 individuals reporting test-confirmed COVID-19 illness at least 2 months before the survey had a mean (SD) age of 44.6 (16.3) years; 568 (3.8%) were Asian, 1484 (10.0%) were Black, 1408 (9.5%) were Hispanic, and 10 811 (73.2%) were White. A total of 10 037 respondents (68.0%) were women and 4730 (32.0%) were men. Of the 1683 individuals reporting post-COVID-19 condition, 955 (56.7%) reported at least 1 cognitive symptom experienced daily, compared with 3552 of 13 084 (27.1%) of those who did not report post-COVID-19 condition. More daily cognitive symptoms were associated with a greater likelihood of reporting at least moderate interference with functioning (unadjusted odds ratio [OR], 1.31 [95% CI, 1.25-1.36]; adjusted [AOR], 1.30 [95% CI, 1.25-1.36]), lesser likelihood of full-time employment (unadjusted OR, 0.95 [95% CI, 0.91-0.99]; AOR, 0.92 [95% CI, 0.88-0.96]) and greater severity of depressive symptoms (unadjusted coefficient, 1.40 [95% CI, 1.29-1.51]; adjusted coefficient 1.27 [95% CI, 1.17-1.38). After including depressive symptoms in regression models, associations were also found between cognitive symptoms and at least moderate interference with everyday functioning (AOR, 1.27 [95% CI, 1.21-1.33]) and between cognitive symptoms and lower odds of full-time employment (AOR, 0.92 [95% CI, 0.88-0.97]). Conclusions and Relevance: The findings of this survey study of US adults suggest that cognitive symptoms are common among individuals with post-COVID-19 condition and associated with greater self-reported functional impairment, lesser likelihood of full-time employment, and greater depressive symptom severity. Screening for and addressing cognitive symptoms is an important component of the public health response to post-COVID-19 condition.

A digital intervention for cognitive deficits following COVID-19: a randomized clinical trial.

Post-COVID-19 cognitive deficits are common, persistent, and disabling. Evidence on effective treatments is limited. The goal of this study was to investigate the efficacy of a digital intervention to reduce cognitive and functional deficits in adults with persistent post-COVID-19 cognitive dysfunction. We used the remotely-delivered intervention in a randomized clinical trial conducted from July 13, 2021 to April 26, 2023. We hypothesized that participants in the intervention group would improve in measures of cognition and daily functioning. Participants were adults with cognitive deficits persisting >4 weeks following acute COVID-19 illness. Of 183 participants screened, 110 were enrolled; 98 participants (78.6% female; mean age = 48.1) completed at least one study visit. Participants were randomized 1:1 to the intervention (AKL-T01) or waitlist control. AKL-T01 is a digital therapeutic using a videogame interface to target attention and executive control. The intervention was delivered remotely for 6 weeks. The primary outcome was change in performance on a sustained attention measure (Digit Symbol Matching Task). The difference in the primary outcome between the intervention (n = 49) and controls (n = 49) was not statistically significant (F [3,261] = 0.12, p = 0.95). Secondary cognitive outcomes of task-switching (F[3,262] = 2.78, p = 0.04) and processing speed (F[3,267] = 4.57, p = 0.004) improved in the intervention relative to control. Secondary measures of functioning also improved in the intervention relative to control, including disability (F[1,82] = 4.02, p = 0.05) and quality of life (F[3,271] = 2.66, p = 0.05). Exploratory analyses showed a greater reduction in total fatigue (F[1,85] = 4.51, p = 0.04), cognitive fatigue (F[1,85] = 7.20, p = 0.009), and anxiety (F[1,87] = 7.42, p = 0.008) in the intervention relative to control. Despite the lack of improvement in sustained attention, select post-COVID-19 cognitive deficits may be ameliorated by targeted cognitive training with AKL-T01, with associated improvements in quality of life and fatigue. If replicated, the scalable nature of this digital intervention may help address substantial need for accessible, effective treatments among individuals with long COVID.

Diffusion Tensor Imaging Along Perivascular Spaces (DTI-ALPS) to Assess Effects of Age, Sex, and Head Size on Interstitial Fluid Dynamics in Healthy Subjects.

Diffusion tensor imaging along perivascular spaces (DTI-ALPS) is a novel MRI method for assessing brain interstitial fluid dynamics, potentially indexing glymphatic function. Failed glymphatic clearance is implicated in Alzheimer's disease (AD) pathophysiology. We assessed the contribution of age and female sex (strong AD risk factors) to DTI-ALPS index in healthy subjects. We also for the first time assessed the effect of head size. In accord with prior studies, we show reduced DTI-ALPS index with aging, and in men compared to women. However, head size may be a major contributing factor to this counterintuitive sex difference.