Brain Fluid Clearance After Traumatic Brain Injury Measured Using Dynamic Positron Emission Tomography.

Brain fluid clearance by pathways including the recently described paravascular glymphatic system is a critical homeostatic mechanism by which metabolic products, toxins, and other wastes are removed from the brain. Brain fluid clearance may be especially important after traumatic brain injury (TBI), when blood, neuronal debris, inflammatory cells, and other substances can be released and/or deposited. Using a non-invasive dynamic positron emission tomography (PET) method that models the rate at which an intravenously injected radiolabeled molecule (in this case 11C-flumazenil) is cleared from ventricular cerebrospinal fluid (CSF), we estimated the overall efficiency of brain fluid clearance in humans who had experienced complicated-mild or moderate TBI 3-6 months before neuroimaging (n = 7) as compared to healthy controls (n = 9). While there was no significant difference in ventricular clearance between TBI subjects and controls, there was a significant group difference in dependence of ventricular clearance upon tracer delivery/blood flow to the ventricles. Specifically, in controls, ventricular clearance was highly, linearly dependent upon blood flow to the ventricle, but this relation was disrupted in TBI subjects. When accounting for blood flow and group-specific alterations in blood flow, ventricular clearance was slightly (non-significantly) increased in TBI subjects as compared to controls. Current results contrast with past studies showing reduced glymphatic function after TBI and are consistent with possible differential effects of TBI on glymphatic versus non-glymphatic clearance mechanisms. Further study using multi-modal methods capable of assessing and disentangling blood flow and different aspects of fluid clearance is needed to clarify clearance alterations after TBI.

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.

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.

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.

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.

Association Between the Attention Network Test, Neuropsychological Measures, and Disability in Post-Acute Traumatic Brain Injury.

Cognitive impairment after traumatic brain injury (TBI) is persistent and disabling. Assessing cognitive function in a reliable and valid manner, using measures that are sensitive to the integrity of underlying neural substrates, is crucial in clinical research. The Attention Network Test (ANT) is one such assessment measure that has demonstrated associations with neural regions involved in attention; however, clinical utility of the ANT is limited because its relationship with neuropsychological measures of cognitive function (i.e., its construct validity) has not yet been established in TBI. We evaluated the association between the ANT and 1) a neuropsychological battery assessing executive function and memory and 2) global function assessed by the Glasgow Outcome Scale-Extended (GOSE). Forty-eight adults with complicated mild-severe TBI were evaluated ∼5 months post-injury. Using principal component analysis and multi-variate linear regression adjusted for age, gender, education, and cause of injury, we found that ANT reaction time and executive network scores predicted a principal component assessing processing speed and executive function. Conversely, the ANT did not predict a principal component assessing memory. The ANT was weakly associated with the GOSE. Among persons with TBI during the post-acute phase of recovery, the ANT has good construct validity as evidenced by its associations with neuropsychological measures of processing speed and executive function, but not memory. Given that ANT networks are known to relate to specific neuroanatomical regions, the ANT may be a useful outcome measure for evaluating novel therapeutics targeting attention and executive functions after TBI.

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.

Feasibility and Acceptability of a Remotely Delivered Executive Function Intervention That Combines Computerized Cognitive Training and Metacognitive Strategy Training in Chronic Stroke.

Executive dysfunction after stroke is associated with limitations in daily activities and disability. Existing interventions for executive dysfunction show inconsistent transfer to everyday activities and require frequent clinic visits that can be difficult for patients with chronic mobility challenges to access. To address this barrier, we developed a telehealth-based executive function intervention that combines computerized cognitive training and metacognitive strategy. The goal of this study was to describe intervention development and to provide preliminary evidence of feasibility and acceptability in three individuals who completed the treatment protocol. The three study participants were living in the community and had experienced a stroke >6 months prior. We assessed satisfaction (Client Satisfaction Questionnaire-8 [CSQ-8]), credibility (Credibility and Expectancy Questionnaire), and feasibility (percent of sessions completed). All three subjects rated the treatment in the highest satisfaction category on the CSQ-8, found the treatment to be credible, and expected improvement. Participants completed a median of 96% of computerized cognitive training sessions and 100% of telehealth-delivered metacognitive strategy training sessions. Individuals with chronic stroke may find a remotely delivered intervention that combines computerized cognitive training and metacognitive strategy training to be feasible and acceptable. Further evaluation with larger samples in controlled trials is warranted.

Multinational perspectives on changes to psychiatric care during the COVID-19 pandemic: a survey of practicing psychiatrists.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in significant upheaval in psychiatric care. Despite survey data collected from psychiatric patients and broad samples of individuals in single countries, there is little quantitative or qualitative data on changes to psychiatric care from the perspective of mental health providers themselves across developing countries. METHODS: To address this gap, we surveyed 27 practicing psychiatrists from Central and Eastern Europe, as well as Africa, the Middle East, and Latin America. RESULTS: Respondents observed a marked increase in anxiety in their patients, with increased (though less prominent) symptoms of depression, somatization, and addiction. They reported largescale changes in the structure of psychiatric treatment, chiefly a decline in psychiatric admissions and closing/repurposing of psychiatric beds. Results supported strong "buy in" from clinicians regarding the use of telehealth, though some clinicians perceived a reduction in the ability to connect with, and build alliances with, their patients. Finally, clinicians described an improvement in the image and meaning of psychiatry in society, increased awareness of mental illness, and greater value placed on mental health in the general population. CONCLUSIONS: These changes warrant further empirical study as to their potential long-term ramifications, particularly as the COVID-19 pandemic persists and new waves of infection occur periodically throughout the world. The increased psychiatric burden on the population coupled with the apparent salience of mental health and well-being in the public consciousness represents a global opportunity for psychiatry to advocate for further treatment, research, and education.

Cognitive impairment predicts engagement in inpatient stroke rehabilitation.

Patient engagement during inpatient rehabilitation is an important component of rehabilitation therapy, as lower levels of engagement are associated with poorer outcomes. Cognitive deficits may impact patient engagement during inpatient stroke rehabilitation. Here, we assess whether patient performance on the cognitive tasks of the 30-min National Institute of Neurologic Disorders and Stroke - Canadian Stroke Network (NINDS-CSN) screening battery predicts engagement in inpatient stroke rehabilitation. Prospective data from 110 participants completing inpatient stroke rehabilitation at an academic medical center were utilized for the present analyses. Cognitive functioning was assessed at inpatient stroke rehabilitation admission using the NINDS-CSN cognitive battery. Patient engagement was evaluated at discharge from an inpatient rehabilitation unit using the Hopkins Rehabilitation Engagement Rating Scale. The results demonstrate that the NINDS-CSN cognitive battery, specifically subtests measuring executive functioning, attention and processing speed, predicts patient engagement in inpatient stroke rehabilitation. Cognitively impaired patients undergoing rehabilitation may benefit from modifications and interventions to increase engagement and improve functional outcomes.

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.

Disease correlates of rim lesions on quantitative susceptibility mapping in multiple sclerosis.

Quantitative susceptibility mapping (QSM), an imaging technique sensitive to brain iron, has been used to detect paramagnetic rims of iron-laden active microglia and macrophages in a subset of multiple sclerosis (MS) lesions, known as rim+ lesions, that are consistent with chronic active lesions. Because of the potential impact of rim+ lesions on disease progression and tissue damage, investigating their influence on disability and neurodegeneration is critical to establish the impact of these lesions on the disease course. This study aimed to explore the relationship between chronic active rim+ lesions, identified as having a hyperintense rim on QSM, and both clinical disability and imaging measures of neurodegeneration in patients with MS. The patient cohort was composed of 159 relapsing-remitting multiple sclerosis patients. The Expanded Disability Status Scale (EDSS) and Brief International Cognitive Assessment for Multiple Sclerosis, which includes both the Symbol Digit Modalities Test and California Verbal Learning Test-II, were used to assess clinical disability. Cortical thickness and thalamic volume were evaluated as imaging measures of neurodegeneration. A total of 4469 MS lesions were identified, of which 171 QSM rim+ (3.8%) lesions were identified among 57 patients (35.8%). In a multivariate regression model, as the overall total lesion burden increased, patients with at least one rim+ lesion on QSM performed worse on both physical disability and cognitive assessments, specifically the Symbol Digit Modalities Test (p = 0.010), California Verbal Learning Test-II (p = 0.030), and EDSS (p = 0.001). In a separate univariate regression model, controlling for age (p < 0.001) and having at least one rim+ lesion was related to more cortical thinning (p = 0.03) in younger patients (< 45 years). Lower thalamic volume was associated with older patients (p = 0.038) and larger total lesion burden (p < 0.001); however, the association did not remain significant with rim+ lesions (p = 0.10). Our findings demonstrate a novel observation that chronic active lesions, as identified on QSM, modify the impact of lesion burden on clinical disability in MS patients. These results support further exploration of rim+ lesions for therapeutic targeting in MS to reduce disability and subsequent neurodegeneration.

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.

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.

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..

Discharge Rehabilitation Measures Predict Activity Limitations in Patients With Stroke 6 Months After Inpatient Rehabilitation.

OBJECTIVE: The aim of this study was to identify rehabilitation measures at discharge from acute inpatient stroke rehabilitation that predict activity limitations at 6 mos postdischarge. DESIGN: This is a retrospective analysis of a prospective, longitudinal, observational cohort study. It was conducted in an acute inpatient rehabilitation unit at an urban, academic medical center. Activity limitations in patients ( N = 141) with stroke of mild-moderate severity were assessed with the activity measure for post-acute care at inpatient stroke rehabilitation discharge and 6-mo follow-up. Rehabilitation measures at discharge were investigated as predictors for activity limitations at 6 mos. RESULTS: Measures of balance (Berg Balance Scale), functional limitations in motor-based activities (functional independence measure-motor subscore), and motor impairment (motricity index), in addition to discharge activities measure for post-acute care scores, strongly predicted activity limitations in basic mobility and daily activities at 6 mos (51% and 41% variance explained, respectively). Functional limitations in cognition (functional independence measure-cognitive subscore) and executive function impairment (Trail Making Test-part B), in addition to the discharge activities measure for post-acute care score, modestly predicted limitations in cognitively based daily activities at 6 mos (12% of variance). CONCLUSIONS: Standardized rehabilitation measures at inpatient stroke rehabilitation discharge can predict future activity limitations, which may improve prediction of outcome post-stroke and aid in postdischarge treatment planning.

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.