Self-managing symptoms of Long COVID: an education and strategies research protocol.

Post-acute sequelae of SARS-COV-2 (PASC) is growing in prevalence, and involves symptoms originating from the central neurological, cardiovascular, respiratory, gastrointestinal, autonomic nervous, or immune systems. There are non-specific symptoms such as fatigue, headaches, and brain fog, which cannot be ascribed to a single system. PASC places a notable strain on our healthcare system, which is already laden with a large number of acute-COVID-19 patients. Furthermore, it impedes social, academic and vocational functioning, and impacts family life, relationships, and work/financial life. The treatment for PASC needs to target this non-specific etiology and wide-ranging sequelae. In conditions similar to PASC, such as "chemo brain," and prolonged symptoms of concussion, the non-specific symptoms have shown to be effectively managed through education and strategies for self-management and Mindfulness interventions. However, such interventions have yet to be empirically evaluated in PASC to our knowledge. In response to this gap, we have developed a virtual education intervention synthesized by psychiatrists and clinical psychologists for the current study. We will undertake a two-phase randomized controlled trial to determine the feasibility (Phase 1; N = 90) and efficacy (Phase 2; sample sized based on phase 1 results) of the novel 8 week Education and Self-Management Strategies group compared to a mindfulness skills program, both delivered virtually. Main outcomes include confidence/ability to self-manage symptoms, quality of life, and healthcare utilization. This study stands to mitigate the deleterious intrusiveness of symptoms on everyday life in patients with PASC, and may also help to reduce the impact of PASC on the healthcare system. Clinical trial registration:https://classic.clinicaltrials.gov/ct2/show/NCT05268523; identifier NCT05268523.

Feasibility of group telerehabilitation for individuals with chronic acquired brain injury: integrating clinical care and research.

BACKGROUND: Acquired brain injury (ABI) is a leading cause of lifelong disability, but access to treatment in the chronic stages has significant barriers. Group-based, remotely delivered neurorehabilitation reduces costs, travel barriers, and infection risk; however, its feasibility for patients with ABI is not well-established. OBJECTIVES: To investigate the feasibility of remotely group-based cognitive and mood therapies for persons with chronic ABI. METHODS: Three hundred and eighty-eight adults with chronic ABI participated in group tele-neurorehabilitation modules comprising Cognitive Behavioral Therapy, Goal Management Training®, Relaxation and Mindfulness Skills Training, and/or a novel Concussion Education & Symptom Management program. Assessments comprised quantitative metrics, surveys, as well as qualitative semi-structured interviews in a subset of participants. RESULTS: High retention, adherence, and satisfaction were observed. Facilitators of treatment included accessibility, cost-effectiveness, and convenience. Adoption of technology was high, but other people's technological interruptions were a barrier. Self-reported benefits specific to group-based format included improved mood, stress management, coping, interpersonal relationships, cognitive functioning, and present-mindedness. CONCLUSIONS: The present study examined chronic ABI patients' perceptions of telerehabilitation. Patients found remotely delivered, group-based mood, and cognitive interventions feasible with easy technology adoption. Group format was considered a benefit. Recommendations are provided to inform design of remotely delivered ABI programs.

Group-based mood and cognitive telerehabilitation is feasible for persons with chronic acquired brain injury, with high reported satisfaction.Screening for technical proficiency and providing ongoing technical support improves therapy adherence and retention.Integration of clinical care and research is feasible for delivering remote therapies to persons with brain injury.

Preliminary efficacy and predictors of response to a remotely-delivered symptom self-management program for persistent symptoms after concussion.

BACKGROUND: More than a quarter of adults with concussion endure prolonged symptoms of >3 months. We developed the Concussion Education Self-Management program to help people manage persisting symptoms. Here, we assess feasibility, preliminary efficacy, and correlates of response. METHODS: N = 80 adults participated in the program; ages ranged from 18 to 65 years and time post-injury ranged from 6 months to 18 years. Weekly sessions, delivered remotely and in groups, comprised education and strategies for management of cognitive, emotional, and physical symptoms. Primary outcome: Confidence to self-manage symptoms. Secondary outcomes: Quality of life; mood/anxiety/stress. Predictors of response: Self-reported cognitive, emotional and physical symptoms at intake. RESULTS: Pre- to post-program improvements were observed in confidence to self-manage, p < 0.03; quality of life, p < 0.001; depression, p < 0.001; anxiety, p < 0.001; and stress, p < 0.001. Considering confidence to self-manage, those with fewer cognitive and physical symptoms benefitted more (p's < 0.0005 and p < 0.01, respectively). DISCUSSION: This program shows promise for improving self-management of prolonged symptoms. Those with high symptom burden may need extra sessions to benefit. This is a cost-effective and scalable program that can reach people regardless of geographic location or impediments to travel.

Longitudinal Patterns of Functional Connectivity in Moderate-to-Severe Traumatic Brain Injury.

Longitudinal neuroimaging studies aid our understanding of recovery mechanisms in moderate-to-severe traumatic brain injury (TBI); however, there is a dearth of longitudinal functional connectivity research. Our aim was to characterize longitudinal functional connectivity patterns in two clinically important brain networks, the frontoparietal network (FPN) and the default mode network (DMN), in moderate-to-severe TBI. This inception cohort study of prospectively collected longitudinal data used resting-state functional magnetic resonance imaging (fMRI) to characterize functional connectivity patterns in the FPN and DMN. Forty adults with moderate-to-severe TBI (mean ± standard deviation [SD]; age = 39.53 ± 16.49 years, education = 13.92 ± 3.20 years, lowest Glasgow Coma Scale score = 6.63 ± 3.24, sex = 70% male) were scanned at approximately 0.5, 1-1.5, and 3+ years post-injury. Seventeen healthy, uninjured participants (mean ± SD; age = 38.91 ± 15.57 years, education = 15.11 ± 2.71 years, sex = 29% male) were scanned at baseline and approximately 11 months afterwards. Group independent component analyses and linear mixed-effects modeling with linear splines that contained a knot at 1.5 years post-injury were employed to investigate longitudinal network changes, and associations with covariates, including age, sex, and injury severity. In patients with TBI, functional connectivity in the right FPN increased from approximately 0.5 to 1.5 years post-injury (unstandardized estimate = 0.19, standard error [SE] = 0.07, p = 0.009), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.21, SE = 0.11, p = 0.009), and marginally declined afterwards (estimate = -0.10, SE = 0.06, p = 0.079). Functional connectivity in the DMN increased from approximately 0.5 to 1.5 years (estimate = 0.15, SE = 0.05, p = 0.006), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.19, SE = 0.08, p = 0.021), and was estimated to decline from 1.5 to 3+ years (estimate = -0.04, SE = 0.04, p = 0.303). Similarly, the left FPN increased in functional connectivity from approximately 0.5 to 1.5 years post-injury (estimate = 0.15, SE = 0.05, p = 0.002), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.18, SE = 0.07, p = 0.008), and was estimated to decline thereafter (estimate = -0.04, SE = 0.03, p = 0.254). At approximately 0.5 years post-injury, patients showed hypoconnectivity compared with healthy, uninjured participants at baseline. Covariates were not significantly associated in any of the models. Findings of early improvement but a tapering and possible decline in connectivity thereafter suggest that compensatory effects are time-limited. These later reductions in connectivity mirror growing evidence of behavioral and structural decline in chronic moderate-to-severe TBI. Targeting such declines represents a novel avenue of research and offers potential for improving clinical outcomes.

Household physical activity is positively associated with gray matter volume in older adults.

BACKGROUND: Total physical activity is positively associated with brain volume and cognition in older adults. While we have ample evidence that recreational physical activity influences brain health, the contributions of other daily activities are less understood. In particular, the associations between household physical activity and brain health in older adults is underexplored. The purpose of this study was to identify associations between household physical activity, brain volume, and cognition in a sample of cognitively unimpaired older adults. METHODS: We report data from 66 cognitively unimpaired older adults (71 ± 4 years) who participated in a health evaluation, cognitive assessment, and structural brain imaging. Physical activity was assessed using the Phone-FITT questionnaire and separated into household and recreational physical activity. We quantified whole brain volume, gray matter volume, and white matter volume, and assessed cognitive performance in four domains: memory, working memory/attention, processing speed, and executive function. Associations between physical activity, brain volume, and cognition were investigated in an omnibus approach using two multivariate analysis of variance (MANOVA) models. The first model assessed the associations between physical activity and brain volume adjusting for age, sex, Framingham Risk score (FRS) and intracranial volume. The second model assessed the associations between physical activity and overall cognitive performance adjusting for age, sex, FRS and education. Post hoc regression analyses were conducted to investigate significant MANOVA results. We also conducted further regression analyses to investigate associations with hippocampal and frontal lobe volume. RESULTS: Household, but not recreational, physical activity was positively associated with brain volume measurements (F = 3.07, p = .035), specifically gray matter volume (t = 2.51, p = .015). Further exploratory analyses identified that household physical activity was associated with hippocampal (p = .015) and frontal lobe (p = .010) volume. No significant relationships were observed between household or recreational physical activity and cognition. CONCLUSION: Time spent engaging in household physical activity was positively associated with brain volume, specifically gray matter volume, in older adults. Highlighting the benefits associated with household chores may motivate older adults to be more active by providing a more attainable, low risk form of physical activity.

Cardiovascular risk and encoding-related hippocampal connectivity in older adults.

BACKGROUND: Cardiovascular conditions contribute to brain volume loss, reduced cerebrovascular health, and increased dementia risk in aging adults. Altered hippocampal connectivity has also been observed in individuals with cardiovascular conditions, yet the functional consequences of these changes remain unclear. In the present study, we collected functional magnetic resonance imaging data during memory encoding and used a psychophysiological interaction analysis to examine whether cardiovascular burden, indexed using the Framingham risk score, was associated with encoding-related hippocampal connectivity and task performance in cognitively-intact older adults between 65 and 85 years of age. Our goal was to better understand the early functional consequences of vascular and metabolic dysfunction in those at risk for cognitive decline. RESULTS: High Framingham risk scores were associated with lower total brain volumes. In addition, those with high Framingham risk scores showed an altered relationship between left hippocampal-medial prefrontal coupling and task performance compared to those with low Framingham risk scores. Specifically, we found a significant interaction of Framingham risk and learning on connectivity between the left hippocampus and primarily left midline prefrontal regions comprising the left ventral anterior cingulate cortex and medial prefrontal cortex. Those with lower Framingham risk scores showed a pattern of weaker connectivity between left hippocampal and medial prefrontal regions associated with better task performance. Those with higher Framingham risk scores showed the opposite pattern; stronger connectivity was associated with better performance. CONCLUSIONS: Findings from the current study show that amongst older adults with cardiovascular conditions, higher Framingham risk is associated with lower brain volume and altered left hippocampal-medial prefrontal coupling during task performance compared to those with lower Framingham risk scores. This may reflect a compensatory mechanism in support of memory function and suggests that older adults with elevated cardiovascular risk are vulnerable to early Alzheimer disease-like dysfunction within the episodic memory system.

Brain-behavior relationships in source memory: Effects of age and memory ability.

There is considerable evidence for age-related decrements in source memory retrieval, but the literature on the neural correlates of these impairments is mixed. In this study, we used functional magnetic resonance imaging to examine source memory retrieval-related brain activity, and the monotonic relationship between retrieval-related brain activity and source memory accuracy, as a function of both healthy aging (younger vs older) and memory ability within the older adult group (Hi-Old vs Lo-Old). Participants studied lists of word pairs, half visually, half aurally; these were re-presented visually in a scanned test phase and participants indicated if the pair was 'seen' or 'heard' in the study phase. The Lo-Old, but not the Hi-Old, showed source memory performance decrements compared to the Young. During retrieval of source memories, younger and older adults engaged lateral and medial prefrontal cortex (PFC) and medial posterior parietal (and occipital) cortices. The groups differed in how brain activity related to source memory accuracy in dorsal anterior cingulate cortex, precuneus/cuneus, and the inferior parietal cortex; in each of these areas, greater activity was associated with poorer accuracy in the Young, but with higher accuracy in the Hi-Old (anterior cingulate and precuneus/cuneus) and Lo-Old (inferior parietal lobe). Follow-up pairwise group interaction analyses revealed that greater activity in right parahippocampal gyrus was associated with better source memory in the Hi-Old, but not in the Lo-Old. We conclude that older adults recruit additional brain regions to compensate for age-related decline in source memory, but the specific regions involved differ depending on their episodic memory ability.

Brain Function Is Linked to LDL Cholesterol in Older Adults with Cardiovascular Risk.

OBJECTIVES: To determine how cardiovascular risk is associated with working memory task performance and task-related suppression of default-mode network (DMN) activity in cognitively intact older adults. DESIGN: A cross-sectional functional magnetic resonance imaging study of older adults with cardiovascular risk factors. SETTING: Rotman Research Institute, Baycrest Health Sciences. PARTICIPANTS: Thirty older adults with cardiovascular risk factors. MEASUREMENTS: Participants provided health information and a blood sample, and underwent functional magnetic resonance imaging during a working memory task and during a breath-hold task to assess cerebrovascular reactivity. RESULTS: Higher plasma low-density lipoprotein cholesterol (LDL-C) was associated with poorer working memory task performance (P = 0.008) and reduced task-related DMN suppression (P = 0.005). A composite index of cardiovascular risk, the Framingham General Cardiovascular Risk Profile, showed no associations with task performance or task-related DMN suppression. These findings were independent of white matter burden and cerebrovascular reactivity and thus cannot be accounted for by individual differences in neurovascular health. CONCLUSION: These findings suggest a deleterious effect of elevated LDL-C on working memory task performance and task-related DMN suppression in older adults with cardiovascular risk. The relations between the Framingham General Cardiovascular Risk Profile, cognitive task performance, and DMN function require further study.

A systematic review of type 2 diabetes mellitus and hypertension in imaging studies of cognitive aging: time to establish new norms.

The rising prevalence of type 2 diabetes (T2DM) and hypertension in older adults, and the deleterious effect of these conditions on cerebrovascular and brain health, is creating a growing discrepancy between the "typical" cognitive aging trajectory and a "healthy" cognitive aging trajectory. These changing health demographics make T2DM and hypertension important topics of study in their own right, and warrant attention from the perspective of cognitive aging neuroimaging research. Specifically, interpretation of individual or group differences in blood oxygenation level dependent magnetic resonance imaging (BOLD MRI) or positron emission tomography (PET H2O(15)) signals as reflective of differences in neural activation underlying a cognitive operation of interest requires assumptions of intact vascular health amongst the study participants. Without adequate screening, inclusion of individuals with T2DM or hypertension in "healthy" samples may introduce unwanted variability and bias to brain and/or cognitive measures, and increase potential for error. We conducted a systematic review of the cognitive aging neuroimaging literature to document the extent to which researchers account for these conditions. Of the 232 studies selected for review, few explicitly excluded individuals with T2DM (9%) or hypertension (13%). A large portion had exclusion criteria that made it difficult to determine whether T2DM or hypertension were excluded (44 and 37%), and many did not mention any selection criteria related to T2DM or hypertension (34 and 22%). Of all the surveyed studies, only 29% acknowledged or addressed the potential influence of intersubject vascular variability on the measured BOLD or PET signals. To reinforce the notion that individuals with T2DM and hypertension should not be overlooked as a potential source of bias, we also provide an overview of metabolic and vascular changes associated with T2DM and hypertension, as they relate to cerebrovascular and brain health.

Neural correlates of cognitive remediation in patients with mood disorders.

Little is known about the brain changes that mediate improvement following cognitive remediation. We used neuropsychological tests and functional magnetic resonance imaging to study working memory and recollection memory in patients with mood disorders, before (PRE) and after (POST) 10 weeks of cognitive remediation. Thirty-eight patients completed a recollection memory task at PRE (28 had complete PRE and POST scans) and 35 patients completed an n-back working memory task at PRE (23 had complete PRE and POST scans). We also compared patients at PRE with two groups of healthy controls subjects (n=18 for the recollection memory task and n=15 for the working memory task). At PRE, compared to controls, patients had (i) poorer backward digit span scores, (ii) lower accuracy scores and weaker frontopolar activation during the 2-back condition, and (iii) poorer recollection scores and altered medial temporal activation on the recollection memory task. Following remediation, patients (i) improved on the backward digit span, (ii) activation increased in lateral and medial prefrontal, superior temporal, and lateral parietal regions in the 2-back condition, and (iii) recollection-related activation increased in the bilateral hippocampus. Improvements in 2-back accuracy correlated with activation increases in lateral and medial prefrontal and lateral parietal regions, and improved recollection scores correlated with activation increases in the left hippocampus. PRE-POST improvements on the backward digit span correlated with PRE-POST improvements in 2-back task accuracy; however, there was no direct association between improvement on the backward digit span following training and change in functional activation. These findings suggest that cognitive remediation may lead to behavioural improvements on tests of working memory. The relation between behavioural change and changes in functional activation following remediation requires further study.

Youth are more Vulnerable to False Memories than Middle-Aged Adults due to Liberal Response Bias.

OBJECTIVE: Numerous studies show changes in vulnerability to false memory formation across development and into senescence. No study, however, has compared false memory formation in the critical transition period spanning late adolescence to middle adulthood. METHOD: Using the Deese-Roediger-McDermott (DRM) paradigm, we explored the effects of age and of emotion on false memory formation in youth (16 to 23 years of age) and in middle-aged adults (29 to 58 years of age). RESULTS: We found that youth endorsed more false lure items than middle-aged adults. This increased vulnerability to false memory formation stemmed from a more liberal response bias in the younger group. CONCLUSIONS: Youth have a more liberal response criterion than middle-aged adults that contributes to an increased vulnerability to false memory formation. Subsequent age-related changes in response bias may reflect the maturation of frontal and temporal regions. In youth, a more liberal response bias may contribute to the heightened propensity for poor decision-making seen in this population.

Emotion regulation in children with behavior problems: linking behavioral and brain processes.

Past studies have shown that aggressive children exhibit rigid (rather than flexible) parent-child interactions; these rigid repertoires may provide the context through which children fail to acquire emotion-regulation skills. Difficulties in regulating emotion are associated with minimal activity in dorsal systems in the cerebral cortex, for example, the anterior cingulate cortex. The current study aimed to integrate parent-child and neurocognitive indices of emotion regulation and examine their associations for the first time. Sixty children (8-12 years old) referred for treatment for aggression underwent two assessments. Brain processes related to emotion regulation were assessed using dense-array EEG with a computerized go/no-go task. The N2 amplitudes thought to tap inhibitory control were recorded, and a source analysis was conducted. In the second assessment, parents and children were videotaped while trying to solve a conflict topic. State space grids were used to derive two dynamic flexibility parameters from the coded videotapes: (a) the number of transitions between emotional states and (b) the dispersion of emotional states, based on proportional durations in each state. The regression results showed that flexibility measures were not related to N2 amplitudes. However, flexibility measures were significantly associated with the ratio of dorsal to ventral source activation: for transitions, ΔR 2 = .27, F (1, 34) = 13.13, p = .001; for dispersion, ΔR 2 = .29, F (1, 35) = 14.76, p < .001. Thus, in support of our main hypothesis, greater dyadic flexibility was associated with a higher ratio of dorsomedial to ventral activation, suggesting that children with more flexible parent-child interactions are able to recruit relatively more dorsomedial activity in challenging situations.

Neuroticism as a mediator of treatment response to SSRIs in major depressive disorder.

BACKGROUND: Serotonin function has been implicated in both major depressive disorder and neuroticism. In the current investigation, we examined the hypothesis that any change in depression severity is mediated through the reduction of neuroticism, but only for those compounds which target serotonin receptors. METHODS: Ninety-three outpatients in the midst of a major depressive episode received one of three antidepressant medications, classified into two broad types: selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs (i.e. reversible monoamine oxidase inhibitors [RIMAs] and noradrenergic and dopaminergic reuptake blockers [NDMs]). Patients completed the Hamilton Rating Scale for Depression, Beck Depression Inventory II and Revised NEO Personality Inventory prior to and following approximately 16 weeks of treatment. Structural equation modeling was used to test two models: a mediation model, in which neuroticism change is the mechanism by which SSRIs exert a therapeutic effect upon depressive symptoms, and a complication model, in which neuroticism change is a mere epiphenomenon of depression reduction in response to SSRIs. RESULTS: The mediation model provided a good fit to the data; the complication model did not. Patients treated with SSRIs demonstrated greater neuroticism change than those treated with non-SSRIs, and greater neuroticism change was associated with greater depressive symptom change. These effects held for both self-reported and clinician-rated depressive symptom severity. LIMITATIONS: Replication within a randomized control trial with multiple assessment periods is required. CONCLUSION: Neuroticism mediates changes in depression in response to treatment with SSRIs, such that any treatment effect of SSRIs occurs through neuroticism reduction.

The time course of social-emotional processing in early childhood: ERP responses to facial affect and personal familiarity in a Go-Nogo task.

To date, little is known about the neural underpinnings of social-emotional processes in young children. The present study investigated the time course of children's ERP responses to facial expression and personal familiarity, and the effect of these variables on ERP measures of effortful attention in a Go-Nogo task. Dense-array EEG was collected from 48 4-6-year-old children who were presented with pictures of their mothers' and strangers' happy and angry faces. ERPs were scored following face presentation and following a subsequent cue signaling a Go or Nogo response. Responses to face presentation showed early perceptual components that were larger following strangers' faces, suggesting facilitated rapid processing of personally important faces. A mid-latency frontocentral negativity was greatest following angry mothers' faces, indicating increased attentional monitoring and/or recognition memory evoked by an angry parent. Finally a right-lateralized late positive component was largest following angry faces, suggesting extended processing of negatively valenced social stimuli in general. Following the Go-Nogo response cue, a right-lateralized mid-latency negativity thought to measure effortful attention was larger in Nogo than Go trials, and following angry than happy faces, possibly reflecting increased effortful control required in those conditions. The present study suggests that overlapping but differentiated networks for both rapid and elaborative processing of important socio-affective information are established by 4-6 years. Moreover, the extended spatial and temporal distribution of components suggests a pattern of response to social stimuli in which more rapid processes may index personal familiarity, whereas temporally extended processes are sensitive to affective valence on both familiar and unfamiliar faces.