Brief diesel exhaust exposure acutely impairs functional brain connectivity in humans: a randomized controlled crossover study.

BACKGROUND: While it is known that exposure to traffic-related air pollution causes an enormous global toll on human health, neurobiological underpinnings therein remain elusive. The study addresses this gap in knowledge. METHODS: We performed the first controlled human exposure study using functional MRI with an efficient order-randomized double-blind crossover study of diesel exhaust (DE) and control (filtered air; FA) in 25 healthy adults (14 males, 11 females; 19-49 years old; no withdrawals). Analyses were carried out using a mixed effects model in FLAME. Z (Gaussianised T/F) statistic images were thresholded non-parametrically using clusters determined by Z > 2.3 and a (corrected) cluster significance threshold of p = 0.05. RESULTS: All 25 adults went through the exposures and functional MRI imaging were collected. Exposure to DE yielded a decrease in functional connectivity compared to exposure to FA, shown through the comparison of DE and FA in post-exposure measurement of functional connectivity. CONCLUSION: We observed short-term pollution-attributable decrements in default mode network functional connectivity. Decrements in brain connectivity causes many detrimental effects to the human body so this finding should guide policy change in air pollution exposure regulation. TRIAL REGISTRATION: University of British Columbia Clinical Research Ethics Board (# H12-03025), Vancouver Coastal Health Ethics Board (# V12-03025), and Health Canada's Research Ethics Board (# 2012-0040).

Increased myelination plays a central role in white matter neuroplasticity.

White matter (WM) neuroplasticity in the human brain has been tracked non-invasively using advanced magnetic resonance imaging techniques, with increasing evidence for improved axonal transmission efficiency as a central mechanism. The current study is the culmination of a series of studies, which characterized the structure-function relationship of WM transmission efficiency in the cortico-spinal tract (CST) during motor learning. Here, we test the hypothesis that increased transmission efficiency is linked directly to increased myelination using myelin water imaging (MWI). MWI was used to evaluate neuroplasticity-related improvements in the CST. The MWI findings were then compared to diffusion tensor imaging (DTI) results, with the secondary hypothesis that radial diffusivity (RD) would have a stronger relationship than axial diffusivity (AD) if the changes were due to increased myelination. Both MWI and RD data showed the predicted pattern of significant results, strongly supporting that increased myelination plays a central role in WM neuroplasticity.

Long-Term Motor Recovery After Severe Traumatic Brain Injury: Beyond Established Limits.

OBJECTIVE: To report neural plasticity changes after severe traumatic brain injury. SETTING: Case-control study. PARTICIPANTS: Canadian soldier, Captain Trevor Greene survived a severe open-traumatic brain injury during a 2006 combat tour in Afghanistan. DESIGN: Longitudinal follow-up for more than 6 years. MAIN MEASURES: Twelve longitudinal functional magnetic imaging (fMRI) examinations were conducted to investigate lower limb activation changes in association with clinical examination. Trevor Greene's lower limb fMRI activation was compared with control fMRI activation of (1) mental imagery of similar movement and (2) matched control subject data. RESULTS: Trevor Greene's motor recovery and corresponding fMRI activation increased significantly over time (F = 32.54, P < .001). Clinical measures of functional recovery correlated strongly with fMRI motor activation changes (r = 0.81, P = .001). By comparison, while Trevor Greene's mental imagery activated similar motor regions, there was no evidence of fMRI activation change over time. While comparable, control motor activation did not change over time and there was no significant mental imagery activation. CONCLUSION: Motor function recovery can occur beyond 6 years after severe traumatic brain injury, both in neural plasticity and clinical outcome. This demonstrates that continued benefits in physical function due to rehabilitative efforts can be achieved for many years following injury. The finding challenges current practices and assumptions in rehabilitation following traumatic brain injury.

Impact of APOE-ε alleles on brain structure and cognitive function in healthy older adults: A VBM and DTI replication study.

BACKGROUND: The Apolipoprotein E (APOE) gene has been established in the Alzheimer's disease (AD) literature to impact brain structure and function and may also show congruent effects in healthy older adults, although findings in this population are much less consistent. The current study aimed to replicate and expand the multimodal approach employed by Honea et al. Structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and neuropsychological measures were used to investigate the impact of APOE-ε status on grey matter structure, white matter integrity, and cognitive functioning. METHODS: Data were obtained from the Alzheimer's Disease Initiative Phase 3 (ADNI3) database. Baseline MRI, DTI and cognitive composite scores for memory (ADNI-Mem) and executive function (ADNI-EF) were acquired from 116 healthy controls. Participants were grouped according to APOE allele presence (APOE-ε2+ N = 17, APOE-ε3ε3 N = 64, APOE-ε4+ N = 35). Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were used to compare grey matter volume (GMV) and white matter integrity, respectively, between APOE-ε2+ and APOE-ε3ε3 controls, and again between APOE-ε4+ and APOE-ε3ε3 controls. Multivariate analysis of covariance (MANCOVA) was used to examine the effects of APOE polymorphism on memory and EF across all APOE groups with age, sex and education as regressors of no interest. Cognitive scores were correlated (Pearson r) with imaging metrics within groups. RESULTS: No significant differences were seen across groups, within groups in MRI metrics, or cognitive performance (p>0.05, corrected for multiple comparisons). CONCLUSIONS: The current study partially replicated and extended previous findings from an earlier multimodal study (Honea 2009). Future studies should clarify APOE mechanisms in healthy ageing by adding other imaging, cognitive, and lifestyle metrics and longitudinal design in larger sample sizes.

The Piano Man: A Case Report of Anterior Thalamic Infarct with Dementia and Preserved Music Ability.

OBJECTIVE: The thalamus is the integrative hub of the brain with reciprocal connections throughout the cortex. This case report describes a right-handed 81-year-old male patient who experienced sudden onset cognitive impairment following a focal left anterior thalamic infarct. METHODS: With consent/assent, the patient was seen for a short neuropsychological assessment 6 weeks post stroke. Neuropsychological assessment included review of medical history, collateral intake, the Toronto Cognitive Assessment, Frontal Systems Behavior Scale-Family Rating Form, the Neuropsychiatric Inventory Questionnaire, and piano performance. RESULTS: The assessment revealed impaired performance on measures of orientation, memory, executive function, and language, as well as symptoms including hallucinations, apathy, and hypersomnolence, consistent with thalamic dementia. Remarkably, in this context, the patient maintained an ability to play piano and read music. CONCLUSIONS: The case has implications for understanding the complex integrative functions of the thalamus, including how profound impairment can simultaneously present with cognitive strengths that may not be captured by performance on neuropsychological testing. This case also suggests that magnetic resonance imaging may be indicated in cases presenting with vascular risk factors and sudden onset cognitive impairment, given that computed tomography may not be sensitive to small subcortical infarcts.

A comparison of white matter microstructure and correlates with neuropsychological measures in younger and older adults.

OBJECTIVE: With a globally aging population, there is a need to better understand how brain structure relates to function in healthy older and younger adults. METHODS: 34 healthy participants divided into older (17; Mean = 70.9, SD = 5.4) and younger adults (17; Mean = 28.1, SD = 2.8) underwent diffusion-weighted imaging and neuropsychological assessment, including the California Verbal Learning Test 2nd Edition and the Trail Making Test (TMT-A and TMT-B). Differences in white matter microstructure for older and younger adults and the association between DTI metrics (fractional anisotropy, FA; mean diffusivity, MD) and cognitive performance were analyzed using tract-based spatial statistics (p < 0.05, corrected). RESULTS: Older adults had significantly lower FA and higher MD than younger adults in widespread brain regions. There was a significant negative correlation between executive function (TMT-B) and MD for older adults in the right superior/anterior corona radiata and the corpus callosum. No significant relationship was detected between DTI metrics and executive function in younger adults or with memory performance in either group. CONCLUSIONS: The findings underscore the need to examine brain-behaviour relationships as a function of age. Future studies should include comprehensive assessments in larger lifespan samples to better understand the aging brain.

Intrinsic functional connectivity strength of SuperAgers in the default mode and salience networks: Insights from ADNI.

There exists a group of older individuals who appear to be resistant to age-related memory decline. These "SuperAgers" have been shown to demonstrate preservation of cortical thickness and functional connectivity strength across the cortex which positively correlates with memory performance. Over the last decade, roughly 30 articles have been published regarding SuperAgers; however, to our knowledge, no replications of these studies have been published. The current study sought to conceptually replicate Zhang and colleagues' (2020) findings that SuperAgers demonstrate stronger intrinsic functional connectivity within the default mode (DMN) and salience networks (SN), and that connectivity strength within these networks correlates with memory performance. We identified 20 SuperAgers and 20 matched Normal Agers in the control cohort of the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We compared the functional connectivity strength of the DMN and SN between these groups, and used the Rey Auditory Verbal Learning Test (RAVLT) to evaluate correlations between functional connectivity and memory performance. Our results did not replicate Zhang and colleagues' (2020) results, as we found negligible differences between SuperAgers and Normal Agers in the DMN and SN, and no significant correlations between functional connectivity and memory performance after accounting for multiple comparisons. More replications are needed to confirm existing work. In addition, more research with larger SuperAger samples and more consistent definitions of SuperAging is needed, so that we can better understand this remarkable group of older adults.

Integration of sex/gender and utilization of ecological Momentary assessment of cognition in clinical populations: a scoping review.

Objectives: We aimed to describe the methods of smartphone-based cognitive ecological momentary assessment designs in clinical populations, with an intention to evaluate how the role of sex and/or gender has been considered in the design and analyses, particularly including female-specific physiology. Methods: This scoping review was conducted based on JBI scoping review methodology. On March 2nd, 2023, we searched for literature across four databases. Screening of the results and data extraction were conducted in duplicate according to the a priori methods in the pre-registered protocol. Results: 31 articles were included in this review. Participants ranged in age from 15-85 years old with various clinical disorders. Prompts were given between 1-7 times per day for 7-84 days. Executive function was the most frequently assessed cognitive domain. Over half the studies (n = 17, 55%) did not investigate the effects of sex and/or gender, and only one study considered the impact of hormonal therapy. Many studies (n = 14, 45%) used sex and gender interchangeably or incorrectly. Conclusions: Studies varied in design, with heterogeneity in the reporting of methodological information. The lack of attention to sex/gender on neuropsychological outcomes can lead to confusion and contradiction regarding its potential impact on cognition in clinical populations. This may hinder the identification of effective interventions for those assigned female at birth who have been overlooked or considered indistinguishable from their male counterparts. Given the well-documented impact of sex/gender on cognition, it is essential that future neuropsychological research, especially EMA-based studies, prioritize investigating sex/gender to ensure better outcomes for all.

How does the brain age in individuals with multiple sclerosis? A systematic review.

Multiple Sclerosis (MS) is a complex neurological disorder that involves demyelination, lesions and atrophy in both white and gray matter. Such changes in the central nervous system are diagnostic in MS and has a strong relationship with both physical and cognitive symptoms. As a result, magnetic resonance imaging (MRI) scans as a metric of brain atrophy have emerged as an important outcome measure in MS studies. Recently, research has begun to focus on the contribution of aging to the structural changes in the brain associated with MS; prompting questions about whether there is an amplifying effect of aging superimposed on MS-related brain atrophy. To examine current evidence of how the brain ages in individuals with MS, a systematic review of the literature was performed. Specific questions were focused on how aging affects gray and white matter structure, whether patterns of brain atrophy differ in younger and older cohorts and if there are structural differences in the brain as a function of sex in aging people with MS. This review considered studies that used MRI to examine the effects of aging in adults with MS. Twenty-one studies met eligibility criteria. Findings across these studies revealed that gray matter atrophy was more pronounced in older adults with MS, particularly in subcortical regions such as the thalamus; that the rates of atrophy were similar but varied by region for younger and older cohorts; and that males may experience more brain atrophy than females. Further studies that use multimodal MRI acquisition methods are needed to capture changes in both males and females over time, particularly in middle to older adulthood.

Stress and traumatic brain injury: An inherent bi-directional relationship with temporal and synergistic complexities.

Traumatic brain injury (TBI) and stress are prevalent worldwide and can both result in life-altering health problems. While stress often occurs in the absence of TBI, TBI inherently involves some element of stress. Furthermore, because there is pathophysiological overlap between stress and TBI, it is likely that stress influences TBI outcomes. However, there are temporal complexities in this relationship (e.g., when the stress occurs) that have been understudied despite their potential importance. This paper begins by introducing TBI and stress and highlighting some of their possible synergistic mechanisms including inflammation, excitotoxicity, oxidative stress, hypothalamic-pituitary-adrenal axis dysregulation, and autonomic nervous system dysfunction. We next describe different temporal scenarios involving TBI and stress and review the available literature on this topic. In doing so we find initial evidence that in some contexts stress is a highly influential factor in TBI pathophysiology and recovery, and vice versa. We also identify important knowledge gaps and suggest future research avenues that will increase our understanding of this inherent bidirectional relationship and could one day result in improved patient care.

The relationship between cardiovascular risk and lifestyle activities on hippocampal volumes in normative aging.

Background: Despite the life-course perspective of popular aging models, few studies on healthy aging to date have examined both younger and older adulthood. The current study examined how cumulative vascular risk factors and self-reported levels of physical, social, and cognitive activity are associated with differences in hippocampal volumes in healthy younger and older adults. Methods: 34 neurologically healthy participants were separated into two age cohorts: a younger adult group (age 25-35, n = 17) and an older adult group (age 65-82, n = 17). Participants underwent a 3 T T1 MRI and completed a series of questionnaires. Voxel-based morphometry examined whole-brain grey matter density differences between groups. Hippocampal volumes were computed. Analyses examined the association between hippocampal volumes, cumulative vascular risk, and self-reported levels of physical, social, and cognitive activity, both within and across groups. Results: Between-group comparisons revealed greater cortical atrophy in older relative to young adults in regions including the left and right hippocampus and temporal fusiform cortex. Across-group analyses revealed a significant negative association between cardiovascular risk scores and bilateral hippocampal volumes across age groups. A significant negative association was identified between frequency of social activities and bilateral hippocampal volumes in older adults only. No significant associations were found between left or right hippocampal volumes and total, cognitive, or physical activities in both within- and across-group analyses. Conclusion: Greater cumulative vascular risk is associated with smaller hippocampal volumes across age cohorts. Findings suggest that social activities with low cognitive load may not be beneficial to structural brain outcomes in older age.

Functional near infrared spectroscopy activation during an executive function task differs between healthy older and younger adults.

Background: Healthy aging can include declines in processing speed and executive function. Further research is needed to characterize the neurobiological underpinnings of these cognitive changes in older adulthood. The current study used functional near infrared spectroscopy (fNIRS), an optical neuroimaging technique, to examine differences in cerebral oxygenation between healthy older adults (OA) and younger adults (YA) during a measure of cognitive interference. Methods: Thirty-four participants were sampled from two age groups: YA (mean age = 28.1 years, SD = 2.8, F = 9) and OA (mean age = 70.9 years, SD = 5.4, F = 9). Participants completed the Multi-Source Interference Task (MSIT), a measure of executive function with high and low-demand conditions, while undergoing fNIRS recordings using a TechEn CW6 system with 34-source-detector channels, situated over the prefrontal cortex. Functional activation patterns, accuracy, and reaction time were compared between and within groups for each condition. Results: Behaviourally, during the control condition, OA and YA had comparable accuracy, although OA had significantly slower reaction times than YA. During the interference condition, OA had significantly lower accuracy and slower reaction times than YA. Results demonstrated a significant difference between groups with an age-related increase in HbO for OA in both conditions (p < 0.05). Within groups, OA showed greater activation during the control condition, while YA demonstrated greater activation during the interference condition. Conclusions: The findings suggest that OA recruit additional neural resources to achieve similar behavioural performance during low-level cognitive interference, but that compensation in OA may be insufficient to support behavioural performance at higher levels of interference.

A Systematic Review of Neuroimaging Studies Comparing Individuals with Subjective Cognitive Decline to Healthy Controls.

BACKGROUND: Individuals with subjective cognitive decline (SCD) are hypothesized to be the earliest along the cognitive continuum between healthy aging and Alzheimer's disease (AD), although more research is needed on this topic. Given that treatment approaches may be most effective pre-clinically, a primary objective of emerging research is to identify biological markers of SCD using neuroimaging methods. OBJECTIVE: The current review aimed to comprehensively present the neuroimaging studies on SCD to date. METHODS: PubMed and PsycINFO databases were searched for neuroimaging studies of individuals with SCD. Quality assessments were completed using the Appraisal tool for Cross-Sectional Studies. RESULTS: In total, 62 neuroimaging studies investigating differences between participants with SCD and healthy controls were identified. Specifically, the number of studies were as follows: 36 MRI, 6 PET, 8 MRI/PET, 4 EEG, 7 MEG, and 1 SPECT. Across neuroimaging modalities, 48 of the 62 included studies revealed significant differences in brain structure and/or function between groups. CONCLUSION: Neuroimaging methods can identify differences between healthy controls and individuals with SCD. However, inconsistent results were found within and between neuroimaging modalities. Discrepancies across studies may be best accounted for by methodological differences, notably variable criteria for SCD, and differences in participant characteristics and risk factors for AD. Clinic based recruitment and cross-sectional study design were common and may bias the literature. Future neuroimaging investigations of SCD should consistently incorporate the standardized research criteria for SCD (as recommended by the SCD-Initiative), include more details of their SCD sample and their symptoms, and examine groups longitudinally.

Functional mapping in the corpus callosum: a 4T fMRI study of white matter.

INTRODUCTION: The idea of fMRI activation in white matter (WM) is controversial. Our recent work has used two different approaches to investigate whether there is evidence for WM fMRI. The first approach used words and faces to elicit interhemispheric transfer activation in the posterior corpus callosum (Sperry task). The second approach used checkerboard stimuli to elicit similar activation in the anterior corpus callosum (Poffenberger task). Using these different tasks, it has been possible to detect WM activation in different regions. In the current study, we report the results of a critical experiment: demonstrating that callosal activation can be experimentally manipulated within the same set of individuals. METHODS: All subjects completed both the Sperry and Poffenberger tasks. Functional MRI data were acquired at 4T, using an asymmetric spin echo spiral sequence. Data were analyzed with FSL using a model-based approach. Analyses focused on group and individual activations in WM. RESULTS AND DISCUSSION: Corpus callosum activation was elicited for both tasks, with activation varying according to task type. A statistical contrast of the two tasks revealed posterior callosal activation for the Sperry task and anterior callosal activation for the Poffenberger task. The Sperry task showed activation in the isthmus and middle body of the corpus callosum at the group level and in 100% of subjects. The Poffenberger task showed activation in the genu and middle body of the corpus callosum at the group level and in 94% of subjects. The WM activation replicated prior results, with the additional strength of functional mapping within the same group of individuals.

Investigation of fMRI activation in the internal capsule.

BACKGROUND: Functional magnetic resonance imaging (fMRI) in white matter has long been considered controversial. Recently, this viewpoint has been challenged by an emerging body of evidence demonstrating white matter activation in the corpus callosum. The current study aimed to determine whether white matter activation could be detected outside of the corpus callosum, in the internal capsule. Data were acquired from a 4 T MRI using a specialized asymmetric spin echo spiral sequence. A motor task was selected to elicit activation in the posterior limb of the internal capsule. RESULTS: White matter fMRI activation was examined at the individual and group levels. Analyses revealed that activation was present in the posterior limb of the internal capsule in 80% of participants. These results provide further support for white matter fMRI activation. CONCLUSIONS: The ability to visualize functionally active tracts has strong implications for the basic scientific study of connectivity and the clinical assessment of white matter disease.

Tracking cognitive changes in new-onset epilepsy: functional imaging challenges.

Functional imaging has potential for tracking changes in cognition during the onset and evolution of epilepsy. Although the concept of imaging such changes over time is an exciting new direction, feasibility remains an open question. The current article outlines a case example in which functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs) were used to monitor memory changes before and after selective temporal lobe resection. From this example, three key methodologic challenges for new-onset epilepsy are identified and discussed. The first challenge relates to the interpretation of results in regions near epileptogenic tissue. We argue that this is best addressed by collecting information from multiple modalities to test for convergent evidence. The second challenge relates to optimizing the methods for sensitivity to detecting changes. In this case, enhanced imaging methods and a region-of-interest approach provide necessary focus. The third and final challenge relates to the practical difficulties of conducting research in new-onset epilepsy cases. We suggest that greater integration of imaging research within the clinical setting is needed.

Differences in symptoms of depression between females and males with relapsing-remitting multiple sclerosis.

INTRODUCTION: Depressive symptoms are experienced by up to 50% of individuals diagnosed with Multiple Sclerosis (MS). Furthermore, depressive symptoms are sometimes experienced differently for females and males in the general population, but it is unclear if this is true for people with Relapsing-Remitting MS (RRMS). The current study aimed to investigate whether there are differences between females and males with RRMS in overall depression scores as well as the types of depressive symptoms reported (somatic or cognitive). METHOD: Demographic and Beck Depression Inventory, 2nd edition (BDI-II) raw scores for females and males with RRMS were downloaded with permission from the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) Placebo database. A total of 494 individuals (n=354 females) with RRMS were included in analyses. Non-parametric Wilcoxon rank-sum tests were used to compare BDI-II Total Scores, Somatic Scores, and Cognitive Scores between females and males with RRMS. RESULTS: Females reported significantly greater overall symptoms of depression compared to males. Furthermore, females endorsed significantly greater somatic symptoms than males. There were no significant differences in females' reports of cognitive symptoms compared to males. CONCLUSIONS: Depressive symptoms in RRMS are experienced differently for females and males. Females with RRMS report higher levels of overall depression and somatic depressive symptoms compared to males with RRMS; this knowledge may help inform best strategies for treatment planning. Future studies should investigate depressive symptoms in females and males with progressive forms of MS, and track symptom changes longitudinally.

Functional connectivity pre-post exercise intervention in individuals with relapsing-remitting multiple sclerosis.

OBJECTIVE: Exercise interventions have emerged as a promising approach for managing symptoms associated with multiple sclerosis (MS). However, changes in brain function underlying exercise-related improvements in symptoms of MS have not been fully investigated, and in no instances have they been investigated using a graph theory approach. For the first time, the effects of an exercise intervention on functional brain network connectivity were examined using graph theory analyses of resting-state functional MRI (fMRI) data among individuals with relapsing-remitting MS (RRMS). METHODS: Resting-state fMRI data were obtained from 10 participants before and after 12 weeks of a speeded walking intervention. Functional connectivity data were preprocessed in Data Processing Assistant for Resting-State fMRI Advanced (DPARSF A version 4.2) and analyzed in GraphVar2.02 to compute global and local graph theory metrics. To examine differences in graph metrics before and after the intervention, one-sample permutation tests were performed. RESULTS: There were no significant pre to post exercise intervention changes in global metrics. Changes in local metrics (i.e. clustering coefficient, local efficiency, degree centrality and betweenness centrality) were mixed, with both increases and decreases observed. CONCLUSION: Following a 12-week speeded walking exercise intervention, there were no significant increases or decreases in global graph metrics and results at the level of local metrics were equivocal in individuals with RRMS. Further research with experimental designs that include baseline and longitudinal follow-up, as well as larger sample sizes, is needed to understand the underlying mechanisms of symptom improvement following exercise in RRMS.