Determine how characteristics of deployment mild traumatic brain injury (TBI) and blast exposure influence the relationship between the functional brain connectome with cognitive outcomes and symptom severity.

N = 181 Iraq and Afghanistan combat veterans completed structured clinical interviews, cognitive testing, self-report questionnaires, and magnetoencephalography (MEG). MEG data were acquired in the resting-state with eyes open. MEG data were beamformed to identify brain regions active at rest. Functional brain connectomes representing the unique network present for a given individual were created using active brain regions identified for each participant. Network metrics describing these connectomes were calculated at the participant level. Cognitive tests included the WAIS-IV, Trail Making Test Parts A&B, and the Controlled Oral Word Association test. Due to differences in normative data across tests, raw scores were used in analyses. Symptom measures included the PTSD Checklist - 5 (PCL-5), Patient Health Questionnaire (PHQ-9), Neurobehavioral Symptoms Inventory (NSI), Quality of Life After Brain Injury (QOLIBRI), Pittsburgh Sleep Quality Index (PsQi), the Distress Tolerance Scale (DTS), and the PROMIS Pain Interference Scale (PROMIS-PI).

Hierarchical linear regression analyses revealed that several network metrics were significantly related to both cognitive outcomes and symptom severity after adjusting for demographic covariates and clinical characteristics.

The relationship between Global Efficiency (GE) and cognitive outcomes was moderated by deployment TBI on the WAIS-IV Full Scale Index (FSI), Perceptual Reasoning Index (PRI), and General Ability Index (GAI). In all cases, when deployment TBI was absent, greater GE was associated with poorer cognitive scores. The relationship between GE and symptom severity was moderated by the severity of blast exposure. Greater GE was associated with lower symptom severity at lower blast severities for the PHQ-9 and QOLIBRI A (thinking) and E (negative emotions). Moderation effects were also observed for the PSQI. In the absence of deployment TBI, greater GE was associated with better sleep quality; however, in the presence of deployment TBI, greater GE was associated with poorer sleep quality. Other connectome-outcome relationships were not consistently moderated by Deployment TBI or blast history

Results demonstrated relationships between several aspects the functional connectome of the brain with both cognitive outcomes and symptom severity beyond effects of common demographic and clinical variables. Moderation analyses revealed that the relationship between GE of the connectome and outcomes is frequently disrupted by deployment TBI and blast. GE is a measure of the ease of information transfer through the network. These results identified consistent relationships between GE and outcomes in the absence of deployment TBI or blast, but these relationships disappear when deployment TBI or blast are present. Participants in this study were on average 11 years post-TBI or blast exposure, suggesting these are chronic rather than acute effects. GE was significantly correlated with most symptom severity measures as well as the WAIS-IV PRI, GAI, VCI, and FSI. Future efforts to normalize the relationship between GE and outcomes following TBI may improve rehabilitation outcomes and directly affect areas of concern commonly reported by service members following TBI or blast exposure.

Motor imagery is defined as a dynamic state during which a subject mentally simulates a given action without overt movements. Our aim was to use near-infrared spectroscopy to investigate differences in cerebral hemodynamic during motor imagery of self-feeding with chopsticks using the dominant or non-dominant hand.

Twenty healthy right-handed people participated in this study. The motor imagery task involved eating sliced cucumber pickles using chopsticks with the dominant (right) or non-dominant (left) hand. Activation of regions of interest (pre-supplementary motor area, supplementary motor area, pre-motor area, pre-frontal cortex, and sensorimotor cortex was assessed.

Motor imagery vividness of the dominant hand tended to be significantly higher than that of the non-dominant hand. The time of peak oxygenated hemoglobin was significantly earlier in the right pre-frontal cortex than in the supplementary motor area and left pre-motor area. Hemodynamic correlations were detected in more regions of interest during dominant-hand motor imagery than during non-dominant-hand motor imagery.

Hemodynamic might be affected by differences in motor imagery vividness caused by variations in motor manipulation.

Cognitive deficits in patients diagnosed with schizophrenia are a core feature of the disorder. There are currently no treatments for these cognitive deficits. Our aim was to examine and compare patterns of increased versus decreased activity in the central executive network (CEN), salience network (SN), and default mode network (DMN) between healthy controls (HCs) and patients diagnosed with schizophrenia (SZs) as well as to explore the influence of task load on these networks between HCs and SZs.

Analyses focused on a secondary dataset comprising Blood Oxygen-Level Dependent (BOLD) data collected from 25 HCs and 27 SZs who completed a working memory (WM) task (N-back) with 5 load conditions while undergoing functional magnetic resonance imaging (fMRI). Region of interest (ROI) data were analyzed using linear mixed-effects models.

Group activation differences were found in the posterior salience network (pSN), default mode network (DMN), dorsal default mode network (dDMN), and ventral default mode network (vDMN) showing greater activity for SZs. Specifically, pSN, DMN, dDMN, and vDMN all showed increased activity in SZs compared to HCs. The curve of brain activity was consistent between HCs and SZs with the exception of the vDMN, where HCs show greater activation at modest mental workload (quadratic curve) and SZs showed greater brain activation at lower mental workload (linear). In the CEN, there were no group differences, and the response curve was the same for both groups.

These group differences demonstrate network difference between HCs and SZs and could show value in treatments targeting cognitive deficits in SZs from a large-scale brain network connectivity perspective. Future studies are needed to confirm these results with larger sample size in order to examine potential subtleties of interactions between these networks.

The prevalence of mild to moderate cognitive impairment, including episodic memory deficits, in people living with HIV (PLWH) remains high despite the life-extending success of antiretroviral pharmacotherapy. With PLWH now reaching near-normal life expectancy, questions concerning a potential synergy between age- and HIV disease-related effects, including degradation in fronto-limbic circuits, neural systems also compromised in Parkinson’s disease (PD), have emerged.

This cross-sectional study examined the similarities and differences in component processes of verbal episodic memory and their neural correlates in 42 PLWH, 41 individuals with PD, and 37 controls (CTRL) (all participants aged 45-79 years). Learning over five trials, short-delay (SD) and long-delay, (LD), free-recall (FR) and cued-recall (CR) indices were assessed using the California Verbal Learning Test-2. Retention scores for FR and CR were derived adjusting for Trial 5 performance. All memory scores were age- and education-corrected based on the control group and reported as Z-scores. Regional brain volumes were calculated using 3T MRI data and the SRI24 atlas to delineate frontal (precentral, superior, orbital, middle, inferior, supplemental motor, and medial) and limbic (hippocampus, thalamus) regions. Brain volumes were age- and head-sized corrected based on 238 controls (19-86 years old).

Compared with the CTRL group, the HIV and PD groups were impaired on learning across trials and on SD and LD free- and cued-recall, with no group difference between the HIV and PD groups on any score. All three groups benefited similarly from cues compared with free-recall. The HIV and PD groups did not differ from CTRL on retention scores. Regarding brain volumes, the HIV group had smaller middle frontal volumes than the PD or CTRL groups and smaller thalamic volumes than the PD group. Correlational analyses (Bonferroni correction for 8 comparisons, p<.01) indicated that fewer total number of words recalled on Trial 5, learning over Trials 1-5, total words recalled on SD-CR, LD-FR, and LD-CR were associated with smaller orbitofrontal volume in the HIV but not the PD group; the correlations between orbitofrontal volume and memory scores were significantly different between the HIV and PD groups. In PD, but not HIV, lower retention scores on SD-FR and LD-CR correlated to smaller hippocampal volume.

Impairment in learning and cued recall performance indicate that both encoding and retrieval processes are affected in PLWH and PD. Neural correlates of verbal memory differed between groups, with orbitofrontal volume associated with learning and recall in PLWH, whereas hippocampal volume was associated with retention scores in PD. Together, these results suggest that different nodes within the fronto-limbic mnemonic circuitry underlie the mutual verbal episodic memory deficits observed in older PLWH and PD. Support: AA023165, AA005965, AA107347, AA010723, NS07097, MH113406, and the Michael J. Fox Foundation for Parkinson’s Research

Smartphone-based cognitive assessments can provide unique information about cognition that is difficult or impossible with traditional cognitive assessments. Using high-frequency measurement “burst” designs, we have shown that older adults are capable and willing to participate in smartphone-based research, that this method dramatically improves between-subject reliability compared to traditional methods and demonstrates extraordinary test-retest reliabilities, and that high-frequency measurement can reveal time of day effects that are increased in those with elevated Alzheimer’s disease biomarkers. In this symposium session, we will provide an overview of our current work in older adults at risk for AD and highlight new analyses on the interaction between day to day variability in sleep and cognition. We will also cover our approach for measuring smartphone latencies, a critical aspect of bring-your-own-device (BYOD) studies.

The Ambulatory Research in Cognition (ARC) smartphone application for iOS and Android administers custom-designed tests of associate memory, processing speed, and spatial working memory. ARC uses a measurement burst design in which very brief (typically 60s or less) tests are completed at random times several times per day for up to one week. Measurement burst designs rely on principles from ecological momentary assessment, and can be described with a simple formula: 1. Test often and everywhere, 2. Keep assessments brief, and 3. Combine the data across sessions to increase reliability. At the Knight Alzheimer’s Disease Research Center at Washington University in St Louis, we have enrolled over 400 participants (ages 60-99 years) at risk for AD in ARC studies. These participants are comprehensively assessed with traditional cognitive tests, clinical examinations, neuroimaging, and fluid biomarkers. ARC also assesses sleep with the Pittsburgh Sleep Quality Index that captures essential sleep parameters, which are assessed daily during each 7-day measurement burst. Analyses of sleep and cognition focused on parameters including total sleep time, number of awakenings, sleep quality ratings, and an extremes analysis comparing cognition after nights with more sleep and after nights with less sleep.

Overall, participants reporting less total sleep time and more awakenings had lower memory and processing speed scores. This remained significant after modeling covariates including age, self-reported gender, education, and APOE ε4 status. Compared to nights with the most sleep, memory was worse after the nights with the poorest sleep.

When considering AD biomarkers in these analyses, participants with elevated AD biomarkers, including neurofilament light chain (NfL) and phosphorylated-tau181 (p-tau181), demonstrated more impacts of poor sleep on cogntion, such that the nights with the least sleep tended to impact cognition more than in those with normal biomarker levels, suggesting an important role for sleep in maintaining cognition in preclinical and early symptomatic AD. Interestingly, self-reported sleep quality was not associated with ARC cognitive tests, consistent with studies emphasizing the need for more quantitative assessments of sleep quality. In addition to these sleep data, we will review publications using the ARC platform, including a recently accepted manuscript in JINS (Nicosia et al., 2022).

Chronic insomnia is a highly prevalent disorder affecting approximately one-in-three Americans. Insomnia is associated with increased cognitive and brain arousal. Compared to healthy individuals, those with insomnia tend to show greater activation/connectivity within the default mode network (DMN) of the brain, consistent with the hyperarousal theory. We investigated whether it would be possible to suppress activation of the DMN to improve sleep using a type of repetitive transcranial magnetic stimulation (rTMS) known as continuous theta burst stimulation (cTBS).

Participants (n=9, 6 female; age=25.4, SD=5.9 years) meeting criteria for insomnia/sleep disorder on standardized scales completed a counterbalanced sham-controlled crossover design in which they served as their own controls on two separate nights of laboratory monitored sleep on separate weeks. Each session included two resting state functional magnetic resonance imaging (fMRI) sessions separated by a brief rTMS session. Stimulation involved a 40 second cTBS stimulation train applied over an easily accessible cortical surface node of the DMN located at the left inferior parietal lobe. After scanning/stimulation, the participant was escorted to an isolated sleep laboratory bedroom, fitted with polysomnography (PSG) electrodes, and allowed an 8-hour sleep opportunity from 2300 to 0700. PSG was monitored continuously and scored for standard outcomes, including total sleep time (TST), percentage of time various sleep stages, and number of arousals.

Consistent with our hypothesis, a single session of active cTBS produced a significant reduction of functional connectivity (p < .05, FDR corrected) within the DMN. In contrast, the sham condition produced no changes in functional connectivity from pre- to post-treatment. Furthermore, after controlling for age, we also found that the active treatment was associated with meaningful trends toward greater overnight improvements in sleep compared to the sham condition. First, the active cTBS condition was associated with significantly greater TST compared to sham (F(1,7)=14.19, p=.007, partial eta-squared=.67). Overall, individuals obtained 26.5 minutes more sleep on the nights that they received the active cTBS compared to the sham condition. Moreover, the active cTBS condition was associated with a significant increase in the percentage of time in rapid eye movement (REM%) sleep compared to the sham condition (F(1,7)=7.05, p=.033, partial eta-squared=.50), which was significant after controlling for age. Overall, active treatment was associated with an increase of 6.76% more of total sleep time in REM compared to sham treatment. Finally, active cTBS was associated with fewer arousals from sleep (t(8) = -1.84, p = .051, d = .61), with an average of 15.1 fewer arousals throughout the night than sham.

Overall, these findings suggest that this simple and brief cTBS approach can alter DMN brain functioning in the expected direction and was associated with trends toward improved objectively measured sleep, including increased TST and REM% and fewer arousals during the night following stimulation. These findings emerged after only a single 40-second treatment, and it remains to be seen whether multiple treatments over several days or weeks can sustain or even improve upon these outcomes.

Processing speed declines with age and is a strong predictor of age-related cognitive decline in other domains, and in predicting who will need help with tasks of daily living in later years. Higher cardiorespiratory fitness (CRF) reflects better cardiopulmonary health and is related to maintenance of processing speed and cognition into late life. On the other hand, white matter lesions (WML) are reflective of age-related brain network disconnections from damage to white matter tracts in the brain. Lower CRF and higher WML burden have each been related to poorer cognitive performance. Although higher CRF provides a protective effect on cognition, the combined effects of CRF and WML on processing speed have yet to be determined. Specifically, whether CRF and WML independently affect processing speed or if WML moderates the effect of CRF on processing speed is yet to be established. We predicted WML may moderate CRF benefits on cognitive aging if CRF-related cognitive benefits are weakened by high WML load. Here, we test this question with the gold-standard measure of CRF, maximal exercise oxygen uptake (relative VO2 max, mL/kg/min) during a graded exercise test, and a validated neuropsychological measure of processing speed, the Digit Symbol Substitution Test (DSST).

CRF, DSST scores, and WML volumes of cognitively normal adults (n=91) aged 55-80 years were included in this analysis. The WML data was corrected for total intracranial volume and was log transformed. A linear regression model included the number of accurately completed items on the DSST as the dependent variable and age, sex, relative VO2 max, WML volumes and the interaction between relative VO2 max and WML volume as the predictor variables.

Main effects of age, sex, VO2 max and WML volume on the DSST were observed. Greater age, higher WML volume, and lower relative VO2 max were associated with poorer performance on the DSST. In addition, females (n=55) performed better than males (n=36) on the DSST. No significant interaction was observed between VO2 max and WML volume on DSST scores.

Our results show that 1) WML and relative VO2 max independently contribute to processing speed performance in older adults as measured by the DSST, and 2) WML do not moderate the relation between VO2 max and the DSST. Strengths of this study include gold-standard measurement of CRF and WML volumes as predictors of performance on the DSST in older adults. Further research is warranted to understand how vascular aging and brain health indicators interactively or interdependently impact cognition in aging.

Mild traumatic brain injury (mTBI) remains one of the most silent recurrent head injuries reported in the United States. mTBI accounts for nearly 75 percent of all traumatic brain injuries in the American population. Brain injury is often associated with impulsivity, but the association between resting state functional connectivity (rsFC) and impulsivity at multiple stages since time-since-injury (TSI) is unclear. We hypothesized that rsFC within the default mode network (DMN) would predict impulsivity across multiples stages of recovery in mild TBI.

Participants healthy controls (HC: n=35 total [15 male, 20 female], age M=24.40, SD=5.95; mTBI: n=121 total [43 male; 78 female], age M=24.76, SD=7.48). Participants completed a cross-sectional study design at various post-injury time points ranging from (2W, 1M,3M,6M,12M). Participants a neuroimaging session and behavioral tasks including a psychomotor vigilance task. Impulsivity was assessed as a combination of false starts and impulsive responses on behavioral tasks. The neuroimaging session included a rsFC scan. To predict impulsivity from brain connectivity, we conducted a series of stepwise linear regression analyses with the 11 functional brain connections (extracted as Fisher’s z-transformed correlations between regions) as predictors and each of the 13 neurocognitive factor scores separately. We focus here on the outcomes for the impulsivity factor.

Results showed greater positive connectivity between the and Right Frontal Pole and the anterior cingulate cortex (ACC; seed) (ß = .158, t = 1.98, p = .049) which was associated with greater impulsivity. Individuals in the 2W group demonstrated one significant predictor (R = .632, R2 = .399, F = 5.32, p = .050). Largely, there was greater positive connectivity between the Right Frontal Pole and the ACC (seed) and (ß = .632, t = 2.31, p = .050) which was associated with higher impulsivity at the 2W time-since-injury. No predictors emerged for the 1M, 3M, or 6M conditions. However, individuals in the 12M group demonstrated two significant predictor connections (R = .497, R2 = .247, F = 5.73, p = .007). Overall, a linear combination of greater negative (anticorrelated) connectivity between the Right Frontal Pole and the mPFC (seed) (/? = -.576, t = -3.53, p = .002) and greater positive connectivity between the Paracingulate Cortex (seed) and the Left Lateral Prefrontal Cortex (ß = .368, t = 2.14, p = .039) was also associated with greater impulsivity in individuals with mTBI at 12M.

These findings suggest functional connectivity between the anterior node of the DMN and prefrontal cortex regions involved in behavioral control was predictive of higher impulsivity in individuals with mTBI at 2W and 12M post injury, but not at other time frames. Interestingly, these connections differed at the two time points. Acutely, greater impulsivity was associated with greater connectivity among regions involved in error detection, exploration, and emotion. At one year, the connections involve regions associated with error monitoring and inhibitory processes. This may reflect compensatory strategy development during recovery.

Agricultural workers are immersed in environments associated with increased risk for adverse psychiatric and neurological outcomes. Agricultural work-related risks to brain health include exposure to pesticides, heavy metals, and organic dust. Despite this, there is a gap in our understanding of the underlying brain systems impacted by these risks. This study explores clinical and cognitive domains, and functional brain activity in agricultural workers. We hypothesized that a history of agricultural work-related risks would be associated with poorer clinical and cognitive outcomes as well as changes in functional brain activity within cortico-striatal regions.

The sample comprised 17 agricultural workers and a comparison group of 45 non-agricultural workers recruited in the Northern Colorado area. All participants identified as White and non-Hispanic. The mean age of participants was 51.7 years (SD = 21.4, range 18-77), 60% identified as female, and 37% identified as male. Participants completed the National Institute of Health Toolbox (NIH Toolbox) and Montreal Cognitive Assessment (MoCA) on their first visit. During the second visit, they completed NIH Patient-Reported Outcomes Measurement Information System (PROMIS) measures and underwent functional magnetic resonance imaging (fMRI; N = 15 agriculture and N = 35 non-agriculture) while completing a working memory task (Sternberg). Blood oxygen-level dependent (BOLD) response was compared between participants. Given the small sample size, the whole brain voxel-wise group comparison threshold was set at alpha = .05, but not otherwise corrected for multiple comparisons. Cohen’s d effect sizes were estimated for all voxels.

Analyses of cognitive scores showed significant deficits in episodic memory for the agricultural work group. Additionally, the agricultural work group scored higher on measures of self-reported anger, cognitive concerns, and social participation. Analyses of fMRI data showed increased BOLD activity around the orbitofrontal cortex (medium to large effects) and bilaterally in the entorhinal cortex (large effects) for the agricultural work group. The agricultural work group also showed decreased BOLD activity in the cerebellum and basal ganglia (medium to large effects).

To our knowledge, this study provides the first-ever evidence showing differences in brain activity associated with a history of working in agriculture. These findings of poorer memory, concerns about cognitive functioning, and increased anger suggest clinical relevance. Social participation associated with agricultural work should be explored as a potential protective factor for cognition and brain health. Brain imaging data analyses showed increased activation in areas associated with motor functioning, cognitive control, and emotion. These findings are limited by small sample size, lack of diversity in our sample, and coarsely defined risk. Despite these limitations, the results are consistent with an overall concern that risks associated with agricultural work can lead to cognitive and psychiatric harm via changes in brain health. Replications and future studies with larger sample sizes, more diverse participants, and more accurately defined risks (e.g., pesticide exposure) are needed.

Vitamin D is engaged in various neural processes, with low vitamin D linked to depression and cognitive dysfunction. There are gender differences in depression and vitamin D level. However, the relationship between depression, gender, vitamin D, cognition, and brain function has yet to be determined.

One hundred and twenty-two patients with major depressive disorder (MDD) and 119 healthy controls underwent resting-state functional MRI and fractional amplitude of low-frequency fluctuations (fALFF) was calculated to assess brain function. Serum concentration of vitamin D (SCVD) and cognition (i.e. prospective memory and sustained attention) were also measured.

We found a significant group-by-gender interaction effect on SCVD whereby MDD patients showed a reduction in SCVD relative to controls in females but not males. Concurrently, there was a female-specific association of SCVD with cognition and MDD-related fALFF alterations in widespread brain regions. Remarkably, MDD- and SCVD-related fALFF changes mediated the relation between SCVD and cognition in females.

Apart from providing insights into the neural mechanisms by which low vitamin D contributes to cognitive impairment in MDD in a gender-dependent manner, these findings might have clinical implications for assignment of female patients with MDD and cognitive dysfunction to adjuvant vitamin D supplementation therapy, which may ultimately advance a precision approach to personalized antidepressant choice.

Associations between childhood trauma (CT), social support (SS), brain functions and major depressive disorder (MDD) is unknown.

This study aimed to investigate whether brain functions mediated associations between CT, SS, and MDD.

164 MDD and 98 healthy controls (HC) were recruited and measured by HAMD-24 and HAMA. Some completed CT questionnaire (CTQ) and social support rating scale (SSRS). We examined amplitude of low-frequency fluctuation (ALFF) between the two groups and correlations between HAMD-24, HAMA and ALFF in MDD. Then, the peak voxels of the ALFF changed regions were used as seeds to analyze whole-brain functional connectivity (FC). Next, correlations between FC and clinical variables of MDD were performed. Last, mediation analysis was used to further determine whether ALFF or FC could mediate the associations between CT, SS, and different clinical variables in MDD patients.

Compared to HC, MDD showed decreased ALFF in right posterior cingulate (PCC_R), left postcentral gyrus, right precentral gyrus, and left thalamus (THA_L), but increased ALFF in right medial frontal gyrus, left subgenual anterior cingulate, and left middle occipital gyrus as well as decreased FC in bilateral PCC and THA_R. HAMD-24 had negative correlation with ALFF of THA_L, while positive with sexual abuse (SA) score in MDD. Mediation analysis revealed that FC of PCC_R mediated association between SA and baseline HAMD-24, and itself or together with SS mediated association between CT and onset age of MDD.

CT may influence the depression severity and onset age of MDD by moderating FC of PCC_R only or together with SS.