Data-driven MRI analysis reveals fitness-related functional change in default mode network and cognition following an exercise intervention.

Previous research has indicated that cardiorespiratory fitness (CRF) is structurally and functionally neuroprotective in older adults. However, questions remain regarding the mechanistic role of CRF on cognitive and brain health. The purposes of this study were to investigate if higher pre-intervention CRF was associated with greater change in functional brain connectivity during an exercise intervention and to determine if the magnitude of change in connectivity was related to better post-intervention cognitive performance. The sample included low-active older adults (n = 139) who completed a 6-month exercise intervention and underwent neuropsychological testing, functional neuroimaging, and CRF testing before and after the intervention. A data-driven multi-voxel pattern analysis was performed on resting-state MRI scans to determine changes in whole-brain patterns of connectivity from pre- to post-intervention as a function of pre-intervention CRF. Results revealed a positive correlation between pre-intervention CRF and changes in functional connectivity in the precentral gyrus. Using the precentral gyrus as a seed, analyses indicated that CRF-related connectivity changes within the precentral gyrus were derived from increased correlation strength within clusters located in the Dorsal Attention Network (DAN) and increased anti-correlation strength within clusters located in the Default Mode Network (DMN). Exploratory analysis demonstrated that connectivity change between the precentral gyrus seed and DMN clusters were associated with improved post-intervention performance on perceptual speed tasks. These findings suggest that in a sample of low-active and mostly lower-fit older adults, even subtle individual differences in CRF may influence the relationship between functional connectivity and aspects of cognition following a 6-month exercise intervention.

Light aerobic exercise modulates executive function and cortical excitability.

Single bouts of aerobic exercise can modulate cortical excitability and executive cognitive function, but less is known about the effect of light-intensity exercise, an intensity of exercise more achievable for certain clinical populations. Fourteen healthy adults (aged 22 to 30) completed the following study procedures twice (≥7 days apart) before and after 30 min of either light aerobic exercise (cycling) or seated rest: neurocognitive battery (multitasking performance, inhibitory control and spatial working memory), paired-pulse TMS measures of cortical excitability. Significant improvements in response times during multitasking performance and increases in intracortical facilitation (ICF) were seen following light aerobic exercise. Light aerobic exercise can modulate cortical excitability and some executive function tasks. Populations with deficits in multitasking ability may benefit from this intervention.

Multisystem afflictions in former National Football League players.

BACKGROUND: The long-term health consequences of participation in American style football (ASF) are not well understood. METHODS: We conducted a retrospective cohort study of men who had played in the NFL after 1960. Participants were studied using a standardized self-administered questionnaire designed to determine both the exposure history to ASF and the prevalence of chronic pain, sleep apnea, cardiometabolic disease, and neurocognitive impairment. Logistic regression and negative binomial regression models were used to assess associations between age, ethnicity, body-mass index during professional football career, field position, and football career duration with individual and multiple afflictions. RESULTS: In this cohort of former NFL players (n = 3745), approximately one quarter of the eligible former players (27%) reported two or more medical afflictions (chronic pain, cardiometabolic disease, sleep apnea, or neurocognitive impairment). Career duration was significantly associated with an increase in the number of comorbidities. Age, race, and body-mass index were associated with all affliction categories, other than neurocognitive impairment, which was similarly prevalent in middle-aged players and older players. Earlier age when first playing the sport was protective against cardiometabolic affliction. CONCLUSIONS: Former NFL players report significant combinations of cross-system afflictions. Future work will be required to determine mechanistic underpinnings. However, attention to the whole player, rather than specific organ systems seems critical to improve long-term health outcomes in former ASF professional athletes.

Feasibility of Aerobic Exercise in the Subacute Phase of Recovery From Traumatic Brain Injury: A Case Series.

BACKGROUND AND PURPOSE: Aerobic exercise is as important for individuals with traumatic brain injury (TBI) as for the general population; however, the approach to aerobic training may require some adaptation. The objective of the trial program was to examine the feasibility of introducing aerobic physical exercise programs into the subacute phase of multidisciplinary rehabilitation from moderate to severe TBI, which includes computerized cognitive training. CASE DESCRIPTION: Five individuals undergoing inpatient rehabilitation with moderate or severe TBIs who also have concomitant physical injuries. All of these individuals were in the subacute phase of recovery from TBIs. INTERVENTION: An 8-week progressive aerobic physical exercise program. Participants were monitored to ensure that they could both adhere to and tolerate the exercise program. In addition to the physical exercise, individuals were undergoing their standard rehabilitation procedures that included cognitive training. Neuropsychological testing was performed to gain an understanding of each individual's cognitive function. OUTCOMES: Participants adhered to both aerobic exercise and cognitive training. Poor correlations were noted between heart rate reserve and ratings of perceived effort. Two minor adverse events were reported. DISCUSSION: Despite concomitant physical injuries and cognitive impairments, progressive aerobic exercise programs seem feasible and well tolerated in subacute rehabilitation from moderate to severe TBI. Findings highlight the difficulty in measuring exercise intensity in this population.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A235).

Slowing of Parameterized Resting-State Electroencephalography After Mild Traumatic Brain Injury.

Reported changes in electroencephalography (EEG)-derived spectral power after mild traumatic brain injury (mTBI) remains inconsistent across existing literature. However, this may be a result of previous analyses depending solely on observing spectral power within traditional canonical frequency bands rather than accounting for the aperiodic activity within the collected neural signal. Therefore, the aim of this study was to test for differences in rhythmic and arrhythmic time series across the brain, and in the cognitively relevant frontoparietal (FP) network, and observe whether those differences were associated with cognitive recovery post-mTBI. Resting-state electroencephalography (rs-EEG) was collected from 88 participants (56 mTBI and 32 age- and sex-matched healthy controls) within 14 days of injury for the mTBI participants. A battery of executive function (EF) tests was collected at the first session with follow-up metrics collected approximately 2 and 4 months after the initial visit. After spectral parameterization, a significant between-group difference in aperiodic-adjusted alpha center peak frequency within the FP network was observed, where a slowing of alpha peak frequency was found in the mTBI group in comparison to the healthy controls. This slowing of week 2 (collected within 2 weeks of injury) aperiodic-adjusted alpha center peak frequency within the FP network was associated with increased EF over time (evaluated using executive composite scores) post-mTBI. These findings suggest alpha center peak frequency within the FP network as a candidate prognostic marker of EF recovery and may inform clinical rehabilitative methods post-mTBI.

Midlife physical activity engagement is associated with later-life brain health.

The relationship between midlife physical activity (PA), and cognition and brain health in later life is poorly understood with conflicting results from previous research. Investigating the contribution of midlife PA to later-life cognition and brain health in high-risk populations will propel the development of health guidance for those most in need. The current study examined the association between midlife PA engagement and later-life cognition, grey matter characteristics and resting-state functional connectivity in older individuals at high-risk for Alzheimer's disease. The association between midlife PA and later-life cognitive function was not significant but was moderated by later-life PA. Meanwhile, greater midlife moderate-to-vigorous PA was associated with greater grey matter surface area in the left middle frontal gyrus. Moreover, greater midlife total PA was associated with diminished functional connectivity between bilateral middle frontal gyri and middle cingulum, supplementary motor areas, and greater functional connectivity between bilateral hippocampi and right cerebellum, Crus II. These results indicate the potentially independent contribution of midlife PA to later-life brain health.

Resting-state MRI functional connectivity as a neural correlate of multidomain lifestyle adherence in older adults at risk for Alzheimer's disease.

Prior research has demonstrated the importance of a healthy lifestyle to protect brain health and diminish dementia risk in later life. While a multidomain lifestyle provides an ecological perspective to voluntary engagement, its association with brain health is still under-investigated. Therefore, understanding the neural mechanisms underlying multidomain lifestyle engagement, particularly in older adults at risk for Alzheimer's disease (AD), gives valuable insights into providing lifestyle advice and intervention for those in need. The current study included 139 healthy older adults with familial risk for AD from the Prevent-AD longitudinal aging cohort. Self-reported exercise engagement, cognitive activity engagement, healthy diet adherence, and social activity engagement were included to examine potential phenotypes of an individual's lifestyle adherence. Two adherence profiles were discovered using data-driven clustering methodology [i.e., Adherence to healthy lifestyle (AL) group and Non-adherence to healthy lifestyle group]. Resting-state functional connectivity matrices and grey matter brain features obtained from magnetic resonance imaging were used to classify the two groups using a support vector machine (SVM). The SVM classifier was 75% accurate in separating groups. The features that show consistently high importance to the classification model were functional connectivity mainly between nodes located in different prior-defined functional networks. Most nodes were located in the default mode network, dorsal attention network, and visual network. Our results provide preliminary evidence of neurobiological characteristics underlying multidomain healthy lifestyle choices.

Musical Experience Relates to Insula-Based Functional Connectivity in Older Adults.

Engaging in musical activities throughout the lifespan may protect against age-related cognitive decline and modify structural and functional connectivity in the brain. Prior research suggests that musical experience modulates brain regions that integrate different modalities of sensory information, such as the insula. Most of this research has been performed in individuals classified as professional musicians; however, general musical experiences across the lifespan may also confer beneficial effects on brain health in older adults. The current study investigated whether general musical experience, characterized using the Goldsmith Music Sophistication Index (Gold-MSI), was associated with functional connectivity in older adults (age = 65.7 ± 4.4, n = 69). We tested whether Gold-MSI was associated with individual differences in the functional connectivity of three a priori hypothesis-defined seed regions in the insula (i.e., dorsal anterior, ventral anterior, and posterior insula). We found that older adults with more musical experience showed greater functional connectivity between the dorsal anterior insula and the precentral and postcentral gyrus, and between the ventral anterior insula and diverse brain regions, including the insula and prefrontal cortex, and decreased functional connectivity between the ventral anterior insula and thalamus (voxel p < 0.01, cluster FWE p < 0.05). Follow-up correlation analyses showed that the singing ability subscale score was key in driving the association between functional connectivity differences and musical experience. Overall, our findings suggest that musical experience, even among non-professional musicians, is related to functional brain reorganization in older adults.

Brain Structure and Function Predict Adherence to an Exercise Intervention in Older Adults.

INTRODUCTION: Individual differences in brain structure and function in older adults are potential proxies of brain reserve or maintenance and may provide mechanistic predictions of adherence to exercise. We hypothesized that multimodal neuroimaging features would predict adherence to a 6-month randomized controlled trial of exercise in 131 older adults (age, 65.79 ± 4.65 yr, 63% female), alone and in combination with psychosocial, cognitive, and health measures. METHODS: Regularized elastic net regression within a nested cross-validation framework was applied to predict adherence to the intervention in three separate models (brain structure and function only; psychosocial, health, and demographic data only; and a multimodal model). RESULTS: Higher cortical thickness in somatosensory and inferior frontal regions and less surface area in primary visual and inferior frontal regions predicted adherence. Higher nodal functional connectivity (degree count) in default, frontoparietal, and attentional networks and less nodal strength in primary visual and temporoparietal networks predicted exercise adherence ( r = 0.24, P = 0.004). Survey and clinical measures of gait and walking self-efficacy, biological sex, and perceived stress also predicted adherence ( r = 0.17, P = 0.056); however, this prediction was not significant when tested against a null test statistic. A combined multimodal model achieved the highest predictive strength ( r = 0.28, P = 0.001). CONCLUSIONS: Our results suggest that there is a substantial utility of using brain-based measures in future research into precision and individualized exercise interventions older adults.

Resting state functional connectivity provides mechanistic predictions of future changes in sedentary behavior.

Sedentary behaviors are increasing at the cost of millions of dollars spent in health care and productivity losses due to physical inactivity-related deaths worldwide. Understanding the mechanistic predictors of sedentary behaviors will improve future intervention development and precision medicine approaches. It has been posited that humans have an innate attraction towards effort minimization and that inhibitory control is required to overcome this prepotent disposition. Consequently, we hypothesized that individual differences in the functional connectivity of brain regions implicated in inhibitory control and physical effort decision making at the beginning of an exercise intervention in older adults would predict the change in time spent sedentary over the course of that intervention. In 143 healthy, low-active older adults participating in a 6-month aerobic exercise intervention (with three conditions: walking, dance, stretching), we aimed to use baseline neuroimaging (resting state functional connectivity of two a priori defined seed regions), and baseline accelerometer measures of time spent sedentary to predict future pre-post changes in objectively measured time spent sedentary in daily life over the 6-month intervention. Our results demonstrated that functional connectivity between (1) the anterior cingulate cortex and the supplementary motor area and (2) the right anterior insula and the left temporoparietal/temporooccipital junction, predicted changes in time spent sedentary in the walking group. Functional connectivity of these brain regions did not predict changes in time spent sedentary in the dance nor stretch and tone conditions, but baseline time spent sedentary was predictive in these conditions. Our results add important knowledge toward understanding mechanistic associations underlying complex out-of-session sedentary behaviors within a walking intervention setting in older adults.

Local Prefrontal Cortex TMS-Induced Reactivity Is Related to Working Memory and Reasoning in Middle-Aged Adults.

INTRODUCTION: The prefrontal cortex (PFC) plays a crucial role in cognition, particularly in executive functions. Cortical reactivity measured with Transcranial Magnetic Stimulation combined with Electroencephalography (TMS-EEG) is altered in pathological conditions, and it may also be a marker of cognitive status in middle-aged adults. In this study, we investigated the associations between cognitive measures and TMS evoked EEG reactivity and explored whether the effects of this relationship were related to neurofilament light chain levels (NfL), a marker of neuroaxonal damage. METHODS: Fifty two healthy middle-aged adults (41-65 years) from the Barcelona Brain Health Initiative cohort underwent TMS-EEG, a comprehensive neuropsychological assessment, and a blood test for NfL levels. Global and Local Mean-Field Power (GMFP/LMFP), two measures of cortical reactivity, were quantified after left prefrontal cortex (L-PFC) stimulation, and cognition was set as the outcome of the regression analysis. The left inferior parietal lobe (L-IPL) was used as a control stimulation condition. RESULTS: Local reactivity was significantly associated with working memory and reasoning only after L-PFC stimulation. No associations were found between NfL and cognition. These specific associations were independent of the status of neuroaxonal damage indexed by the NfL biomarker and remained after adjusting for age, biological sex, and education. CONCLUSION: Our results demonstrate that TMS evoked EEG reactivity at the L-PFC, but not the L-IPL, is related to the cognitive status of middle-aged individuals and independent of NfL levels, and may become a valuable biomarker of frontal lobe-associated cognitive function.

Relationships between enriching early life experiences and cognitive function later in life are mediated by educational attainment.

The study of how engagement in enriching cognitive, physical and social activities in childhood impacts cognitive function decades later will advance our understanding of how modifiable lifestyle activities promote cognition across the lifespan. 88 healthy older adults (aged 60-80 years) returned a retrospective questionnaire regarding their participation in seven lifestyle activities (musical instrument playing, language learning, sport participation, art/dance lessons, scouting, volunteering, family vacations) before age 13 years. After controlling for current age, educational attainment, socioeconomic status of the mother and current engagement in lifestyle activities, a greater number of activities were significantly associated with better vocabulary abilities, episodic memory and fluid intelligence. The relationships with vocabulary and fluid intelligence were mediated by educational attainment. We postulate that engagement in a higher number of enriching early life activities is a reflection of both one's sociocontextual environment and engagement with that environment. This engagement leads to attributes relevant for educational aspirations/attainment, ultimately contributing to factors that have a lifespan impact on cognitive function.

Acute exercise effects on inhibitory control and the pupillary response in young adults.

Previous research has established an impact of acute exercise on cognitive performance, which has inspired investigations into neurobiological mechanisms that may underlie the observed benefits. Pupillary responses have been posited to reflect activation of such underlying neurobiological mechanisms. The current study recruited healthy young adults to investigate the effects of a single bout of moderate-to-vigorous intensity aerobic exercise on subsequent performance and pupillary responses during an inhibitory control task. Results showed that an acute bout of exercise was related to shorter reaction times and increased tonic pupil dilation during an inhibitory control task. Although pupillary responses did not mediate the acute exercise effect on inhibitory control, higher cardiorespiratory fitness was associated with greater phasic pupil dilation following exercise relative to seated rest. The current study supported the plausibility of the pupillary response as a marker of LC-NE system activation that is sensitive to acute exercise. Whether pupillary responses could account for transient benefits of acute exercise on brain and cognition remains unclear.

Enriching activities during childhood are associated with variations in functional connectivity patterns later in life.

Enriching early life experiences (e.g., sport, art, music, volunteering, language learning) during a critical period of brain development may promote structural and functional brain changes that are still present decades later (>60 years). We assessed whether a greater variety of enriching early life activities (EELA) before age 13 years were associated with individual differences in cortical and subcortical (hippocampus and amygdala) structure and function later in life (older adults aged 60-80 years). Results indicated no association between EELA and amygdala and hippocampus volumes, but higher functional connectivity between the amygdala and the insula was associated with more variety of EELA. EELA was not associated with cortical thickness controlling for sex, but sex-specific associations with the right pars opercularis were found. EELA was further associated with variations in functional connectivity patterns of the orbitofrontal cortex, driven by connecitivty to regions within the visual, somatosensory and limbic networks. Early life enriching activities appear to contribute to potential mechanisms of cognitive reserve (functional processes) more so than brain reserve (structure) later in life.

Associations Between Cardiorespiratory Fitness, Cardiovascular Risk, and Cognition Are Mediated by Structural Brain Health in Midlife.

Background Evidence in older adults suggests that higher cardiorespiratory fitness and lower cardiovascular risk are associated with greater cognition. However, given that changes in the brain that lead to cognitive decline begin decades before the onset of symptoms, understanding the mechanisms by which modifiable cardiovascular factors are associated with brain health in midlife is critical and can lead to the development of strategies to promote and maintain brain health as we age. Methods and Results In 501 middle-aged (aged 40-65 years) adult participants of the BBHI (Barcelona Brain Health Initiative), we found differential associations among cardiorespiratory fitness, cardiovascular risk, and cognition and cortical thickness. Higher cardiorespiratory fitness was significantly associated with better visuospatial abilities and frontal loading abstract problem solving (ß=3.16, P=0.049) in the older middle-aged group (aged 55-65 years). In contrast, cardiovascular risk was negatively associated with better visuospatial reasoning and problem-solving abilities (ß=-0.046, P=0.002), flexibility (ß=-0.054, P<0.001), processing speed (ß=-0.115, P<0.001), and memory (ß=-0.120, P<0.001). Cortical thickness in frontal regions mediated the relationship between cardiorespiratory fitness and cognition, whereas cortical thickness in a disperse network spanning multiple cortical regions across both hemispheres mediated the relationship between cardiovascular risk and cognition. Conclusions The relationships between modifiable cardiovascular factors, cardiorespiratory fitness, and cardiovascular risk, and cognition are present in healthy middle-aged adults. These relationships are also mediated by brain structure highlighting a potential mechanistic pathway through which higher cardiorespiratory fitness and lower cardiovascular risk can positively impact cognitive function in midlife.

The Daily Activity Study of Health (DASH): A pilot randomized controlled trial to enhance physical activity in sedentary older adults.

Sedentary behavior increases the risk for multiple chronic diseases, early mortality, and accelerated cognitive decline in older adults. Interventions to reduce sedentary behavior among older adults are needed to improve health outcomes and reduce the burden on healthcare systems. We designed a randomized controlled trial that uses a self-affirmation manipulation and gain-framed health messaging to effectively reduce sedentary behavior in older adults. This message-based intervention lasts 6 weeks, recruiting 80 healthy but sedentary older adults from the community, between the ages of 60 and 95 years. Participants are randomly assigned to one of two groups: 1) an intervention group, which receives self-affirmation followed by gain-framed health messages daily or 2) a control group, which receives daily loss-framed health messages only. Objective physical activity engagement is measured by accelerometers. Accelerometers are deployed a week before, during, and the last week of intervention to examine potential changes in sedentary time and physical activity engagement. Participants undertake structural and functional (resting and task-based) MRI scans, neuropsychological tests, computerized behavioral measures, and neurobehavioral inventories at baseline and after the intervention. A 3-month follow-up assesses the long-term maintenance of any engendered behaviors from the intervention period. This study will assess the effectiveness of a novel behavioral intervention at reducing sedentarism in older adults and examine the neurobehavioral mechanisms underlying any such changes.

Reappraising the concept of massive transfusion in trauma.

INTRODUCTION: The massive-transfusion concept was introduced to recognize the dilutional complications resulting from large volumes of packed red blood cells (PRBCs). Definitions of massive transfusion vary and lack supporting clinical evidence. Damage-control resuscitation regimens of modern trauma care are targeted to the early correction of acute traumatic coagulopathy. The aim of this study was to identify a clinically relevant definition of trauma massive transfusion based on clinical outcomes. We also examined whether the concept was useful in that early prediction of massive transfusion requirements could allow early activation of blood bank protocols. METHODS: Datasets on trauma admissions over a 1 or 2-year period were obtained from the trauma registries of five large trauma research networks. A fractional polynomial was used to model the transfusion-associated probability of death. A logistic regression model for the prediction of massive transfusion, defined as 10 or more units of red cell transfusions, was developed. RESULTS: In total, 5,693 patient records were available for analysis. Mortality increased as transfusion requirements increased, but the model indicated no threshold effect. Mortality was 9% in patients who received none to five PRBC units, 22% in patients receiving six to nine PRBC units, and 42% in patients receiving 10 or more units. A logistic model for prediction of massive transfusion was developed and validated at multiple sites but achieved only moderate performance. The area under the receiver operating characteristic curve was 0.81, with specificity of only 50% at a sensitivity of 90% for the prediction of 10 or more PRBC units. Performance varied widely at different trauma centers, with specificity varying from 48% to 91%. CONCLUSIONS: No threshold for definition exists at which a massive transfusion specifically results in worse outcomes. Even with a large sample size across multiple trauma datasets, it was not possible to develop a transportable and clinically useful prediction model based on available admission parameters. Massive transfusion as a concept in trauma has limited utility, and emphasis should be placed on identifying patients with massive hemorrhage and acute traumatic coagulopathy.

The Barcelona Brain Health Initiative: Cohort description and first follow-up.

The Barcelona Brain Health Initiative is a longitudinal cohort study that began in 2017 and aims to understand and characterize the determinants of brain health maintenance in middle aged adults. A cohort of 4686 individuals between the ages of 40 and 65 years free from any neurological or psychiatric diseases was established, and we collected extensive demographic, socio-economic information along with measures of self-perceived health and lifestyles (general health, physical activity, cognitive activity, socialization, sleep, nutrition and vital plan). Here we report on the baseline characteristics of the participants, and the results of the one-year follow-up evaluation. Participants were mainly women, highly educated, and with better lifestyles compared with the general population. After one year 60% of participants completed the one-year follow-up, and these were older, with higher educational level and with better lifestyles in some domains. In the absence of any specific interventions to-date, these participants showed small improvements in physical activity and sleep, but decreased adherence to a Mediterranean diet. These changes were negatively associated with baseline scores, and poorer habits at baseline were predictive of an improvement in lifestyle domains. Of the 2353 participants who completed the one-year follow-up, 73 had been diagnosed with new neurological and neuropsychiatric diseases. Changes in vital plan at follow-up, as well as gender, sleep quality and sense of coherence at baseline were shown to be significant risk factors for the onset of these diagnoses. Notably, gender risk factor decreased in importance as we adjusted by sleep habits, suggesting its potential mediator effects. These findings stress the importance of healthy lifestyles in sustaining brain health, and illustrate the individual benefit that can be derived from participation in longitudinal observational studies. Modifiable lifestyles, specifically quality of sleep, may partially mediate the effect of other risk factors in the development of some neuropsychiatric conditions.

Greater childhood cardiorespiratory fitness is associated with better top-down cognitive control: A midfrontal theta oscillation study.

The aim of the current study was to examine the association between cardiorespiratory fitness and electroencephalogram-based neural oscillations, using midfrontal theta, during an inhibitory control task in children. One-hundred seventy-one school-aged children (mean age = 8.9 ± 0.6 years; 46% girls) were recruited. Cardiorespiratory fitness was assessed by a test of maximal oxygen consumption (VO2peak ) while inhibitory control performance was measured via a modified flanker task with an electroencephalogram. Behavioral findings demonstrated that higher cardiorespiratory fitness was associated with higher response accuracy regardless of task difficulty as well as lower response variability during trials with lower cognitive demand. Neuroelectric outcomes revealed that higher cardiorespiratory fitness was correlated with smaller modulation of theta (4-7 Hz) oscillatory power regardless of task difficulty. Collectively, the current findings indicate that higher cardiorespiratory fitness is associated with better performance on a task that modulates inhibitory control, signified by higher, and more stable, task performance. More importantly, higher childhood cardiorespiratory fitness is associated with better top-down control and cortical communication, as reflected by midfrontal theta. Such findings support the critical role of cardiorespiratory fitness in brain health during childhood.

Aftereffects of Intermittent Theta-Burst Stimulation in Adjacent, Non-Target Muscles.

To assess motor cortex neurophysiology, including the mechanisms of neuroplasticity, transcranial magnetic stimulation (TMS) is typically applied to the motor "hotspot"- the optimal site for inducing a twitch in a given target muscle. It is known that the effects of suprathreshold repetitive TMS (rTMS) spread along functional connections beyond the specific cortical stimulation target, and yet, it is unknown whether the aftereffects of subthreshold intermittent theta-burst stimulation (iTBS), an ultra-high frequency patterned rTMS protocol, extend beyond the targeted muscle. We investigated whether and to what extent iTBS induces changes in the cortical output to other intrinsic hand muscles with adjacent cortical representation to the target. Sixteen healthy adults underwent neuronavigated TMS-iTBS targeting the first dorsal interosseus (FDI) hotspot. Proportion of motor evoked potentials (MEPs) at the resting motor threshold (RMT), baseline MEP amplitude, and iTBS-induced changes in MEP amplitude were compared between FDI, abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. MEP amplitudes recorded from the three muscles at RMT and suprathreshold intensities indicated the chosen hotspots were relatively selective for FDI. Nevertheless, iTBS induced significant facilitation of MEPs recorded from both FDI and APB, but not ADM. Surprisingly, the MEP modulation was greater in APB, even when controlling for the baseline MEP amplitude. These results indicate that iTBS modulation of cortico-spinal excitability extends beyond the representation of the targeted muscle. Results have implications both for how iTBS may be used in clinical treatment and for the safety guidelines for the application of iTBS.