Tractography-Based Modeling Explains Treatment Outcomes in Patients Undergoing Deep Brain Stimulation for Obsessive-Compulsive Disorder.

BACKGROUND: Deep brain stimulation (DBS) is an established and expanding therapy for treatment-refractory obsessive-compulsive disorder. Previous work has suggested that a white matter circuit providing hyperdirect input from the dorsal cingulate and ventrolateral prefrontal regions to the subthalamic nucleus could be an effective neuromodulatory target. METHODS: We tested this concept by attempting to retrospectively explain through predictive modeling the ranks of clinical improvement as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in 10 patients with obsessive-compulsive disorder who underwent DBS to the ventral anterior limb of internal capsule with subsequent programming uninformed by the putative target tract. RESULTS: Rank predictions were carried out using the tract model by a team that was completely uninvolved in DBS planning and programming. Predicted Y-BOCS improvement ranks significantly correlated with actual Y-BOCS improvement ranks at the 6-month follow-up (r = 0.75, p = .013). Predicted score improvements correlated with actual Y-BOCS score improvements (r = 0.72, p = .018). CONCLUSIONS: Here, we provide data in a first-of-its-kind report suggesting that normative tractography-based modeling can blindly predict treatment response in DBS for obsessive-compulsive disorder.

Decoding Depression Severity From Intracranial Neural Activity.

BACKGROUND: Disorders of mood and cognition are prevalent, disabling, and notoriously difficult to treat. Fueling this challenge in treatment is a significant gap in our understanding of their neurophysiological basis. METHODS: We recorded high-density neural activity from intracranial electrodes implanted in depression-relevant prefrontal cortical regions in 3 human subjects with severe depression. Neural recordings were labeled with depression severity scores across a wide dynamic range using an adaptive assessment that allowed sampling with a temporal frequency greater than that possible with typical rating scales. We modeled these data using regularized regression techniques with region selection to decode depression severity from the prefrontal recordings. RESULTS: Across prefrontal regions, we found that reduced depression severity is associated with decreased low-frequency neural activity and increased high-frequency activity. When constraining our model to decode using a single region, spectral changes in the anterior cingulate cortex best predicted depression severity in all 3 subjects. Relaxing this constraint revealed unique, individual-specific sets of spatiospectral features predictive of symptom severity, reflecting the heterogeneous nature of depression. CONCLUSIONS: The ability to decode depression severity from neural activity increases our fundamental understanding of how depression manifests in the human brain and provides a target neural signature for personalized neuromodulation therapies.

Automated optimization of deep brain stimulation parameters for modulating neuroimaging-based targets.

Objective.Therapeutic efficacy of deep brain stimulation (DBS) in both established and emerging indications, is highly dependent on accurate lead placement and optimized clinical programming. The latter relies on clinicians' experience to search among available sets of stimulation parameters and can be limited by the time constraints of clinical practice. Recent innovations in device technology have expanded the number of possible electrode configurations and parameter sets available to clinicians, amplifying the challenge of time constraints. We hypothesize that patient specific neuroimaging data can effectively assist the clinical programming using automated algorithms.Approach.This paper introduces the DBS Illumina 3D algorithm as a tool which uses patient-specific imaging to find stimulation settings that optimizes activating a target area while minimizing the stimulation of areas outside the target that could result in unknown or undesired side effects. This approach utilizes preoperative neuroimaging data paired with the postoperative reconstruction of the lead trajectory to search the available stimulation space and identify optimized stimulation parameters. We describe the application of this algorithm in three patients with treatment-resistant depression who underwent bilateral implantation of DBS in subcallosal cingulate cortex and ventral capsule/ventral striatum using tractography optimized targeting with an imaging defined target previously described.Main results.Compared to the stimulation settings selected by the clinicians (informed by anatomy), stimulation settings produced by the algorithm that achieved similar or greater target coverage, produced a significantly smaller stimulation area that spilled outside the target (P= 0.002).Significance. The DBS Illumina 3D algorithm is seamlessly integrated with the clinician programmer software and effectively and rapidly assists clinicians with the analysis of image based anatomy, and provides a starting point to search the highly complex stimulation parameter space and arrive at the stimulation settings that optimize activating a target area.

Imaging versus electrographic connectivity in human mood-related fronto-temporal networks.

BACKGROUND: The efficacy of psychiatric DBS is thought to be driven by the connectivity of stimulation targets with mood-relevant fronto-temporal networks, which is typically evaluated using diffusion-weighted tractography. OBJECTIVE: Leverage intracranial electrophysiology recordings to better predict the circuit-wide effects of neuromodulation to white matter targets. We hypothesize strong convergence between tractography-predicted structural connectivity and stimulation-induced electrophysiological responses. METHODS: Evoked potentials were elicited by single-pulse stimulation to two common DBS targets for treatment-resistant depression - the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VCVS) - in two patients undergoing DBS with stereo-electroencephalographic (sEEG) monitoring. Evoked potentials were compared with predicted structural connectivity between DBS leads and sEEG contacts using probabilistic, patient-specific diffusion-weighted tractography. RESULTS: Evoked potentials and tractography showed strong convergence in both patients in orbitofrontal, ventromedial prefrontal, and lateral prefrontal cortices for both SCC and VCVS stimulation targets. Low convergence was found in anterior cingulate (ACC), where tractography predicted structural connectivity from SCC targets but produced no evoked potentials during SCC stimulation. Further, tractography predicted no connectivity to ACC from VCVS targets, but VCVS stimulation produced robust evoked potentials. CONCLUSION: The two connectivity methods showed significant convergence, but important differences emerged with respect to the ability of tractography to predict electrophysiological connectivity between SCC and VCVS to regions of the mood-related network. This multimodal approach raises intriguing implications for the use of tractography in surgical targeting and provides new data to enhance our understanding of the network-wide effects of neuromodulation.

Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression.

BACKGROUND: Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states. METHODS: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined. RESULTS: A reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results. CONCLUSIONS: These preliminary results suggest that the Hb might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.

Cerebral perfusion is associated with blast exposure in military personnel without moderate or severe TBI.

Due to the use of improvised explosive devices, blast exposure and mild traumatic brain injury (mTBI) have become hallmark injuries of the Iraq and Afghanistan wars. Although the mechanisms of the effects of blast on human neurobiology remain active areas of investigation, research suggests that the cerebrovasculature may be particularly vulnerable to blast via molecular processes that impact cerebral blood flow. Given that recent work suggests that blast exposure, even without a subsequent TBI, may have negative consequences on brain structure and function, the current study sought to further understand the effects of blast exposure on perfusion. One hundred and eighty military personnel underwent pseudo-continuous arterial spin labeling (pCASL) imaging and completed diagnostic and clinical interviews. Whole-brain analyses revealed that with an increasing number of total blast exposures, there was significantly increased perfusion in the right middle/superior frontal gyri, supramarginal gyrus, lateral occipital cortex, and posterior cingulate cortex as well as bilateral anterior cingulate cortex, insulae, middle/superior temporal gyri and occipital poles. Examination of other neurotrauma and clinical variables such as close-range blast exposures, mTBI, and PTSD yielded no significant effects. These results raise the possibility that perfusion may be an important neural marker of brain health in blast exposure.

Positron emission tomography of tau in Iraq and Afghanistan Veterans with blast neurotrauma.

Military personnel are often exposed to multiple instances of various types of head trauma. As a result, there has been increasing concern recently over identifying when head trauma has resulted in a brain injury and what, if any, long-term consequences those brain injuries may have. Efforts to develop equipment to protect soldiers from these long-term consequences will first require understanding the types of head trauma that are likely responsible. In this study, we sought to identify the types of head trauma most likely to lead to the deposition of tau, a protein identified as a likely indicator of long-term negative consequences of brain injury. To define the types of head trauma in a military population, we applied a factor analysis to interviews from a larger cohort of 428 Veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders. Three factors were identified: Blast Exposure, Symptom Duration, and Blunt Concussion. Sixteen male Veterans from this study and one additional male civilian (aged 25-69, mean 35.2 years) underwent simultaneous positron emission tomography/magnetic resonance imaging using a tracer that binds to tau protein, the ligand T807/AV-1451 (Flortaucipir). Standard uptake value ratios to the isthmus of the cingulate were calculated from a 20-minute time frame 70 min post-injection. We found that tracer uptake throughout the brain was associated with Blast Exposure factor beta weights, but not with either Symptom Duration or Blunt Concussion. Associations with uptake were located primarily in the cerebellar, occipital, inferior temporal and frontal regions. The data suggest that in this small, relatively young cohort of Veterans, elevated T807/AV-1451 uptake is associated with exposure to blast neurotrauma. These findings are unanticipated, as they do not match histopathological descriptions of tau pathology associated with head trauma. Continued work will be necessary to understand the nature of the regional T807/AV-1451 uptake and any associations with clinical symptoms.

Verbal Memory Deficits in OEF/OIF/OND Veterans Exposed to Blasts at Close Range.

OBJECTIVES: This study investigated the relationship between close proximity to detonated blast munitions and cognitive functioning in OEF/OIF/OND Veterans. METHODS: A total of 333 participants completed a comprehensive evaluation that included assessment of neuropsychological functions, psychiatric diagnoses and history of military and non-military brain injury. Participants were assigned to a Close-Range Blast Exposure (CBE) or Non-Close-Range Blast Exposure (nonCBE) group based on whether they had reported being exposed to at least one blast within 10 meters. RESULTS: Groups were compared on principal component scores representing the domains of memory, verbal fluency, and complex attention (empirically derived from a battery of standardized cognitive tests), after adjusting for age, education, PTSD diagnosis, sleep quality, substance abuse disorder, and pain. The CBE group showed poorer performance on the memory component. Rates of clinical impairment were significantly higher in the CBE group on select CVLT-II indices. Exploratory analyses examined the effects of concussion and multiple blasts on test performance and revealed that number of lifetime concussions did not contribute to memory performance. However, accumulating blast exposures at distances greater than 10 meters did contribute to poorer performance. CONCLUSIONS: Close proximity to detonated blast munitions may impact memory, and Veterans exposed to close-range blast are more likely to demonstrate clinically meaningful deficits. These findings were observed after statistically adjusting for comorbid factors. Results suggest that proximity to blast should be considered when assessing for memory deficits in returning Veterans. Comorbid psychiatric factors may not entirely account for cognitive difficulties. (JINS, 2018, 24, 466-475).

Neuroimaging of deployment-associated traumatic brain injury (TBI) with a focus on mild TBI (mTBI) since 2009.

OBJECTIVES: A substantial body of recent research has aimed to better understand the clinical sequelae of military trauma through the application of advanced brain imaging procedures in Veteran populations. The primary objective of this review was to highlight a portion of these recent studies to demonstrate how imaging tools can be used to understand military-associated brain injury. METHODS: We focus here on the phenomenon of mild traumatic brain injury (mTBI) given its high prevalence in the Veteran population and current recognition of the need to better understand the clinical implications of this trauma. This is intended to provide readers with an initial exposure to the field of neuroimaging of mTBI with a brief introduction to the concept of traumatic brain injury, followed by a summary of the major imaging techniques that have been applied to the study of mTBI. RESULTS: Taken together, the collection of studies reviewed demonstrates a clear role for neuroimaging towards understanding the various neural consequences of mTBI as well as the clinical complications of such brain changes. CONCLUSIONS: This information must be considered in the larger context of research into mTBI, including the potentially unique nature of blast exposure and the long-term consequences of mTBI.

Posttraumatic stress disorder symptom severity is associated with reduced default mode network connectivity in individuals with elevated genetic risk for psychopathology.

BACKGROUND: Accumulating evidence suggests that posttraumatic stress disorder (PTSD) is associated with disrupted default mode network (DMN) connectivity, but findings across studies have not been uniform. Individual differences in relevant genes may account for some of the reported variability in the relationship between DMN connectivity and PTSD. In this study, we investigated this possibility using genome-wide association study (GWAS) derived polygenic risk scores (PRSs) for relevant psychiatric traits. We hypothesized that the association between PTSD and DMN connectivity would be moderated by genetic risk for one or more psychiatric traits such that individuals with elevated polygenic risk for psychopathology and severe PTSD would exhibit disrupted DMN connectivity. METHODS: Participants were 156 white, non-Hispanic veterans of the wars in Iraq and Afghanistan who were genotyped and underwent resting state functional magnetic resonance imaging and clinical assessment. PRSs for neuroticism, anxiety, major depressive disorder, and cross-disorder risk (based on five psychiatric disorders) were calculated using summary statistics from published large-scale consortia-based GWASs. RESULTS: Cross-disorder polygenic risk influenced the relationship between DMN connectivity and PTSD symptom severity such that individuals at greater genetic risk showed a significant negative association between PTSD symptom severity and connectivity between the posterior cingulate cortex and right middle temporal gyrus. Polygenic risk for neuroticism, anxiety, and major depressive disorder did not influence DMN connectivity directly or through an interaction with PTSD. CONCLUSIONS: Findings illustrate the potential power of genome-wide PRSs to advance understanding of the relationship between PTSD and DMN connectivity, a putative neural endophenotype of the disorder.

Characterization of Differences in Functional Connectivity Associated with Close-Range Blast Exposure.

Despite the prevalence of blast injuries in recent overseas conflicts, knowledge of their impact on neural health is lacking. We have recently published work demonstrating differences in functional magnetic resonance imaging (fMRI) connectivity that were specific to close-range blast exposure (CBE), as opposed to other prevalent military-related factors. Here, we replicate this finding in an independent sample of 135 veterans, again finding that CBE, regardless of concussion, is predictive of persistent changes in brain physiology. Although there was weak overlap anatomically, in both samples, the group differences could be described as spreading of anticorrelation. Using the combined sample, we now seek to identify likely mechanisms that could bring about this effect. We compared participants with (n = 116) and without (n = 153) CBE by analyzing two networks through group difference maps and correlation distributions to assess spatially homogenous and heterogeneous effects. As boundaries between positive and negative correlations in fcMRI are determined by noise covariates, we compared analyses with and without global signal regression. We found evidence of widespread altered connectivity that was spatially heterogeneous across participants, and that the role of global signal regression was network dependent. These findings are not consistent with expected results from damaged white matter or impaired neural function. Rather, potential biological interpretations include disrupted cerebral blood flow or impaired neurovascular coupling, which have each been observed in animal models of blast exposure. Further targeted work will be necessary to distinguish the contribution of each of these mechanisms to producing changes in brain function associated with CBE.

Cerebrovascular reactivity changes in asymptomatic female athletes attributable to high school soccer participation.

As participation in women's soccer continues to grow and the longevity of female athletes' careers continues to increase, prevention and care for mTBI in women's soccer has become a major concern for female athletes since the long-term risks associated with a history of mTBI are well documented. Among women's sports, soccer exhibits among the highest concussion rates, on par with those of men's football at the collegiate level. Head impact monitoring technology has revealed that "concussive hits" occurring directly before symptomatic injury are not predictive of mTBI, suggesting that the cumulative effect of repetitive head impacts experienced by collision sport athletes should be assessed. Neuroimaging biomarkers have proven to be valuable in detecting brain changes that occur before neurocognitive symptoms in collision sport athletes. Quantifying the relationship between changes in these biomarkers and head impacts experienced by female soccer athletes may prove valuable to developing preventative measures for mTBI. This study paired functional magnetic resonance imaging with head impact monitoring to track cerebrovascular reactivity changes throughout a season and to test whether the observed changes could be attributed to mechanical loading experienced by female athletes participating in high school soccer. Marked cerebrovascular reactivity changes were observed in female soccer athletes, relative both to non-collision sport control measures and pre-season measures and were localized to fronto-temporal aspects of the brain. These changes persisted 4-5 months after the season ended and recovered by 8 months after the season. Segregation of the total soccer cohort into cumulative loading groups revealed that population-level changes were driven by athletes experiencing high cumulative loads, although athletes experiencing lower cumulative loads still contributed to group changes. The results of this study imply a non-linear relationship between cumulative loading and cerebrovascular changes with a threshold, above which the risk, of injury likely increases significantly.

5-HT2A Gene Variants Moderate the Association between PTSD and Reduced Default Mode Network Connectivity.

The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study (STAR(*)D; McMahon et al., 2006), interacted with PTSD to predict reduced connectivity between the posterior cingulate cortex (PCC) and the right medial prefrontal cortex and right middle temporal gyrus (MTG). rs130058 (HTR1B) was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP × PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT2A receptors in the neurobiology of PTSD.

Intrinsic functional connectivity predicts individual differences in distractibility.

Distractor suppression, the ability to filter and ignore task-irrelevant information, is critical for efficient task performance. While successful distractor suppression relies on a balance of activity in neural networks responsible for attention maintenance (dorsal attention network; DAN), reorientation (ventral attention network; VAN), and internal thought (default mode network, DMN), the degree to which intrinsic connectivity within and between these networks contributes to individual differences in distractor suppression ability is not well-characterized. For the purposes of understanding these interactions, the current study collected resting-state fMRI data from 32 Veterans and, several months later (7±5 months apart), performance on the additional singleton paradigm, a measure of distractor suppression. Using multivariate support vector regression models composed of resting state connectivity between regions of the DAN, VAN, and DMN, and a leave-one-subject-out cross-validation procedure, we were able to predict an individual's task performance, yielding a significant correlation between the actual and predicted distractor suppression (r=0.48, p=0.0053). Network-level analyses revealed that greater within-network DMN connectivity was predictive of better distractor suppression, while greater connectivity between the DMN and attention networks was predictive of poorer distractor suppression. The strongest connection hubs were determined to be the right frontal eye field and temporoparietal junction of the DAN and VAN, respectively, and medial (ventromedial prefrontal and posterior cingulate cortices) and bilateral prefrontal regions of the DMN. These results are amongst a small but growing number of studies demonstrating that resting state connectivity is related to stable individual differences in cognitive ability, and suggest that greater integrity and independence of the DMN is related to better attentional ability.

Tracking ongoing cognition in individuals using brief, whole-brain functional connectivity patterns.

Functional connectivity (FC) patterns in functional MRI exhibit dynamic behavior on the scale of seconds, with rich spatiotemporal structure and limited sets of whole-brain, quasi-stable FC configurations (FC states) recurring across time and subjects. Based on previous evidence linking various aspects of cognition to group-level, minute-to-minute FC changes in localized connections, we hypothesized that whole-brain FC states may reflect the global, orchestrated dynamics of cognitive processing on the scale of seconds. To test this hypothesis, subjects were continuously scanned as they engaged in and transitioned between mental states dictated by tasks. FC states computed within windows as short as 22.5 s permitted robust tracking of cognition in single subjects with near perfect accuracy. Accuracy dropped markedly for subjects with the lowest task performance. Spatially restricting FC information decreased accuracy at short time scales, emphasizing the distributed nature of whole-brain FC dynamics, beyond univariate magnitude changes, as valuable markers of cognition.

Military blast exposure, ageing and white matter integrity.

Mild traumatic brain injury, or concussion, is associated with a range of neural changes including altered white matter structure. There is emerging evidence that blast exposure-one of the most pervasive causes of casualties in the recent overseas conflicts in Iraq and Afghanistan-is accompanied by a range of neurobiological events that may result in pathological changes to brain structure and function that occur independently of overt concussion symptoms. The potential effects of brain injury due to blast exposure are of great concern as a history of mild traumatic brain injury has been identified as a risk factor for age-associated neurodegenerative disease. The present study used diffusion tensor imaging to investigate whether military-associated blast exposure influences the association between age and white matter tissue structure integrity in a large sample of veterans of the recent conflicts (n = 190 blast-exposed; 59 without exposure) between the ages of 19 and 62 years. Tract-based spatial statistics revealed a significant blast exposure × age interaction on diffusion parameters with blast-exposed individuals exhibiting a more rapid cross-sectional age trajectory towards reduced tissue integrity. Both distinct and overlapping voxel clusters demonstrating the interaction were observed among the examined diffusion contrast measures (e.g. fractional anisotropy and radial diffusivity). The regions showing the effect on fractional anisotropy included voxels both within and beyond the boundaries of the regions exhibiting a significant negative association between fractional anisotropy and age in the entire cohort. The regional effect was sensitive to the degree of blast exposure, suggesting a 'dose-response' relationship between the number of blast exposures and white matter integrity. Additionally, there was an age-independent negative association between fractional anisotropy and years since most severe blast exposure in a subset of the blast-exposed group, suggesting a specific influence of time since exposure on tissue structure, and this effect was also independent of post-traumatic stress symptoms. Overall, these data suggest that blast exposure may negatively affect brain-ageing trajectories at the microstructural tissue level. Additional work examining longitudinal changes in brain tissue integrity in individuals exposed to military blast forces will be an important future direction to the initial findings presented here.

FMRI of visual working memory in high school football players.

Visual working memory deficits have been observed in at-risk athletes. This study uses a visual N-back working memory functional magnetic resonance imaging task to longitudinally assess asymptomatic football athletes for abnormal activity. Athletes were increasingly "flagged" as the season progressed. Flagging may provide early detection of injury.

The role of location of subconcussive head impacts in FMRI brain activation change.

Monte-Carlo permutation analysis was used to identify sets of head impacts most predictive of functional magnetic resonance imaging (fMRI) changes in football players. The relative distribution of impact location was found to be more predictive of brain activation changes than the number of impacts, suggesting that fMRI changes are related to systematic playing style.

Cerebrovascular reactivity alterations in asymptomatic high school football players.

Cerebrovascular reactivity (CVR) is impaired following brain injury, increasing susceptibility to subsequent injury. CVR was tracked in football and non-collision athletes throughout one season. CVR transiently decreased in football athletes during the first half of the season. Results indicate the brain adapts slowly to increases in loading, increasing risk for injury.

Post-Season Neurophysiological Deficits Assessed by ImPACT and fMRI in Athletes Competing in American Football.

Neurocognitive assessment, functional magnetic resonance imaging, and head impact monitoring were used to evaluate neurological changes in high school football players throughout competitive seasons. A substantial number of asymptomatic athletes exhibited neurophysiological changes that persisted post-season, with abnormal measures significantly more common in athletes receiving 50 or more hits per week during the season.