EXAMINING BRAIN NETWORK MODULARITY IN U.S. MILITARY PERSONNEL WITH BLAST VS. NON-BLAST RELATED MILD TRAUMATIC BRAIN INJURY

Problem: Traumatic brain injury (TBI) is a major health concern to the public, accounting for alarming numbers of hospitalizations and emergency department visits per year. mTBI is of particular concern because of the injury’s ‘invisible’ nature. There are a lack of clinical findings on current evidence-based diagnostic protocols, and sufferers of this “silent” injury persistently complain of changes in functioning compared to their baseline abilities. Methods: 103 active duty service members from the SCORE study comprised 3 groups: mTBI resulting from blast (bmTBI; n=32), mTBI not resulting from blast (e.g. falls, motor vehicle accidents) (mTBI; n=29), and orthopedic controls (OC; n=42). Participants completed an fMRI task assessing effort and a standardized neuropsychological battery. Whole-brain network modularity analysis was completed to determine the pathophysiology secondary to TBI, whether the pathophysiology differs based on the nature of injury, and whether altered modularity relates to cognition. Results: Analysis of variance tests (ANOVA) revealed greater modularity in bmTBI than mTBI and OC at increased effort levels. Repeated measures ANOVAs revealed that increasing modularity values (Q) in bmTBI corresponded with increased effort level demands, while the Q in mTBI and OC was consistent across effort levels. Pearson correlations revealed minimal associations between Q and measures of processing speed. No significant correlations between Q and neuropsychological measures were observed in the OC group. Conclusions: This study suggests that the pathophysiology of blast injury alters the modular structure of the brain in TBI to a greater extent than in TBI from other etiologies

Individualized precision targeting of dorsal attention and default mode networks with rTMS in traumatic brain injury-associated depression

At the group level, antidepressant efficacy of rTMS targets is inversely related to their normative connectivity with subgenual anterior cingulate cortex (sgACC). Individualized connectivity may yield better targets, particularly in patients with neuropsychiatric disorders who may have aberrant connectivity. However, sgACC connectivity shows poor test-retest reliability at the individual level. Individualized resting-state network mapping (RSNM) can reliably map inter-individual variability in brain network organization. Thus, we sought to identify individualized RSNM-based rTMS targets that reliably target the sgACC connectivity profile. We used RSNM to identify network-based rTMS targets in 10 healthy controls and 13 individuals with traumatic brain injury-associated depression (TBI-D). These RSNM targets were compared with consensus structural targets and targets based on individualized anti-correlation with a group-mean-derived sgACC region ( sgACC-derived targets ). The TBI-D cohort was also randomized to receive active (n = 9) or sham (n = 4) rTMS to RSNM targets with 20 daily sessions of sequential high-frequency left-sided stimulation and low-frequency right-sided stimulation. We found that the group-mean sgACC connectivity profile was reliably estimated by individualized correlation with default mode network (DMN) and anti-correlation with dorsal attention network (DAN). Individualized RSNM targets were thus identified based on DAN anti-correlation and DMN correlation. These RSNM targets showed greater test-retest reliability than sgACC-derived targets. Counterintuitively, anti-correlation with the group-mean sgACC connectivity profile was also stronger and more reliable for RSNM-derived targets than for sgACC-derived targets. Improvement in depression after RSNM-targeted rTMS was predicted by target anti-correlation with the portions of sgACC. Active treatment also led to increased connectivity within and between the stimulation sites, the sgACC, and the DMN. Overall, these results suggest that RSNM may enable reliable individualized rTMS targeting, although further research is needed to determine whether this personalized approach can improve clinical outcomes

Structural Network Properties and Their Relation to Cognitive Flexibility and Neurological Risk Factors in Adult Survivors of Pediatric Brain Tumors

Neuroimaging techniques have been used to investigate the neurobiological mechanisms of cognitive deficits in survivors of childhood brain tumors. Graph theory is a quantitative method that characterizes brains as a complex system. By modeling brain regions as ‘nodes’ and white matter tracts between each brain region pair as ‘edges,’ graph theory provides metrics that quantify the topological properties of networks. Given that brain tumor survivorship is associated with focal and diffuse impairments, a network analysis can provide complementary information to previous neuroimaging studies in this clinical group. This study used diffusion-weighted imaging and deterministic tractography to examine the properties of the structural networks in 38 adult survivors of pediatric brain tumors (Mean age=22.5, 55% female, mean years post diagnosis=14.1 (6.2), Range post diagnosis = 4.5-30 years). Results of this study suggest that long term survivorship is associated with altered structural networks with respect to measures of integration, segregation, and centrality. Further, properties of the network mediate differences in cognitive flexibility performance between survivors and healthy peers, and mediate the relationship between cumulative neurological risk and cognitive flexibility performance

THE NEUROPHYSIOLOGICAL EFFECTS OF BLAST EXPOSURE AND MILD TRAUMATIC BRAIN INJURY IN SPECIAL OPERATIONS FORCES SOLDIERS

Introduction: Special Operations Forces (SOF) Soldiers sustain frequent low-level occupational blast and mild traumatic brain injury (mTBI). The cumulative impact of blast exposure and mTBI on long-term neurological health is poorly understood. Tracking changes in physiological outcomes that quantify brain tissue damage may elucidate early neurophysiological alterations linking neurotraumatic exposures to chronic neurodegenerative sequalae. The purpose of this study was to investigate the effect of occupational blast exposure and the interaction effect of mTBI on changes to regional brain volumes, structural connectivity, and blood biomarkers UCH-L1, NSE, t-tau, NfL and GFAP in SOF Soldiers. Methods: Soldiers (n=88) underwent neuroimaging assessments including T1, T2, and diffusion weighted magnetic resonance imaging at two timepoints. Time between visits varied between participants from 13 to 131 months. Cortical reconstruction, volumetric segmentation, and structural connectivity matrix construction was performed. A subset (n=16) had biomarker serum concentrations quantified. Months of blast exposure between visits was used to predict change in neuroimaging and blood biomarker outcomes between visits using general linear models. Post-hoc subgroup analyses and interactions were assessed. Results: Greater occupational blast exposure predicted increased lateral ventricular volume (F1,86= 5.45; p=0.022), left frontal lobe gray matter volume (F1,86=4.06; p=0.047), right parietal lobe gray matter volume (F1,86=4.15; p=0.045), decreased cerebellum gray matter volume (F1,86=5.70; p=0.019), and decreased serum t-tau (F1,14=6.42; p=0.02; B=-3.85 pg/mL; R2=0.31) Although mTBI did not moderate these relationships, trends suggest that brain volume changes attributed to blast exposure might be exacerbated by mTBI. Conclusion: Specific neurostructural changes and biomarker decreases are associated with chronic exposure to occupational blast. Sustained mTBI may intensify blast-related structural changes. Increasing lateral ventricle volume and decreasing t-tau both implicate glymphatic dysfunction as a possible blast exposure consequence and a target for future research. Biomarker concentrations in this SOF samples exceeded civilian brain injury levels, rendering current clinical cut-offs unusable. Replication is a needed in a larger sample. The observed cerebellum cortex loss should be investigated further with clinical and performance measures for coordination and balance. These findings may guide prevention, treatment, and inform neurodegenerative consequence risk prediction, ultimately leading to improved long-term neurological health outcomes for SOF Soldiers.Doctor of Philosoph

STRUCTURAL AND FUNCTIONAL ALTERATIONS IN NEOCORTICAL CIRCUITS AFTER MILD TRAUMATIC BRAIN INJURY

National concern over traumatic brain injury (TBI) is growing rapidly. Recent focus is on mild TBI (mTBI), which is the most prevalent injury level in both civilian and military demographics. A preeminent sequelae of mTBI is cognitive network disruption. Advanced neuroimaging of mTBI victims supports this premise, revealing alterations in activation and structure-function of excitatory and inhibitory neuronal systems, which are essential for network processing. However, clinical neuroimaging cannot resolve the cellular and molecular substrates underlying such changes. Therefore, to understand the full scope of mTBI-induced alterations it is necessary to study cortical networks on the microscopic level, where neurons form local networks that are the fundamental computational modules supporting cognition. Recently, in a well-controlled animal model of mTBI, we demonstrated in the excitatory pyramidal neuron system, isolated diffuse axonal injury (DAI), in concert with electrophysiological abnormalities in nearby intact (non-DAI) neurons. These findings were consistent with altered axon initial segment (AIS) intrinsic activity functionally associated with structural plasticity, and/or disturbances in extrinsic systems related to parvalbumin (PV)-expressing interneurons that form GABAergic synapses along the pyramidal neuron perisomatic/AIS domains. The AIS and perisomatic GABAergic synapses are domains critical for regulating neuronal activity and E-I balance. In this dissertation, we focus on the neocortical excitatory pyramidal neuron/inhibitory PV+ interneuron local network following mTBI. Our central hypothesis is that mTBI disrupts neuronal network structure and function causing imbalance of excitatory and inhibitory systems. To address this hypothesis we exploited transgenic and cre/lox mouse models of mTBI, employing approaches that couple state-of-the-art bioimaging with electrophysiology to determine the structural- functional alterations of excitatory and inhibitory systems in the neocortex

Therapeutic Target Identification, Validation and Drug Discovery for Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a recognized cause of long-term disability worldwide with mild TBI accounting for 80% of all head traumas. Growing evidence links mTBI, and particularly repetitive mTBI (r-mTBI), with long lasting pathological and cognitive deficits that can serve as a risk factor for neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, Chronic Traumatic Encephalopathy and others. So far, there is no FDA-approved treatment to mitigate the consequences of r-mTBI, mainly due to the lack of an effective therapeutic target and a poor translatability of existing preclinical studies, which fail to mimic heterogeneous nature of TBI. In the current thesis, I used a mouse model of r-mTBI which was treated with two different drugs, nilvadipine and anatabine, that have been previously shown to decrease inflammation and neurodegenerative mechanisms and improve cognition. To address the heterogenous nature of r-mTBI, I used several cohorts of mice which vary in age at injury (young vs old), number of hits (5 vs 24), acute or chronic duration of treatment, and the time of the first treatment intervention post injury (immediate vs delayed). I have found that both nilvadipine and anatabine, in their respective treatment paradigms, improved cognitive deficits, decreased neuroinflammation, and reduced tau pathology. Moreover, nilvadipine was equally effective in both young and old 5-hit r-mTBI mice during the acute treatment. Anatabine was shown to be effective as a delayed treatment starting at 3 months after the last injury in r-mTBI mice with both 5 and 24 hits. We further conducted a phosphoproteome analysis to identify common alterations in response to r-mTBI and tested therapeutics. Despite a high heterogeneity of the phosphoproteome profile between the analyzed cohorts, our data identified several molecules (ARPP21, Syt-1) which were equally altered in response to treatment in all r-mTBI cohorts and may represent potential therapeutic targets that are effective across different models of r-mTBI. Future studies will focus on the total proteome analysis and a subsequent validation of these potential targets