Special Operations Forces (SOF) sustain repeated low-level blast (LLB) exposures; while most remain resilient, a subset develop depression, sleep disruption and reduced wellbeing that threaten readiness. We asked whether sub-concussive LLB chronically injures an insula-centered cortico-striato-thalamic network and whether network architecture explains divergent outcomes. In a mouse model parameterized to SOF blast exposure monitoring data, ninety 3-psi blasts over three weeks produced persistent diffusion and connectivity deficits across insular, striatal, pallidal and thalamic nodes, accompanied by tauopathy, neuroinflammation, vascular amyloid, and durable sleep and metabolic abnormalities. In SOF Soldiers, measures of cumulative LLB exposure predicted right insula-striatal diffusion/neurite disruption and increased depression risk. Interventional multi-mediator modeling showed that right insula-striatal microstructural injury mediated the effect of LLB to increase depression risk, while moderator screening identified features that amplify or buffer this mediation, defining risk and resilience zones. These findings enable precision blast-medicine integrating exposure dose, circuit biomarkers and moderator profiles.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Theories of altered inhibitory/excitatory signaling in autism spectrum disorder (ASD) suggest that gamma amino butyric acid (GABA) and glutamate (Glu) abnormalities may underlie social and sensory challenges in ASD. Magnetic resonance spectroscopy was used to measure Glu and GABA+ levels in the amygdala-hippocampus region and cerebellum in autistic children (n = 30), a clinical control group with sensory abnormalities (SA) but not ASD (n = 30), and children with typical development (n = 37). All participants were clinically assessed using the Autism Diagnostic Interview-Revised, the Autism Diagnostic Observation Scale-2, and the Child Sensory Profile-2. The Social Responsiveness Scale-2, Sniffin Sticks Threshold Test, and the University of Pennsylvania Smell Identification Test were administered to assess social impairment and olfactory processing. Overall, autistic children showed increased cerebellar Glu levels compared to TYP children. Evidence for altered excitatory/inhibitory signaling in the cerebellum was more clear-cut when analyses were restricted to male participants. Further, lower cerebellar GABA+/Glu ratios were correlated to more severe social impairment in both autistic and SA males, suggesting that the cerebellum may play a transdiagnostic role in social impairment. Future studies of inhibitory/excitatory neural markers, powered to investigate the role of sex, may aid in parsing out disorder-specific neurochemical profiles.

Understanding how diffuse mild traumatic brain injuries can provoke common and persistent post-concussive symptoms (PCS), such as impaired sleep, is crucial to prevent and treat chronic disability and neurodegeneration. We mapped the spatially-resolved single cell landscape of diffuse mTBI pathology in a mouse model of blast exposure; identifying brainstem injuries predictive of later PCS. Repeated mTBI was necessary to establish chronic microglial activation and phagocytosis of myelin in the pontine reticular formation; where IL33 release by oligodendrocytes predicted microgliopathy. In postmortem brainstem tissues from patients with traumatic brain injury, chronic microglial activation and myelin phagocytosis was evident up to 20 years after diffuse mTBI caused by blast. In living patients with chronic blast mTBI, myelin injury in pontine projections mediated sleep disturbance and other PCS, with a dose dependent effect of mTBI number on sleep disturbance severity. These results support a mechanism for diffuse mTBIs to cause delayed persistent PCS.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that impairs the control of attention and behavioral inhibition in affected individuals. Recent genome-wide association findings have revealed an association between glutamate and GABA gene sets and ADHD symptoms. Consistently, people with ADHD show altered glutamate and GABA content in the brain circuitry that is important for attention control function. Yet, it remains unknown how glutamate and GABA content in the attention control circuitry change when people are controlling their attention, and whether these changes can predict impaired attention control in people with ADHD. To study these questions, we recruited 18 adults with ADHD (31–51 years) and 16 adults without ADHD (28–54 years). We studied glutamate + glutamine (Glx) and GABA content in the fronto-striatal circuitry while participants performed attention control tasks. We found that Glx and GABA concentrations at rest did not differ between participants with ADHD or without ADHD. However, while participants were performing the attention control tasks, participants with ADHD showed smaller Glx and GABA increases than participants without ADHD. Notably, smaller GABA increases in participants with ADHD significantly predicted their poor task performance. Together, these findings provide the first demonstration showing that attention control deficits in people with ADHD may be related to insufficient responses of the GABAergic system in the fronto-striatal circuitry.

BACKGROUND:The excitotoxic molecule, domoic acid (DA), is a marine algal toxin known to induce overt hippocampal neurotoxicity. Recent experimental and epidemiological studies suggest adverse neurological effects at exposure levels near the current regulatory limit (20 ppm, ∼0.075-0.1mg/kg). At these levels, cognitive effects occur in the absence of acute symptoms or evidence of neuronal death. OBJECTIVES:This study aimed to identify adverse effects on the nervous system from prolonged, dietary DA exposure in adult, female Macaca fascicularis monkeys. METHODS:Monkeys were orally exposed to 0, 0.075, and 0.15mg/kg per day for an average of 14 months. Clinical blood counts, chemistry, and cytokine levels were analyzed in the blood. In-life magnetic resonance (MR) imaging assessed volumetric and tractography differences in and between the hippocampus and thalamus. Histology of neurons and glia in the fornix, fimbria, internal capsule, thalamus, and hippocampus was evaluated. Hippocampal RNA sequencing was used to identify differentially expressed genes. Enrichment of gene networks for neuronal health, excitotoxicity, inflammation/glia, and myelin were assessed with Gene Set Enrichment Analysis. RESULTS:Clinical blood counts, chemistry, and cytokine levels were not altered with DA exposure in nonhuman primates. Transcriptome analysis of the hippocampus yielded 748 differentially expressed genes (fold change≥1.5; p≤0.05), reflecting differences in a broad molecular profile of intermediate early genes (e.g., FOS, EGR) and genes related to myelin networks in DA animals. Between exposed and control animals, MR imaging showed comparable connectivity of the hippocampus and thalamus and histology showed no evidence of hypomyelination. Histological examination of the thalamus showed a larger microglia soma size and an extension of cell processes, but suggestions of a GFAP+astrocyte response showed no indication of astrocyte hypertrophy. DISCUSSION:In the absence of overt hippocampal excitotoxicity, chronic exposure of Macaca fascicularis monkeys to environmentally relevant levels of DA suggested a subtle shift in the molecular profile of the hippocampus and the microglia phenotype in the thalamus that was possibly reflective of an adaptive response due to prolonged DA exposure. https://doi.org/10.1289/EHP10923.

A preliminary study is reported in which six human subjects were scanned while performing a simple form of computer programming. Functional magnetic resonance imaging typically precludes the use of ordinary computing equipment due to safety concerns when items with metallic parts are in the scanning room. We used a special visual programming environment, “Kokopelli’s World,” for which an optics-only trackball was sufficient. This research methodology is described. Aspects of the experience of programming, by one of the authors, in the fMRI scanner are reported. An analysis of the data from the scanning is presented, and brain areas where activity for coding exceeded activity for a control task were identified and are presented here. These observations suggest hypotheses and directions for future research. One hypothesis is that particular aspects of programming are inherently and measurably pleasurable.

Reduced GABA concentrations at rest in the fronto-striatal circuitry are repeatedly implicated in cognitive symptoms of ADHD. However, recent evidence has suggested that GABA and its precursor, glutamate, are capable of undergoing dynamic modifications in response to environments. Yet, it remains unclear how the dynamics between glutamate and GABA may change when people are exerting their control of attention, and whether they would predict attention control deficits in ADHD. To study this question, we used MR spectroscopy to quantify GABA and glutamate+glutamine (Glx) concentrations in the anterior cingulate cortex (ACC) and the caudate nucleus in the fronto-striatal circuitry while subjects were performing attention control tasks. We studied 19 adults with ADHD (31-51 years) and 16 adults without ADHD (28-54). We found GABA and Glx concentrations during the tasks increased in both subjects with or without ADHD, but the extent of increases was significantly reduced in subjects with ADHD. Notably, E/I ratios (Glx/GABA) also increased and significantly predicted error rates while subjects with or without ADHD performed the Stroop and Flanker tasks. Critically, regression models including E/I ratios, GABA concentrations, and the ADHD diagnosis significantly predicted task performance in these tasks. Furthermore, clear interactions among these factors predicted the impaired attention control in the Flanker task in subjects with ADHD. These findings demonstrate for the first time that E/I ratios in the ACC and the caudate nucleus increased when people exerted their control of attention, and suggest that reduced GABA contribution to E/I ratio in these two brain regions may account for cognitive deficits in ADHD.

We aimed to evaluate diffusion tensor imaging (DTI) in infants born extremely preterm, to determine the effect of erythropoietin (Epo) on DTI, and to correlate DTI with neurodevelopmental outcomes at 2 years of age for infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Infants who underwent MRI with DTI at 36 weeks postmenstrual age were included. Neurodevelopmental outcomes were evaluated by Bayley Scales of Infant and Toddler Development (BSID-III). Generalized linear models were used to assess the association between DTI parameters and treatment group, and then with neurodevelopmental outcomes. A total of 101 placebo- and 93 Epo-treated infants underwent MRI. DTI white matter mean diffusivity (MD) was lower in placebo- compared to Epo-treated infants in the cingulate and occipital regions, and occipital white matter fractional isotropy (FA) was lower in infants born at 24–25 weeks vs. 26–27 weeks. These values were not associated with lower BSID-III scores. Certain decreases in clustering coefficients tended to have lower BSID-III scores. Consistent with the PENUT Trial findings, there was no effect on long-term neurodevelopment in Epo-treated infants even in the presence of microstructural changes identified by DTI.

Successful learning requires the control of attention to monitor performance and compare actual versus expected outcomes. Neural activity in the ventral tegmental area (VTA) has been linked to attention control in animals. However, it is unknown whether the strength of VTA connections is related to conflict monitoring in humans. To study the relationship between VTA connections and conflict monitoring, we acquired diffusion tensor imaging (DTI) data on 50 second language learners who we have previously studied. We performed probabilistic tractography to document VTA connections with the dorsal striatum and the anterior cingulate cortex (ACC), and administered the Flanker task in which subjects were required to monitor and report conflicts in visual stimuli. Reaction times (RTs) indexed students' conflict monitoring. Probabilistic tractography revealed distinct neural connections between the VTA and the dorsal striatum and ACC. Correlational analyses between tractography and flanker RTs revealed that the strength of VTA connections with the left caudate nucleus was negatively correlated with RTs recorded in the presence of conflicts. This provides the first evidence to suggest that VTA connections with the left caudate nucleus are related to conflict monitoring in humans.

Repetitive mild traumatic brain injury (rmTBI) is known to disturb axonal integrity and may play an important role in the pathogenic cascades leading to neurodegeneration. One critical approach to reduce the future onset of neurodegeneration is to intervene in this process at an early stage following a brain injury. Previously we showed that direct application of the microtubule-stabilizing drug, paclitaxel, on the brain following controlled cortical impact improved motor function and reduced lesion size. Herein, we extended these findings to a model of mild brain injury induced by repeated closed-skull impacts. Paclitaxel was administered intranasally to circumvent its poor transport across the blood-brain barrier. Mice received five mild closed-skull impacts (one per day for five days). Intranasal paclitaxel was administered once only, immediately after the first impact. We found that paclitaxel prevented injury-induced deficits in a spatial memory task in a water tread maze. In vivo magnetic resonance imaging (MRI) and positron emission tomography with 18F-flurodeoxyglucose (FDG-PET) revealed that paclitaxel prevented structural injury and hypometabolism. On MRI, apparent, injury-induced microbleeds were observed in 100% of vehicle-treated rmTBI mice, but not in paclitaxel-treated subjects. FDG-PET revealed a 42% increase in whole brain glucose metabolism in paclitaxel-treated mice as compared to vehicle-treated rmTBI. Immunohistochemistry found reduced evidence of axonal injury and synaptic loss. Our results indicate that intranasal paclitaxel administration imparts neuroprotection against brain injury and cognitive impairment in mice. The results from this study support the idea that microtubule-stabilization strategies hold therapeutic promise in mitigating traumatic brain injury.

BACKGROUND:Structural cerebral asymmetries are hypothesized to provide an architectural foundation for functional asymmetries and behavioral lateralities. Studies of structural asymmetries typically focus on gray matter measures that are influenced by gross deformation fields used for normalization, and thus characterize a combination of different morphologic influences on structural asymmetries.NEW METHOD:A deformation-based morphometry approach was developed to characterize structural asymmetries at different spatial scales of resolution, which can provide relatively more specific inference about the morphologic reason(s) for structural asymmetries, using a dataset of 347 typically developing children (7.00-12.92 years).RESULTS:Significant structural asymmetries were observed for a larger lobar spatial scale (e.g., frontal petalia) and for a smaller gyral/sulcal spatial scale of resolution (e.g., marginal sulcus). Total intracranial volume was significantly associated with asymmetries at the larger spatial scale of normalization, while age was significantly associated with asymmetries at the smaller scale of normalization. There were no significant anti- or fluctuating asymmetry effects based on Hartigan Dip Tests and Bonnett Tests, respectively.COMPARISON WITH EXISTING METHOD(S):While spatially similar asymmetries were observed in both gray matter and deformation field data (e.g., medial planum temporale/Heschl's gyrus), the deformation approach characterizes asymmetries based on three iterations of successively smaller scales of normalization.CONCLUSIONS:Structural asymmetries can be identified in normalization deformations with a procedure that is tailored for sensitivity to structures at different spatial scales of resolution where there may be different mechanisms for the expression of asymmetry.

ABSTRACTDomoic acid (DA) is an excitatory neurotoxin produced by marine algae and responsible for Amnesiac Shellfish Poisoning in humans. Current regulatory limits (~0.075-0.1 mg/kg/day) protect against acute toxicity, but recent studies suggest that the chronic consumption of DA below the regulatory limit may produce subtle neurotoxicity in adults, including decrements in memory. As DA-algal blooms are increasing in both severity and frequency, we sought to better understand the effects of chronic DA exposure on reproductive and neurobehavioral endpoints in a preclinical nonhuman primate model. To this end, we initiated a long-term study using adult, female Macaca fascicularis monkeys exposed to daily, oral doses of 0.075 or 0.15 mg/kg of DA for a range of 321-381, and 346-554 days, respectively. This time period included a pre-pregnancy, pregnancy, and postpartum period. Throughout these times, trained data collectors observed intentional tremors in some exposed animals during biweekly clinical examinations.The present study explores the basis of this neurobehavioral finding with in vivo imaging techniques, including diffusion tensor magnetic resonance imaging and spectroscopy. Diffusion tensor analyses revealed that, while DA exposed macaques did not significantly differ from controls, increases in DA-related tremors were negatively correlated with fractional anisotropy, a measure of structural integrity, in the internal capsule, fornix, pons, and corpus callosum. Brain concentrations of lactate, a neurochemical closely linked with astrocytes, were also weakly, but positively associated with tremors. These findings are the first documented results suggesting that chronic oral exposure to DA at concentrations near the current human regulatory limit are related to structural and chemical changes in the adult primate brain.

Excessive pain during medical procedures is a widespread problem. Severe pain is especially problematic for severe burn patients who often endure dozens of wound cleanings/debridements and dozens of physical therapy sessions over a period of weeks or months after their initial injury. Pain medications help substantially, but are typically inadequate to control such intense pain from mechanical stimulation of pain receptors during severe burn wound cleaning/debridement. Immersive Virtual Reality (VR) distraction, a nonpharmacologic analgesic used in addition to traditional pain medications, may help bring pain down to more tolerable levels during medical procedures. Patients report 35–50% reductions in procedural pain while in a distracting immersive world, and fMRI brain scans show large drops in pain-related brain activity during virtual reality analgesia ( www.vrpain.com ). Contrary to concerns that distraction would not work with patients in severe to excruciating pain, preliminary results show that VR distraction is most effective for patients who need it the most, those with the highest pain intensity levels. VR is thought to reduce pain by blocking people's view of the real world, directing patients' attention into the virtual world, leaving less attention available to process incoming signals from pain receptors. Consistent with an attentional mechanism, results of laboratory studies show that highly immersive VR systems (hypothesized to be more attention demanding) reduce pain more effectively than less immersive VR systems. We review evidence from clinical and laboratory research studies exploring Virtual Reality analgesia, concentrating primarily on the work ongoing within our group. We briefly describe preliminary results of VR applications for settings other than burn patients; dental fears patients, venipuncture, cerebral palsy patients during physical therapy, older male patients undergoing endoscopic trans-urethral microwave thermo-therapy of an enlarged benign prostate, and patients in pain from a blunt force trauma injury. Finally, we briefly discuss recent and future improvements in VR distraction technology.

Two studies were conducted of students with and without persisting Specific Learning Disabilities (SLDs-WL) in Grades 4 to 9 (M = 11 years, 11 months) that supported the hypotheses that CELF 4 parent ratings for listening (language by ear), speaking (language by mouth), reading (language by eye), and writing (language by hand) were correlated with both (a) normed, standardized behavioral measures of listening, speaking, reading, and writing achievement (Study 1, 94 boys and 61 girls); and (b) fMRI connectivity or DTI white matter integrity involving brain regions for primary motor functions or motor planning and control, or motor timing in a subsample of right handers who did not wear metal (Study 2, 28 boys and 16 girls). Results of these assessment studies, which have implications for planning instruction for three SLDs-WL (dysgraphia, dyslexia, and oral and written language learning disability [OWL LD]), show that more than multisensory instruction is relevant. Language by ear, by mouth, by eye, and by hand, as well as motor planning, control, and output skills and motor timing should also be considered. Research is also reviewed that supports other processes beyond multisensory input alone that should also be considered for students with SLDs-WL.

A multi-center imaging trial by the American College of Radiology Imaging Network (ACRIN) “A Multicenter, phase II assessment of tumor hypoxia in glioblastoma using 18F Fluoromisonidazole (FMISO) with PET and MRI (ACRIN 6684)”, was conducted to assess hypoxia in patients with glioblastoma (GBM). The aims of this study were to support the role of proton magnetic resonance spectroscopic imaging (1H MRSI) as a prognostic marker for brain tumor patients in multi-center clinical trials. Seventeen participants from four sites had analyzable 3D MRSI datasets acquired on Philips, GE or Siemens scanners at either 1.5T or 3T. MRSI data were analyzed using LCModel to quantify metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate (Lac). Receiver operating characteristic curves for NAA/Cho, Cho/Cr, lactate/Cr, and lactate/NAA were constructed for overall survival at 1-year (OS-1) and 6-month progression free survival (PFS-6). The OS-1 for the 17 evaluable patients was 59% (10/17). Receiver operating characteristic analyses found the NAA/Cho in tumor (AUC = 0.83, 95% CI: 0.61 to 1.00) and in peritumoral regions (AUC = 0.95, 95% CI 0.85 to 1.00) were predictive for survival at 1 year. PFS-6 was 65% (11/17). Neither NAA/Cho nor Cho/Cr was effective in predicting 6-month progression free survival. Lac/Cr in tumor was a significant negative predictor of PFS-6, indicating that higher lactate/Cr levels are associated with poorer outcome. (AUC = 0.79, 95% CI: 0.54 to 1.00). In conclusion, despite the small sample size in the setting of a multi-center trial comprising different vendors, field strengths, and varying levels of expertise at data acquisition, MRS markers NAA/Cho, Lac/Cr and Lac/NAA predicted overall survival at 1 year and 6-month progression free survival. This study validates that MRSI may be useful in evaluating the prognosis in glioblastoma and should be considered for incorporating into multi-center clinical trials.

Executive function (EF) skills enhance learning across domains, and are particularly linked to the acquisition of a second language. Previous studies have shown that bilingual individuals show enhanced EF skills in cognitive tasks where they attended a targeted dimension of a stimulus while inhibiting other competing cues. Brain imaging revealed that bilingual young adults’ performances in the Stroop color-naming task were related to the volume of anterior cingulate cortex (ACC) and inferior frontal lobe. Subjects who had greater white-matter in the frontal cortex showed enhanced performances in the same task, suggesting that brain fiber pathways connecting ACC to the frontal region may be related to the Stroop color-naming task. No studies to date have examined the tissue properties of brain fiber pathways connecting these brain regions and their association with subjects’ EF performances. Importantly, there are no data establishing whether bilingual subjects exhibit different reaction times when words are presented in their first versus second language. To study these questions, we used behavioral and unbiased whole-brain analyses, recruiting 21 Chinese students. Using the Stroop color-naming task, we measured subjects’ reaction times (RTs) in which color names were displayed using fonts that matched the named color (congruent task) or mismatched the color (incongruent task). Students performed the task twice, first in English, the subjects’ second language, then in Chinese, the subjects’ primary language. Results from whole-brain analysis showed that students’ RTs in both the English and Chinese tasks were significantly correlated with the mode of anisotropy (MO) in a brain cluster containing the forceps minor and anterior thalamic radiation in the right hemisphere. We also found that fractional anisotropy (FA) significantly predicted students’ RTs, with higher FA predicting shorter RT. Taken together, our findings demonstrate that right forceps minor and anterior thalamic radiation predict EF skills, suggesting that this brain feature may be important for young bilingual adults using their first and second languages to direct their attention when conflicting cues are present.