David D. Stephenson's research while affiliated with The Mind Research Network and other places

Substance use disorders among juveniles are a major public health concern and are often intertwined with other psychosocial risk factors including antisocial behavior. Identifying etiological risks and mechanisms promoting substance use disorders remains a high priority for informing more focused interventions in high-risk populations. The present study examined brain gray matter structure in relation to substance use severity among n = 152 high-risk, incarcerated boys (aged 14–20). Substance use severity was positively associated with gray matter volume across several frontal/striatal brain regions including amygdala, pallidum, putamen, insula, and orbitofrontal cortex. Effects were apparent when using voxel-based-morphometric analysis, as well as in whole-brain, data-driven, network-based approaches (source-based morphometry). These findings support the hypothesis that elevated gray matter volume in striatal reward circuits may be an endogenous marker for vulnerability to severe substance use behaviors among youth.

Pediatric mild traumatic brain injury (pmTBI) has received increased public attention over the past decade, especially for children who experience persistent post-concussive symptoms (PCS). Common methods for obtaining pediatric PCS rely on both self- and parental report, exhibit moderate test-retest reliability, and variable child-parent agreement, and may yield high false positives. The current study investigated the impact of age and biological sex on PCS reporting (Post-Concussion Symptom Inventory) in patients with pmTBI (n = 286) at retrospective, 1 week, 4 months, and 1 year post-injury time points, as well as reported symptoms in healthy controls (HC; n = 218) at equivalent assessment times. HC and their parents reported higher PCS for their retrospective rating relative to the other three other study visits. Child-parent agreement was highest for female adolescents, but only approached acceptable ranges (≥ 0.75) immediately post-injury. Poor-to-fair child/parental agreement was observed for most other study visits for pmTBI and at all visits for HC. Parents rated female adolescents as being more symptomatic than their male counterparts in spite of small (pmTBI) or no (HC) sex-related differences in self-reported ratings, suggestive of a potential cultural bias in parental ratings. Test-retest reliability for self-report was typically below acceptable ranges for both pmTBI and HC groups, with reliability decreasing for HC and increasing for pmTBI as a function of time between visits. Parental test-retest reliability was higher for females. Although continued research is needed, current results support the use of child self-report over parental ratings for estimating PCS burden. Results also highlight the perils of relying on symptom self-report for diagnostic and prognostic purposes.

Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) are each leading causes of mortality and morbidity worldwide, and present additional treatment considerations when comorbid (TBI+HS) due to competing pathophysiological responses. The current study rigorously quantified injury biomechanics with high precision sensors and examined whether blood-based surrogate markers were altered in general trauma as well as post-neurotrauma. Eighty-nine sexually mature male and female Yucatan swine were subjected to a closed-head TBI+HS (40% of circulating blood volume; N=68), HS only (N=9), or sham trauma (N=12). Markers of systemic (e.g., glucose, lactate) and neural functioning were obtained at baseline, 35 and 295 minutes post-trauma. Opposite and approximately two-fold differences existed for both magnitude (device>head) and duration (head>device) of quantified injury biomechanics. Circulating levels of neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) demonstrated differential sensitivity for both general trauma (HS) and neurotrauma (TBI+HS) relative to shams in a temporally dynamic fashion. GFAP and NFL were both strongly associated with changes in systemic markers during general trauma, and exhibited consistent time-dependent changes in individual sham animals. Finally, circulating GFAP was associated with histopathological markers of diffuse axonal injury and blood-brain barrier breach, as well as variations in device kinematics following TBI+HS. Current findings therefore highlight the need to directly quantify injury biomechanics with head mounted sensors and suggest that GFAP, NFL and UCH-L1 are sensitive to multiple forms of trauma rather than having a single pathological indication (e.g., GFAP=astrogliosis).

Cognitive impairment and post-concussive symptoms (PCS) represent hallmark sequelae of pediatric mild traumatic brain injury (pmTBI). Few studies have directly compared cognition as a function of PCS status longitudinally. Cognitive outcomes were therefore compared for asymptomatic pmTBI, symptomatic pmTBI, and healthy controls (HC) during sub-acute (SA; 1-11 days) and early chronic (EC; approximately 4 months) post-injury phases. We predicted worse cognitive performance for both pmTBI groups relative to HC at the SA visit. At the EC visit, we predicted continued impairment from the symptomatic group, but no difference between asymptomatic pmTBI and HCs. A battery of clinical (semi-structured interviews and self-report questionnaires) and neuropsychological measures were administered to 203 pmTBI and 139 HC participants, with greater than 80% retention at the EC visit. A standardized change method classified pmTBI into binary categories of asymptomatic or symptomatic based on PCS scores. Symptomatic pmTBI performed significantly worse than HCs on processing speed, attention, and verbal memory at SA visit, whereas lower performance was only present for verbal memory for asymptomatic pmTBI. Lower performance in verbal memory persisted for both pmTBI groups at the EC visit. Surprisingly, a minority (16%) of pmTBI switched from asymptomatic to symptomatic status at the EC visit. Current findings suggest that PCS and cognition are more closely coupled during the first week of injury but become decoupled several months post-injury. Evidence of lower performance in verbal memory for both asymptomatic and symptomatic pmTBI suggests that cognitive recovery may be a process separate from the resolution of subjective symptomology.

Individuals with acute and chronic traumatic brain injury (TBI) are associated with unique white matter (WM) structural abnormalities, including fractional anisotropy (FA) differences. Our research group previously used FA as a feature in a linear support vector machine (SVM) pattern classifier, observing high classification between individuals with and without acute TBI (i.e., an area under the curve [AUC] value of 75.50%). However, it is not known whether FA could similarly classify between individuals with and without history of chronic TBI. Here, we attempted to replicate our previous work with a new sample, investigating whether FA could similarly classify between incarcerated men with (n = 80) and without (n = 80) self-reported history of chronic TBI. Additionally, given limitations associated with FA, including underestimation of FA values in WM tracts containing crossing fibers, we extended upon our previous study by incorporating neurite orientation dispersion and density imaging (NODDI) metrics, including orientation dispersion (ODI) and isotropic volume (Viso). A linear SVM based classification approach, similar to our previous study, was incorporated here to classify between individuals with and without self-reported chronic TBI using FA and NODDI metrics as separate features. Overall classification rates were similar when incorporating FA and NODDI ODI metrics as features (AUC: 82.50%). Additionally, NODDI-based metrics provided the highest sensitivity (ODI: 85.00%) and specificity (Viso: 82.50%) rates. The current study serves as a replication and extension of our previous study, observing that multiple diffusion MRI metrics can reliably classify between individuals with and without self-reported history of chronic TBI.

Background and Objectives The clinical and physiological time-course for recovery following pediatric mild traumatic brain injury (pmTBI) remains actively debated. The primary objective of the current study was to prospectively examine structural brain changes (cortical thickness and subcortical volumes) and age-at-injury effects. A priori study hypotheses predicted reduced cortical thickness and hippocampal volumes up to 4 months post-injury, which would be inversely associated with age-at-injury. Methods Prospective cohort study design with consecutive recruitment. Study inclusion adapted from American Congress of Rehabilitation Medicine (upper threshold) and Zurich Concussion in Sport Group (minimal threshold) and diagnosed by Emergency Department and Urgent Care clinicians. Major neurological, psychiatric or developmental disorders were exclusionary. Clinical (Common Data Element) and structural (3 Tesla MRI) evaluations within 11 days (sub-acute visit [SA]) and at 4 months (early chronic visit [EC]) post-injury. Age and sex-matched healthy children (HC) to control for repeat testing/neurodevelopment. Clinical outcomes based on self-report and cognitive testing. Structural images quantified with FreeSurfer (version 7.1.1). Results 208 pmTBI (age=14.4±2.9; 40.4% female) and 176 HC (age=14.2±2.9; 42.0% female) included in final analyses (>80% retention). Reduced cortical thickness (right rostral middle frontal gyrus; d =−0.49) and hippocampal volumes ( d =−0.24) observed for pmTBI, but not associated with age-at-injury. Hippocampal volume recovery was mediated by loss of consciousness/post-traumatic amnesia. Significantly greater post-concussive symptoms and cognitive deficits were observed at SA and EC visits, but were not associated with the structural abnormalities. Structural abnormalities slightly improved balanced classification accuracy above and beyond clinical gold standards (∆+3.9%), with a greater increase in specificity (∆+7.5%) relative to sensitivity (∆+0.3%). Discussion Current findings indicate structural brain abnormalities may persist up to four months post-pmTBI, and are partially mediated by initial markers of injury severity. These results contribute to a growing body of evidence suggesting prolonged physiological recovery post-pmTBI. In contrast, there was no evidence for age-of-injury effects or for physiological correlates of persistent symptoms in our sample.

The underlying pathophysiology of paediatric mild traumatic brain injury and the time-course for biological recovery remains widely debated, with clinical care principally informed by subjective self-report. Similarly, clinical evidence indicate that adolescence is a risk factor for prolonged recovery, but the impact of age-at-injury on biomarkers has not been determined in large, homogeneous samples. The current study collected diffusion magnetic resonance imaging data in consecutively recruited patients (N = 203; 8-18 years old) and age and sex-matched healthy controls (N = 170) in a prospective cohort design. Patients were evaluated sub-acutely (1-11 days post-injury) as well as at four months post-injury (early-chronic phase). Healthy participants were evaluated at similar times to control for neurodevelopment and practice effects. Clinical findings indicated persistent symptoms at four months for a significant minority of patients (22%), along with residual executive dysfunction and verbal memory deficits. Results indicated increased fractional anisotropy and reduced mean diffusivity for patients, with abnormalities persisting up to four months post-injury. Multicompartmental geometric models indicated that estimates of intracellular volume fractions were increased in patients, whereas estimates of free water fractions were decreased. Critically, unique areas of white matter pathology (increased free water fractions or increased neurite dispersion) were observed when standard assumptions regarding parallel diffusivity were altered in multicompartmental models to be more biologically plausible. Cross-validation analyses indicated that some diffusion findings were more reproducible when approximately 70% of the total sample (142 patients, 119 controls) were used in analyses, highlighting the need for large-sample sizes to detect abnormalities. Supervised machine learning approaches (random forests) indicated that diffusion abnormalities increased overall diagnostic accuracy (patients vs. controls) by approximately 10% after controlling for current clinical gold standards, with each diffusion metric accounting for only a few unique percentage points. In summary, current results suggest that novel multicompartmental models are more sensitive to paediatric mild traumatic brain injury pathology, and that this sensitivity is increased when using parameters that more accurately reflect diffusion in healthy tissue. Results also suggest that diffusion data may be insufficient to achieve a high degree of objective diagnostic accuracy in patients when used in isolation, which is to be expected given known heterogeneities in pathophysiology, mechanism of injury, and even criteria for diagnoses. Finally, current results suggest ongoing clinical and physiological recovery at four months post-injury.

Objective: This study assessed classification accuracy of paper-and-pencil and computerized cognitive batteries at subacute (SA; 1-11 days) and early chronic (EC; ∼4 months) phases of pediatric mild traumatic brain injury (pmTBI). Two statistical approaches focused on single-subject performance (individual task scores, total impairments) were used to maximize clinical utility. Method: Two hundred thirty-five pmTBI and 169 healthy controls (HC) participants aged 8-18 were enrolled, with a subset (190 pmTBI; 160 HC) returning for the EC visit. The paper-and-pencil battery included several neuropsychological tests selected from recommended common data elements, whereas computerized testing was performed with the Cogstate Brief Battery. Hierarchical logistic regressions (base model: Parental education and premorbid reading abilities; full model: Base model and cognitive testing variables) were used to examine sensitivity/specificity, with diagnosis as the dependent variable. Results: Number Sequencing and Cogstate One-Card Learning accuracy significantly predicted SA diagnosis (full model accuracy = 71.6%-71.7%, sensitivity = 80.6%-80.8%, specificity = 59.1%-59.6%), while only immediate recall was significant at EC visit (accuracy = 68.5%, sensitivity = 74.6%, specificity = 61.5%). Other measures (Letter Fluency, Cogstate Detection, and One-Card Learning accuracy) demonstrated higher proportions of impairment for pmTBI subacutely (pmTBI: 11.5%-19.8%; HC: 3.7%-6.1%) but did not improve classification accuracy. Evidence of multiple impairments across the entire testing battery significantly predicted diagnosis at both visits (full model accuracy = 66.2%-68.6%, sensitivity = 71.2%-78.9%, specificity = 54.3%-61.5%). Conclusions: Current results suggest similar modest diagnostic accuracy for computerized and paper-and-pencil batteries across multiple pmTBI phases. Moreover, findings suggest the total number of impairments may be more clinically useful than any single test or cognitive domain in terms of diagnostic accuracy at both assessment points. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Accurate characterization of head kinematics following an external blow represents a fundamental aspect of traumatic brain injury (TBI) research. The majority of previous large animal studies have assumed an equivalent relationship between the device delivering the impulsive load and subsequent head kinematics rather than performing direct measurement (sensors or videography). The current study therefore examined factors affecting device/head coupling kinematics in an acceleration TBI model. Experiment 1 indicated ~ 50% reduction in peak angular velocity for swine head relative to the device, with an approximate doubling in temporal duration. The peak angular velocity for the head was not significantly altered by variations in restraint device (straps vs. cables), animal positioning or body mass. In Experiment 2, reducing the impulsive load by 32% resulted in only a 14% reduction in angular velocity of the head (approximately 69% head/device coupling ratio), with more pronounced differences qualitatively observed for angular momentum. A temporal delay was identified in initial device/head coupling, potentially a result of soft tissue deformation. Finally, similar head kinematics were obtained regardless of mounting the sensor directly to the skull or through the scalp (Experiment 3). Current findings highlight the importance of direct measurement of head kinematics for future studies.

Background Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO 4 ) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS. Methods All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO 4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation). Results A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood–brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO 4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO 4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO 4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO 4 or Placebo administration. Conclusions EE-3-SO 4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.