Cognition and post-concussive symptom status after pediatric mild traumatic brain injury.

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.

Sex- and Age-Related Differences in Post-Concussive Symptom Reporting Among Children and Their Parents.

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.

Head Kinematics, Blood Biomarkers, and Histology in Large Animal Models of Traumatic Brain Injury and Hemorrhagic Shock.

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 they are comorbid (TBI+HS) as a result of 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, and at 35 and 295 min post-trauma. Opposite and approximately twofold 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).

Machine learning classification of chronic traumatic brain injury using diffusion tensor imaging and NODDI: A replication and extension study.

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.

Prospective Study of Gray Matter Atrophy Following Pediatric Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: The clinical and physiologic 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 postinjury, 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 neurologic, psychiatric, or developmental disorders were exclusionary. Clinical (Common Data Element) and structural (3 T MRI) evaluations within 11 days (subacute visit [SA]) and at 4 months (early chronic visit [EC]) postinjury. Age- and sex-matched healthy controls (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: A total of 208 patients with pmTBI (age = 14.4 ± 2.9; 40.4% female) and 176 HC (age = 14.2 ± 2.9; 42.0% female) were included in the 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/posttraumatic amnesia. Significantly greater postconcussive 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 that structural brain abnormalities may persist up to 4 months post-pmTBI and are partially mediated by initial markers of injury severity. These results contribute to a growing body of evidence suggesting prolonged physiologic recovery post-pmTBI. In contrast, there was no evidence for age-at-injury effects or physiologic correlates of persistent symptoms in our sample.

Multicompartmental models and diffusion abnormalities in paediatric mild traumatic brain injury.

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 indicates 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 MRI 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 subacutely (1-11 days post-injury) as well as at 4 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 4 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 4 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 ∼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 versus controls) by ∼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 indicate 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 indicate ongoing clinical and physiological recovery at 4 months post-injury.

Non-Linear Device Head Coupling and Temporal Delays in Large Animal Acceleration Models of Traumatic Brain Injury.

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.

Investigating the diagnostic accuracy of a paper-and-pencil and a computerized cognitive test battery for pediatric mild traumatic brain 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).

Test-Retest Reliability of a Semi-Structured Interview to Aid in Pediatric Traumatic Brain Injury Diagnosis.

OBJECTIVE: Retrospective self-report is typically used for diagnosing previous pediatric traumatic brain injury (TBI). A new semi-structured interview instrument (New Mexico Assessment of Pediatric TBI; NewMAP TBI) investigated test-retest reliability for TBI characteristics in both the TBI that qualified for study inclusion and for lifetime history of TBI. METHOD: One-hundred and eight-four mTBI (aged 8-18), 156 matched healthy controls (HC), and their parents completed the NewMAP TBI within 11 days (subacute; SA) and 4 months (early chronic; EC) of injury, with a subset returning at 1 year (late chronic; LC). RESULTS: The test-retest reliability of common TBI characteristics [loss of consciousness (LOC), post-traumatic amnesia (PTA), retrograde amnesia, confusion/disorientation] and post-concussion symptoms (PCS) were examined across study visits. Aside from PTA, binary reporting (present/absent) for all TBI characteristics exhibited acceptable (≥0.60) test-retest reliability for both Qualifying and Remote TBIs across all three visits. In contrast, reliability for continuous data (exact duration) was generally unacceptable, with LOC and PCS meeting acceptable criteria at only half of the assessments. Transforming continuous self-report ratings into discrete categories based on injury severity resulted in acceptable reliability. Reliability was not strongly affected by the parent completing the NewMAP TBI. CONCLUSIONS: Categorical reporting of TBI characteristics in children and adolescents can aid clinicians in retrospectively obtaining reliable estimates of TBI severity up to a year post-injury. However, test-retest reliability is strongly impacted by the initial data distribution, selected statistical methods, and potentially by patient difficulty in distinguishing among conceptually similar medical concepts (i.e., PTA vs. confusion).

17α-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial.

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-SO4) 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-SO4 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-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 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-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration. CONCLUSIONS: EE-3-SO4 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.

Reproducibility and Characterization of Head Kinematics During a Large Animal Acceleration Model of Traumatic Brain Injury.

Acceleration parameters have been utilized for the last six decades to investigate pathology in both human and animal models of traumatic brain injury (TBI), design safety equipment, and develop injury thresholds. Previous large animal models have quantified acceleration from impulsive loading forces (i.e., machine/object kinematics) rather than directly measuring head kinematics. No study has evaluated the reproducibility of head kinematics in large animal models. Nine (five males) sexually mature Yucatan swine were exposed to head rotation at a targeted peak angular velocity of 250 rad/s in the coronal plane. The results indicated that the measured peak angular velocity of the skull was 51% of the impulsive load, was experienced over 91% longer duration, and was multi- rather than uni-planar. These findings were replicated in a second experiment with a smaller cohort (N = 4). The reproducibility of skull kinematics data was mostly within acceptable ranges based on published industry standards, although the coefficients of variation (8.9% for peak angular velocity or 12.3% for duration) were higher than the impulsive loading parameters produced by the machine (1.1 vs. 2.5%, respectively). Immunohistochemical markers of diffuse axonal injury and blood-brain barrier breach were not associated with variation in either skull or machine kinematics, suggesting that the observed levels of variance in skull kinematics may not be biologically meaningful with the current sample sizes. The findings highlight the reproducibility of a large animal acceleration model of TBI and the importance of direct measurements of skull kinematics to determine the magnitude of angular velocity, refine injury criteria, and determine critical thresholds.

The clinical relevance of gray matter atrophy and microstructural brain changes across the psychosis continuum.

Patients with psychotic spectrum disorders (PSD) exhibit similar patterns of atrophy and microstructural changes that may be associated with common symptomatology (e.g., symptom burden and/or cognitive impairment). Gray matter concentration values (proxy for atrophy), fractional anisotropy (FA), mean diffusivity (MD), intracellular neurite density (Vic) and isotropic diffusion volume (Viso) measures were therefore compared in 150 PSD (schizophrenia, schizoaffective disorder, and bipolar disorder Type I) and 63 healthy controls (HC). Additional analyses evaluated whether regions showing atrophy and/or microstructure abnormalities were better explained by DSM diagnoses, symptom burden or cognitive dysfunction. PSD exhibited increased atrophy within bilateral medial temporal lobes and subcortical structures. Gray matter along the left lateral sulcus showed evidence of increased atrophy and MD. Increased MD was also observed in homotopic fronto-temporal regions, suggesting it may serve as a precursor to atrophic changes. Global cognitive dysfunction, rather than DSM diagnoses or psychotic symptom burden, was the best predictor of increased gray matter MD. Regions of decreased FA (i.e., left frontal gray and white matter) and Vic (i.e., frontal and temporal regions and along central sulcus) were also observed for PSD, but were neither spatially concurrent with atrophic regions nor associated with clinical symptoms. Evidence of expanding microstructural spaces in gray matter demonstrated the greatest spatial overlap with current and potentially future regions of atrophy, and was associated with cognitive deficits. These results suggest that this particular structural abnormality could potentially underlie global cognitive impairment that spans traditional diagnostic categories.

Survival Rates and Biomarkers in a Large Animal Model of Traumatic Brain Injury Combined With Two Different Levels of Blood Loss.

INTRODUCTION: The pathology resulting from concurrent traumatic brain injury (TBI) and hemorrhagic shock (HS; TBI+HS) are leading causes of mortality and morbidity worldwide following trauma. However, the majority of large animal models of TBI+HS have utilized focal/contusional injuries rather than incorporating the types of brain trauma (closed-head injury caused by dynamic acceleration) that typify human injury. OBJECTIVE: To examine survival rates and effects on biomarkers from rotational TBI with two levels of HS. METHODS: Twenty-two sexually mature Yucatan swine (30.39 ±â€Š2.25 kg; 11 females) therefore underwent either Sham trauma procedures (n = 6) or a dynamic acceleration TBI combined with either 55% (n = 8) or 40% (n = 8) blood loss in this serial study. RESULTS: Survival rates were significantly higher for the TBI+40% (87.5%) relative to TBI+55% (12.5%) cohort, with the majority of TBI+55% animals expiring within 2 h post-trauma from apnea. Blood-based neural biomarkers and immunohistochemistry indicated evidence of diffuse axonal injury (increased NFL/Aß42), blood-brain barrier breach (increased immunoglobulin G) and inflammation (increased glial fibrillary acidic protein/ionized calcium-binding adaptor molecule 1) in the injured cohorts relative to Shams. Invasive hemodynamic measurements indicated increased shock index and decreased pulse pressure in both injury cohorts, with evidence of partial recovery for invasive hemodynamic measurements in the TBI+40% cohort. Similarly, although both injury groups demonstrated ionic and blood gas abnormalities immediately postinjury, metabolic acidosis continued to increase in the TBI+55% group ∼85 min postinjury. Somewhat surprisingly, both neural and physiological biomarkers showed significant changes within the Sham cohort across the multi-hour experimental procedure, most likely associated with prolonged anesthesia. CONCLUSION: Current results suggest the TBI+55% model may be more appropriate for severe trauma requiring immediate medical attention/standard fluid resuscitation protocols whereas the TBI+40% model may be useful for studies of prolonged field care.

Severity of Ongoing Post-Concussive Symptoms as a Predictor of Cognitive Performance Following a Pediatric Mild Traumatic Brain Injury.

OBJECTIVE: This study aimed to examine the predictors of cognitive performance in patients with pediatric mild traumatic brain injury (pmTBI) and to determine whether group differences in cognitive performance on a computerized test battery could be observed between pmTBI patients and healthy controls (HC) in the sub-acute (SA) and the early chronic (EC) phases of injury. METHOD: 203 pmTBI patients recruited from emergency settings and 159 age- and sex-matched HC aged 8-18 rated their ongoing post-concussive symptoms (PCS) on the Post-Concussion Symptom Inventory and completed the Cogstate brief battery in the SA (1-11 days) phase of injury. A subset (156 pmTBI patients; 144 HC) completed testing in the EC (~4 months) phase. RESULTS: Within the SA phase, a group difference was only observed for the visual learning task (One-Card Learning), with pmTBI patients being less accurate relative to HC. Follow-up analyses indicated higher ongoing PCS and higher 5P clinical risk scores were significant predictors of lower One-Card Learning accuracy within SA phase, while premorbid variables (estimates of intellectual functioning, parental education, and presence of learning disabilities or attention-deficit/hyperactivity disorder) were not. CONCLUSIONS: The absence of group differences at EC phase is supportive of cognitive recovery by 4 months post-injury. While the severity of ongoing PCS and the 5P score were better overall predictors of cognitive performance on the Cogstate at SA relative to premorbid variables, the full regression model explained only 4.1% of the variance, highlighting the need for future work on predictors of cognitive outcomes.

Differing functional mechanisms underlie cognitive control deficits in psychotic spectrum disorders.

Background: Functional underpinnings of cognitive control deficits in unbiased samples (i.e., all comers) of patients with psychotic spectrum disorders (PSD) remain actively debated. While many studies suggest hypofrontality in the lateral prefrontal cortex (PFC) and greater deficits during proactive relative to reactive control, few have examined the full hemodynamic response. Methods: Patients with PSD (n = 154) and healthy controls (n = 65) performed the AX continuous performance task (AX-CPT) during rapid (460 ms) functional neuroimaging and underwent full clinical characterization. Results: Behavioural results indicated generalized cognitive deficits (slower and less accurate) across proactive and reactive control conditions in patients with PSD relative to healthy controls. We observed a delayed/prolonged neural response in the left dorsolateral PFC, the sensorimotor cortex and the superior parietal lobe during proactive control for patients with PSD. These proactive hemodynamic abnormalities were better explained by negative rather than by positive symptoms or by traditional diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR), with subsequent simulations unequivocally demonstrating how these abnormalities could be erroneously interpreted as hypoactivation. Conversely, true hypoactivity, unassociated with clinical symptoms or DSM-IV-TR diagnoses, was observed within the ventrolateral PFC during reactive control. Limitations: In spite of guidance for AX-CPT use in neuroimaging studies, one-third of patients with PSD could not perform the task above chance and were more clinically impaired. Conclusion: Current findings question the utility of the AX-CPT for neuroimaging-based appraisal of cognitive control across the full spectrum of patients with PSD. Previously reported lateral PFC "hypoactivity" during proactive control may be more indicative of a delayed/prolonged neural response, important for rehabilitative purposes. Negative symptoms may better explain certain behavioural and hemodynamic abnormalities in patients with PSD relative to DSM-IV-TR diagnoses.

Resting-State Power and Regional Connectivity After Pediatric Mild Traumatic Brain Injury.

BACKGROUND: Physiological recovery from pediatric mild traumatic brain injury (pmTBI) as a function of age remains actively debated, with the majority of studies relying on subjective symptom report rather than objective markers of brain physiology. PURPOSE: To examine potential abnormalities in fractional amplitude of low-frequency fluctuations (fALFF) or regional homogeniety (ReHo) during resting-state fMRI following pmTBI. STUDY TYPE: Prospective cohort. POPULATION: Consecutively recruited pmTBI (N = 105; 8-18 years old) and age- and sex-matched healthy controls (HC; N = 113). FIELD STRENGTH/SEQUENCE: 3T multiecho gradient T1 -weighted and single-shot gradient-echo echo-planar imaging. ASSESSMENT: All pmTBI participants were assessed 1 week and 4 months postinjury (HC assessed at equivalent timepoints after the first visit). Comprehensive demographic, clinical, and cognitive batteries were performed in addition to primary investigation of fALFF and ReHo. All pmTBI were classified as "persistent" or "recovered" based on both assessment periods. STATISTICAL TESTS: Chi-square, nonparametric, and generalized linear models for demographic data. Generalized estimating equations for clinical and cognitive data. Voxelwise general linear models (AFNI's 3dMVM) for fALFF and ReHo assessment. RESULTS: Evidence of recovery was observed for some, but not all, clinical and cognitive measures at 4 months postinjury. fALFF was increased in the left striatum for pmTBI relative to HC both at 1 week and 4 months postinjury; whereas no significant group differences (P > 0.001) were observed for ReHo. Age-at-injury did not moderate either resting-state metric across groups. In contrast to analyses of pmTBI as a whole, there were no significant (P > 0.001) differences in either fALFF or ReHo in patients with persistent postconcussive symptoms compared to recovered patients and controls at 4 months postinjury. DATA CONCLUSIONS: Our findings suggest prolonged clinical recovery and alterations in the relative amplitude of resting-state fluctuations up to 4 months postinjury, but no clear relationship with age-at-injury or subjective symptom report. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: 2 J. MAGN. RESON. IMAGING 2020;52:1701-1713.

Evidence for asymmetric inhibitory activity during motor planning phases of sensorimotor synchronization.

Sensorimotor synchronization (SMS) is frequently dependent on coordination of excitatory and inhibitory activity across hemispheres, as well as the cognitive control over environmental distractors. However, the timing (motor planning versus execution) and cortical regions involved in these processes remain actively debated. Functional magnetic resonance imaging data were therefore analyzed from 34 strongly right-handed healthy adults performing a cued (to initiate motor planning) SMS task with either their right or left hand (motor execution phase) based on spatially congruent or incongruent visual stimuli. Behavioral effects of incongruent stimuli were limited to the first stimulus. Functionally, greater activation was observed in left sensorimotor cortex (SMC) and right cerebellar Lobule V for congruent versus incongruent stimuli. A negative blood-oxygen level dependent response, a putative marker of neural inhibition, was present in bilateral SMC, right supplemental motor area (SMA) and bilateral cerebellar Lobule V during the motor planning, but not execution phase. The magnitude of the inhibitory response was greater in right cortical regions and cerebellar Lobule V. Homologue connectivity was associated with inhibitory activity in the right SMA, suggesting that individual differences in intrinsic connectivity may mediate transcallosal inhibition. In summary, results suggest increased inhibition (i.e., greater negative BOLD response) within the right relative to left hemisphere, which was released once motor programs were executed. Both task and intrinsic functional connectivity results highlight a critical role of the left SMA in interhemispheric inhibition and motor planning.

Neurosensory Screening and Symptom Provocation in Pediatric Mild Traumatic Brain Injury.

OBJECTIVE: To evaluate diagnostic/prognostic implications of neurosensory testing during the subacute stage in patients with pediatric mild traumatic brain injury (pmTBI). SETTING: Recruitment from pediatric emergency department and urgent care clinics, assessment in a controlled environment. PARTICIPANTS: In total, 146 pmTBI patients evaluated 7.4 ± 2.3 days and approximately 4 months postinjury; 104 age/sex-matched healthy controls (HCs) at equivalent time points. DESIGN: Prospective cohort study. MAIN MEASURES: Neurosensory examination based on sequence of 10 established tests of vestibular-ocular, oculomotor, vestibulospinal, and visual functioning. RESULTS: The amount of symptom provocation (positive change from pretest symptomatology) was significantly increased in pmTBI relative to HCs on every subtest 1 week postinjury, as were deficits in monocular accommodative amplitude and King-Devick Test errors. However, symptom provocation did not meaningfully alter diagnostic sensitivity/specificity relative to more easily obtained pretest symptom ratings. Evidence of clinically significant symptom provocation 1 week postinjury improved sensitivity (Δ = +12.9%) of identifying patients with persistent postconcussive symptoms 4 months postinjury on an independent symptom measure. CONCLUSIONS: The diagnostic sensitivity/specificity of neurosensory testing in acutely concussed youth may be limited at 1 week postinjury as a function of natural recovery occurring in most emergency department cohorts. Neurosensory screening may have greater utility for identifying patients who experience delayed recovery.

Comparison of Methods for Classifying Persistent Post-Concussive Symptoms in Children.

Pediatric mild traumatic brain injury (pmTBI) has received increased public scrutiny over the past decade, especially regarding children who experience persistent post-concussive symptoms (PPCS). However, several methods for defining PPCS exist in clinical and scientific literature, and even healthy children frequently exhibit non-specific, concussive-like symptoms. Inter-method agreement (six PPCS methods), observed misclassification rates, and other psychometric properties were examined in large cohorts of consecutively recruited adolescent patients with pmTBI (n = 162) 1 week and 4 months post-injury and in age/sex-matched healthy controls (HC; n = 117) at equivalent time intervals. Six published PPCS methods were stratified into Simple Change (e.g., International Statistical Classification of Diseases and Related Health Problems, 10th revision [ICD-10]) and Standardized Change (e.g., reliable change indices) algorithms. Among HC, test-retest reliability was fair to good across the 4-month assessment window, with evidence of bias (i.e., higher symptom ratings) during retrospective relative to other assessments. Misclassification rates among HC were higher (>30%) for Simple Change algorithms, with poor inter-rater reliability of symptom burden across HC and their parents. A 49% spread existed in terms of the proportion of pmTBI patients "diagnosed" with PPCS at 4 months, with superior inter-method agreement among standardized change algorithms. In conclusion, the self-reporting of symptom burden is only modestly reliable in typically developing adolescents over a 4-month period, with additional evidence for systematic bias in both adolescent and parental ratings. Significant variation existed for identifying pmTBI patients who had "recovered" (i.e., those who did not meet individual criteria for PPCS) from concussion across the six definitions, representing a considerable challenge for estimating the true incidence rate of PPCS in published literature. Although relatively straightforward to obtain, current findings question the utility of the most commonly used Simple Change scores for diagnosis of PPCS in clinical settings.

Proactive inhibition deficits with normal perfusion after pediatric mild traumatic brain injury.

Although much attention has been generated in popular media regarding the deleterious effects of pediatric mild traumatic brain injury (pmTBI), a paucity of empirical evidence exists regarding the natural course of biological recovery. Fifty pmTBI patients (12-18 years old) were consecutively recruited from Emergency Departments and seen approximately 1 week and 4 months post-injury in this prospective cohort study. Data from 53 sex- and age-matched healthy controls (HC) were also collected. Functional magnetic resonance imaging was obtained during proactive response inhibition and at rest, in conjunction with independent measures of resting cerebral blood flow. High temporal resolution imaging enabled separate modeling of neural responses for preparation and execution of proactive response inhibition. A priori predictions of failed inhibitory responses (i.e., hyperactivation) were observed in motor circuitry (pmTBI>HC) and sensory areas sub-acutely and at 4 months post-injury. Paradoxically, pmTBI demonstrated hypoactivation (HC>pmTBI) during target processing, along with decreased activation within prefrontal cognitive control areas. Functional connectivity within motor circuitry at rest suggested that deficits were limited to engagement during the inhibitory task, whereas normal resting cerebral perfusion ruled out deficits in basal perfusion. In conclusion, current results suggest blood oxygen-level dependent deficits during inhibitory control may exceed commonly held beliefs about physiological recovery following pmTBI, potentially lasting up to 4 months post-injury.