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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.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.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%).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).

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).

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.

Prior study of patients with urgency urinary incontinence by functional magnetic resonance imaging showed altered function in areas of the brain associated with interoception and salience and with attention. Our randomized controlled trial of hypnotherapy for urgency urinary incontinence demonstrated marked improvement in urgency urinary incontinence symptoms at 2 months. A subsample of these women with urgency urinary incontinence underwent functional magnetic resonance imaging before and after treatment.This study aimed to determine if hypnotherapy treatment of urgency urinary incontinence compared with pharmacotherapy was associated with altered brain activation or resting connectivity on functional magnetic resonance imaging.A subsample of women participating in a randomized controlled trial comparing hypnotherapy vs pharmacotherapy for treatment of urgency urinary incontinence was evaluated with functional magnetic resonance imaging. Scans were obtained pretreatment and 8 to 12 weeks after treatment initiation. Brain activation during bladder filling and resting functional connectivity with an empty and partially filled bladder were assessed. Brain regions of interest were derived from those previously showing differences between healthy controls and participants with untreated urgency urinary incontinence in our prior work and included regions in the interoceptive and salience, ventral attentional, and dorsal attentional networks.After treatment, participants in both groups demonstrated marked improvement in incontinence episodes (P.001). Bladder-filling task functional magnetic resonance imaging data from the combined groups (n=64, 30 hypnotherapy, 34 pharmacotherapy) demonstrated decreased activation of the left temporoparietal junction, a component of the ventral attentional network (P.01) compared with baseline. Resting functional connectivity differed only with the bladder partially filled (n=54). Compared with pharmacotherapy, hypnotherapy participants manifested increased functional connectivity between the anterior cingulate cortex and the left dorsolateral prefrontal cortex, a component of the dorsal attentional network (P.001).Successful treatment of urgency urinary incontinence with both pharmacotherapy and hypnotherapy was associated with decreased activation of the ventral (bottom-up) attentional network during bladder filling. This may be attributable to decreased afferent stimuli arising from the bladder in the pharmacotherapy group. In contrast, decreased ventral attentional network activation associated with hypnotherapy may be mediated by the counterbalancing effects of the dorsal (top-down) attentional network.

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.

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.

Background and ObjectivesThe 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.MethodsProspective 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).ResultsA 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%).DiscussionCurrent 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.

Highlights • Evidence of an ongoing and potentially incomplete shift toward visual dominance observed in adolescents. • Modality-specific stratifications of the prefrontal cortex were not present. • Minimal functional evidence of proactive cognitive control and attention-related modulations was observed following cue presentation in adolescents. • Current results suggest increased reliance on reactive control and ongoing transition toward sensory-specific information processing during adolescence rather than specialization., Attention is inherently biased towards the visual modality during most multisensory scenarios in adults, but the developmental trajectory towards visual dominance has not been fully elucidated. More recent evidence in primates and adult humans suggests a modality-specific stratification of the prefrontal cortex. The current study therefore used functional magnetic resonance imaging (fMRI) to investigate the neuronal correlates of proactive (following cues) and reactive (following probes) cognitive control for simultaneous audio-visual stimulation in 67 healthy adolescents (13–18 years old). Behavioral results were only partially supportive of visual dominance in adolescents, with both reduced response times and accuracy during attend-visual relative to attend-auditory trials. Differential activation of medial and lateral prefrontal cortex for processing incongruent relative to congruent stimuli (reactive control) was also only observed during attend-visual trials. There was no evidence of modality-specific prefrontal cortex stratification during the active processing of multisensory stimuli or during separate functional connectivity analyses. Attention-related modulations were also greater within visual relative to auditory cortex, but were less robust than observed in previous adult studies. Collectively, current results suggest a continued transition towards visual dominance in adolescence, as well as limited modality-specific specialization of prefrontal cortex and attentional modulations of unisensory cortex.

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.

Traumatic brain injury (TBI) and severe blood loss (SBL) frequently co-occur in human trauma, resulting in high levels of mortality and morbidity. Importantly, each of the individual post-injury cascades is characterized by complex and potentially opposing pathophysiological responses, complicating optimal resuscitation and therapeutic approaches. Large animal models of poly-neurotrauma closely mimic human physiology, but a systematic literature review of published models has been lacking. The current review suggests a relative paucity of large animal poly-neurotrauma studies (N = 52), with meta-statistics revealing trends for animal species (exclusively swine), characteristics (use of single biological sex, use of juveniles) and TBI models. Although most studies have targeted blood loss volumes of 35–45%, the associated mortality rates are much lower relative to Class III/IV human trauma. This discrepancy may result from potentially mitigating experimental factors (e.g., mechanical ventilation prior to or during injury, pausing/resuming blood loss based on physiological parameters, administration of small volume fluid resuscitation) that are rarely associated with human trauma, highlighting the need for additional work in this area.

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.

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 (V(ic)) and isotropic diffusion volume (V(iso)) 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 V(ic) (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.

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 ± 2.25 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/Aβ42), 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.

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.

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.

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.

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.

Background Disrupted proactive cognitive control, a form of early selection and active goal maintenance, is hypothesized to underlie the broad cognitive deficits observed in patients with schizophrenia (SPs). Current research suggests that the disrupted activation within and connectivity between regions of the cognitive control network contribute to disrupted proactive cognitive control; however, no study has examined these mechanisms using an AX Continuous Performance Test task in schizophrenia. Methods Twenty-six SPs (17 male subjects; mean age 34.46 ± 8.77 years) and 28 healthy control participants (HCs; 16 male subjects; mean age 31.43 ± 7.23 years) underwent an electroencephalogram while performing the AX Continuous Performance Test. To examine the extent of activation and level of connectivity within the cognitive control network, power, intertrial phase clustering, and intersite phase clustering metrics were calculated and analyzed. Results SPs exhibited expected general decrements in behavioral performance relative to HCs and a more selective deficit in conditions requiring proactive cognitive control. Additionally, SPs exhibited deficits in midline theta power and connectivity during proactive cognitive control trials. Specifically, HCs exhibited significantly greater theta power for B cues relative to A cues, whereas SPs exhibited no significant differences between A- and B-cue theta power. Additionally, differential theta connectivity patterns were observed in SPs and HCs. Behavioral measures of proactive cognitive control predicted functional outcomes in SPs. Conclusions This study suggests that low-frequency midline theta activity is selectively disrupted during proactive cognitive control in SPs. The disrupted midline theta activity may reflect a failure of SPs to proactively recruit cognitive control processes.

Accurate identification and classification of patients suffering from mild traumatic brain injury (mTBI) is a significant challenge faced by clinicians and researchers. To examine if there are different pathophysiological responses to concussive injury in different populations, evaluated here comparing collegiate athletes versus age-matched non-athletes. Resting-state fMRI data were acquired in the acute phase of concussion from 30 collegiate athletes and from 30 injury and age matched non-athletes. Resting-state functional connectivity measures revealed group differences with reduced connectivity in the anterior cingulate cortex (p

Background Chronic alcohol use disorders (AUDs) and traumatic brain injury (TBI) are highly comorbid and share commonly affected neuronal substrates (i.e., prefrontal cortex, limbic system, and cerebellum). However, no studies have examined how combined physical trauma and heavy drinking affect neurocircuitry relative to heavy drinking alone. Methods The current study investigated whether comorbid AUDs and mild or moderate TBI (AUDs+TBI) would negatively affect maladaptive drinking behaviors ( n = 90 AUDs+TBI; n = 62 AUDs) as well as brain structure (i.e., increased atrophy; n = 62 AUDs+TBI; n = 44 AUDs) and function (i.e., activation during gustatory cue reactivity; n = 55 AUDs+TBI; n = 37 AUDs) relative to AUDs alone. Results Participants reported a much higher incidence of trauma (59.2%) compared with the general population. There were no differences in demographic and clinical measures between groups, suggesting that they were well matched. Although maladaptive drinking behaviors tended to be worse for the AUDs+TBI group, effect sizes were small and not statistically significant. Increased alcohol-cue reactivity was observed in bilateral anterior insula and orbitofrontal cortex, anterior cingulate cortex, medial prefrontal cortex, posterior cingulate cortex, dorsal striatum, thalamus, brainstem, and cerebellum across both groups relative to a carefully matched appetitive control. However, there were no significant differences in structural integrity or functional activation between AUDs+TBI and AUDs participants, even when controlling for AUD severity. Conclusions Current results indicate that a combined history of mild or moderate TBI was not sufficient to alter drinking behaviors and/or underlying neurocircuitry at detectable levels relative to heavy drinking alone. Future studies should examine the potential long-term effects of combined alcohol and trauma on brain functioning.

The need for algorithms that capture subject-specific abnormalities (SSA) in neuroimaging data is increasingly recognized across many neuropsychiatric disorders. However, the effects of initial distributional properties (e.g., normal versus non-normally distributed data), sample size, and typical preprocessing steps (spatial normalization, blurring kernel and minimal cluster requirements) on SSA remain poorly understood. The current study evaluated the performance of several commonly used z-transform algorithms [leave-one-out (LOO); independent sample (IDS); Enhanced Z-score Microstructural Assessment of Pathology (EZ-MAP); distribution-corrected z-scores (DisCo-Z); and robust z-scores (ROB-Z)] for identifying SSA using simulated and diffusion tensor imaging data from healthy controls (N = 50). Results indicated that all methods (LOO, IDS, EZ-MAP and DisCo-Z) with the exception of the ROB-Z eliminated spurious differences that are present across artificially created groups following a standard z-transform. However, LOO and IDS consistently overestimated the true number of extrema (i.e., SSA) across all sample sizes and distributions. The EZ-MAP and DisCo-Z algorithms more accurately estimated extrema across most distributions and sample sizes, with the exception of skewed distributions. DTI results indicated that registration algorithm (linear versus non-linear) and blurring kernel size differentially affected the number of extrema in positive versus negative tails. Increasing the blurring kernel size increased the number of extrema, although this effect was much more prominent when a minimum cluster volume was applied to the data. In summary, current results highlight the need to statistically compare the frequency of SSA in control samples or to develop appropriate confidence intervals for patient data.

It has been known for decades that head motion/other artifacts affect the blood oxygen level-dependent signal. Recent recommendations predominantly focus on denoising resting state data, which may not apply to task data due to the different statistical relationships that exist between signal and noise sources. Several blind-source denoising strategies (FIX and AROMA) and more standard motion parameter (MP) regression (0, 12, or 24 parameters) analyses were therefore compared across four sets of event-related functional magnetic resonance imaging (erfMRI) and block-design (bdfMRI) datasets collected with multiband 32- (repetition time [TR] = 460 ms) or older 12-channel (TR = 2,000 ms) head coils. The amount of motion varied across coil designs and task types. Quality control plots indicated small to moderate relationships between head motion estimates and percent signal change in both signal and noise regions. Blind-source denoising strategies eliminated signal as well as noise relative to MP24 regression; however, the undesired effects on signal depended both on algorithm (FIX > AROMA) and design (bdfMRI > erfMRI). Moreover, in contrast to previous results, there were minimal differences between MP12/24 and MP0 pipelines in both erfMRI and bdfMRI designs. MP12/24 pipelines were detrimental for a task with both longer block length (30 ± 5 s) and higher correlations between head MPs and design matrix. In summary, current results suggest that there does not appear to be a single denoising approach that is appropriate for all fMRI designs. However, even nonaggressive blind-source denoising approaches appear to remove signal as well as noise from task-related data at individual subject and group levels.

Background Patients with psychotic spectrum disorders share overlapping clinical/biological features, making it often difficult to separate them into a discrete nosology (i.e., Diagnostic and Statistical Manual of Mental Disorders [DSM]). Methods The current study investigated whether a continuum classification scheme based on symptom burden would improve conceptualizations for cognitive and real-world dysfunction relative to traditional DSM nosology. Two independent samples (New Mexico [NM] and Bipolar and Schizophrenia Network on Intermediate Phenotypes [B-SNIP]) of patients with schizophrenia (NM: N = 93; B-SNIP: N = 236), bipolar disorder Type I (NM: N = 42; B-SNIP: N = 195) or schizoaffective disorder (NM: N = 15; B-SNIP: N = 148) and matched healthy controls (NM: N = 64; B-SNIP: N = 717) were examined. Linear regressions examined how variance differed as a function of classification scheme (DSM diagnosis, negative and positive symptom burden, or a three-cluster solution based on symptom burden). Results Symptom-based classification schemes (continuous and clustered) accounted for a significantly larger portion of captured variance of real-world functioning relative to DSM diagnoses across both samples. The symptom-based classification schemes accounted for large percentages of variance for general cognitive ability and cognitive domains in the NM sample. However, in the B-SNIP sample, symptom-based classification schemes accounted for roughly equivalent variance as DSM diagnoses. A potential mediating variable across samples was the strength of the relationship between negative symptoms and impaired cognition. Conclusions Current results support suggestions that a continuum perspective of psychopathology may be more powerful for explaining real-world functioning than the DSM diagnostic nosology, whereas results for cognitive dysfunction were sample dependent.

ObjectiveThe nosology for classifying structural MRI findings following pediatric mild traumatic brain injury (pmTBI) remains actively debated. Radiologic common data elements (rCDE) were developed to standardize reporting in research settings. However, some rCDE are more specific to trauma (probable rCDE). Other more recently proposed rCDE have multiple etiologies (possible rCDE), and may therefore be more common in all children. Independent cohorts of patients with pmTBI and controls were therefore recruited from multiple sites (New Mexico and Ohio) to test the dual hypothesis of a higher incidence of probable rCDE (pmTBI > controls) vs similar rates of possible rCDE on structural MRI.MethodsPatients with subacute pmTBI (n = 287), matched healthy controls (HC; n = 106), and orthopedically injured (OI; n = 71) patients underwent imaging approximately 1 week postinjury and were followed for 3–4 months.ResultsProbable rCDE were specific to pmTBI, occurring in 4%–5% of each sample, rates consistent with previous large-scale CT studies. In contrast, prevalence rates for incidental findings and possible rCDE were similar across groups (pmTBI vs OI vs HC). The prevalence of possible rCDE was also the only finding that varied as a function of site. Possible rCDE and incidental findings were not associated with postconcussive symptomatology or quality of life 3–4 months postinjury.ConclusionCollectively, current findings question the trauma-related specificity of certain rCDE, as well how these rCDE are radiologically interpreted. Refinement of rCDE in the context of pmTBI may be warranted, especially as diagnostic schema are evolving to stratify patients with structural MRI abnormalities as having a moderate injury.

While attentional bias modification therapy (ABMT) alters drug-related behaviors in some substance users, results have been mixed in individuals with cocaine use disorders (CUD). The current study examined whether ABMT affected brain functioning during independent measures of cue reactivity (i.e., cocaine versus food cues) and cognitive control (i.e., incongruent versus congruent trials), and whether brain activity was associated with baseline or post-intervention cocaine use. 37 participants (62% male) were randomly assigned to ABMT or control therapy. Clinical and neuroimaging assessments occurred at baseline and immediately post-intervention, with additional clinical testing at 2 weeks and 3 months following intervention. Cocaine use was assessed through self-report. Slower reaction times and increased functional activation (prefrontal cortex, posterior parietal cortex) were observed for incongruent versus congruent stimuli and increased functional activation for cocaine relative to food videos (ventral striatum, dorsolateral prefrontal cortex and orbitofrontal cortex). The default-mode network (DMN) was not deactivated during exposure to cocaine videos. The degree of activation during cocaine relative to food cues was associated with baseline cocaine use (insula only) and reduction in use following treatment (insula and anterior DMN) above and beyond clinical variables. Cognitive control network activity was not associated with cocaine use at baseline or following treatment. ABMT therapy did not differentially affect cocaine use or functional activation during either task. Current results suggest a relationship between cue reactivity network activation and cocaine use, but question the efficacy of ABMT in changing brain function during cue reactivity or cognitive control tasks.

Attentional bias (i.e., differences in reaction time between drug and neutral cues) has been associated with a variety of drug-use behaviors (e.g., craving, abstinence). Reduction of bias may ultimately reduce use.The current study examined whether attentional bias modification therapy (ABMT) reduced the frequency of drug use behaviors in individuals with cocaine use disorder (CUD).Participants (n = 37) were randomly assigned to ABMT or control therapy, which systematically varied how frequently probes replaced neutral (ABMT = 100%; control therapy = 50%) relative to drug stimuli. Each intervention included 5 training sessions comprising a total of 2640 trials over 4 weeks. Clinical assessments occurred at baseline, post-intervention, 2 weeks and 3 months posttreatment.There were no baseline differences between groups on drug-use behaviors or other clinical measures. Contrary to predictions, both groups exhibited slower rather than faster reaction times for cocaine stimuli (p = 0.005) at baseline, with no relationship between bias and baseline measures of drug-use behavior.ABMT was not more effective than our control therapy at reducing attentional bias, reducing craving or changing other drug use behaviors. Current results suggest additional replication studies are needed to assess ABMT's efficacy in reducing drug-use behaviors in CUD.

Although diffusion magnetic resonance imaging (dMRI) has been widely used to characterize the effects of repetitive mild traumatic brain injury (rmTBI), to date no studies have investigated how novel geometric models of microstructure relate to more typical diffusion tensor imaging (DTI) sequences. Moreover, few studies have evaluated the sensitivity of different registration pipelines (non-linear, linear and tract-based spatial statistics) for detecting dMRI abnormalities in clinical populations. Results from single-subject analyses in healthy controls (HC) indicated a strong negative relationship between fractional anisotropy (FA) and orientation dispersion index (ODI) in both white and gray matter. Equally important, only moderate relationships existed between all other estimates of free/intracellular water volume fractions and more traditional DTI metrics (FA, mean, axial and radial diffusivity). These findings suggest that geometric measures provide differential information about the cellular microstructure relative to traditional DTI measures. Results also suggest greater sensitivity for non-linear registration pipelines that maximize the anatomical information available in T1-weighted images. Clinically, rmTBI resulted in a pattern of decreased FA and increased ODI, largely overlapping in space, in conjunction with increased intracellular and free water fractions, highlighting the potential role of edema following repeated head trauma. In summary, current results suggest that geometric models of diffusion can provide relatively unique information regarding potential mechanisms of pathology that contribute to long-term neurological damage.

The neuroimaging community has seen a renewed interest in algorithms that provide a location-independent summary of subject-specific abnormalities (SSA) to assess individual lesion load. More recently, these methods have been extended to assess whether multiple individuals within the same cohort exhibit extrema in the same spatial location (e.g., voxel or region of interest). However, the statistical validity of this approach has not been rigorously established. The current study evaluated the potential for a spatial bias in the distribution of SSA using several common z-transformation algorithms (leave-one-out [LOO]; independent sample [IDS]; Enhanced Z-Score Microstructural Assessment of Pathology [EZ-MAP]; distribution-corrected z-scores [DisCo-Z]) using both simulated data and DTI data from 50 healthy controls. Results indicated that methods which z-transformed data based on statistical moments from a reference group (LOO, DisCo-Z) led to bias in the spatial location of extrema for the comparison group. In contrast, methods that z-transformed data using an independent third group (EZ-MAP, IDS) resulted in no spatial bias. Importantly, none of the methods exhibited bias when results were summed across all individual elements. The spatial bias is primarily driven by sampling error, in which differences in the mean and standard deviation of the untransformed data have a higher probability of producing extrema in the same spatial location for the comparison but not reference group. In conclusion, evaluating SSA overlap within cohorts should be either be avoided in deference to established group-wise comparisons or performed only when data is available from an independent third group.

The original version of this article contained mistakes in the article title, and the authors would like to correct them. The article title should be "Are there any differential responses to concussive injury in civilian versus athletic populations: a neuroimaging study".

The role of ventral versus dorsolateral prefrontal regions in instantiating proactive and reactive cognitive control remains actively debated, with few studies parsing cue versus probe-related activity. Rapid sampling (460 ms), long cue-probe delays, and advanced analytic techniques (deconvolution) were therefore used to quantify the magnitude and variability of neural responses during the AX Continuous Performance Test (AX-CPT; N = 46) in humans. Behavioral results indicated slower reaction times during reactive cognitive control (AY trials) in conjunction with decreased accuracy and increased variability for proactive cognitive control (BX trials). The anterior insula/ventrolateral prefrontal cortex (aI/VLPFC) was commonly activated across comparisons of both proactive and reactive cognitive control. In contrast, activity within the dorsomedial and dorsolateral prefrontal cortex was limited to reactive cognitive control. The instantiation of proactive cognitive control during the probe period was also associated with sparse neural activation relative to baseline, potentially as a result of the high degree of neural and behavioral variability observed across individuals. Specifically, the variability of the hemodynamic response function (HRF) within motor circuitry increased after the presentation of B relative to A cues (i.e., late in HRF) and persisted throughout the B probe period. Finally, increased activation of right aI/VLPFC during the cue period was associated with decreased motor circuit activity during BX probes, suggesting a possible role for the aI/VLPFC in proactive suppression of neural responses. Considered collectively, current results highlight the flexible role of the VLPFC in implementing cognitive control during the AX-CPT task but suggest large individual differences in proactive cognitive control strategies.

There is growing public concern about neurodegenerative changes (e.g., Chronic Traumatic Encephalopathy) that may occur chronically following clinically apparent and clinically silent (i.e., sub-concussive blows) pediatric mild traumatic brain injury (pmTBI). However, there are currently no biomarkers that clinicians can use to objectively diagnose patients or predict those who may struggle to recover. Non-invasive neuroimaging, electrophysiological and neuromodulation biomarkers have promise for providing evidence of the so-called "invisible wounds" of pmTBI. Our systematic review, however, belies that notion, identifying a relative paucity of high-quality, clinically impactful, diagnostic or prognostic biomarker studies in the sub-acute injury phase (36 studies on unique samples in 28 years), with the majority focusing on adolescent pmTBI. Ultimately, well-powered longitudinal studies with appropriate control groups, as well as standardized and clearly-defined inclusion criteria (time post-injury, injury severity and past history) are needed to truly understand the complex pathophysiology that is hypothesized (i.e., still needs to be determined) to exist during the acute and sub-acute stages of pmTBI and may underlie post-concussive symptoms.

Neurosensory abnormalities are frequently observed following pediatric mild traumatic brain injury (pmTBI) and may underlie the expression of several common concussion symptoms and delay recovery. Importantly, active evaluation of neurosensory functioning more closely approximates real-world (e.g., physical and academic) environments that provoke symptom worsening. The current study determined whether symptom provocation (i.e., during neurosensory examination) improved classification accuracy relative to pre-examination symptom levels and whether symptoms varied as a function of point of care. Eighty-one pmTBI were recruited from the pediatric emergency department (PED; n = 40) or outpatient concussion clinic (n = 41), along with matched (age, sex, and education) healthy controls (HC; n = 40). All participants completed a brief (∼ 12 min) standardized neurosensory examination and clinical questionnaires. The magnitude of symptom provocation upon neurosensory examination was significantly higher for concussion clinic than for PED patients. Symptom provocation significantly improved diagnostic classification accuracy relative to pre-examination symptom levels, although the magnitude of improvement was modest, and was greater in the concussion clinic. In contrast, PED patients exhibited worse performance on measures of balance, vision, and oculomotor functioning than the concussion clinic patients, with no differences observed between both samples and HC. Despite modest sample sizes, current findings suggest that point of care represents a critical but highly under-studied variable that may influence outcomes following pmTBI. Studies that rely on recruitment from a single point of care may not generalize to the entire pmTBI population in terms of how neurosensory deficits affect recovery.

Numerous questions surround the nature of reward processing in the developing adolescent brain, particularly in regard to polysubstance use. We therefore sought to examine incentive-elicited brain activation in the context of three common substances of abuse (cannabis, tobacco, and alcohol). Due to the role of the nucleus accumbens (NAcc) in incentive processing, we compared activation in this region during anticipation of reward and loss using a monetary incentive delay (MID) task. Adolescents (ages 14–18; 66% male) were matched on age, gender, and frequency of use of any common substances within six distinct groups: cannabis-only (n = 14), tobacco-only (n = 34), alcohol-only (n = 12), cannabis + tobacco (n = 17), cannabis + tobacco + alcohol (n = 17), and non-using controls (n = 38). All groups showed comparable behavioral performance on the MID task. The tobacco-only group showed decreased bilateral nucleus accumbens (NAcc) activation during reward anticipation as compared to the alcohol-only group, the control group, and both polysubstance groups. Interestingly, no differences emerged between the cannabis-only group and any of the other groups. Results from this study suggest that youth who tend toward single-substance tobacco use may possess behavioral and/or neurobiological characteristics that differentiate them from both their substance-using and non-substance-using peers.

Functional magnetic resonance imaging (fMRI) of the blood oxygen level dependent (BOLD) response has commonly been used to investigate the neuropathology underlying cognitive and sensory deficits in patients with schizophrenia (SP) by examining the positive phase of the BOLD response, assuming a fixed shape for the hemodynamic response function (HRF). However, the individual phases (positive and post-stimulus undershoot (PSU)) of the HRF may be differentially affected by a variety of underlying pathologies. The current experiment used a multisensory detection task with a rapid event-related fMRI paradigm to investigate both the positive and PSU phases of the HRF in SP and healthy controls (HC). Behavioral results indicated no significant group differences during task performance. Analyses that examined the shape of the HRF indicated two distinct group differences. First, SP exhibited a reduced and/or prolonged PSU following normal task-related positive BOLD activation in secondary auditory and visual sensory areas relative to HC. Second, SP did not show task-induced deactivation in the anterior node of the default-mode network (aDMN) relative to HC. In contrast, when performing traditional analyses that focus on the positive phase, there were no group differences. Interestingly, the magnitude of the PSU in secondary auditory and visual areas was positively associated with the magnitude of task-induced deactivation within the aDMN, suggesting a possible common neural mechanism underlying both of these abnormalities (failure in neural inhibition). Results are consistent with recent views that separate neural processes underlie the two phases of the HRF and that they are differentially affected in SP. Hum Brain Mapp 37:745-755, 2016. © 2015 Wiley Periodicals, Inc.

Despite studies showing the relevance of different decision-making abilities, including response inhibition, to likelihood of using substances during adolescence, few have examined these neural processes among high-risk, substance-using youth. The current study explored associations between alcohol and marijuana use and functional activation differences during Stroop performance among a large sample (N = 80) of ethnically-diverse, high-risk youth in an fMRI-based task. In the absence of associations between substance use and task behavioral performance, adolescents with greater alcohol use showed less activation during the more cognitively difficult portion of the task across clusters in bilateral cuneus and precuneus, and right and left superior temporal gyrus. No associations were observed with marijuana use. The current results may suggest neural patterns of deactivation in regions important for cognitive control, such that alcohol use may confer additional risk for future decreased inhibition among these high-risk adolescents. The ability to inhibit prepotent responses has been shown to predict later response to treatment, and early interventions to encourage further development of cognitive control could represent promising options for treatment.

Mild traumatic brain injury patients (mTBI) frequently report symptoms of increased distractability and sensory disturbances during mutisensory stimulation. These common post-concussive symptoms could putatively result from dysfunction within the cognitive control network (CCN; top-down) or from unisensory cortex (bottom-up) itself. Functional magnetic resonance imaging (fMRI) and high-resolution structural data were therefore prospectively collected during a multisensory (audio-visual) cognitive control task from 46 mTBI patients within 3 weeks of injury and 46 matched healthy controls (HC), with a subset of participants returning at 4 months. Multisensory stimuli were presented at two frequencies to manipulate cognitive and perceptual load. Patients self-reported more cognitive, emotional, somatic, vestibular and visual symptoms relative to HC, which improved, but did not entirely resolve, over the 4 month follow-up period. There were no group differences in behavior or functional activation during cognitive control (incongruent--congruent trials). In contrast, patients exhibited abnormal activation within different regions of visual cortex that depended on whether attention was focused on auditory or visual information streams. Patients also exhibited increased activation within bilateral inferior parietal lobules during higher cognitive/perceptual loads, suggesting a compensatory mechanism to achieve similar levels of behavioral performance. Functional abnormalities within the visual cortex and inferior parietal lobules were only partially resolved at 4 months post-injury, suggesting that neural abnormalities may take longer to resolve than behavioral measures used in most clinical settings. In summary, current results indicate that abnormalities within unisensory cortex (particularly visual areas) following mTBI, which likely contribute to deficits commonly reported during multisensory stimulation.

Algorithms that are capable of capturing subject-specific abnormalities (SSA) in neuroimaging data have long been an area of focus for diverse neuropsychiatric conditions such as multiple sclerosis, schizophrenia, and traumatic brain injury. Several algorithms have been proposed that define SSA in patients (i.e., comparison group) relative to image intensity levels derived from healthy controls (HC) (i.e., reference group) based on extreme values. However, the assumptions underlying these approaches have not always been fully validated, and may be dependent on the statistical distributions of the transformed data. The current study evaluated variations of two commonly used techniques ("pothole" method and standardization with an independent reference group) for identifying SSA using simulated data (derived from normal, t and chi-square distributions) and fractional anisotropy maps derived from 50 HC. Results indicated substantial group-wise bias in the estimation of extreme data points using the pothole method, with the degree of bias being inversely related to sample size. Statistical theory was utilized to develop a distribution-corrected z-score (DisCo-Z) threshold, with additional simulations demonstrating elimination of the bias and a more consistent estimation of extremes based on expected distributional properties. Data from previously published studies examining SSA in mild traumatic brain injury were then re-analyzed using the DisCo-Z method, with results confirming the evidence of group-wise bias. We conclude that the benefits of identifying SSA in neuropsychiatric research are substantial, but that proposed SSA approaches require careful implementation under the different distributional properties that characterize neuroimaging data.

Background Previous studies of response inhibition in patients with schizophrenia have focused on reactive inhibition tasks (e.g., stop-signal, go/no-go), primarily observing lateral prefrontal cortex abnormalities. However, recent studies suggest that purposeful and sustained (i.e., proactive) inhibition may also be affected in these patients. Methods Patients with chronic schizophrenia and healthy controls underwent fMRI while inhibiting motor responses during multisensory (audiovisual) stimulation. Resting state data were also collected. Results We included 37 patients with schizophrenia and 37 healthy controls in our study. Both controls and patients with schizophrenia successfully inhibited the majority of overt motor responses. Functional results indicated basic inhibitory failure in the lateral premotor and sensorimotor cortex, with opposing patterns of positive (schizophrenia) versus negative (control) activation. Abnormal activity was associated with independently assessed signs of psychomotor retardation. Patients with schizophrenia also exhibited unique activation of the pre-supplementary motor area (pre-SMA)/SMA and precuneus relative to baseline as well as a failure to deactivate anterior nodes of the default mode network. Independent resting-state connectivity analysis indicated reduced connectivity between anterior (task results) and posterior regions of the sensorimotor cortex for patients as well as abnormal connectivity between other regions (cerebellum, thalamus, posterior cingulate gyrus and visual cortex). Limitations Aside from rates of false-positive responses, true proactive response inhibition tasks do not provide behavioural metrics that can be independently used to quantify task performance. Conclusion Our results suggest that basic cortico-cortico and intracortical connections between the sensorimotor cortex and adjoining regions are impaired in patients with schizophrenia and that these impaired connections contribute to inhibitory failures (i.e., a positive rather than negative hemodynamic response).

Growing evidence suggests that temporally proximal acute concussions and repetitive subconcussive head injuries may lead to long-term neurological deficits. However, the underlying mechanisms of injury and their relative time-scales are not well documented in human injury models. The current study therefore investigated whether biomarkers of brain chemistry (magnetic resonance [MR] spectroscopy: N-acetylaspartate [NAA], combined glutamate and glutamine [Glx], total creatine [Cre], choline compounds [Cho], and myo-inositol [mI]) and structure (cortical thickness, white matter [WM]/subcortical volume) differed between mixed martial artists (MMA; n = 13) and matched healthy controls (HC) without a history of contact sport participation (HC; n = 14). A subset of participants (MMA = 9; HC = 10) returned for follow-up visits, with MMA (n = 3) with clinician-documented acute concussions also scanned serially. As expected, MMA self-reported a higher incidence of previous concussions and significantly more cognitive symptoms during prior concussion recovery. Fighters also exhibited reduced memory and processing speed relative to controls on neuropsychological testing coupled with cortical thinning in the left posterior cingulate gyrus and right occipital cortex at baseline assessment. Over a 1-year follow-up period, MMA experienced a significant decrease in both WM volume and NAA concentration, as well as relative thinning in the left middle and superior frontal gyri. These longitudinal changes did not correlate with self-reported metrics of injury (i.e., fight diary). In contrast, HC did not exhibit significant longitudinal changes over a 4-month follow-up period (p 0.05). Collectively, current results provide preliminary evidence of progressive changes in brain chemistry and structure over a relatively short time period in individuals with high exposure to repetitive head hits. These findings require replication in independent samples.

Mild traumatic brain injury patients (mTBI) frequently report symptoms of increased distractability and sensory disturbances during mutisensory stimulation. These common post-concussive symptoms could putatively result from dysfunction within the cognitive control network (CCN; top-down) or from unisensory cortex (bottom-up) itself. Functional magnetic resonance imaging (fMRI) and high-resolution structural data were therefore prospectively collected during a multisensory (audio-visual) cognitive control task from 46 mTBI patients within 3 weeks of injury and 46 matched healthy controls (HC), with a subset of participants returning at 4 months. Multisensory stimuli were presented at two frequencies to manipulate cognitive and perceptual load. Patients self-reported more cognitive, emotional, somatic, vestibular and visual symptoms relative to HC, which improved, but did not entirely resolve, over the 4 month follow-up period. There were no group differences in behavior or functional activation during cognitive control (incongruent – congruent trials). In contrast, patients exhibited abnormal activation within different regions of visual cortex that depended on whether attention was focused on auditory or visual information streams. Patients also exhibited increased activation within bilateral inferior parietal lobules during higher cognitive/perceptual loads, suggesting a compensatory mechanism to achieve similar levels of behavioral performance. Functional abnormalities within the visual cortex and inferior parietal lobules were only partially resolved at 4 months post-injury, suggesting that neural abnormalities may take longer to resolve than behavioral measures used in most clinical settings. In summary, current results indicate that abnormalities within unisensory cortex (particularly visual areas) following mTBI, which likely contribute to deficits commonly reported during multisensory stimulation.

Background Treatment of urgency urinary incontinence has focused on pharmacologically treating detrusor overactivity. Recent recognition that altered perception of internal stimuli (interoception) plays a role in urgency urinary incontinence suggests that exploration of abnormalities of brain function in this disorder could lead to better understanding of urgency incontinence and its treatment. Objective We sought to: (1) evaluate the relationship between bladder filling, perceived urgency, and activation at brain sites within the interoceptive network in urgency urinary incontinence; (2) identify coactivation of other brain networks that could affect interoception during bladder filling in urgency incontinence; and (3) demonstrate interaction between these sites prior to bladder filling by evaluating their resting-state connectivity. Study Design We performed an observational cohort study using functional magnetic resonance imaging to compare brain function in 53 women with urgency urinary incontinence and 20 controls. Whole-brain voxelwise analyses of covariance were performed to examine differences in functional brain activation between groups during a task consisting of bladder filling, hold (static volume), and withdrawal phases. The task was performed at 3 previously established levels of baseline bladder volume, the highest exceeding strong desire to void volume. All women continuously rated their urge on a 0- to 10-point Likert scale throughout the task and a mixed measures analysis of variance was used to test for differences in urge ratings. Empirically derived regions of interest from analysis of activation during the task were used as seeds for examining group differences in resting-state functional connectivity. Results In both urgency urinary incontinent participants and controls, changes in urge ratings were greatest during bladder filling initiated from a high baseline bladder volume and urgency incontinent participants' rating changes were greater than controls. During this bladder-filling phase urgency incontinent participant's activation of the interoceptive network was greater than controls, including in the left insula and the anterior and middle cingulate cortex. Urgency incontinent participant's activation was also greater than controls at sites in the ventral attention network and posterior default mode network. Urgency incontinent participant's connectivity was greater than controls between a middle cingulate seed point and the dorsal attention network, a "top-down" attentional network. Control connectivity was greater between the midcingulate seed point and the ventral attention network, a "bottom-up" attentional network. Conclusion Increasing urge was associated with greater urgency incontinent participant than control activation of the interoceptive network and activation in networks that are determinants of self-awareness (default mode network) and of response to unexpected external stimuli (ventral attention network). Differences in connectivity between interoceptive networks and opposing attentional networks (ventral attention network vs dorsal attention network) were present even before bladder filling (in the resting state). These findings are strong evidence for a central nervous system component of urgency urinary incontinence that could be mediated by brain-directed therapies.

Parsing multisensory information from a complex external environment is a fundamental skill for all organisms. However, different organizational schemes currently exist for how multisensory information is processed in human (supramodal; organized by cognitive demands) versus primate (organized by modality/cognitive demands) lateral prefrontal cortex (LPFC). Functional magnetic resonance imaging results from a large cohort of healthy controls (N = 64; Experiment 1) revealed a rostral-caudal stratification of LPFC for auditory versus visual attention during an audio-visual Stroop task. The stratification existed in spite of behavioral and functional evidence of increased interference from visual distractors. Increased functional connectivity was also observed between rostral LPFC and auditory cortex across independent samples (Experiments 2 and 3) and multiple methodologies. In contrast, the caudal LPFC was preferentially activated during visual attention but functioned in a supramodal capacity for resolving multisensory conflict. The caudal LPFC also did not exhibit increased connectivity with visual cortices. Collectively, these findings closely mirror previous nonhuman primate studies suggesting that visual attention relies on flexible use of a supramodal cognitive control network in caudal LPFC whereas rostral LPFC is specialized for directing attention to auditory inputs (i.e., human auditory fields).