A Transdiagnostic, Hierarchical Taxonomy of Psychopathology Following Traumatic Brain Injury (HiTOP-TBI).

Psychopathology, including depression, anxiety, and post-traumatic stress, is a significant yet inadequately addressed feature of moderate-severe traumatic brain injury (TBI). Progress in understanding and treating post-TBI psychopathology may be hindered by limitations associated with conventional diagnostic approaches, specifically the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). The Hierarchical Taxonomy of Psychopathology (HiTOP) offers a promising, transdiagnostic alternative to psychiatric classification that may more effectively capture the experiences of individuals with TBI. However, HiTOP lacks validation in the TBI population. To address this gap, we administered a comprehensive questionnaire battery, including 56 scales assessing homogeneous symptom components and maladaptive traits within HiTOP, to 410 individuals with moderate-severe TBI. We evaluated the reliability and unidimensionality of each scale and revised those with psychometric problems. Using a top-down, exploratory latent variable approach (bass-ackwards modeling), we subsequently constructed a hierarchical model of psychopathological dimensions tailored to TBI. The results showed that, relative to norms, participants with moderate-severe TBI experienced greater problems in the established HiTOP internalizing and detachment spectra, but fewer problems with thought disorder and antagonism. Fourteen of the 56 scales demonstrated psychometric problems, which often appeared reflective of the TBI experience and associated disability. The Hierarchical Taxonomy of Psychopathology Following Traumatic Brain Injury (HiTOP-TBI) model encompassed broad internalizing and externalizing spectra, splitting into seven narrower dimensions: Detachment, Dysregulated Negative Emotionality, Somatic Symptoms, Compensatory and Phobic Reactions, Self-Harm and Psychoticism, Rigid Constraint, and Harmful Substance Use. This study presents the most comprehensive empirical classification of psychopathology after TBI to date. It introduces a novel, TBI-specific transdiagnostic questionnaire battery and model, which addresses the limitations of conventional DSM and ICD diagnoses. The empirical structure of psychopathology after TBI largely aligned with the established HiTOP model (e.g., a detachment spectrum). However, these constructs need to be interpreted in relation to the unique experiences associated with TBI (e.g., considering the injury's impact on the person's social functioning). By overcoming the limitations of conventional diagnostic approaches, the HiTOP-TBI model has the potential to accelerate our understanding of the causes, correlates, consequences, and treatment of psychopathology after TBI.

Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365-377.

Biomarkers of Neurobiologic Recovery in Adults With Sport-Related Concussion.

Importance: Sport-related concussion (SRC), a form of mild traumatic brain injury, is a prevalent occurrence in collision sports. There are no well-established approaches for tracking neurobiologic recovery after SRC. Objective: To examine the levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in Australian football athletes who experience SRC. Design, Setting, and Participants: A cohort study recruiting from April 10, 2021, to September 17, 2022, was conducted through the Victorian Amateur Football Association, Melbourne, Australia. Participants included adult Australian football players with or without SRC. Data analysis was performed from May 26, 2023, to March 27, 2024. Exposure: Sport-related concussion, defined as at least 1 observable sign and/or 2 or more symptoms. Main Outcomes and Measures: Primary outcomes were serum GFAP and NfL levels at 24 hours, and 1, 2, 4, 6, 8, 12, and 26 weeks. Secondary outcomes were symptoms, cognitive performance, and return to training times. Results: Eighty-one individuals with SRC (median age, 22.8 [IQR, 21.3-26.0] years; 89% male) and 56 control individuals (median age, 24.6 [IQR, 22.4-27.3] years; 96% male) completed a total of 945 of 1057 eligible testing sessions. Compared with control participants, those with SRC exhibited higher GFAP levels at 24 hours (mean difference [MD] in natural log, pg/mL, 0.66 [95% CI, 0.50-0.82]) and 4 weeks (MD, 0.17 [95% CI, 0.02-0.32]), and NfL from 1 to 12 weeks (1-week MD, 0.31 [95% CI, 0.12-0.51]; 2-week MD, 0.38 [95% CI, 0.19-0.58]; 4-week MD, 0.31 [95% CI, 0.12-0.51]; 6-week MD, 0.27 [95% CI, 0.07-0.47]; 8-week MD, 0.36 [95% CI, 0.15-0.56]; and 12-week MD, 0.25 [95% CI, 0.04-0.46]). Growth mixture modeling identified 2 GFAP subgroups: extreme prolonged (16%) and moderate transient (84%). For NfL, 3 subgroups were identified: extreme prolonged (7%), moderate prolonged (15%), and minimal or no change (78%). Individuals with SRC who reported loss of consciousness (LOC) (33% of SRC cases) had higher GFAP at 24 hours (MD, 1.01 [95% CI, 0.77-1.24]), 1 week (MD, 0.27 [95% CI, 0.06-0.49]), 2 weeks (MD, 0.21 [95% CI, 0.004-0.42]) and 4 weeks (MD, 0.34 [95% CI, 0.13-0.55]), and higher NfL from 1 week to 12 weeks (1-week MD, 0.73 [95% CI, 0.42-1.03]; 2-week MD, 0.91 [95% CI, 0.61-1.21]; 4-week MD, 0.90 [95% CI, 0.59-1.20]; 6-week MD, 0.81 [95% CI, 0.50-1.13]; 8-week MD, 0.73 [95% CI, 0.42-1.04]; and 12-week MD, 0.54 [95% CI, 0.22-0.85]) compared with SRC participants without LOC. Return to training times were longer in the GFAP extreme compared with moderate subgroup (incident rate ratio [IRR], 1.99 [95% CI, 1.69-2.34]; NfL extreme (IRR, 3.24 [95% CI, 2.63-3.97]) and moderate (IRR, 1.43 [95% CI, 1.18-1.72]) subgroups compared with the minimal subgroup, and for individuals with LOC compared with those without LOC (IRR, 1.65 [95% CI, 1.41-1.93]). Conclusions and Relevance: In this cohort study, a subset of SRC cases, particularly those with LOC, showed heightened and prolonged increases in GFAP and NfL levels, that persisted for at least 4 weeks. These findings suggest that serial biomarker measurement could identify such cases, guiding return to play decisions based on neurobiologic recovery. While further investigation is warranted, the association between prolonged biomarker elevations and LOC may support the use of more conservative return to play timelines for athletes with this clinical feature.

Mental and Physical Health Comorbidities in Traumatic Brain Injury: A Non-TBI Controls Comparison.

OBJECTIVE: To examine whether aging with a TBI was associated with a greater burden of health-related comorbidities compared with a non-TBI control cohort and examine the associations between comorbidity burden, emotional outcomes, and health-related quality of life (HRQoL) after TBI across ages. DESIGN: Cross-sectional. SETTING: Research center or telephone. PARTICIPANTS: The study included 559 participants (NTBI=291, NControls=268). Participants with TBI were recruited during inpatient rehabilitation and had sustained a moderate-severe TBI 1-33 years previously. Non-TBI controls were a convenience sample recruited through advertisements in the community. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The number of cardiovascular, general physical health, and mental health comorbidities was compared between cohorts and age strata using Poisson regression. The relationships between comorbidities, age, emotional outcomes (Generalized Anxiety Disorder Scale-7, Patient Health Questionnaire-9), and HRQoL (PROMIS Global Health Measure) were examined with linear regression. Distinct subgroups of comorbidities were identified using latent class analysis. Associations between comorbidity classes with demographic and outcome variables were evaluated using multinomial logistic and linear regressions, respectively. RESULTS: TBI participants had a significantly higher comorbidity burden than controls, primarily driven by elevated rates of mental health disorders (RR=2.71, 95% confidence interval [1.37, 5.35]). Cardiovascular and physical health comorbidities were not elevated in the TBI group compared with controls. Both cohorts had 3 similar comorbidity subgroups, suggesting consistent patterns of co-occurring health conditions regardless of TBI exposure. Physical and mental health comorbidities were associated with elevated depression and anxiety symptoms and diminished HRQoL after TBI compared with controls. CONCLUSION: TBI was associated with greater mental, but not physical, health comorbidities in the decades after injury. However, physical and mental health comorbidities significantly affected emotional and HRQoL status after TBI, underscoring a greater need for long-term support for individuals with TBI coping with both physical and mental health comorbidities.

Investigating the Association Between Extended Participation in Collision Sports and Fluid Biomarkers Among Masters Athletes.

Traumatic brain injuries (TBIs) and concussions are prevalent in collision sports, and there is evidence that levels of exposure to such sports may increase the risk of neurological abnormalities. Elevated levels of fluid-based biomarkers have been observed after concussions or among athletes with a history of participating in collision sports, and certain biomarkers exhibit sensitivity toward neurodegeneration. This study investigated a cohort of 28 male amateur athletes competing in "Masters" competitions for persons >35 years of age. The primary objective of this study was to compare the levels of blood and saliva biomarkers associated with brain injury, inflammation, aging, and neurodegeneration between athletes with an extensive history of collision sport participation (i.e., median = 27 years; interquartile range = 18-44, minimum = 8) and those with no history. Plasma proteins associated with neural damage and neurodegeneration were measured using Simoa® assays, and saliva was analyzed for markers associated with inflammation and telomere length using quantitative real-time polymerase chain reaction. There were no significant differences between collision and non-collision sport athletes for plasma levels of glial fibrillary acidic protein, neurofilament light, ubiquitin C-terminal hydrolase L1, tau, tau phosphorylated at threonine 181, and brain-derived neurotrophic factor. Moreover, salivary levels of genes associated with inflammation and telomere length were similar between groups. There were no significant differences between groups in symptom frequency or severity on the Sport Concussion Assessment Tool-5th Edition. Overall, these findings provide preliminary evidence that biomarkers associated with neural tissue damage, neurodegeneration, and inflammation may not exhibit significant alterations in asymptomatic amateur athletes with an extensive history of amateur collision sport participation.

Neurodesk: an accessible, flexible and portable data analysis environment for reproducible neuroimaging.

Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source Neurodesk platform ( https://www.neurodesk.org/ ) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud.

Altered grey matter structural covariance in chronic moderate-severe traumatic brain injury.

Traumatic brain injury (TBI) alters brain network connectivity. Structural covariance networks (SCNs) reflect morphological covariation between brain regions. SCNs may elucidate how altered brain network topology in TBI influences long-term outcomes. Here, we assessed whether SCN organisation is altered in individuals with chronic moderate-severe TBI (≥ 10 years post-injury) and associations with cognitive performance. This case-control study included fifty individuals with chronic moderate-severe TBI compared to 75 healthy controls recruited from an ongoing longitudinal head injury outcome study. SCNs were constructed using grey matter volume measurements from T1-weighted MRI images. Global and regional SCN organisation in relation to group membership and cognitive ability was examined using regression analyses. Globally, TBI participants had reduced small-worldness, longer characteristic path length, higher clustering, and higher modularity globally (p < 0.05). Regionally, TBI participants had greater betweenness centrality (p < 0.05) in frontal and central areas of the cortex. No significant associations were observed between global network measures and cognitive ability in participants with TBI (p > 0.05). Chronic moderate-severe TBI was associated with a shift towards a more segregated global network topology and altered organisation in frontal and central brain regions. There was no evidence that SCNs are associated with cognition.

The utility of the Cognitive Reserve Index questionnaire in chronic traumatic brain injury.

Objective: This study examined the relationship between cognitive reserve measured with the Cognitive Reserve Index questionnaire (CRIq) and cognitive and functional outcomes in a chronic traumatic brain injury (TBI) cohort compared to a non-TBI cohort. The utility of the CRIq was compared to common proxies of cognitive reserve (premorbid IQ and years of education) in TBI and non-TBI cohorts. Method: Participants were 105 individuals with moderate-severe TBI (10-33 years post injury) and 91 participants without TBI. Cognitive outcome was examined across four cognitive factors; verbal memory, visual ability and memory, executive attention, and episodic memory. Functional outcome was measured using the Glasgow Outcome Scale Extended. The CRIq total score and three subscale scores (education, work, leisure) were examined. Results: In the TBI cohort, associations were identified between two CRIq subscales and cognitive factors (CRIq education and verbal memory; CRIq work and executive attention). There were no associations between CRIq leisure and cognitive outcomes, or between CRIq and functional outcome. Model selection statistics suggested premorbid IQ and years of education provided a better fit than the CRIq for the relationship between cognitive reserve with two cognitive factors and functional outcome, with neither model providing an improved fit for the remaining two cognitive factors. This finding was broadly consistent in the non-TBI cohort. Conclusion: Cognitive reserve contributes significantly to long-term clinical outcomes following moderate-severe TBI. The relationship between cognitive reserve and long-term cognitive and functional outcomes following TBI is best characterised with traditional proxies of cognitive reserve, mainly premorbid IQ, rather than the CRIq.

Utility of Acute and Subacute Blood Biomarkers to Assist Diagnosis in CT-Negative Isolated Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have recently been Food and Drug Administration approved as predictors of intracranial lesions on CT after mild traumatic brain injury (mTBI). However, most cases with mTBI are CT negative, and no biomarkers are approved to assist diagnosis in these individuals. In this study, we aimed to determine the optimal combination of blood biomarkers to assist mTBI diagnosis in otherwise healthy adults younger than 50 years presenting to an emergency department within 6 hours of injury. To further understand the utility of biomarkers, we assessed how biological sex, presence or absence of loss of consciousness and/or post-traumatic amnesia (LOC/PTA), and delayed presentation affected classification performance. METHODS: Blood samples, symptom questionnaires, and cognitive tests were prospectively conducted for participants with mTBI recruited from The Alfred Hospital Level 1 Emergency & Trauma Center and uninjured controls. Follow-up testing was conducted at 7 days. Simoa quantified plasma GFAP, UCH-L1, tau, neurofilament light chain (NfL), interleukin (IL)-6, and IL-1ß. Area under the receiver operating characteristic (AUC) analysis assessed classification accuracy for diagnosed mTBI, and logistic regression models identified optimal biomarker combinations. RESULTS: Plasma IL-6 (AUC 0.91, 95% CI 0.86-0.96), GFAP (AUC 0.85, 95% CI 0.78-0.93), and UCH-L1 (AUC 0.79, 95% CI 0.70-0.88) best differentiated mTBI (n = 74) from controls (n = 44) acutely (<6 hours), with NfL (AUC 0.81, 95% CI 0.72-0.90) the only marker to have such utility subacutely (7 days). Biomarker performance was similar between sexes and for participants with and without LOC/PTA, with the exception at 7 days, where GFAP and IL-6 retained some utility in female participants (GFAP: AUC 0.71, 95% CI 0.55-0.88; IL-6: AUC 0.71, 95% CI 0.55-0.87) and in those with LOC/PTA (GFAP: AUC 0.73, 95% CI 0.59-0.86; IL-6: AUC 0.71, 95% CI 0.57-0.84). Acute IL-6 (R 2 = 0.50, 95% CI 0.34-0.64) outperformed GFAP and UCH-L1 combined (R 2 = 0.35, 95% CI 0.17-0.50), with the best acute model featuring GFAP and IL-6 (R 2 = 0.54, 95% CI 0.34-0.68). DISCUSSION: These findings indicate that adding IL-6 to a panel of brain-specific proteins such as GFAP and UCH-L1 might assist in the acute diagnosis of mTBI in adults younger than 50 years. Multiple markers had high classification accuracy in participants without LOC/PTA. When compared with the best-performing acute markers, subacute measures of plasma NfL resulted in minimal reduction in classification accuracy. Future studies will investigate the optimal time frame over which plasma IL-6 might assist diagnostic decisions and how extracranial trauma affects utility.

Reduced total number of enlarged perivascular spaces in post-traumatic epilepsy patients with unilateral lesions - a feasibility study.

BACKGROUND: We investigated the value of automated enlarged perivascular spaces (ePVS) quantification to distinguish chronic traumatic brain injury (TBI) patients with post-traumatic epilepsy (PTE+) from chronic TBI patients without PTE (PTE-) in a feasibility study. METHODS: Patients with and without PTE were recruited and underwent an MRI post-TBI. Multimodal auto identification of ePVS algorithm was applied to T1-weighted MRIs to segment ePVS. The total number of ePVS was calculated and corrected for white matter volume, and an asymmetry index (AI) derived. RESULTS: PTE was diagnosed in 7 out of the 99 participants (male=69) after a median time of less than one year since injury (range 10-22). Brain lesions were observed in all 7 PTE+ cases (unilateral=4, 57%; bilateral=3, 43%) as compared to 40 PTE- cases (total 44%; unilateral=17, 42%; bilateral=23, 58%). There was a significant difference between PTE+ (M=1.21e-4, IQR [8.89e-5]) and PTE- cases (M=2.79e-4, IQR [6.25e-5]) in total corrected numbers of ePVS in patients with unilateral lesions (p=0.024). No differences in AI, trauma severity and lesion volume were seen between groups. CONCLUSION: This study has shown that automated quantification of ePVS is feasible and provided initial evidence that individuals with PTE with unilateral lesions may have fewer ePVS compared to TBI patients without epilepsy. Further studies with larger sample sizes should be conducted to determine the value of ePVS quantification as a PTE-biomarker.

Transdiagnostic MRI markers of psychopathology following traumatic brain injury: a systematic review and network meta-analysis protocol.

INTRODUCTION: Psychopathology following traumatic brain injury (TBI) is a common and debilitating consequence that is often associated with reduced functional and psychosocial outcomes. There is a lack of evidence regarding the neural underpinnings of psychopathology following TBI, and whether there may be transdiagnostic neural markers that are shared across traditional psychiatric diagnoses. The aim of this systematic review and meta-analysis is to examine the association of MRI-derived markers of brain structure and function with both transdiagnostic and specific psychopathology following moderate-severe TBI. METHODS AND ANALYSIS: A systematic literature search of Embase (1974-2022), Ovid MEDLINE (1946-2022) and PsycINFO (1806-2022) will be conducted. Publications in English that investigate MRI correlates of psychopathology characterised by formal diagnoses or symptoms of psychopathology in closed moderate-severe TBI populations over 16 years of age will be included. Publications will be excluded that: (a) evaluate non-MRI neuroimaging techniques (CT, positron emission tomography, magnetoencephalography, electroencephalogram); (b) comprise primarily a paediatric cohort; (c) comprise primarily penetrating TBI. Eligible studies will be assessed against a modified Joanna Briggs Institute Critical Appraisal Instrument and data will be extracted by two independent reviewers. A descriptive analysis of MRI findings will be provided based on qualitative synthesis of data extracted. Quantitative analyses will include a meta-analysis and a network meta-analysis where there are sufficient data available. ETHICS AND DISSEMINATION: Ethics approval is not required for the present study as there will be no original data collected. We intend to disseminate the results through publication to a high-quality peer-reviewed journal and conference presentations on completion. PROSPERO REGISTRATION NUMBER: CRD42022358358.

Acute effects of single and repeated mild traumatic brain injury on levels of neurometabolites, lipids, and mitochondrial function in male rats.

Introduction: Mild traumatic brain injuries (mTBIs) are the most common form of acquired brain injury. Symptoms of mTBI are thought to be associated with a neuropathological cascade, potentially involving the dysregulation of neurometabolites, lipids, and mitochondrial bioenergetics. Such alterations may play a role in the period of enhanced vulnerability that occurs after mTBI, such that a second mTBI will exacerbate neuropathology. However, it is unclear whether mTBI-induced alterations in neurometabolites and lipids that are involved in energy metabolism and other important cellular functions are exacerbated by repeat mTBI, and if such alterations are associated with mitochondrial dysfunction. Methods: In this experiment, using a well-established awake-closed head injury (ACHI) paradigm to model mTBI, male rats were subjected to a single injury, or five injuries delivered 1 day apart, and injuries were confirmed with a beam-walk task and a video observation protocol. Abundance of several neurometabolites was evaluated 24 h post-final injury in the ipsilateral and contralateral hippocampus using in vivo proton magnetic resonance spectroscopy (1H-MRS), and mitochondrial bioenergetics were evaluated 30 h post-final injury, or at 24 h in place of 1H-MRS, in the rostral half of the ipsilateral hippocampus. Lipidomic evaluations were conducted in the ipsilateral hippocampus and cortex. Results: We found that behavioral deficits in the beam task persisted 1- and 4 h after the final injury in rats that received repetitive mTBIs, and this was paralleled by an increase and decrease in hippocampal glutamine and glucose, respectively, whereas a single mTBI had no effect on sensorimotor and metabolic measurements. No group differences were observed in lipid levels and mitochondrial bioenergetics in the hippocampus, although some lipids were altered in the cortex after repeated mTBI. Discussion: The decrease in performance in sensorimotor tests and the presence of more neurometabolic and lipidomic abnormalities, after repeated but not singular mTBI, indicates that multiple concussions in short succession can have cumulative effects. Further preclinical research efforts are required to understand the underlying mechanisms that drive these alterations to establish biomarkers and inform treatment strategies to improve patient outcomes.

Network analysis of anxiety and depressive symptoms one year after traumatic brain injury.

We used network analysis to explore interrelationships between anxiety and depressive symptoms after traumatic brain injury (TBI). At one year post-injury, 882 adult civilians who received inpatient rehabilitation for moderate-severe TBI self-reported anxiety and depressive symptoms (Hospital Anxiety and Depression Scale). The severity of TBI was characterized acutely by the duration of post-traumatic amnesia (PTA), and TBI-related functional disability was rated by an examiner at one year post-injury using a structured interview (Glasgow Outcome Scale - Extended). We estimated two cross-sectional, partial correlation networks. In the first network, anxiety and depressive symptoms were densely interconnected yet formed three distinct, data-driven communities: Hyperarousal, Depression, and General Distress. Worrying thoughts and having difficulty relaxing were amongst the most central symptoms, showing strong connections with other symptoms within and between communities. In the second network, TBI severity was directly negatively associated with hyperarousal symptoms but indirectly positively associated with depressive symptoms via greater functional disability. The results highlight the potential utility of simultaneous, transdiagnostic assessment and treatment of anxiety and depressive symptoms after moderate-severe TBI. Worrying thoughts, having difficulty relaxing, and the experience of disability may be important targets for treatment, although future studies examining symptom dynamics within individuals and over time are required.

Traumatic brain injury alters the relationship between brain structure and episodic memory.

BACKGROUND: Focal and diffuse pathology resulting from traumatic brain injury (TBI) often disrupts brain circuitry that is critical for episodic memory, including medial temporal lobe and prefrontal regions. Prior studies have focused on unitary accounts of temporal lobe function, associating verbally learned material and brain morphology. Medial temporal lobe structures, however, are domain-sensitive, preferentially supporting different visual stimuli. There has been little consideration of whether TBI preferentially disrupts the type of visually learned material and its association with cortical morphology following injury. Here, we investigated whether (1) episodic memory deficits differ according to the stimulus type, and (2) the pattern in memory performance can be linked to changes in cortical thickness. METHODS: Forty-three individuals with moderate-severe TBI and 38 demographically similar healthy controls completed a recognition task in which memory was assessed for three categories of stimuli: faces, scenes, and animals. The association between episodic memory accuracy on this task and cortical thickness was subsequently examined within and between groups. RESULTS: Our behavioral results support the notion of category-specific impairments: the TBI group had significantly impaired accuracy for memory for faces and scenes, but not animals. Moreover, the association between cortical thickness and behavioral performance was only significant for faces between groups. CONCLUSION: Taken together, these behavioral and structural findings provide support for an emergent memory account, and highlight that cortical thickness differentially affects episodic memory for specific categories of stimuli.

Bifactor analysis of the Hospital Anxiety and Depression Scale (HADS) in individuals with traumatic brain injury.

Anxiety and depression symptoms are commonly experienced after traumatic brain injury (TBI). However, studies validating measures of anxiety and depression for this population are scarce. Using novel indices derived from symmetrical bifactor modeling, we evaluated whether the Hospital Anxiety and Depression Scale (HADS) reliably differentiated anxiety and depression in 874 adults with moderate-severe TBI. The results showed that there was a dominant general distress factor accounting for 84% of the systematic variance in HADS total scores. The specific anxiety and depression factors accounted for little residual variance in the respective subscale scores (12% and 20%, respectively), and overall, minimal bias was found in using the HADS as a unidimensional measure. Further, in a subsample of 184 participants, the HADS subscales did not clearly discriminate between formal anxiety and depressive disorders diagnosed via clinical interview. Results were consistent when accounting for degree of disability, non-English speaking background, and time post-injury. In conclusion, variance in HADS scores after TBI predominately reflects a single underlying latent variable. Clinicians and researchers should exercise caution in interpreting the individual HADS subscales and instead consider using the total score as a more valid, transdiagnostic measure of general distress in individuals with TBI.

Associations of Enlarged Perivascular Spaces With Brain Lesions, Brain Age, and Clinical Outcomes in Chronic Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Enlarged perivascular spaces (ePVS) have been identified as a key signature of glymphatic system dysfunction in neurologic conditions. The incidence and clinical implications of ePVS after traumatic brain injury (TBI) are not yet understood. We investigated whether individuals with chronic moderate-to-severe TBI had an increased burden of ePVS and whether ePVS burden is modulated by the presence of focal lesions, older brain age, and poorer sleep quality. We examined whether an increased burden of ePVS was associated with poorer cognitive and emotional outcomes. METHODS: Using a cross-sectional design, participants with a single moderate-to-severe chronic TBI (sustained ≥10 years ago) were recruited from an inpatient rehabilitation program. Control participants were recruited from the community. Participants underwent 3T brain MRI, neuropsychological assessment, and clinical evaluations. ePVS burden in white matter was quantified using automated segmentation. The relationship between the number of ePVS, group membership, focal lesions, brain age, current sleep quality, and outcome was modeled using negative binomial and linear regressions. RESULTS: This study included 100 participants with TBI (70% male; mean age = 56.8 years) and 75 control participants (54.3% male; mean age = 59.8 years). The TBI group had a significantly greater burden of ePVS (prevalence ratio rate [PRR] = 1.29, p = 0.013, 95% CI 1.05-1.57). The presence of bilateral lesions was associated with greater ePVS burden (PRR = 1.41, p = 0.021, 95% CI 1.05-1.90). There was no association between ePVS burden, sleep quality (PRR = 1.01, p = 0.491, 95% CI 0.98-1.048), and sleep duration (PRR = 1.03, p = 0.556, 95% CI 0.92-1.16). ePVS was associated with verbal memory (ß = -0.42, p = 0.006, 95% CI -0.72 to -0.12), but not with other cognitive domains. The burden of ePVS was not associated with emotional distress (ß = -0.70, p = 0.461, 95% CI -2.57 to 1.17) or brain age (PRR = 1.00, p = 0.665, 95% CI 0.99-1.02). DISCUSSION: TBI is associated with a greater burden of ePVS, especially when there have been bilateral brain lesions. ePVS was associated with reduced verbal memory performance. ePVS may indicate ongoing impairments in glymphatic system function in the chronic postinjury period.

5-HT4 Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action.

BACKGROUND: Cognitive deficits are often comorbid with mood disorders and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT4 receptor agonists show promise as potential procognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting-state neural networks. However, so far the effect of 5-HT4 receptor agonism on resting-state functional connectivity (rsFC) in the brain in humans is unknown. METHODS: We collected resting-state functional magnetic resonance imaging scans from 50 healthy volunteers, of whom 25 received 6 days × 1 mg prucalopride (a highly selective 5-HT4 receptor agonist) and 25 received placebo in a randomized double-blind design. RESULTS: Network analyses identified that participants in the prucalopride group had enhanced rsFC between the central executive network and the posterior/anterior cingulate cortex. Seed analyses also showed greater rsFC between the left and right rostral anterior cingulate cortex and the left lateral occipital cortex, and reduced rsFC between the hippocampus and other default mode network regions. CONCLUSIONS: Similar to other potentially procognitive medications, low-dose prucalopride in healthy volunteers appeared to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the default mode network. This suggests a mechanism for the behavioral cognitive enhancement previously seen with 5-HT4 receptor agonists in humans and supports the potential for 5-HT4 receptor agonists to be used in clinical psychiatric populations.

Neurodesk: An accessible, flexible, and portable data analysis environment for reproducible neuroimaging.

Neuroimaging data analysis often requires purpose-built software, which can be challenging to install and may produce different results across computing environments. Beyond being a roadblock to neuroscientists, these issues of accessibility and portability can hamper the reproducibility of neuroimaging data analysis pipelines. Here, we introduce the Neurodesk platform, which harnesses software containers to support a comprehensive and growing suite of neuroimaging software (https://www.neurodesk.org/). Neurodesk includes a browser-accessible virtual desktop environment and a command line interface, mediating access to containerized neuroimaging software libraries on various computing platforms, including personal and high-performance computers, cloud computing and Jupyter Notebooks. This community-oriented, open-source platform enables a paradigm shift for neuroimaging data analysis, allowing for accessible, flexible, fully reproducible, and portable data analysis pipelines.