Impact of repeated blast exposure on active-duty United States Special Operations Forces.

United States (US) Special Operations Forces (SOF) are frequently exposed to explosive blasts in training and combat, but the effects of repeated blast exposure (RBE) on SOF brain health are incompletely understood. Furthermore, there is no diagnostic test to detect brain injury from RBE. As a result, SOF personnel may experience cognitive, physical, and psychological symptoms for which the cause is never identified, and they may return to training or combat during a period of brain vulnerability. In 30 active-duty US SOF, we assessed the relationship between cumulative blast exposure and cognitive performance, psychological health, physical symptoms, blood proteomics, and neuroimaging measures (Connectome structural and diffusion MRI, 7 Tesla functional MRI, [11C]PBR28 translocator protein [TSPO] positron emission tomography [PET]-MRI, and [18F]MK6240 tau PET-MRI), adjusting for age, combat exposure, and blunt head trauma. Higher blast exposure was associated with increased cortical thickness in the left rostral anterior cingulate cortex (rACC), a finding that remained significant after multiple comparison correction. In uncorrected analyses, higher blast exposure was associated with worse health-related quality of life, decreased functional connectivity in the executive control network, decreased TSPO signal in the right rACC, and increased cortical thickness in the right rACC, right insula, and right medial orbitofrontal cortex-nodes of the executive control, salience, and default mode networks. These observations suggest that the rACC may be susceptible to blast overpressure and that a multimodal, network-based diagnostic approach has the potential to detect brain injury associated with RBE in active-duty SOF.

Invaluable Benefits of 10 Years of the International Collaboration of Aphasia Trialists (CATs).

Aphasia research has traditionally been considered a (unidisciplinary) niche topic in medical science. The international Collaboration of Aphasia Trialists (CATs) is a global collaboration of multidisciplinary aphasia researchers. Over the past 10 years, CATs has collectively taken a rigorous approach to systematically address persistent challenges to aphasia research quality. This article summarizes the achievements over the past decade. CATs' achievements include: standardizing terminology, advancing aphasia research design by aphasia expert consensus recommendations, developing a core data set and intervention descriptors, facilitating the involvement of people with the language impairment aphasia in the research process, translating, and adapting assessment tools into global languages, encouraging data sharing, developing innovative secondary data analysis methodologies and promoting the transparency and accessibility of high quality aphasia research reports. CATs' educational and scientific achievements over the past 10 years far exceed what individual researchers in the field could have ever achieved.

Optimizing Brain Health of United States Special Operations Forces.

United States Special Operations Forces (SOF) personnel are frequently exposed to explosive blasts in training and combat. However, the effects of repeated blast exposure on the human brain are incompletely understood. Moreover, there is currently no diagnostic test to detect repeated blast brain injury (rBBI). In this "Human Performance Optimization" article, we discuss how the development and implementation of a reliable diagnostic test for rBBI has the potential to promote SOF brain health, combat readiness, and quality of life.

Automated detection of axonal damage along white matter tracts in acute severe traumatic brain injury.

New techniques for individualized assessment of white matter integrity are needed to detect traumatic axonal injury (TAI) and predict outcomes in critically ill patients with acute severe traumatic brain injury (TBI). Diffusion MRI tractography has the potential to quantify white matter microstructure in vivo and has been used to characterize tract-specific changes following TBI. However, tractography is not routinely used in the clinical setting to assess the extent of TAI, in part because focal lesions reduce the robustness of automated methods. Here, we propose a pipeline that combines automated tractography reconstructions of 40 white matter tracts with multivariate analysis of along-tract diffusion metrics to assess the presence of TAI in individual patients with acute severe TBI. We used the Mahalanobis distance to identify abnormal white matter tracts in each of 18 patients with acute severe TBI as compared to 33 healthy subjects. In all patients for which a FreeSurfer anatomical segmentation could be obtained (17 of 18 patients), including 13 with focal lesions, the automated pipeline successfully reconstructed a mean of 37.5 ± 2.1 white matter tracts without the need for manual intervention. A mean of 2.5 ± 2.1 tracts resulted in partial or failed reconstructions and needed to be reinitialized upon visual inspection. The pipeline detected at least one abnormal tract in all patients (mean: 9.1 ± 7.9) and accurately discriminated between patients and controls (AUC: 0.91). The number and neuroanatomic location of abnormal tracts varied across patients and levels of consciousness. The premotor, temporal, and parietal sections of the corpus callosum were the most commonly damaged tracts (in 10, 9, and 8 patients, respectively), consistent with prior histopathological studies of TAI. TAI measures were not associated with concurrent behavioral measures of consciousness. In summary, we provide proof-of-principle evidence that an automated tractography pipeline has translational potential to detect and quantify TAI in individual patients with acute severe TBI.

Long-Term Effects of Repeated Blast Exposure in United States Special Operations Forces Personnel: A Pilot Study Protocol.

Emerging evidence suggests that repeated blast exposure (RBE) is associated with brain injury in military personnel. United States (U.S.) Special Operations Forces (SOF) personnel experience high rates of blast exposure during training and combat, but the effects of low-level RBE on brain structure and function in SOF have not been comprehensively characterized. Further, the pathophysiological link between RBE-related brain injuries and cognitive, behavioral, and physical symptoms has not been fully elucidated. We present a protocol for an observational pilot study, Long-Term Effects of Repeated Blast Exposure in U.S. SOF Personnel (ReBlast). In this exploratory study, 30 active-duty SOF personnel with RBE will participate in a comprehensive evaluation of: 1) brain network structure and function using Connectome magnetic resonance imaging (MRI) and 7 Tesla MRI; 2) neuroinflammation and tau deposition using positron emission tomography; 3) blood proteomics and metabolomics; 4) behavioral and physical symptoms using self-report measures; and 5) cognition using a battery of conventional and digitized assessments designed to detect subtle deficits in otherwise high-performing individuals. We will identify clinical, neuroimaging, and blood-based phenotypes that are associated with level of RBE, as measured by the Generalized Blast Exposure Value. Candidate biomarkers of RBE-related brain injury will inform the design of a subsequent study that will test a diagnostic assessment battery for detecting RBE-related brain injury. Ultimately, we anticipate that the ReBlast study will facilitate the development of interventions to optimize the brain health, quality of life, and battle readiness of U.S. SOF personnel.

Young Adults With Acquired Brain Injury Show Longitudinal Improvements in Cognition After Intensive Cognitive Rehabilitation.

PURPOSE: The aim of this study was to assess the effect of an intensive cognitive and communication rehabilitation (ICCR) program on language and other cognitive performance in young adults with acquired brain injury (ABI). METHOD: Thirty young adults with chronic ABI participated in this study. Treatment participants (n = 22) attended ICCR 6 hours/day, 4 days/week for at least one 12-week semester. Deferred treatment/usual care control participants (n = 14) were evaluated before and after at least one 12-week semester. Pre- and postsemester standardized cognitive assessment items were assigned to subdomains. Between-groups and within-group generalized linear mixed-effects models assessed the effect of time point on overall item accuracy and differences by item subdomain. Subdomain analyses were adjusted for multiple comparisons. RESULTS: Between-groups analyses revealed that treatment participants improved significantly faster over time than deferred treatment/usual care participants in overall item accuracy and specifically on items in the verbal expression subdomain. Investigating the three-way interaction between time point, group, and etiology revealed that the overall effects of the treatment were similar for individuals with nontraumatic and traumatic brain injuries. The treatment group showed an overall effect of treatment and significant gains over time in the verbal expression, written expression, memory, and problem solving subdomains. The control group did not significantly improve over time on overall item accuracy and showed significant subdomain-level gains in auditory comprehension, which did not survive correction. CONCLUSIONS: Sustaining an ABI in young adulthood can significantly disrupt key developmental milestones, such as attending college and launching a career. This study provides strong evidence that integrating impairment-based retraining of language and other cognitive skills with "real-world" application in academically focused activities promotes gains in underlying cognitive processes that are important for academic success as measured by standardized assessment items. These findings may prompt a revision to the current continuum of rehabilitative care for young adults with ABI. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.19320068.

Role of parvalbumin in fatigue-induced changes in force and cytosolic calcium transients in intact single mouse myofibers.

One of the most important cytosolic Ca2+ buffers present in mouse fast-twitch myofibers, but not in human myofibers, is parvalbumin (PV). Previous work using conventional PV gene (PV) knockout (PV-KO) mice suggests that lifelong PV ablation increases fatigue resistance, possibly due to compensations in mitochondrial volume. In this work, PV ablation was induced only in adult mice (PV-KO), and contractile and cytosolic Ca2+ responses during fatigue were studied in isolated muscle and intact single myofibers. Results were compared with control littermates (PV-Ctr). We hypothesized that the reduced myofiber cytosolic Ca2+ buffering developed only in adult PV-KO mice leads to a larger cytosolic free Ca2+ concentration ([Ca2+]c) during repetitive contractions, increasing myofiber fatigue resistance. Extensor digitorum longus (EDL) muscles from PV-KO mice had higher force in unfused stimulations (∼50%, P < 0.05) and slowed relaxation (∼46% higher relaxation time, P < 0.05) versus PV-Ctr, but muscle fatigue resistance or fatigue-induced changes in relaxation were not different between genotypes (P > 0.05). In intact single myofibers from flexor digitorum brevis (FDB) muscles, basal and tetanic [Ca2+]c during fatiguing contractions were higher in PV-KO (P < 0.05), accompanied by a greater slowing in estimated sarcoplasmic reticulum (SR) Ca2+-pumping versus PV-Ctr myofibers (∼84% reduction, P < 0.05), but myofiber fatigue resistance was not different between genotypes (P > 0.05). Our results demonstrate that although the estimated SR Ca2+ uptake was accelerated in PV-KO, the total energy demand by the major energy consumers in myofibers, the cross-bridges, and SR Ca2+ ATPase were not altered enough to affect the energy supply for contractions, and therefore fatigue resistance remained unaffected.NEW & NOTEWORTHY Parvalbumin (PV) is a cytosolic Ca2+ buffer that is present in mouse myofibers but not in human muscle. We show that inducible knockout of PV leads to increases in myofiber cytosolic free Ca2+ concentrations and slowing of Ca2+ pumping during fatigue versus control mice. However, PV ablation does not interfere with fatigue-induced slowing in relaxation or fatigue resistance. These data support the use of mouse muscle as a suitable model to investigate human muscle fatigue.

Multi-level outcomes for young adults with acquired brain injury through a remote intensive cognitive rehabilitation approach: a pilot intervention study.

OBJECTIVE: To investigate the effects of the Intensive Cognitive and Communication Rehabilitation (ICCR) program for young adults with acquired brain injury (ABI) using a quasi-experimental pilot intervention study design while transitioning to remote implementation. METHOD: Twelve young adults with chronic ABI (treatment n = 7; control n = 5) participated in ICCR (i.e., lectures, seminars, individual cognitive rehabilitation (CR), technology training) for six hours/day, four days/week, for one or two 12-week semesters. Outcomes included classroom metrics, individual therapy performance, including Goal Attainment Scaling (GAS), standardized cognitive-linguistic assessments, and participation and health-related quality of life (QOL) measures. RESULTS: In the first semester (in-person and remote), treatment participants significantly improved in classroom exams; individual therapy (i.e., memory, writing, GAS); executive function and participation measures, but not QOL. In the second semester (remote), treatment participants significantly improved in classroom exams; essay writing; individual therapy (i.e., writing and GAS); and memory assessment, but not in participation or QOL. Treatment participants enrolled in consecutive semesters significantly improved in classroom exams, individual therapy (i.e., memory), participation and QOL, but not on standardized cognitive assessments. Controls demonstrated no significant group-level gains. CONCLUSION: These preliminary results highlight the benefit of intensive, integrated, and contextualized CR for this population and show promise for its remote delivery.

Role of IL-33 receptor (ST2) deletion in diaphragm contractile and mitochondrial function in the Sugen5416/hypoxia model of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right ventricular failure. Skeletal muscle maladaptations limit physical activity and may contribute to disease progression. The role of alarmin/inflammatory signaling in PAH respiratory muscle dysfunction is unknown. We hypothesized that diaphragm mitochondrial and contractile functions are impaired in SU5416/hypoxia-induced pulmonary hypertension due to increased systemic IL-33 signaling. We induced pulmonary hypertension in adult C57Bl/6 J (WT) and ST2 (IL1RL1) gene ablated mice by SU5416/hypoxia (SuHx). We measured diaphragm fiber mitochondrial respiration, inflammatory markers, and contractile function ex vivo. SuHx reduced coupled and uncoupled permeabilized myofiber respiration by ∼40 %. During coupled respiration with complex I substrates, ST2-/- attenuated SuHx inhibition of mitochondrial respiration (genotype × treatment interaction F[1,67] = 3.3, p = 0.07, η2 = 0.04). Flux control ratio and coupling efficiency were not affected by SuHx or genotype. A higher substrate control ratio for succinate was observed in SuHx fibers and attenuated in ST2-/- fibers (F[1,67] = 5.3, p < 0.05, η2 = 0.07). Diaphragm TNFα, but not IL-33 or NFkB, was increased in SuHx vs. DMSO in both genotypes (F[1,43] = 4.7, p < 0.05, η2 = 0.1). Diaphragm force-frequency relationships were right-shifted in SuHx vs. WT (F[3,440] = 8.4, p < 0.05, η2 = 0.0025). There was no effect of ST2-/- on the force-frequency relationship. Force decay during a fatigue protocol at 100 Hz, but not at 40 Hz, was attenuated by SuHx vs. DMSO in both genotypes (F[1,41] = 5.6, p < 0.05, η2 = 0.11). SuHx mice exhibit a modest compensation in diaphragm contractility and mitochondrial dysfunction during coupled respiration; the latter partially regulated through ST2 signaling.

Acquired Brain Injury in Adults: A Review of Pathophysiology, Recovery, and Rehabilitation.

PURPOSE: To summarize existing literature from a range of fields (i.e., neurology, neuropsychology, neuroscience, neuroimaging, rehabilitation, speech-language pathology) that is relevant to the development and/or revision of cognitive rehabilitation programs for individuals with acquired brain injury (ABI) and in particular, for young adults. METHOD: This paper reviews a range of ABI-associated topics including: 1) mechanisms of injury; 2) biological, individual-specific, and behavioral drivers of recovery; and 3) current methods of cognitive rehabilitation. It then narrows focus to young adults, a frequently affected and growing population to sustain ABI. The paper concludes by providing: 1) suggestions for key components of cognitive rehabilitation for young adults with ABI; 2) an example from our own research providing intensive academically-focused cognitive rehabilitation for young adults with ABI pursuing college; and 3) recommendations for future behavioral and neuroimaging studies in this area. CONCLUSIONS: ABI is on the rise in the United States. Young adults have been sustaining ABI at higher rates over the past several decades. These injuries occur when they would otherwise be advancing their academic and career goals, making the cognitive deficits that often accompany ABI especially devastating for this group. Review of existing literature suggests cognitive rehabilitation programs that combine aspects of restorative, comprehensive, and contextualized approaches could promote recovery for young adults with ABI. Future intervention studies may benefit from including both behavioral and neural outcomes to best understand how principles of neuroplasticity- naturally embedded within many cognitive rehabilitation approaches-could be manipulated to promote cognitive recovery and long-lasting brain reorganization in this group.

Investigating Language and Domain-General Processing in Neurotypicals and Individuals With Aphasia - A Functional Near-Infrared Spectroscopy Pilot Study.

Brain reorganization patterns associated with language recovery after stroke have long been debated. Studying mechanisms of spontaneous and treatment-induced language recovery in post-stroke aphasia requires a network-based approach given the potential for recruitment of perilesional left hemisphere language regions, homologous right hemisphere language regions, and/or spared bilateral domain-general regions. Recent hardware, software, and methodological advances in functional near-infrared spectroscopy (fNIRS) make it well-suited to examine this question. fNIRS is cost-effective with minimal contraindications, making it a robust option to monitor treatment-related brain activation changes over time. Establishing clear activation patterns in neurotypical adults during language and domain-general cognitive processes via fNIRS is an important first step. Some fNIRS studies have investigated key language processes in healthy adults, yet findings are challenging to interpret in the context of methodological limitations. This pilot study used fNIRS to capture brain activation during language and domain-general processing in neurotypicals and individuals with aphasia. These findings will serve as a reference when interpreting treatment-related changes in brain activation patterns in post-stroke aphasia in the future. Twenty-four young healthy controls, seventeen older healthy controls, and six individuals with left hemisphere stroke-induced aphasia completed two language tasks (i.e., semantic feature, picture naming) and one domain-general cognitive task (i.e., arithmetic) twice during fNIRS. The probe covered bilateral frontal, parietal, and temporal lobes and included short-separation detectors for scalp signal nuisance regression. Younger and older healthy controls activated core language regions during semantic feature processing (e.g., left inferior frontal gyrus pars opercularis) and lexical retrieval (e.g., left inferior frontal gyrus pars triangularis) and domain-general regions (e.g., bilateral middle frontal gyri) during hard versus easy arithmetic as expected. Consistent with theories of post-stroke language recovery, individuals with aphasia activated areas outside the traditional networks: left superior frontal gyrus and left supramarginal gyrus during semantic feature judgment; left superior frontal gyrus and right precentral gyrus during picture naming; and left inferior frontal gyrus pars opercularis during arithmetic processing. The preliminary findings in the stroke group highlight the utility of using fNIRS to study language and domain-general processing in aphasia.

Typicality-based semantic treatment for anomia results in multiple levels of generalisation.

This study investigated the effects of typicality-based semantic feature analysis (SFA) treatment on generalisation across three levels: untrained related items, semantic/phonological processing tasks, and measures of global language function. Using a single-subject design with group-level analyses, 27 persons with aphasia (PWA) received typicality-based SFA to improve their naming of atypical and/or typical exemplars. Progress on trained, untrained, and monitored items was measured weekly. Pre- and post-treatment assessments were administered to evaluate semantic/phonological processing and overall language ability. Ten PWA served as controls. For the treatment participants, the likelihood of naming trained items accurately was significantly higher than for monitored items over time. When features of atypical items were trained, the likelihood of naming untrained typical items accurately was significantly higher than for untrained atypical items over time. Significant gains were observed on semantic/phonological processing tasks and standardised assessments after therapy. Different patterns of near and far transfer were seen across treatment response groups. Performance was also compared between responders and controls. Responders demonstrated significantly more improvement on a semantic processing task than controls, but no other significant change score differences were found between groups. In addition to positive treatment effects, typicality-based SFA naming therapy resulted in generalisation across multiple levels.

Nonlinguistic Cognitive Factors Predict Treatment-Induced Recovery in Chronic Poststroke Aphasia.

OBJECTIVE: To determine if pretreatment nonlinguistic cognition predicted language treatment outcomes and if so, which specific nonlinguistic cognitive subskills predicted naming therapy outcomes. DESIGN: Retrospective. SETTING: Research clinic. PARTICIPANTS: Study 1 included data from 67 persons with aphasia who underwent language treatment and a pretreatment cognitive-linguistic assessment battery (N=67). Study 2 included data from 27 study 1 participants who completed additional pretreatment nonlinguistic cognitive assessments. INTERVENTIONS: 120-minute sessions of sentence comprehension (n=26) or naming treatment (n=41) 2 times per week for up to 10-12 weeks. MAIN OUTCOME MEASURES: Proportion of potential maximal gain (PMG) (assessed immediately after treatment [10-12wk]; formula=mean posttreatment score-mean pretreatment score/total number of trained items-mean pretreatment score) and proportion of potential maximal gain maintained (PMGM) (assessed 12wk after posttreatment [22-24wk]; formula=mean maintenance score-mean pretreatment score/total number of trained items-mean pretreatment score) as outcome variables; and pretreatment assessment scores as predictor variables. RESULTS: In study 1, 37% of participants demonstrated nonlinguistic cognitive deficits. Principal component analyses reduced assessment data to 2 components: linguistic and nonlinguistic cognition. Backward elimination regression revealed that higher linguistic and nonlinguistic cognitive function significantly predicted higher PMG after language therapy. In study 2, principal component analysis of only the nonlinguistic cognitive measures identified 3 components: executive function, verbal short-term memory, and visual short-term memory. Controlling for pretreatment apraxia of speech and auditory comprehension deficits, regression analyses revealed that higher executive function and visual short-term memory significantly predicted higher PMG and PMGM after naming therapy. CONCLUSIONS: Pretreatment nonlinguistic cognitive function significantly influenced language treatment outcomes and maintenance of therapy gains.

The Intensive Cognitive-Communication Rehabilitation Program for Young Adults With Acquired Brain Injury.

Purpose This study investigated the effects of an intensive cognitive-communication rehabilitation (ICCR) program for young individuals with chronic acquired brain injury. Method ICCR included classroom lectures; metacognitive instruction, modeling, and application; technology skills training; and individual cognitive-linguistic therapy. Four individuals participated in the intensive program (6 hr with 1-hr lunch break × 4 days × 12 weeks of treatment): 3 participants completed 3 consecutive semesters, and 1 participant completed 1 semester. Two controls did not receive treatment and completed assessments before and after the 12-week treatment interval only. Results All 4 experimental participants demonstrated significant improvements on at least 1 standardized cognitive-linguistic measure, whereas controls did not. Furthermore, time point significantly predicted participants' scores on 2 of the 4 standardized outcome measures, indicating that as duration in ICCR increased, scores also increased. Participants who completed multiple semesters of ICCR also improved in their therapy and personal goals, classroom behavior, life participation, and quality of life. Conclusion After ICCR, participants showed gains in their cognitive-linguistic functioning, classroom participation, and individual therapy. They also demonstrated improvements outside the classroom and in their overall well-being. There is a gap between the large population of young adults with acquired brain injury who wish to return to higher education and a lack of rehabilitation programs supporting reentry into academic environments; ICCR is a first step in reducing that gap.

Benchmarks of Significant Change After Aphasia Rehabilitation.

OBJECTIVE: To establish benchmarks of significant change for aphasia rehabilitation outcome measures (ie, Western Aphasia Battery-Aphasia Quotient [WAB-AQ], Communicative Effectiveness Index [CETI], Boston Naming Test [BNT]) and assess if those benchmarks significantly differ across subgroups (ie, time post onset, dose frequency, treatment type). DATA SOURCES: A comprehensive literature search of 12 databases, reference lists of previous reviews, and evidence-based practice materials was conducted. STUDY SELECTION: Randomized controlled trials, quasi-experimental studies, single-subject design, and case studies that used a standardized outcome measure to assess change were included. Titles and full-text articles were screened using a dual review process. Seventy-eight studies met criteria for inclusion. DATA EXTRACTION: Data were extracted independently, and 25% of extractions were checked for reliability. All included studies were assigned quality indicator ratings and an evidence level. DATA SYNTHESIS: Random-effects meta-analyses were conducted separately for each study design group (ie, within-/between-group comparisons). For within-group designs, the summary effect size after aphasia rehabilitation was 5.03 points (95% confidence interval, 3.95-6.10, P<.001) on the WAB-AQ, 10.37 points (6.08-14.66, P<.001) on the CETI, and 3.30 points (2.43-4.18, P<.001) on the BNT. For between-group designs, the summary effect size was 5.05 points (1.64-8.46, P=.004) on the WAB-AQ and 0.55 points (-1.33 to 2.43, P=.564) on the BNT, the latter of which was not significant. Subgroup analyses for the within-group designs showed no significant differences in the summary effect size as a function of dose frequency or treatment type. CONCLUSIONS: This study established benchmarks of significant change on 3 standardized outcome measures used in aphasia rehabilitation.