One of the most important cytosolic Ca
buffers present in mouse fast-twitch myofibers, but not in human myofibers, is parvalbumin (PV). Previous work using conventional PV gene (
) knockout (PV-KO) ...mice suggests that lifelong
ablation increases fatigue resistance, possibly due to compensations in mitochondrial volume. In this work,
ablation was induced only in adult mice (PV-KO), and contractile and cytosolic Ca
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 Ca
buffering developed only in adult PV-KO mice leads to a larger cytosolic free Ca
concentration (Ca
) during repetitive contractions, increasing myofiber fatigue resistance. Extensor digitorum longus (EDL) muscles from PV-KO mice had higher force in unfused stimulations (∼50%,
< 0.05) and slowed relaxation (∼46% higher relaxation time,
< 0.05) versus PV-Ctr, but muscle fatigue resistance or fatigue-induced changes in relaxation were not different between genotypes (
> 0.05). In intact single myofibers from flexor digitorum brevis (FDB) muscles, basal and tetanic Ca
during fatiguing contractions were higher in PV-KO (
< 0.05), accompanied by a greater slowing in estimated sarcoplasmic reticulum (SR) Ca
-pumping versus PV-Ctr myofibers (∼84% reduction,
< 0.05), but myofiber fatigue resistance was not different between genotypes (
> 0.05). Our results demonstrate that although the estimated SR Ca
uptake was accelerated in PV-KO, the total energy demand by the major energy consumers in myofibers, the cross-bridges, and SR Ca
ATPase were not altered enough to affect the energy supply for contractions, and therefore fatigue resistance remained unaffected.
Parvalbumin (PV) is a cytosolic Ca
buffer that is present in mouse myofibers but not in human muscle. We show that inducible knockout of
leads to increases in myofiber cytosolic free Ca
concentrations and slowing of Ca
pumping during fatigue versus control mice. However,
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.
•Are diaphragm abnormalities present in the SU5416/hypoxia model of pulmonary hypertension (PH)?.•Are the abnormalities dependent on alarmin signaling through the IL-33 receptor, ST2?.•This model of ...PH results in modest mitochondrial dysfunction in coupled respiration and mild compensation in diaphragm contractility.•The mitochondrial dysfunction is partially regulated through ST2/IL-33 alarmin signaling.
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 F1,67 = 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 (F1,67 = 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 (F1,43 = 4.7, p < 0.05, η2 = 0.1). Diaphragm force-frequency relationships were right-shifted in SuHx vs. WT (F3,440 = 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 (F1,41 = 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.
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.
While EEG and fNIRS signal processing is essential to increase the contrast to noise ratio (CNR) of measured brain responses, the nature of the signals and processing methods differ greatly. ...Hemodynamic brain responses in fNIRS are usually masked by local and systemic physiological confounding signals, for instance from superficial (scalp) blood flow, low frequency oscillations (Mayer waves), motion and breathing (Elwell et al., 1999; Yücel et al., 2016; von Lühmann et al., 2019). Generating such data is comparatively straight forward but requires prior knowledge in fNIRS signal characteristics as well as experience in fNIRS signal processing. ...the use of short-separation fNIRS measurements and additional physiological signals, such as accelerometer or photoplethysmography (PPG), has been shown to enable methods that yield improved CNR (Yücel et al., 2015; von Lühmann et al., 2020a), but there are only few openly available multimodal fNIRS datasets (Shin et al., 2017, 2018) and even fewer multimodal datasets that include sufficient resting state periods to enable the approach described above. ...as a remedy, here we provide such a multimodal dataset with (and without) added synthetic HRF ground truth, short-separation fNIRS measurements, accelerometer, and other physiological measurement, for the data science community in order to facilitate the validation of novel methods.
•We proposed an automated tractography approach for individualized TAI detection.•We tested the feasibility of automated tractography in patients with acute severe TBI.•We investigated associations ...with behavioral measures of consciousness.•The TRACULA pipeline successfully reconstructed 93% of the tracts across patients.•The pipeline accurately discriminated between patients and controls (AUC: 0.91)
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.
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).
A comprehensive literature search of 12 databases, reference lists of previous reviews, and evidence-based practice materials was conducted.
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 were extracted independently, and 25% of extractions were checked for reliability. All included studies were assigned quality indicator ratings and an evidence level.
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.
This study established benchmarks of significant change on 3 standardized outcome measures used in aphasia 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 post-semester 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.
To determine if pretreatment nonlinguistic cognition predicted language treatment outcomes and if so, which specific nonlinguistic cognitive subskills predicted naming therapy outcomes.
...Retrospective.
Research clinic.
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.
120-minute sessions of sentence comprehension (n=26) or naming treatment (n=41) 2 times per week for up to 10-12 weeks.
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.
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.
Pretreatment nonlinguistic cognitive function significantly influenced language treatment outcomes and maintenance of therapy gains.
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.
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