Feasibility Testing of the Bionet Sonar Ultrasound Transcutaneous Energy Transmission (UTET) System for Wireless Power and Communication of a LVAD.

PURPOSE: To address the clinical need for totally implantable mechanical circulatory support devices, Bionet Sonar is developing a novel Ultrasonic Transcutaneous Energy Transmission (UTET) system that is designed to eliminate external power and/or data communication drivelines. METHODS: UTET systems were designed, fabricated, and pre-clinically tested using a non-clinical HeartWare HVAD in static and dynamic mock flow loop and acute animal models over a range of pump speeds (1800, 2400, 3000 RPM) and tissue analogue thicknesses (5, 10, 15 mm). RESULTS: The prototypes demonstrated feasibility as evidenced by meeting/exceeding function, operation, and performance metrics with no system failures, including achieving receiver (harvested) power exceeding HVAD power requirements and data communication rates of 10kB/s and pump speed control (> 95% sensitivity and specificity) for all experimental test conditions, and within healthy tissue temperature range with no acute tissue damage. CONCLUSION: During early-stage development and testing, engineering challenges for UTET size reduction and stable and safe operation were identified, with solutions and plans to address the limitations in future design iterations also presented.

Effects of extension ladder fly configuration on climbing safety.

Fall injuries often occur on extension ladders. The extendable fly section of an extension ladder is typically closer to the user than the base section, though this design is minimally justified. This study investigates the effects of reversing the fly on foot placement, frictional requirements, adverse stepping events (repositioning the foot or kicking the rung), and user preferences. Participant foot placement was farther posterior (rung contacted nearer to toes) in the traditional ladder compared to the reversed fly condition during descent, with farther anterior foot placements during ascent. The reversed configuration had similar friction requirements during early/mid stance and significantly lower frictional requirements during late stance. Increased friction requirements during late stance were associated with farther anterior foot placement and further plantar flexed foot orientation. The reversed fly had 5 adverse stepping events versus 22 that occurred in the traditional configuration. Users typically preferred the reversed fly. These results suggest that a reversed extension ladder configuration offers potential benefits in reducing fall-related injuries that should motivate future research and development work.

Electron tomography visualization of HIV-1 virions trapped by fusion inhibitors to host cells in infected tissues.

HIV-1 delivers its genetic material to infect a cell after fusion of the viral and host cell membranes, which takes place after the viral envelope (Env) binds host receptor and co-receptor proteins. Binding of host receptor CD4 to Env results in conformational changes that allow interaction with a host co-receptor (CCR5 or CXCR4). Further conformational rearrangements result in an elongated pre-hairpin intermediate structure in which Env is anchored to the viral membrane by its transmembrane region and to the host cell membrane by its fusion peptide. Although budding virions can be readily imaged by electron tomography (ET) of HIV-1-infected tissues and cultured cells, virions that are fusing (attached to host cells via pre-hairpin intermediates) are not normally visualized, perhaps because the process of membrane fusion is too fast to capture by EM. To image virions during fusion, we used fusion inhibitors to prevent downstream conformational changes in Env that lead to membrane fusion, thereby trapping HIV-1 virions linked to target cells by prehairpin intermediates. ET of HIV-1 pseudovirions bound to CD4+/CCR5+ TZM-bl cells revealed presumptive pre-hairpin intermediates as 2-4 narrow spokes linking a virion to the cell surface. To extend these results to a more physiological setting, we used ET to image tissues and organs derived from humanized bone marrow, liver, thymus (BLT) mice infected with HIV-1 and then treated with CPT31, a high-affinity D-peptide fusion inhibitor linked to cholesterol. Trapped HIV-1 virions were found in all tissues studied (small intestine, mesenteric lymph nodes, spleen, and bone marrow), and spokes representing pre-hairpin intermediates linking trapped virions to cell surfaces were similar in structure and number to those seen in the previous pseudovirus and cultured cell ET study.

Deintensification of Treatment for Low-grade Bladder Tumors: A Collaborative Review by the International Bladder Cancer Group (IBCG).

BACKGROUND AND OBJECTIVE: Management of low-grade (LG) urothelium-confined (Ta stage) non-muscle-invasive bladder cancer (NMIBC) poses a distinct therapeutic challenge. Transurethral resection of bladder tumor (TURBT), the standard treatment, frequently has to be repeated because of high tumor recurrence rates. This places a considerable strain on both patients and health care infrastructure, underscoring the need for alternative management approaches. Herein, the IBCG (International Bladder Cancer Group), conducted a review to explore the efficacy and safety of deintensified treatment strategies for recurrent LG Ta NMIBC. METHODS: We conducted a collaborative review of relevant literature in the PubMed/MEDLINE and Cochrane CENTRAL databases. Our focus was on high-quality evidence, including randomized controlled trials, systematic reviews, and meta-analyses. We also reviewed guidelines published by prominent urological associations. KEY FINDINGS AND LIMITATIONS: Active surveillance, chemoablation, and office fulguration are valid treatment options for recurrent LG Ta NMIBC. These deintensified approaches offer several advantages over TURBT: lower complication rates, less morbidity, lower health care costs, and better quality of life for patients. Importantly, these benefits are achieved without compromising oncological safety. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our review demonstrates that less intensive treatment strategies for recurrent LG Ta NMIBC are both feasible and valuable. The IBCG recommends use of these approaches for carefully selected patients to help lower health care costs and enhance patients' quality of life. PATIENT SUMMARY: We reviewed studies on less invasive management options for low-grade noninvasive bladder cancer, including active surveillance, chemical ablation, and heat treatment. Recent results confirm that these less intense treatment options can reduce the treatment burden and costs for patients and preserve their quality of life without negatively affecting cancer control outcomes.

Improving hydraulic performance of the left atrial assist device using computational fluid dynamics.

BACKGROUND: The left atrial assist device (LAAD) is a novel continuous-flow pump designed to treat patients with heart failure with preserved ejection fraction, a growing type of heart failure, but with limited device-treatment options. The LAAD is implanted in the mitral plane and pumps blood from the left atrium into the left ventricle. The purpose of this study was to refine the initial design of the LAAD, using results from computational fluid dynamics (CFD) analyses to inform changes that could improve hydraulic performance and flow patterns within the LAAD. METHODS: The initial design and three variations were simulated, exploring changes to the primary impeller blades, the housing shape, and the number, size, and curvature of the diffuser vanes. Several pump rotational speeds and flow rates spanning the intended range of use were modeled. RESULTS: Guided by the insight gained from each design iteration, the final design incorporated impeller blades with improved alignment relative to the incoming flow and wider, more curved diffuser vanes that better aligned with the approaching flow from the volute. These design adjustments reduced flow separation within the impeller and diffuser regions. In vitro testing confirmed the CFD predicted improvement in the hydraulic performance of the revised LAAD flow path design. CONCLUSIONS: The CFD results from this study provided insight into the key pump design-related parameters that can be adjusted to improve the LAAD's hydraulic performance and internal flow patterns. This work also provided a foundation for future studies assessing the LAAD's biocompatibility under clinical conditions.

Healthy first-degree relatives from multiplex families versus simplex families have a higher subclinical intestinal inflammation, a distinct fecal microbial signature, and harbor a higher risk of developing Crohn's disease.

BACKGROUND & AIMS: Unaffected first-degree relatives (FDRs) from families with two or more affected FDRs with Crohn's disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex versus simplex families and to investigate the risk of future CD onset accounting for potential confounders. METHODS: We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy FDRs of patients with CD. Genome-wide CD-polygenic risk scores (CD-PRS), urinary fractional excretion of lactulose-to-mannitol ratio (LMR), fecal calprotectin (FCP), and fecal 16S ribosomal RNA microbiome were measured at recruitment. Associations between CD multiplex status and baseline biomarkers were determined using generalized estimating equations models. Cox models were used to assess the risk of future CD onset. RESULTS: There were 4051 participants from simplex families and 334 from CD multiplex families. CD multiplex status was significantly associated with higher baseline FCP (p=0.026) but not with baseline CD-PRS or LMR. Three bacterial genera were found to be differentially abundant between both groups. CD multiplex status at recruitment was independently associated with an increased risk of developing CD (adjusted hazard ratio 3.65, 95% confidence interval 2.18 - 6.11, p < 0.001). CONCLUSION: Within FDRs of patients with CD, participants from multiplex families had a 3-fold increased risk of CD onset, a higher FCP, and an altered bacterial composition, but not genetic burden or altered gut permeability. These results suggest that putative environmental factors might be enriched in FDRs from multiplex families.

Modelling strategies supplemental to foot placement for frontal-plane stability in walking.

Walking is unstable and requires active control. Foot placement is the primary strategy to maintain frontal-plane balance with contributions from lateral ankle torques, ankle push-off and trunk postural adjustments. Because these strategies interact, their individual contributions are difficult to study. Here, we used computational modelling to understand these individual contributions to frontal-plane walking balance control. A three-dimensional bipedal model was developed based on linear inverted pendulum dynamics. The model included controllers that implement the stabilization strategies seen in human walking. The control parameters were optimized to mimic human gait biomechanics for typical spatio-temporal parameters during steady-state walking and when perturbed by mediolateral ground shifts. Using the optimized model as a starting point, the contributions of each stabilization strategy were explored by progressively removing strategies. The lateral ankle and trunk strategies were more important than ankle push-off, with their removal causing up to 20% worse balance recovery compared with the full model, while removing ankle push-off led to minimal changes. Our results imply a potential benefit of preferentially training these strategies in populations with poor balance. Moreover, the proposed model could be used in future work to investigate how walking stability may be preserved in conditions reflective of injury or disease.

Investigation of health care use and a possible prodrome before the first attack in NMOSD and MOGAD.

BACKGROUND: Prodromal phases are well recognized in many inflammatory and neurodegenerative diseases, including multiple sclerosis. We evaluated the possibility of a prodrome in aquaporin-4 antibody positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) using health administrative data. METHODS: We investigated individuals with AQP4 + NMOSD and MOGAD, confirmed by medical chart review, in Ontario, Canada. Each NMOSD and MOGAD participant was matched 1:5 to general population controls by sex, birth year, immigrant status, and region. Total outpatient visits and hospitalizations were compared in the 5 years preceding the incident attack in multivariable negative binomial models. RESULTS: We identified 96 people with AQP4 + NMOSD, matched to 479 controls, and 61 people with MOGAD, matched to 303 controls. In the 5 years preceding the incident attack, health care use was elevated for outpatient visits and hospitalizations for the NMOSD cohort (adjusted rate ratio (aRR): 1.47; 95% confidence interval (CI): 1.25-1.73; aRR: 1.67; 95% CI: 1.19-2.36, respectively) but not for MOGAD. Rate ratios steadily increased in NMOSD for outpatient visits in the 2 years preceding the incident attack. CONCLUSION: Our findings support a prodromal phase preceding clinical onset of AQP4 + NMOSD. Earlier recognition and management of NMOSD patients may be possible.

A novel expression domain of extradenticle underlies the evolutionary developmental origin of the chelicerate patella.

Neofunctionalization of duplicated gene copies is thought to be an important process underlying the origin of evolutionary novelty and provides an elegant mechanism for the origin of new phenotypic traits. One putative case where a new gene copy has been linked to a novel morphological trait is the origin of the arachnid patella, a taxonomically restricted leg segment. In spiders, the origin of this segment has been linked to the origin of the paralog dachshund-2, suggesting that a new gene facilitated the expression of a new trait. However, various arachnid groups that possess patellae do not have a copy of dachshund-2, disfavoring the direct link between gene origin and trait origin. We investigated the developmental genetic basis for patellar patterning in the harvestman Phalangium opilio, which lacks dachshund-2. Here, we show that the harvestman patella is established by a novel expression domain of the transcription factor extradenticle. Leveraging this definition of patellar identity, we surveyed targeted groups across chelicerate phylogeny to assess when this trait evolved. We show that a patellar homolog is present in Pycnogonida (sea spiders) and various arachnid orders, suggesting a single origin of the patella in the ancestor of Chelicerata. A potential loss of the patella is observed in Ixodida. Our results suggest that the modification of an ancient gene, rather than the neofunctionalization of a new gene copy, underlies the origin of the patella. Broadly, this work underscores the value of comparative data and broad taxonomic sampling when testing hypotheses in evolutionary developmental biology.

Ovarian carcinosarcomas: p53 status defines two distinct patterns of oncogenesis and outcomes.

Objectives: Ovarian carcinosarcoma (OCS) is a rare and lethal type of ovarian cancer. Despite its incredibly poor prognosis, it has received little research attention. In this study, we aim to evaluate the molecular features of OCS and elucidate their clinical significance. Study methods: We examined 30 OCS by immunohistochemistry (IHC) and targeted panel sequencing collected from a single institution (2003-2013) as the initial molecularly characterized cohort (Cohort A). From November 2016 to April 2023, we collected an additional 67 OCS cases from three institutions across British Columbia and Alberta as the contemporary cohort (Cohort B) for clinical correlation. The Kaplan-Meier method was used to estimate overall and progression-free survival, and differences in survival rates were compared using the log-rank test. All tests were two-sided. A p-value of less than 0.05 was considered statistically significant. Results: The majority of OCS (82%) in the initial Cohort A were p53-mutated, and the carcinomatous component displayed the histological and molecular features of a high-grade tubo-ovarian serous carcinoma (HGSC-like). In a minority of OCS, the epithelial components were characteristics of endometrioid or clear cell carcinomas, and IHC staining was wild type for p53. In the contemporary Cohort B, we observed the same histological findings related to the p53 IHC staining pattern. The median overall survival of the p53-mutated HGSC-like OCS (47 patients) was significantly higher (43.5 months) compared with that of the p53 wild-type OCS (10 patients, 8.8 months; P < 0.01). Pathogenic BRCA1/2 germline/somatic mutations were observed in 7 patients (17.5%) of HGSC-like OCS, and all these patients were alive at 3 years from diagnosis compared to a 51% 3-year survival among the patients with BRCA1/2 wild-type HGSC-like OCS (33 patients) (p = 0.022). Majority of patients (6/7) with BRCA1/2-mutated OCS received poly (ADP-ribose) polymerase inhibitor as maintenance therapy in this cohort. Conclusions: Most OCSs have a morphologic and molecular profile resembling HGSC; however, some OCSs display a molecular profile that suggests origin through non-serous oncogenic pathways. This molecular distinction has both prognostic and treatment (predictive) implications. These findings underscore the importance of routine p53 IHC testing on all OCS and BRCA1/2 testing on p53-mutated OCS.

Natural recovery of cardiac allograft diastolic function, a retrospective longitudinal report.

Cardiac allografts suffer diastolic dysfunction early post-heart transplantation (HTx) due to ischemic injury, however the natural course of diastology recovery post HTx remains unknown (Tallaj et al., 2007 [1]). We retrospectively reviewed 60 adult HTx patients between 2015 and 2021 at a single site. Invasive hemodynamics and echocardiograms were obtained at 2 weeks and 1, 3, 6, and 12 months post-HTx. RA strain by 2D feature tracking was compared to intracardiac pressure measurements. In all patients, we observed normalization of RV and RA filling pressures by post-operative week 12 and recovery of diastolic dysfunction by month 6. There was an inverse correlation between RV end-diastolic pressure and RA contractile (r = -0.192, p < 0.05) and reservoir (r = -0.128, p < 0.05) functions in the allograft. As the post-transplant care paradigm shifts away from invasive procedures, right atrial indices should be included in imaging-based allograft surveillance studies.

Inflammatory cytokine signalling in vulvovaginal candidiasis: a hot mess driving immunopathology.

Protective immunity to opportunistic fungal infections consists of tightly regulated innate and adaptive immune responses that clear the infection. Immune responses to infections of the vaginal mucosa by Candida species are, however, an exception. In the case of vulvovaginal candidiasis (VVC), the inflammatory response is associated with symptomatic disease, rather than that it results in pathogen clearance. As such VVC can be considered an inflammatory disease, which is a significant public health problem due to its predominance as a female-specific fungal infection. Particularly, women with recurrent VVC (RVVC) suffer from a significant negative impact on their quality of life and mental health. Knowledge of the inflammatory pathogenesis of (R)VVC may guide more effective diagnostic and therapeutic options to improve the quality of life of women with (R)VVC. Here, we review the immunopathogenesis of (R)VVC describing several elements that induce an inflammatory arson, starting with the activation threshold established by vaginal epithelial cells that prevent unnecessary ignition of inflammatory responses, epithelial and inflammasome-dependent immune responses. These inflammatory responses will drive neutrophil recruitment and dysfunctional neutrophil-mediated inflammation. We also review the, sometimes controversial, findings on the involvement of adaptive and systemic responses. Finally, we provide future perspectives on the potential of some unexplored cytokine axes and discuss whether VVC needs to be subdivided into subgroups to improve diagnosis and treatment.

Omega-3 Fatty Acids and Arrhythmias.

The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.

A synthetic peptide mimic kills Candida albicans and synergistically prevents infection.

More than two million people worldwide are affected by life-threatening, invasive fungal infections annually. Candida species are the most common cause of nosocomial, invasive fungal infections and are associated with mortality rates above 40%. Despite the increasing incidence of drug-resistance, the development of novel antifungal formulations has been limited. Here we investigate the antifungal mode of action and therapeutic potential of positively charged, synthetic peptide mimics to combat Candida albicans infections. Our data indicates that these synthetic polymers cause endoplasmic reticulum stress and affect protein glycosylation, a mode of action distinct from currently approved antifungal drugs. The most promising polymer composition damaged the mannan layer of the cell wall, with additional membrane-disrupting activity. The synergistic combination of the polymer with caspofungin prevented infection of human epithelial cells in vitro, improved fungal clearance by human macrophages, and significantly increased host survival in a Galleria mellonella model of systemic candidiasis. Additionally, prolonged exposure of C. albicans to the synergistic combination of polymer and caspofungin did not lead to the evolution of tolerant strains in vitro. Together, this work highlights the enormous potential of these synthetic peptide mimics to be used as novel antifungal formulations as well as adjunctive antifungal therapy.

Structural Catalytic Core of the Members of the Superfamily of Acid Proteases.

The superfamily of acid proteases has two catalytic aspartates for proteolysis of their peptide substrates. Here, we show a minimal structural scaffold, the structural catalytic core (SCC), which is conserved within each family of acid proteases, but varies between families, and thus can serve as a structural marker of four individual protease families. The SCC is a dimer of several structural blocks, such as the DD-link, D-loop, and G-loop, around two catalytic aspartates in each protease subunit or an individual chain. A dimer made of two (D-loop + DD-link) structural elements makes a DD-zone, and the D-loop + G-loop combination makes a psi-loop. These structural markers are useful for protein comparison, structure identification, protein family separation, and protein engineering.

Patient-Reported Preoperative Depression as a Predictor of Psychosocial Outcomes After Gender-Affirming Facial Feminization Surgery.

OBJECTIVE: To understand psychosocial functioning before and after gender-affirming facial feminization surgery (FFS) as well as identify predictors of postoperative psychosocial functioning. SUMMARY BACKGROUND DATA: Few investigations have rigorously explored the impact of gender-affirming FFS on psychosocial functioning in transgender and gender non-binary (TGNB) individuals. This knowledge gap hinders the identification of methods to optimize mental health quality-of-life outcomes after FFS and carries repercussions for access to care. METHODS: Adult TGNB participants awaiting gender-affirming FFS were prospectively enrolled and administered Patient-Reported Outcomes Measurement Information System (PROMIS) instruments assessing anxiety, anger, depression, global mental and physical health, positive affect, emotional support, social isolation, companionship, and meaning and purpose before and 3-6 months after FFS. Paired t-tests compared pre- and postoperative scores. Multivariable linear models identified predictors of postoperative psychosocial outcomes. RESULTS: Among the domains, psychosocial scores improved for anxiety, depression, global mental health, social isolation, and positive affect after FFS. When accounting for potential variables contributing to postoperative psychosocial scores including other gender-affirming surgeries, hormone therapy duration, and private versus public insurance type, we found that preoperative depression scores independently predicted the variance in all other postoperative scores with global mental health (ß=-0.52, 95%CI -0.58--0.31 P<0.001), anxiety (ß=0.40, 95% CI 0.21-0.51, P<0.001), and meaning and purpose (ß=-0.52, 95% CI -0.78--0.42 P<0.001) as the strongest models. CONCLUSIONS: This study suggests that gender-affirming FFS improves psychosocial functioning; however, such improvements are highly influenced by the baseline psychological functioning of each individual. These findings indicate that preoperative psychological functioning may be a potential avenue for improving outcomes after FFS via perioperative psychological interventions.

Diagnostic and prognostic value of the left atrial myopathy evaluation in cardiac amyloidosis using echocardiography.

BACKGROUND: Cardiac amyloidosis (CA) is an under-recognized cause of heart failure. Left atrial (LA) myopathy contributes to a worse prognosis in heart failure and is a feature of transthyretin (ATTR) and light-chain (AL) CA. LA mechanical dispersion (LA-MD) is a novel marker of intra-atrial dyssynchrony implicated in LA myopathy and the future development of atrial fibrillation (AF). AIMS: This study aimed to determine the characteristics and prognostic value of LA myopathy in ATTR and AL cardiomyopathy through a comprehensive LA echocardiographic evaluation. METHODS: ATTR (n = 86) and AL (n = 86) CA patients were compared with hypertensive heart disease (HHT) patients (n = 58). Transthoracic echocardiographic measurements including LA strain and LA-MD were obtained with patient follow-up for mortality. RESULTS: ATTR and AL patients had a median follow-up of 66 months, with 26 mortality events. Left ventricular (LV) mass, diastolic function (average-e' and E/e'), LV global longitudinal strain, and LA volume and function (LA function index and strain) were more impaired in ATTR versus AL; these echocardiographic parameters were more impaired in both amyloid groups compared to HHT patients (P < 0.05). LA-MD was increased in ATTR versus AL [median 72.2 (inter-quartile range 55-88.9) vs. 54 (43.5-64.2), respectively, P < 0.001]. Multivariable logistic regression adjusted for age, presence of AF, LV mass, global and basal strain, and E/e' demonstrated that LA-MD was an independent determinant of ATTR CA (P = 0.014). On multivariable analysis, LA reservoir strain was independently associated with the presence of heart failure in the CA group (P < 0.001). LA minimum volume (cut-off ≥18 mL/m2) was a determinant of mortality in AL CA [Cox proportional hazard ratio (HR) 1.042 (1.003-1.082), P = 0.034 and Kaplan-Meier analysis, P = 0.016]. CONCLUSION: Characterizing LA myopathy has significant diagnostic and prognostic utility in CA. ATTR patients have increased atrial dyssynchrony, which may have implications for AF development. LA reservoir strain was associated with heart failure in CA, whilst LA minimum volume was a predictor of mortality in AL CA.

Concurrent tDCS-fMRI after stroke reveals link between attention network organization and motor improvement.

Restoring motor function after stroke necessitates involvement of numerous cognitive systems. However, the impact of damage to motor and cognitive network organization on recovery is not well understood. To discover correlates of successful recovery, we explored imaging characteristics in chronic stroke subjects by combining noninvasive brain stimulation and fMRI. Twenty stroke survivors (6 months or more after stroke) were randomly assigned to a single session of transcranial direct current stimulation (tDCS) or sham during image acquisition. Twenty healthy subjects were included as controls. tDCS was limited to 10 min at 2 mA to serve as a mode of network modulation rather than therapeutic delivery. Fugl-Meyer Assessments (FMA) revealed significant motor improvement in the chronic stroke group receiving active stimulation (p = 0.0005). Motor changes in this group were correlated in a data-driven fashion with imaging features, including functional connectivity (FC), surface-based morphometry, electric field modeling and network topology, focusing on relevant regions of interest. We observed stimulation-related changes in FC in supplementary motor (p = 0.0029), inferior frontal gyrus (p = 0.0058), and temporo-occipital (p = 0.0095) areas, though these were not directly related to motor improvement. The feature most strongly associated with FMA improvement in the chronic stroke cohort was graph topology of the dorsal attention network (DAN), one of the regions surveyed and one with direct connections to each of the areas with FC changes. Chronic stroke subjects with a greater degree of motor improvement had lower signal transmission cost through the DAN (p = 0.029). While the study was limited by a small stroke cohort with moderate severity and variable lesion location, these results nevertheless suggest a top-down role for higher order areas such as attention in helping to orchestrate the stroke recovery process.