Home Aerobic Training for Cerebellar Degenerative Diseases: a Randomized Controlled Trial.

Balance training has shown some benefits in cerebellar ataxia whereas the effects of aerobic training are relatively unknown. To determine whether a phase III trial comparing home aerobic to balance training in ambulatory patients with cerebellar ataxia is warranted, we conducted a single-center, assessor-blinded, randomized controlled trial. Nineteen subjects were randomized to aerobic training and 17 subjects to balance training. The primary outcome was improvement in ataxia as measured by the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes included safety, training adherence, and balance improvements. There were no differences between groups at baseline. Thirty-one participants completed the trial, and there were no training-related serious adverse events. Compliance to training was over 70%. There was a mean improvement in ataxia symptoms of 1.9 SARA points (SD 1.62) in the aerobic group compared to an improvement of 0.6 points (SD 1.34) in the balance group. Although two measures of balance were equivocal between groups, one measure of balance showed greater improvement with balance training compared to aerobic training. In conclusion, this 6-month trial comparing home aerobic versus balance training in cerebellar ataxia had excellent retention and adherence to training. There were no serious adverse events, and training was not interrupted by minor adverse events like falls or back pain. There was a significant improvement in ataxia symptoms with home aerobic training compared to balance training, and a phase III trial is warranted. Clinical trial registration number: NCT03701776 on October 8, 2018.

GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity.

OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is rising in incidence, and at present, there are limited effective systemic therapies. iCCA tumours are infiltrated by stromal cells, with high prevalence of suppressive myeloid populations including tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Here, we show that tumour-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) and the host bone marrow is central for monopoiesis and potentiation of TAMs, and abrogation of this signalling axis facilitates antitumour immunity in a novel model of iCCA. METHODS: Blood and tumours were analysed from iCCA patients and controls. Treatment and correlative studies were performed in mice with autochthonous and established orthotopic iCCA tumours treated with anti-GM-CSF monoclonal antibody. RESULTS: Systemic elevation in circulating myeloid cells correlates with poor prognosis in patients with iCCA, and patients who undergo resection have a worse overall survival if tumours are more infiltrated with CD68+ TAMs. Mice with spontaneous iCCA demonstrate significant elevation of monocytic myeloid cells in the tumour microenvironment and immune compartments, and tumours overexpress GM-CSF. Blockade of GM-CSF with a monoclonal antibody decreased tumour growth and spread. Mice bearing orthotopic tumours treated with anti-GM-CSF demonstrate repolarisation of immunosuppressive TAMs and MDSCs, facilitating T cell response and tumour regression. GM-CSF blockade dampened inflammatory gene networks in tumours and TAMs. Human tumours with decreased GM-CSF expression exhibit improved overall survival after resection. CONCLUSIONS: iCCA uses the GM-CSF-bone marrow axis to establish an immunosuppressive tumour microenvironment. Blockade of the GM-CSF axis promotes antitumour T cell immunity.

Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.

Estimated Regional White Matter Hyperintensity Burden, Resting State Functional Connectivity, and Cognitive Functions in Older Adults.

OBJECTIVE: White matter hyperintensities (WMH) are linked to deficits in cognitive functioning, including cognitive control and memory; however, the structural, and functional mechanisms are largely unknown. We investigated the relationship between estimated regional disruptions to white matter fiber tracts from WMH, resting state functional connectivity (RSFC), and cognitive functions in older adults. DESIGN: Cross-sectional study. SETTING: Community. PARTICIPANTS: Fifty-eight cognitively-healthy older adults. MEASUREMENTS: Tasks of cognitive control and memory, structural MRI, and resting state fMRI. We estimated the disruption to white matter fiber tracts from WMH and its impact on gray matter regions in the cortical and subcortical frontoparietal network, default mode network, and ventral attention network by overlaying each subject's WMH mask on a normative tractogram dataset. We calculated RSFC between nodes in those same networks. We evaluated the interaction of regional WMH burden and RSFC in predicting cognitive control and memory. RESULTS: The interaction of estimated regional WMH burden and RSFC in cortico-striatal regions of the default mode network and frontoparietal network was associated with delayed recall. Models predicting working memory, cognitive inhibition, and set-shifting were not significant. CONCLUSION: Findings highlight the role of network-level structural and functional alterations in resting state networks that are related to WMH and impact memory in older adults.

The Structural and Functional Neuroanatomy of Post-Stroke Depression and Executive Dysfunction: A Review of Neuroimaging Findings and Implications for Treatment.

Post-stroke depression and executive dysfunction co-occur and are highly debilitating. Few treatments alleviate both depression and executive dysfunction after stroke. Understanding the brain network changes underlying post-stroke depression with executive dysfunction can inform the development of targeted and efficacious treatment. In this review, we synthesize neuroimaging findings in post-stroke depression and post-stroke executive dysfunction and highlight the network commonalities that may underlie this comorbidity. Structural and functional alterations in the cognitive control network, salience network, and default mode network are associated with depression and executive dysfunction after stroke. Specifically, post-stroke depression and executive dysfunction are both linked to changes in intrinsic functional connectivity within resting state networks, functional over-connectivity between the default mode and salience/cognitive control networks, and reduced cross-hemispheric frontoparietal functional connectivity. Cognitive training and noninvasive brain stimulation targeted at these brain network abnormalities and specific clinical phenotypes may help advance treatment for post-stroke depression with executive dysfunction.

Detecting change in community participation with the Enfranchisement scale of the community participation indicators.

OBJECTIVE: This study determined the sensitivity to change of the Enfranchisement scale of the Community Participation Indicators in people with stroke. DATA SOURCES: We analyzed data from two studies of participants with stroke: an intervention study and an observational study. MAIN MEASURES: The Enfranchisement Scale contains two subscales: the Importance subscale (feeling valued by and contributing to the community; range: 14-70) and the Control subscale (choice and control: range: 13-64). DATA ANALYSIS: Assessments were administered 6 months apart. We calculated minimum detectable change and minimal clinically important difference. RESULTS: The Control subscale analysis included 121 participants with a mean age of 61.2 and mild-moderate disability (Functional Independence Measure, mean = 97.9, SD = 24.7). On the Control subscale, participants had a mean baseline score of 51.4 (SD = 10.4), and little mean change (1.3) but with large variation in change scores (SD = 11.5). We found a minimum detectable change of 9 and a minimum clinically important difference of 6. The Importance subscale analysis included 116 participants with a mean age of 60.7 and mild-moderate disability (Functional Independence Measure, mean = 98.9, SD = 24.5). On the Importance subscale, participants had a mean baseline score of 44.1 (SD = 12.7), and again demonstrated little mean change (1.08) but with large variation in change scores (SD = 12.6). We found a minimum detectable change of 11 and a minimum clinically important difference 7. CONCLUSIONS: The Control subscale required 9 points of change, and the Importance subscale required 11 points of change, to achieve statistically and clinically meaningful changes, suggesting adequate sensitivity to change.

FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA. METHODS: FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Follow-up RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition. RESULTS: An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss. CONCLUSIONS: Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies. LAY SUMMARY: Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.

Changes in the Activity Measure for Post-Acute Care Domains in Persons With Stroke During the First Year After Discharge From Inpatient Rehabilitation.

OBJECTIVE: To describe functional changes after inpatient stroke rehabilitation using the Activity Measure for Post-Acute Care (AM-PAC), an assessment measure sensitive to change and with a low risk of ceiling effect. DESIGN: Retrospective, longitudinal cohort study. SETTING: Inpatient rehabilitation unit of an urban academic medical center. PARTICIPANTS: Among 433 patients with stroke admitted from 2012-2016, a total of 269 (62%) were included in our database and 89 of 269 patients (33.1%) discharged from inpatient stroke rehabilitation had complete data. Patients with and without complete data were very similar. The group had a mean age of 68.0±14.2 years, National Institutes of Health Stroke Score of 8.0±8.0, and rehabilitation length of stay of 14.7±7.4 days, with 84% having an ischemic stroke and 22.5% having a recurrent stroke. INTERVENTION: None. MAIN OUTCOME MEASURES: Changes in function across the first year after discharge (DC) were measured in a variety of ways. Continuous mean scores for the basic mobility (BM), daily activity (DA), and applied cognitive domains of the AM-PAC were calculated at and compared between inpatient DC and 6 (6M) and 12 months (12M) post DC. Categorical changes among individuals were classified as "improved," "unchanged," or "declined" between the 3 time points based on the minimal detectable change, (estimated) minimal clinically important difference, and a change ≥1 AM-PAC functional stage (FS). RESULTS: For the continuous analyses, the Friedman test was significant for all domains (P≤.002), with Wilcoxon signed-rank test significant for all domains from DC to 6M (all P<.001) but with no change in BM and DA between 6M and 12M (P>.60) and a decline in applied cognition (P=.002). Despite group improvements from DC to 6M, for categorical changes at an individual level 10%-20% declined and 50%-70% were unchanged. Despite insignificant group differences from 6M-12M, 15%-25% improved and 20%-30% declined in the BM and DA domains. CONCLUSIONS: Despite group gains from DC to 6M and an apparent "plateau" after 6M post stroke, there was substantial heterogeneity at an individual level. Our results underscore the need to consider individual-level outcomes when evaluating progress or outcomes in stroke rehabilitation.

Subgroups Defined by the Montreal Cognitive Assessment Differ in Functional Gain During Acute Inpatient Stroke Rehabilitation.

OBJECTIVE: To validate subgroups of cognitive impairment on the Montreal Cognitive Assessment (MoCA)-defined as normal (score of 25-30), mildly impaired (score of 20-24), and moderately impaired (score less than 19)-by determining whether they differ in rehabilitation gain during inpatient stroke rehabilitation. DESIGN: Observational study. Linear regression models were conducted and predictors included MoCA subgroups and relevant baseline demographic and clinical covariates. Separate models included the cognitive subscale of the FIM instrument as a predictor. SETTING: Inpatient rehabilitation facility of an urban, academic medical center. PARTICIPANTS: Inpatients (N=334) with mild-moderate strokes who were administered the MoCA on admission. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The mean relative functional gain (mRFG) and mean relative functional efficiency (mRFE, which adjusts for length of stay) on the FIM total. RESULTS: MoCA subgroups significantly predicted mRFG and mRFE after accounting for age, sex, education, stroke severity, and recurrent vs first stroke. The normal group exhibited greater mRFG and mRFE than the mildly impaired group, while the moderately impaired group had significantly worse mRFG and mRFE than the mildly impaired group. The moderately impaired group had a significantly smaller proportion of individuals who made a clinically meaningful change on the total-FIM than the mildly impaired and normal groups. MoCA subgroups better accounted for mRFG and mRFE than a standard-of-care cognitive assessment (cognitive-FIM). CONCLUSIONS: Use of MoCA-defined subgroups can assist providers in predicting functional gain in survivors of stroke being treated in inpatient rehabilitation.

Phase I randomized single-blinded controlled study investigating the potential benefit of aerobic exercise in degenerative cerebellar disease.

OBJECTIVES: To investigate whether people with cerebellar degeneration can perform rigorous aerobic exercise and to assess the clinical impact of training. DESIGN: Randomized single-blinded controlled, feasibility study comparing aerobic training to no training. SETTING: Home intervention, assessments conducted at an academic medical center. SUBJECTS: Twenty individuals with cerebellar degeneration caused by a range of genetic disorders. INTERVENTION: Aerobic training consisted of four weeks of stationary bicycle training, five times per week for 30-minute sessions. Intensity ranged from 65% to 80% of the participant's maximal heart rate determined during cardiopulmonary exercise testing. MAIN MEASURES: Primary outcome measure was change in the Scale for the Assessment and Rating of Ataxia scores. Recruitment rate, adherence, drop-out, and adverse events were also determined. The treatment was considered technically feasible if participants achieved target training frequency, duration, and intensity. RESULTS: The 20 participants mean age was 50 years (standard deviation 15.65 years) and average Scale for the Assessment and Rating of Ataxia score was 9.6 (standard deviation 3.13). Ten participants were randomized to aerobic training and 10 to no training. Seven participants in the aerobic group attained target training duration, frequency, and intensity. There was a mean reduction in ataxia severity of 2.1 points (standard deviation 1.26) with four weeks of aerobic training, whereas ataxia severity increased by 0.3 (standard deviation 0.62) in the control group over the same period. Walking speed, balance measures, and fitness also improved in individuals who performed aerobic exercise. CONCLUSIONS: Rigorous aerobic training is feasible in people with cerebellar degeneration. Improvements in ataxia, balance, and gait are promising.

ARID1A, a SWI/SNF subunit, is critical to acinar cell homeostasis and regeneration and is a barrier to transformation and epithelial-mesenchymal transition in the pancreas.

OBJECTIVE: Here, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (ARID1A), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models. DESIGN: Mice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes. RESULTS: Arid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a, leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation. CONCLUSIONS: ARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.

The diagnostic accuracy of the Montreal Cognitive Assessment in inpatient stroke rehabilitation.

The Montreal Cognitive Assessment (MoCA) is a commonly used screening measure for cognitive impairment; however, the diagnostic accuracy and optimal cutoff points in inpatients with mild stroke severity is unknown. We examined the diagnostic accuracy of the MoCA in an acute inpatient stroke rehabilitation unit (N = 95). The criterion neuropsychological assessment was the 30-minute National Institute of Neurological Disorders and Stroke-Canadian Stroke Network battery, modified to include the Symbol-Digit Modalities Test and Trail Making Test A & B. The MoCA had moderately strong diagnostic accuracy in receiver operating curve analyses, with areas under the curve ranging from .80 to .89 depending on the threshold for defining cognitive impairment. Sensitivity ranged from .72 to .87, and was generally greater than specificity, which ranged from .60 to .81. The optimal cutoff on the MoCA for detecting mild or greater cognitive impairment was <25/30. The optimal cutoff using more conservative definitions of cognitive impairment ranged from <23-24/30. Exploratory analyses of MoCA subgroups ("normal," "mildly impaired," and "functionally impaired") differed in the frequency and magnitude of impairment on the criterion neuropsychological assessment. These findings inform the clinical use of the MoCA in individuals with mild stroke in an inpatient rehabilitation setting.

Feasibility of an Electromyography-Triggered Hand Robot for People After Chronic Stroke.

IMPORTANCE: Effective treatment of the affected hand after stroke is crucial for improved functional independence and recovery. OBJECTIVE: To determine the feasibility and clinical utility of an electromyography-triggered hand robot. DESIGN: Single-group repeated-measures design. Participants completed training 3×/wk for 6 wk. Feasibility data included participant feedback, adverse events, and compliance rates. Upper extremity outcomes were collected at baseline, discharge, and 6-wk follow-up. SETTING: Outpatient clinic. PARTICIPANTS: Twelve stroke survivors at least 6 mo poststroke living in the community. INTERVENTION: Eighteen sessions of intensive robotic hand therapy over 6 wk. Each 60-min treatment session was personalized to match the participant's ability. OUTCOMES AND MEASURES: Arm Motor Ability Test (AMAT), Stroke Impact Scale Hand subscale (SIS-H), Stroke Upper Limb Capacity Scale (SULCS), Fugl-Meyer Assessment, Box and Block Test, and dynamometer. RESULTS: All participants completed the training phase. Mild skin pinching or rubbing at dorsal proximal interphalangeal joint and proximal arm fatigue were the most common adverse events. Improvements in raw scores were achieved from baseline to discharge for all outcome measures, except the SULCS. Participants significantly improved from baseline to discharge on the AMAT and the SIS-H, and improvements were maintained at 6-wk follow-up. CONCLUSION AND RELEVANCE: Robotic hand training was feasible, safe, and well tolerated. Participants reported and demonstrated improvements in functional use of the affected arm. Thirty percent of participants achieved clinically significant improvements on the AMAT. We recommend further study of the device in a larger study using the AMAT as a primary outcome measure. WHAT THIS ARTICLE ADDS: It is feasible and safe to implement a robotic hand training protocol for people with moderate to severe arm impairment in an outpatient setting. Robotic training may provide a viable option for this group to actively participate in intensive training of the distal hand.

Effects of repeated abobotulinumtoxinA injections in upper limb spasticity.

INTRODUCTION: The efficacy of single injections of abobotulinumtoxinA (Dysport) is established in adults with upper limb spasticity. In this study we assessed the effects of repeated injections of abobotulinumtoxinA over 1 year. METHODS: Patients (n = 258, safety population) received 500 U, 1,000 U, or 1,500 U (1,500-U dose included 500-U shoulder injections) for up to 4 or 5 treatment cycles. Assessments included treatment-emergent adverse events (TEAEs), muscle tone, passive and active range of motion (XV1, XA ), angle of catch (XV3 ), Disability Assessment Scale (DAS) score, Modified Frenchay Scale (MFS) score, and Physician Global Assessment (PGA) score. RESULTS: The incidence of TEAEs decreased across cycles. Muscle tone reduction and XV1 remained stable across cycles, whereas XV3 and XA continued to improve at the finger, wrist, and elbow flexors. DAS and PGA improved across cycles. MFS improved best with 1,500 U. DISCUSSION: A favorable safety profile and continuous improvements in active movements and perceived and active function were associated with repeated abobotulinumtoxinA injections in upper limb muscles. Muscle Nerve 57: 245-254, 2018.

Ultrasound Strain Imaging to Assess the Biceps Brachii Muscle in Chronic Poststroke Spasticity.

OBJECTIVES: The aim of the study was to assess the feasibility of ultrasound strain imaging in characterizing the biceps brachii muscle in chronic poststroke spasticity. METHODS: We prospectively analyzed strain imaging data from bilateral biceps brachii muscles in 8 healthy volunteers and 7 patients with poststroke chronic spasticity. Axial deformations of the biceps brachii muscle and overlying subcutaneous tissue were produced by external compression using a sandbag (1.0 kg) attached to a transducer. The lengthening and shortening of the biceps brachii muscle and subcutaneous tissue were produced by manual passive elbow extension (from 90° to 0°) and flexion (from 0° to 90°), respectively. We used offline 2-dimensional speckle tracking to estimate axial and longitudinal strain ratios (biceps brachii strain/subcutaneous tissue strain), and the longitudinal tissue velocity of the biceps brachii muscle. Statistical analyses included analysis of variance for testing differences in strain imaging parameters among healthy, nonspastic, and spastic biceps brachii muscles, the Bonferroni correction for further testing differences in US strain imaging among paired groups (healthy versus spastic, nonspastic versus spastic, and healthy versus nonspastic), and the Pearson correlation coefficient for assessing the intraobserver reliability of performing strain imaging in stroke survivors. RESULTS: The differences in strain imaging parameters between healthy and spastic and between nonspastic and spastic biceps brachii muscles were significant at both 90° elbow flexion and maximal elbow extension (P < .01). There was no significant difference in axial strain ratios at 90° of elbow flexion or longitudinal tissue velocities between healthy and nonspastic muscles (P > .05). The intraobserver reliability of performing strain imaging in stroke survivors was good (r = 0.85; P < .01). CONCLUSIONS: Ultrasound strain imaging seems to be feasible for characterizing the biceps brachii muscle in chronic poststroke spasticity.

Fully Implantable Peripheral Nerve Stimulation for Hemiplegic Shoulder Pain: A Multi-Site Case Series With Two-Year Follow-Up.

OBJECTIVE: To explore the feasibility and safety of a single-lead, fully implantable peripheral nerve stimulation system for the treatment of chronic shoulder pain in stroke survivors. PARTICIPANTS: Participants with moderate to severe shoulder pain not responsive to conservative therapies for six months. METHODS: During the trial phase, which included a blinded sham introductory period, a percutaneous single-lead peripheral nerve stimulation system was implanted to stimulate the axillary nerve of the affected shoulder. After a three-week successful trial, participants received an implantable pulse generator with an electrode placed to stimulate the axillary nerve of the affected shoulder. Outcomes included pain, pain interference, pain-free external rotation range of motion, quality of life, and safety. Participants were followed for 24 months. RESULTS: Twenty-eight participants underwent trial stimulation and five participants received an implantable pulse generator. The participants who received the implantable generator experienced an improvement in pain severity (p = 0.0002). All five participants experienced a 50% or greater pain reduction at 6 and 12 months, and four experienced at least a 50% reduction at 24 months. There was an improvement in pain interference (p < 0.0001). There was an improvement in pain-free external ROM (p = 0.003). There were no serious adverse events related to the device or to the procedure. CONCLUSIONS: This case series demonstrates the safety and efficacy of a fully implantable axillary PNS system for chronic HSP. Participants experienced reduction in pain, reduction in pain interference, and improved pain-free external rotation ROM. There were no serious adverse events associated with the system or the procedure.

Randomized Trial on the Effects of Attentional Focus on Motor Training of the Upper Extremity Using Robotics With Individuals After Chronic Stroke.

OBJECTIVE: To compare the long-term effects of external focus (EF) and internal focus (IF) of attention after 4 weeks of arm training. DESIGN: Randomized, repeated-measures, mixed analysis of variance. SETTING: Outpatient clinic. PARTICIPANTS: Individuals with stroke and moderate-to-severe arm impairment living in the community (N=33; withdrawals: n=3). INTERVENTIONS: Four-week arm training protocol on a robotic device (12 sessions). MAIN OUTCOME MEASURES: Joint independence, Fugl-Meyer Assessment, and Wolf Motor Function Test measured at baseline, discharge, and 4-week follow-up. RESULTS: There were no between-group effects for attentional focus. Participants in both groups improved significantly on all outcome measures from baseline to discharge and maintained those changes at 4-week follow-up regardless of group assignment (joint independence EF condition: F1.6,45.4=17.74; P<.0005; partial η2=.39; joint independence IF condition: F2,56=18.66; P<.0005; partial η2=.40; Fugl-Meyer Assessment: F2,56=27.83; P<.0005; partial η2=.50; Wolf Motor Function Test: F2,56=14.05; P<.0005; partial η2=.35). CONCLUSIONS: There were no differences in retention of motor skills between EF and IF participants 4 weeks after arm training, suggesting that individuals with moderate-to-severe arm impairment may not experience the advantages of an EF found in healthy individuals. Attentional focus is most likely not an active ingredient for retention of trained motor skills for individuals with moderate-to-severe arm impairment, whereas dosage and intensity of practice appear to be pivotal. Future studies should investigate the long-term effects of attentional focus for individuals with mild arm impairment.

Association Between 2 Measures of Cognitive Instrumental Activities of Daily Living and Their Relation to the Montreal Cognitive Assessment in Persons With Stroke.

OBJECTIVES: To explore the relation between a computer adaptive functional cognitive questionnaire and a performance-based measure of cognitive instrumental activities of daily living (C-IADL) and to determine whether the Montreal Cognitive Assessment (MoCA) at admission can identify those with C-IADL difficulties at discharge. DESIGN: Prospective cohort study. SETTING: Acute inpatient rehabilitation unit of an academic medical center. PARTICIPANTS: Inpatients (N=148) with a diagnosis of stroke (mean age, 68y; median, 13d poststroke) who had mild cognitive and neurological deficits. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Admission cognitive status was assessed by the MoCA. C-IADL at discharge was assessed by the Executive Function Performance Test (EFPT) bill paying task and Activity Measure of Post-Acute Care (AM-PAC) Applied Cognition scale. RESULTS: Greater cognitive impairment on the MoCA was associated with more assistance on the EFPT bill paying task (ρ=-.63; P<.01) and AM-PAC Applied Cognition scale (ρ=-.43; P<.01). This relation was nonsignificant for higher MoCA scores and EFPT bill paying task scores. The AM-PAC Applied Cognition scale and the EFPT bill paying task had low agreement in classifying functional performance (Cohen's κ=.20). A receiver operating characteristic curve identified optimal MoCA cutoff scores of 20 and 21 for classifying EFPT bill paying task status and AM-PAC Applied Cognition scale status, respectively. For values above 20 and 21, sensitivity increased whereas specificity decreased for classifying functional deficits. Approximately one third of the participants demonstrated C-IADL deficits on at least 1 C-IADL measure at discharge despite having a MoCA score of ≥26 at admission. CONCLUSIONS: Questionnaire and performance-based methods of assessment appear to yield different estimates of C-IADL. Low MoCA scores (<20) are more likely to identify those with C-IADL deficits on the EFPT bill paying task. The results suggest that C-IADL should be assessed in those who have mild or no cognitive difficulties at admission.

Do Surgeon Expectations Predict Clinically Important Improvements in WOMAC Scores After THA and TKA?

BACKGROUND: Failure of THA or TKA to meet a patient's expectations may result in patient disappointment and litigation. However, there is little evidence to suggest that surgeons can consistently anticipate which patients will benefit from those interventions. QUESTIONS/PURPOSES: To determine the ability of surgeons to identify, in advance of surgery, patients who will benefit from THA or TKA and those who will not, where 'benefit' is defined as a clinically important improvement in a validated patient-reported outcomes score. METHODS: In this prospective study, eight high-volume orthopaedic surgeons completed validated THA and TKA expectations questionnaires (score 0-100, 100 being the highest expectation) as part of preoperative assessment of all their patients scheduled for a THA or TKA and enrolled in the Hospital for Special Surgery institutional registry. Enrolled patients completed the WOMAC preoperatively and at 2 years. Successful outcomes were defined as achieving the minimum clinically important difference (MCID) in WOMAC pain and function subscales. Sensitivity, specificity, and receiver operating characteristic (ROC) curves were used to evaluate the ability of surgeons' expectation scores to identify patients likely to achieve the MCID on the WOMAC scale. Analyses were run separately for patients having THA and TKA. We enrolled 259 patients undergoing THA and 247 undergoing TKA, of whom 77% (n = 200) and 77% (n = 191) completed followup surveys 2 years after their procedures, respectively. RESULTS: Surgeons' expectation scores effectively anticipated patients who would improve after THA, but they were no better than chance in identifying patients who would achieve the MCID on the WOMAC score 2 years after TKA. For patients having THA, the areas under the ROC curve were 0.67 (95% CI, 0.53-0.82; p = 0.02) and 0.74 (95% CI, 0.63-0.85; p < 0.01) for WOMAC function and pain outcomes, respectively, indicating good accuracy. Sensitivity and specificity were maximized on WOMAC pain and function scores (sensitivity = 0.69, specificity = 0.72, both for pain and function) at an expectations score of 83 or greater of 100. Surgeons' expectations were more accurate for patients who were men, who had a BMI less than 30 kg/m2, who had more than one comorbidity, and who were older than 65 years. For patients having TKA, surgeons' expectation scores were not better than chance for identifying those who would experience a clinically important improvement on the WOMAC scale (area under ROC curve: Function = 0.51, [95% CI, 0.42-0.61], p = 0.78; Pain = 0.51, [95% CI, 0.40-0.61], p = 0.92). CONCLUSIONS: Most patients having THA and TKA achieved the MCID improvement after surgery. However, the inability of surgeons' expectation scores to discriminate accurately between patients who benefit and those who do not among patients scheduled for THA who are young, with no comorbidities, and with elevated BMIs, and among all patients scheduled for TKA, calls for surgeons to spend more time with these patients to fully understand and address their needs and expectations. Using standardized assessment tools to compare surgeons' expectations and those of their patients may help focus the surgeon-patient discussion further, and address patients' expectations more effectively. LEVEL OF EVIDENCE: Level II, therapeutic study.

Structural connectome disruption at baseline predicts 6-months post-stroke outcome.

In this study, models based on quantitative imaging biomarkers of post-stroke structural connectome disruption were used to predict six-month outcomes in various domains. Demographic information and clinical MRIs were collected from 40 ischemic stroke subjects (age: 68.1 ± 13.2 years, 17 female, NIHSS: 6.8 ± 5.6). Diffusion-weighted images were used to create lesion masks, which were uploaded to the Network Modification (NeMo) Tool. The NeMo Tool, using only clinical MRIs, allows estimation of connectome disruption at three levels: whole brain, individual gray matter regions and between pairs of gray matter regions. Partial Least Squares Regression models were constructed for each level of connectome disruption and for each of the three six-month outcomes: applied cognitive, basic mobility and daily activity. Models based on lesion volume were created for comparison. Cross-validation, bootstrapping and multiple comparisons corrections were implemented to minimize over-fitting and Type I errors. The regional disconnection model best predicted applied cognitive (R(2) = 0.56) and basic mobility outcomes (R(2) = 0.70), while the pairwise disconnection model best predicted the daily activity measure (R(2) = 0.72). These results demonstrate that models based on connectome disruption metrics were more accurate than ones based on lesion volume and that increasing anatomical specificity of disconnection metrics does not always increase model accuracy, likely due to statistical adjustments for concomitant increases in data dimensionality. This work establishes that the NeMo Tool's measures of baseline connectome disruption, acquired using only routinely collected MRI scans, can predict 6-month post-stroke outcomes in various functional domains including cognition, motor function and daily activities. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.