Survival outcome of chemotherapy-naïve castration-resistant prostate cancer treated with new-generation androgen receptor axis-targeted agents in real-world analysis.

PURPOSE: The androgen receptor axis-targeted (ARAT) agents abiraterone and enzalutamide have been introduced against castration-resistant prostate cancer (CRPC). However, determining which of these agents should be used first is a clinical challenge. Therefore, in this study, we compared the efficacy of first-line abiraterone and enzalutamide treatments in chemotherapy-naïve patients with CRPC. METHODS: A total of 242 chemotherapy-naïve CRPC cases treated with first-line ARAT were analyzed. Outcome measures were PSA response, PSA progression-free survival (PSA-PFS), time to treatment failure (TTF), cancer specific survival (CSS), and overall survival (OS). RESULTS: Abiraterone (A) and enzalutamide (E) were administered to 61 and 181 patients, respectively. The median PSA response rate (- 65.4% [A] and - 78.8% [E], p = 0.0341), PSA decline ≥ 30% (55.7% [A] and 72.9% [E], p = 0.0183), PSA-PFS (median 4 months [A] and 8 months [E], p = 0.0126), TTF (median 6 months [A] and 14 months [E], p < 0.0001), CSS (median 45 months [A] and not reached [E], p < 0.0001), and OS (median 28 months [A] and 80 months [E], p < 0.001) were significantly better in the enzalutamide group. In the multivariate analyses for CSS and OS, ALP (p = 0.00376) and ARAT (p < 0.001) (CSS), evidence of metastasis (p = 0.0467), Hb (p = 0.00205), and ARAT (p = 0.00514) (OS) were significant factors, respectively. CONCLUSION: This study showed that PSA response, PSA-PFS, TTF, CSS, and OS were better with first-line enzalutamide administration. Direct inhibition of androgen receptor signaling by enzalutamide is associated with better clinical outcomes.

Propensity score-matched comparison of docetaxel and androgen receptor axis-targeted agents in patients with castration-resistant intraductal carcinoma of the prostate.

OBJECTIVE: To evaluate the efficacy of docetaxel and androgen receptor axis-targeted (ARAT) agents in patients with castration-resistant prostate cancer (CRPC) with intraductal carcinoma of the prostate (IDC-P) using a propensity score-matched analysis. PATIENTS AND METHODS: We retrospectively identified 309 patients with CRPC from February 2007 to February 2016 at Nagoya University and its affiliated hospitals. All patients received initial androgen-deprivation therapy (ADT). After progression to CRPC, they received docetaxel or ARAT (abiraterone or enzalutamide) as first-line life-prolonging therapy. Docetaxel (70-75 mg/m2 ) every 3 weeks vs enzalutamide (160 mg) once daily orally or abiraterone (1 g) once daily plus prednisone (5 mg) twice daily orally was administered. The primary outcome of interest was overall survival (OS) from the time of CRPC diagnosis. A propensity score analysis with a 1:1 ratio using an optimal matching algorithm was used to adjust for confounding factors. RESULTS: Overall, 234 patients were analysed. Propensity score-matching identified 85 patients in each group. There were no significant differences in patient characteristics between the groups. The median OS in the docetaxel group was 38.2 vs 58.3 months in the ARAT group (P = 0.03). For patients with IDC-P, OS was significantly longer in the ARAT group than the docetaxel group (P = 0.01), and there was no significant difference in each group, as in patients without IDC-P (P = 0.67). A multivariate analysis showed that the presence of IDC-P, duration of primary ADT, visceral metastasis, and administration of ARAT as the first-line treatment for CRPC were independent prognostic factors for OS. CONCLUSION: Administration of ARAT as the first-line treatment for CRPC may prolong OS more than that of docetaxel, especially in patients with IDC-P.

Earlier use of androgen receptor-axis-targeted drugs may improve overall survival in patients with non-metastatic castration-resistant prostate cancer.

BACKGROUND: To evaluate the role of androgen receptor-axis-targeted drugs (ARAT) in non-metastatic castration-resistant prostate cancer (nmCRPC) versus mCRPC. METHODS: Chemotherapy-naive patients (n = 114) with CRPC who had no metastasis at the time of diagnosis were included in this retrospective study. All patients were treated with ARAT at Jikei University and its affiliated hospitals from July 2014 to March 2017. The patients were stratified into nmCRPC (n = 81) and mCRPC (n = 33) groups according to their metastatic status at ARAT induction. The primary outcome measure was difference in overall survival (OS) between groups from the time of CRPC diagnosis. The patients were compared for progression-free survival (PFS) and prostate-specific antigen (PSA) response. The predictors of OS were explored by a multivariate Cox model. RESULTS: The baseline demographics did not differ significantly between the groups. The median observation period from the diagnosis of CRPC was 24.5 months (range: 3-135) and 20 months (range: 1-66) in nmCRPC and mCRPC groups, respectively. The nmCRPC group demonstrated better OS from the time of diagnosis of CRPC in Kaplan-Meier analysis than mCRPC group (86 months vs 40 months; P = 0.004), with similar results obtained for PFS (P = 0.048) and PSA response (P = 0.0014). Multivariate analysis demonstrated non-metastatic status, low PSA, and long PSA doubling time (PSADT) at ARAT induction as the significant predictors of longer OS (P = 0.044, 0.0001, and 0.026, respectively). CONCLUSIONS: Early use of ARAT may improve OS, PFS, and PSA response in CRPC. Larger, prospective studies will be required to confirm our findings.

Using Inertial Measurement Units and Electromyography to Quantify Movement during Action Research Arm Test Execution.

In patients after stroke, ability of the upper limb is commonly assessed with standardised clinical tests that provide a complete upper limb assessment. This paper presents quantification of upper limb movement during the execution of Action research arm test (ARAT) using a wearable system of inertial measurement units (IMU) for kinematic quantification and electromyography (EMG) sensors for muscle activity analysis. The test was executed with each arm by a group of healthy subjects and a group of patients after stroke allocated into subgroups based on their clinical scores. Tasks were segmented into movement and manipulation phases. Each movement phase was quantified with a set of five parameters: movement time, movement smoothness, hand trajectory similarity, trunk stability, and muscle activity for grasping. Parameters vary between subject groups, between tasks, and between task phases. Statistically significant differences were observed between patient groups that obtained different clinical scores, between healthy subjects and patients, and between the unaffected and the affected arm unless the affected arm shows normal performance. Movement quantification enables differentiation between different subject groups within movement phases as well as for the complete task. Spearman's rank correlation coefficient shows strong correlations between patient's ARAT scores and movement time as well as movement smoothness. Weak to moderate correlations were observed for parameters that describe hand trajectory similarity and trunk stability. Muscle activity correlates well with grasping activity and the level of grasping force in all groups.

Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

BACKGROUND: An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. METHODS: This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. RESULTS: Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). CONCLUSIONS: The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS.

Contemporary Systemic Therapy Intensification for Prostate Cancer: A Review for General Practitioners in Oncology.

Prostate cancer accounts for a significant proportion of cancer diagnoses in Canadian men. Over the past decade, the therapeutic landscape for the management of metastatic prostate cancer has undergone rapid changes. Novel strategies use hormonal agents, chemotherapy, homologous recombination repair inhibitors, and radioligand therapy or combination strategies in addition to androgen deprivation therapy. In this review, we summarize the available data addressing key therapeutic areas along the disease continuum and focus on practical aspects for general practitioners in oncology managing patients with metastatic prostate cancer.

Evaluation of Trends in Treatment of Metastatic Hormone Sensitive Prostate Cancer (mHSPC) Across Canada During the COVID-19 Pandemic.

BACKGROUND: In metastatic hormone sensitive prostate cancer (mHSPC), treatment intensification with either docetaxel or an androgen-receptor-axis targeted therapy (ARAT), added to androgen deprivation therapy (ADT) is the new standard of care. To better understand patterns of treatment intensification in Canada and specifically how it has been influenced by the COVID-19 pandemic, we conducted a national survey of genitourinary medical oncologists from across Canada. METHODS: Using SurveyMonkey, we conducted an online survey of 119 medical oncologists in Canada from January 15 to January 27, 2021. The survey consisted of 16 questions, including demographics, and asked specifically about their approach to managing mHSPC before and during the pandemic. RESULTS: Overall there were 50/119 (42%) respondents. Most were male (65%), from Ontario (35%), practicing in academic centers (71%), with 45% reporting their practices focused primarily on genitourinary malignancies and one other tumor site. The majority were in practice 1 to 5 years (34%). Overall 65% indicated their practice patterns had changed since the pandemic, with 51% offering more ARATs and less docetaxel chemotherapy. In low volume mHSPC, the use of ARATs increased from 73% to 79%, while the use of docetaxel remained unaltered at 2%. In high volume disease, the use of ARATs increased from 63% to 84%, while the use of docetaxel decreased from 37% to 14%. Use of granulocyte colony stimulating factor (G-CSF) with docetaxel chemotherapy increased by 35%. Post-pandemic, 45% reported they intend to maintain these changes. Only 18% reported they had prostate cancer patients test positive for COVID-19, and all patients recovered. CONCLUSION: Management of patients with mHSPC in Canada has changed during the pandemic, with increased uptake of ARATs and reduced use of docetaxel, a trend expected to continue beyond the pandemic. How this trend will impact uptake of triplet therapy (ADT + ARAT + Docetaxel), downstream treatment choices and overall outcomes remains to be seen.

Sequential therapy with darolutamide in patients with non-metastatic castration-resistant prostate cancer resistant to enzalutamide or apalutamide.

Enzalutamide, apalutamide, and darolutamide are currently recommended for patients with non-metastatic castration-resistant prostate cancer (nmCRPC), but cross-resistance of androgen receptor-axis-targeted therapies (ARAT) occurs. Because darolutamide has a distinct chemical structure to other non-steroidal antiandrogens, it may be effective for nmCRPC patients resistant to enzalutamide or apalutamide. We retrospectively evaluated the efficacy of switching to darolutamide in patients with nmCRPC. We included nine nmCRPC patients who experienced biochemical progression on enzalutamide or apalutamide and were switched over to darolutamide. Five patients (55.5%) had a PSA response >50% decline after starting darolutamide, with an average of 73% PSA decline. Median progression-free survival was 6 months. In conclusion, an ARAT switch from enzalutamide or apalutamide to darolutamide might be effective for nmCRPC. Although the validation in a large-scale cohort is necessary, the switch to darolutamide could be a promising therapeutic option after the progression of 1st line ARAT in nmCRPC patients.

18F-DCFPyL (PSMA) PET as a radiotherapy response assessment tool in metastatic prostate cancer.

Background: Prostate Specific Membrane Antigen (PSMA) - positron emission tomography (PET) guides metastasis-directed radiotherapy (MDRT) in prostate cancer (PrCa). However, its value as a treatment response assessment tool after MDRT remains unclear. Importantly, there is limited understanding of the potential of radiotherapy (RT) to alter PSMA gene (folate hydrolase 1; FOLH1) expression. Methodology: We reviewed a series of 11 men with oligo-metastatic PrCa (25 metastasis sites) treated with MDRT before re-staging with 18F-DCFPyL (PSMA) PET upon secondary recurrence. Acute effects of RT on PSMA protein and mRNA levels were examined with qPCR and immunoblotting in human wild-type androgen-sensitive (LNCap), castrate-resistant (22RV1) and castrate-resistant neuroendocrine (PC3 and DU145) PrCa cell lines. Xenograft tumors were analyzed with immunohistochemistry. Further, we examined PSMA expression in untreated and irradiated radio-resistant (RR) 22RV1 (22RV1-RR) and DU145 (DU145-RR) cells and xenografts selected for survival after high-dose RT. Results: The majority of MDRT-treated lesions showed lack of PSMA-PET/CT avidity, suggesting treatment response even after low biological effective dose (BED) MDRT. We observed similar high degree of heterogeneity of PSMA expression in both human specimens and in xenograft tumors. PSMA was highly expressed in LNCap and 22RV1 cells and tumors but not in the neuroendocrine PC3 and DU145 models. Single fraction RT caused detectable reduction in PSMA protein but not in mRNA levels in LNCap cells and did not significantly alter PSMA protein or mRNA levels in tissue culture or xenografts of the other cell lines. However, radio-resistant 22RV1-RR cells and tumors demonstrated marked decrease of PSMA transcript and protein expression over their parental counterparts. Conclusions: PSMA-PET may be a promising tool to assess RT response in oligo-metastatic PrCa. However, future systematic investigation of this concept should recognize the high degree of heterogeneity of PSMA expression within prostate tumors and the risk for loss of PSMA expression in tumor surviving curative courses of RT.

Real-World Cabazitaxel Use and Outcomes in Metastatic Castrate-Resistant Prostate Cancer: The Impact of Response to First ARPI.

BACKGROUND: For post-docetaxel treatment of metastatic castrate-resistant prostate cancer (mCRPC), cabazitaxel has demonstrated superior third line PFS and OS compared to androgen receptor pathway inhibitors (ARPIs) in patients who progress within 12 months on first ARPI. The impact of first ARPI response, in particular responses beyond 12 months, on cabazitaxel outcomes in real-world populations is uncertain, as are other factors impacting cabazitaxel use. MATERIALS AND METHODS: mCRPC patients in Alberta, Canada who received docetaxel from October 1, 2012 to December 31, 2017 were included. We reviewed mCRPC therapies, correlating cabazitaxel use with patient characteristics and TROPIC trial inclusion/exclusion criteria. OS and PFS were evaluated in patients who received cabazitaxel, stratified by time to progression on first ARPI ≤ 12 months (poor ARPI responders, PAR) or >12 months (strong ARPI responders, SAR), using the Kaplan-Meier method. RESULTS: PAR patients had inferior OS compared to SAR patients (12.3 vs. 24.8 months, P < .001). OS was longer in PAR patients receiving cabazitaxel compared to those not treated with cabazitaxel (16.9 vs. 10.3 months, P = .015), but this benefit was not seen in the SAR group (17.1 vs. 32 months, P = .084). Cabazitaxel use was associated with reduced PFS first line post-docetaxel in SAR (3.5 vs. 14.7 months, P < .001) but not PAR patients. Of 592 patients, 170 (29%) received cabazitaxel post-docetaxel, compared to 280 (47%) and 250 (42%) for abiraterone and enzalutamide. 238 patients (40%) did not have a discussion of cabazitaxel documented. Cabazitaxel use was increased in patients who fit TROPIC trial criteria (P < .001). CONCLUSIONS: In a real-world mCRPC cohort, cabazitaxel use was associated with longer OS among PAR patients, but crucially not among strong ARPI responders. Cabazitaxel was used less frequently and later than ARPIs post-docetaxel. These data help support first ARPI progression time as a consideration in treatment sequencing.

Using Wearable Inertial Sensors to Estimate Clinical Scores of Upper Limb Movement Quality in Stroke.

Neurorehabilitation is progressively shifting from purely in-clinic treatment to therapy that is provided in both clinical and home-based settings. This transition generates a pressing need for assessments that can be performed across the entire continuum of care, a need that might be accommodated by application of wearable sensors. A first step toward ubiquitous assessments is to augment validated and well-understood standard clinical tests. This route has been pursued for the assessment of motor functioning, which in clinical research and practice is observation-based and requires specially trained personnel. In our study, 21 patients performed movement tasks of the Action Research Arm Test (ARAT), one of the most widely used clinical tests of upper limb motor functioning, while trained evaluators scored each task on pre-defined criteria. We collected data with just two wrist-worn inertial sensors to guarantee applicability across the continuum of care and used machine learning algorithms to estimate the ARAT task scores from sensor-derived features. Tasks scores were classified with approximately 80% accuracy. Linear regression between summed clinical task scores (across all tasks per patient) and estimates of sum task scores yielded a good fit (R 2 = 0.93; range reported in previous studies: 0.61-0.97). Estimates of the sum scores showed a mean absolute error of 2.9 points, 5.1% of the total score, which is smaller than the minimally detectable change and minimally clinically important difference of the ARAT when rated by a trained evaluator. We conclude that it is feasible to obtain accurate estimates of ARAT scores with just two wrist worn sensors. The approach enables administration of the ARAT in an objective, minimally supervised or remote fashion and provides the basis for a widespread use of wearable sensors in neurorehabilitation.

Effects of dry needling and exercise therapy on post-stroke spasticity and motor function- protocol of randomized clinical trial.

Background: Spasticity is one of the most common problems after the first stroke. Dry needling (DN) has been presented as a new therapeutic approach used by physiotherapists for the management of post-stroke spasticity. This study aimed to determine whether the addition of exercise therapy to the DN results in better outcomes in wrist flexors spasticity, motor neuron excitability, motor function and range of motion (ROM) in patients with chronic stroke. Methods: We will use a single-blind randomized controlled trial (RCT) in accordance with the CONSORT guidelines. A total of 24 patients with stroke will be included from the University Rehabilitation Clinics. The outcome measures will include Modified Modified Ashworth Scale, Hmax/Mmax ratio, H-reflex latency, Action Research Arm Test, Fugl-Meyer Assessment, and wrist extension active and passive range of motion. Patients in the DN and exercise therapy group will undergo 4 sessions of deep DN in flexor carpi radialis and flexor carpi ulnaris muscles on the affected upper limb and exercise therapy. Participants in the DN group will only receive DN for target muscles. Clinical and neurophysiological tests will be performed at baseline, after four therapy sessions, and at three weeks' follow-up. Discussion: This study will provide evidence for additional effects of exercise therapy to DN in comparison to DN alone on wrist flexors spasticity, motor neuron excitability, upper-limb motor function, and ROM in patients with chronic stroke.

Brain-Computer Interface Coupled to a Robotic Hand Orthosis for Stroke Patients' Neurorehabilitation: A Crossover Feasibility Study.

Brain-Computer Interfaces (BCI) coupled to robotic assistive devices have shown promise for the rehabilitation of stroke patients. However, little has been reported that compares the clinical and physiological effects of a BCI intervention for upper limb stroke rehabilitation with those of conventional therapy. This study assesses the feasibility of an intervention with a BCI based on electroencephalography (EEG) coupled to a robotic hand orthosis for upper limb stroke rehabilitation and compares its outcomes to conventional therapy. Seven subacute and three chronic stroke patients (M = 59.9 ± 12.8) with severe upper limb impairment were recruited in a crossover feasibility study to receive 1 month of BCI therapy and 1 month of conventional therapy in random order. The outcome measures were comprised of: Fugl-Meyer Assessment of the Upper Extremity (FMA-UE), Action Research Arm Test (ARAT), motor evoked potentials elicited by transcranial magnetic stimulation (TMS), hand dynamometry, and EEG. Additionally, BCI performance and user experience were measured. All measurements were acquired before and after each intervention. FMA-UE and ARAT after BCI (23.1 ± 16; 8.4 ± 10) and after conventional therapy (21.9 ± 15; 8.7 ± 11) were significantly higher (p < 0.017) compared to baseline (17.5 ± 15; 4.3 ± 6) but were similar between therapies (p > 0.017). Via TMS, corticospinal tract integrity could be assessed in the affected hemisphere of three patients at baseline, in five after BCI, and four after conventional therapy. While no significant difference (p > 0.05) was found in patients' affected hand strength, it was higher after the BCI therapy. EEG cortical activations were significantly higher over motor and non-motor regions after both therapies (p < 0.017). System performance increased across BCI sessions, from 54 (50, 70%) to 72% (56, 83%). Patients reported moderate mental workloads and excellent usability with the BCI. Outcome measurements implied that a BCI intervention using a robotic hand orthosis as feedback has the potential to elicit neuroplasticity-related mechanisms, similar to those observed during conventional therapy, even in a group of severely impaired stroke patients. Therefore, the proposed BCI system could be a suitable therapy option and will be further assessed in clinical trials.

Prognosis of stroke upper limb recovery with physiological variables using regression tree ensembles.

Objective.This study assesses upper limb recovery prognosis after stroke with solely physiological information, which can provide an objective estimation of recovery.Approach.Clinical recovery was forecasted using EEG-derived Event-Related Desynchronization/Synchronization and coherence, in addition to Transcranial Magnetic Stimulation elicited motor-evoked potentials and upper limb grip and pinch strength. A Regression Tree Ensemble predicted clinical recovery of a stroke database (n= 10) measured after a two-month intervention with the Fugl-Meyer Assessment for the Upper Extremity (FMA-UE) and the Action Research Arm Test (ARAT).Main results.There were no significant differences between predicted and actual outcomes with FMA-UE (p= 0.29) and ARAT (p= 0.5). Median prediction error for FMA-UE and ARAT were of 0.3 (IQR = 6.2) and 3.4 (IQR = 9.4) points, respectively. Predictions with the most pronounced errors were due to an underestimation of high upper limb recovery. The best features for FMA-UE prediction included mostly beta activity over the sensorimotor cortex. Best ARAT prediction features were cortical beta activity, corticospinal tract integrity of the unaffected hemisphere, and upper limb strength.Significance.Results highlighted the importance of measuring cortical activity related to motor control processes, the unaffected hemisphere's integrity, and upper limb strength for prognosis. It was also implied that stroke upper limb recovery prediction is feasible using solely physiological variables with a Regression Tree Ensemble, which can also be used to analyze physiological relationships with recovery.

Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells.

We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC.

A Novel Wearable Device for Motor Recovery of Hand Function in Chronic Stroke Survivors.

Background. In monkey, reticulospinal connections to hand and forearm muscles are spontaneously strengthened following corticospinal lesions, likely contributing to recovery of function. In healthy humans, pairing auditory clicks with electrical stimulation of a muscle induces plastic changes in motor pathways (probably including the reticulospinal tract), with features reminiscent of spike-timing dependent plasticity. In this study, we tested whether pairing clicks with muscle stimulation could improve hand function in chronic stroke survivors. Methods. Clicks were delivered via a miniature earpiece; transcutaneous electrical stimuli at motor threshold targeted forearm extensor muscles. A wearable electronic device (WD) allowed patients to receive stimulation at home while performing normal daily activities. A total of 95 patients >6 months poststroke were randomized to 3 groups: WD with shock paired 12 ms before click; WD with clicks and shocks delivered independently; standard care. Those allocated to the device used it for at least 4 h/d, every day for 4 weeks. Upper-limb function was assessed at baseline and weeks 2, 4, and 8 using the Action Research Arm Test (ARAT), which has 4 subdomains (Grasp, Grip, Pinch, and Gross). Results. Severity across the 3 groups was comparable at baseline. Only the paired stimulation group showed significant improvement in total ARAT (median baseline: 7.5; week 8: 11.5; P = .019) and the Grasp subscore (median baseline: 1; week 8: 4; P = .004). Conclusion. A wearable device delivering paired clicks and shocks over 4 weeks can produce a small but significant improvement in upper-limb function in stroke survivors.

Kinematic Measures of Bimanual Performance are Associated With Callosum White Matter Change in People With Chronic Stroke.

OBJECTIVES: To investigate the relationship between bimanual performance deficits measured using kinematics and callosum (CC) white matter changes that occur in people with chronic stroke. DESIGN: Cross-sectional, observational study of participants with chronic stroke and age-matched controls. SETTING: Recruitment and assessments occurred at a stroke recovery research center. Behavioral assessments were performed in a controlled laboratory setting. Magnetic resonance imaging scans were performed at the Center for Biomedical Imaging. PARTICIPANTS: Individuals were enrolled and completed the study (N=39; 21 participants with chronic stroke; 18 age-matched controls with at least 2 stroke risk factors). MAIN OUTCOME MEASURES: Diffusion imaging metrics were obtained for each individual's CC and corticospinal tract (CST), including mean kurtosis (MK) and fractional anisotropy (FA). A battery of motor assessments, including bimanual kinematics, were collected from individuals while performing bimanual reaching. RESULTS: Participants with stroke had lower FA and MK in the CST of the lesioned hemisphere when compared with the non-lesioned hemisphere. The FA and MK values in the CST were correlated with measures of unimanual hand performance. In addition, participants with stroke had significantly lower FA and MK in the CC than matched controls. CC diffusion metrics positively correlated with hand asymmetry and trunk displacement during bimanual performance, even when correcting for age and lesion volume. CONCLUSIONS: These data confirm previous studies that linked CST integrity to unimanual performance and provide new data demonstrating a link between CC integrity and both bimanual motor deficits and compensatory movements.

Chronicity of Stroke Does Not Affect Outcomes of Somatosensory Stimulation Paired With Task-Oriented Motor Training: A Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: To determine whether chronicity influences outcomes of somatosensory stimulation paired with task-oriented motor training for participants with severe-to-moderate upper extremity hemiparesis. DESIGN: Spearman correlations were used to retrospectively analyze outcomes of a randomized trial. SETTING: University research laboratory at a rehabilitation hospital. PARTICIPANTS: Adults, ranging between 3 and 12 months poststroke (N=55). INTERVENTIONS: About 18 sessions pairing either 2 hours of active (n=33) or sham (n=22) somatosensory stimulation with 4 hours of intensive task-oriented motor training. MAIN OUTCOME MEASURES: The Wolf Motor Function Test (primary), Action Research Arm Test, Stroke Impact Scale, and Fugl-Meyer Assessment were collected as outcome measures. Analyses evaluated whether within-group chronicity correlated with pre-post changes on primary and secondary outcome measures of motor performance. RESULTS: Both groups exhibited improvements on all outcome measures. No significant correlations between chronicity poststroke and the amount of motor recovery were found. CONCLUSION: Somatosensory stimulation improved motor recovery compared with sham treatment in cases of severe-to-moderate hemiparesis between 3 and 12 months poststroke; and the extent of recovery did not correlate with baseline levels of stroke chronicity. Future studies should investigate a wider period of inclusion, patterns of corticospinal reorganization, differences between cortical and subcortical strokes, and include long-term follow-up periods.

Absence of Motor-Evoked Potentials Does Not Predict Poor Recovery in Patients With Severe-Moderate Stroke: An Exploratory Analysis.

OBJECTIVE: To better understand the role of the presence or absence of motor-evoked potentials (MEPs) in predicting functional outcomes following a severe-moderate stroke. DESIGN: Retrospective exploratory analysis. We compared the effects of the stimulation condition (active or sham), MEP status (+ or -), and a combination of stimulation condition and MEP status on outcome. Within-group and between-group changes were assessed with longitudinal repeated measures analysis of variance and longitudinal repeated measures analysis of covariance, respectively. The proportions of participants who achieved minimal clinically important differences (MCIDs) for the main outcome measures were calculated. SETTING: University research laboratory within a rehabilitation hospital. PARTICIPANTS: A total of 129 subjects with severe-moderate stroke-related motor impairments who participated in previous studies combining neuromodulation and motor training. INTERVENTIONS: Neuromodulation (active or sham) and motor training. MAIN OUTCOME MEASURES: Fugl-Meyer Assessment (FMA) and Action Research Arm Test (ARAT). RESULTS: When participants were grouped by stimulation condition or MEP status, all groups improved from baseline to immediate postintervention and follow-up evaluations (all P<.05). Analysis by stimulation condition and MEP status found that the MEP-/active group improved by 4.2 points on FMA (P<.0001) and 1.8 on ARAT (P=.003) post intervention. The MEP+/active group improved by 5.7 points on FMA (P<.0001) and 3.9 points on ARAT (P<.0001) post intervention. There were no between-group differences (P>.05). Regarding MCIDs, in the MEP-/active group, 14.5% of individuals reached MCID on FMA and 8.3% on ARAT post intervention. In the MEP+/active group, 33.3% of individuals reached MCID on FMA and 27.3% on ARAT post intervention. CONCLUSION: As expected, the MEP+ group had the greatest improvement in motor function. However, it was shown that individuals without MEPs can also achieve meaningful changes, as reflected by MCID, when neuromodulation is paired with motor training. To our knowledge, this is the first study to differentiate the effects of neuromodulation by MEP status.