Genetic and phenotypic characterization of Parkinson's disease at the clinic-wide level.

Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis Initiative seeks to characterize molecular and clinical features of every PD patient at the University of Pennsylvania (UPenn). The objectives of this study are to determine the feasibility of genetic characterization in PD and assess clinical features by sex and GBA1/LRRK2 status on a clinic-wide scale. All PD patients with clinical visits at the UPenn PD Center between 9/2018 and 12/2022 were eligible. Blood or saliva were collected, and a clinical questionnaire administered. Genotyping at 14 GBA1 and 8 LRRK2 variants was performed. PD symptoms were compared by sex and gene groups. 2063 patients were approached and 1,689 (82%) were enrolled, with 374 (18%) declining to participate. 608 (36%) females were enrolled, 159 (9%) carried a GBA1 variant, and 44 (3%) carried a LRRK2 variant. Compared with males, females across gene groups more frequently reported dystonia (53% vs 46%, p = 0.01) and anxiety (64% vs 55%, p < 0.01), but less frequently reported cognitive impairment (10% vs 49%, p < 0.01) and vivid dreaming (53% vs 60%, p = 0.01). GBA1 variant carriers more frequently reported anxiety (67% vs 57%, p = 0.04) and depression (62% vs 46%, p < 0.01) than non-carriers; LRRK2 variant carriers did not differ from non-carriers. We report feasibility for near-clinic-wide enrollment and characterization of individuals with PD during clinical visits at a high-volume academic center. Clinical symptoms differ by sex and GBA1, but not LRRK2, status.

Mimicking opioid analgesia in cortical pain circuits.

The anterior cingulate cortex plays a pivotal role in the cognitive and affective aspects of pain perception. Both endogenous and exogenous opioid signaling within the cingulate mitigate cortical nociception, reducing pain unpleasantness. However, the specific functional and molecular identities of cells mediating opioid analgesia in the cingulate remain elusive. Given the complexity of pain as a sensory and emotional experience, and the richness of ethological pain-related behaviors, we developed a standardized, deep-learning platform for deconstructing the behavior dynamics associated with the affective component of pain in mice-LUPE (Light aUtomated Pain Evaluator). LUPE removes human bias in behavior quantification and accelerated analysis from weeks to hours, which we leveraged to discover that morphine altered attentional and motivational pain behaviors akin to affective analgesia in humans. Through activity-dependent genetics and single-nuclei RNA sequencing, we identified specific ensembles of nociceptive cingulate neuron-types expressing mu-opioid receptors. Tuning receptor expression in these cells bidirectionally modulated morphine analgesia. Moreover, we employed a synthetic opioid receptor promoter-driven approach for cell-type specific optical and chemical genetic viral therapies to mimic morphine's pain-relieving effects in the cingulate, without reinforcement. This approach offers a novel strategy for precision pain management by targeting a key nociceptive cortical circuit with on-demand, non-addictive, and effective analgesia.

Assessment of the axilla in women with early-stage breast cancer undergoing primary surgery: a review.

Sentinel node biopsy (SNB) is routinely performed in people with node-negative early breast cancer to assess the axilla. SNB has no proven therapeutic benefit. Nodal status information obtained from SNB helps in prognostication and can influence adjuvant systemic and locoregional treatment choices. However, the redundancy of the nodal status information is becoming increasingly apparent. The accuracy of radiological assessment of the axilla, combined with the strong influence of tumour biology on systemic and locoregional therapy requirements, has prompted many to consider alternative options for SNB. SNB contributes significantly to decreased quality of life in early breast cancer patients. Substantial improvements in workflow and cost could accrue by removing SNB from early breast cancer treatment. We review the current viewpoints and ideas for alternative options for assessing and managing a clinically negative axilla in patients with early breast cancer (EBC). Omitting SNB in selected cases or replacing SNB with a non-invasive predictive model appear to be viable options based on current literature.

Provider Impressions of Inpatient Teleneurology Consultation.

Background and Objectives: Teleneurology usage has increased during the severe acute respiratory syndrome coronavirus 2 pandemic. However, studies evaluating physician impressions of inpatient teleneurology are limited. We implemented a quality improvement initiative to evaluate neurologists' impression following individual inpatient teleneurology consultation at a satellite hospital of a large academic center with no in-person neurology coverage. Methods: A REDCap survey link was embedded within templates used by neurologists for documentation of inpatient consultations to be completed immediately after encounters. All teleneurology encounters with completed surveys at a single satellite hospital of the University of Pennsylvania Health System Neurology Department between May 10, 2021, and August 14, 2022, were included. Individual patient-level and encounter-level data were extracted from the medical record. Results: A total of 374 surveys (response rate of 54.05%) were completed by 19 neurologists; 341 questionnaires were included in the analysis. Seven neurologists who specialized as neurohospitalists completed 231 surveys (67.74% of total surveys completed), while 12 non-neurohospitalists completed 110 (32.36%). The history obtained was rated as worse (14%) or the same (86%) as an in-person consult; none reported the history as better than nonteleneurology encounters. The physician-patient relationship was poor or fair in 25% of the encounters and good or excellent in 75% of visits. The overall experience was judged to be worse than in-person consultation in 32% of encounters, the same in 66%, and better in 2%. Fifty-one percent of providers responded that there were elements of the neurologic examination that might have changed their assessment and plan of care if performed in-person. Encounters with peripheral or neuromuscular-related chief complaints had the most inadequate examinations and worse overall experiences, while the most positive impressions of these clinical experiences were observed among seizure-related chief complaints. Discussion: Determining best practices for inpatient teleneurology should consider the patient chief complaint to use teleneurology in scenarios with the highest likelihood of a positive experience. Further efforts should be made to the patient experience and to improve the remote examination to enhance the applicability of teleneurology to the full spectrum of inpatient neurologic consultations.

Compact single-shot soft X-ray photon spectrometer for free-electron laser diagnostics.

The photon spectrum from free-electron laser (FEL) light sources offers valuable information in time-resolved experiments and machine optimization in the spectral and temporal domains. We have developed a compact single-shot photon spectrometer to diagnose soft X-ray spectra. The spectrometer consists of an array of off-axis Fresnel zone plates (FZP) that act as transmission-imaging gratings, a Ce:YAG scintillator, and a microscope objective to image the scintillation target onto a two-dimensional imaging detector. This spectrometer operates in segmented energy ranges which covers tens of electronvolts for each absorption edge associated with several atomic constituents: carbon, nitrogen, oxygen, and neon. The spectrometer's performance is demonstrated at a repetition rate of 120 Hz, but our detection scheme can be easily extended to 200 kHz spectral collection by employing a fast complementary metal oxide semiconductor (CMOS) line-scan camera to detect the light from the scintillator. This compact photon spectrometer provides an opportunity for monitoring the spectrum downstream of an endstation in a limited space environment with sub-electronvolt energy resolution.

Linked Patient and Provider Impressions of Outpatient Teleneurology Encounters.

Background and Objectives: Teleneurology is common in clinical practice partly due to the SARS CoV-2 pandemic. Impressions about teleneurology from patients and providers alike are generally favorable; some of the reported benefits include ease of access to specialized health care, savings of time and money, and similar quality of care as an in-person visit. However, comparisons between patient and provider impressions about the same teleneurology encounter have not been described. In this study, we describe patient impressions about a teleneurology encounter and evaluate concordance with provider impressions about the same encounter. Methods: Patients and providers at the University of Pennsylvania Hospital Neurology Department were surveyed about their impressions of teleneurology between April 27, 2020, and June 16, 2020. A convenience sample of patients, whose providers completed a questionnaire, were contacted by telephone to solicit their impressions about the same encounter. Unique questionnaires for patients and providers focused on similar themes, such as adequacy of technology, assessment of history obtained, and overall quality of the visit. Summaries of patient responses are reported with the raw percent agreement between patients and providers for similar questions. Results: One hundred thirty-seven patients completed the survey; 64 (47%) were male and 73 (53%) were female. Sixty-six (47%) patients had a primary diagnosis of PD, 42 (30%) a non-PD/parkinsonism movement disorder, and 29 (21%) a nonmovement disorder neurologic disease. One hundred one (76%) were established patient visits and 36 (26%) were new patient visits. Provider responses from 8 different physicians were included. Most of the patients responded that the ease of joining their visit, their comfort engaging with their physicians during their visit, understanding their plan of care after their visit, and the quality of care from their teleneurology visit were satisfactory. Patients and providers agreed about their impressions of the quality of the history obtained (87% agreement), patient-provider relationship (88% agreement), and overall quality of their experience (70% agreement). Discussion: Patients had favorable impressions about their clinical experience with teleneurology and expressed an interest in incorporating telemedicine visits into their ongoing care. Patients and providers were highly concordant for the history obtained, patient-provider relationship, and overall quality.

A systematic review and meta-analysis of e-cigarette use among cancer survivors.

PURPOSE: We conducted a systematic review and meta-analysis to determine the use of e-cigarettes among cancer survivors, factors associated with their use, and prevalence of e-cigarette use as a quit attempt. METHODS: We searched five electronic databases until June 2022. Two authors independently selected studies, appraised their quality, and collected data. RESULTS: Twenty-three publications from eight data sources (national surveys) met our eligibility criteria. The pooled rate of lifetime e-cigarette use among cancer survivors was 15% (95% CI 6-27%); current use was 3% (95% CI 0-8%). Among survivors who currently used traditional cigarettes, 63% (95% CI 57-69%) also used e-cigarettes. The reported rates of weighted lifetime e-cigarette use differed between age groups (18-44 years, up to 46.7%; 45-64, up to 27.2%; ≥65, up to 24.8%). Nine publications reported factors associated with lifetime e-cigarette use (i.e., active use of traditional cigarettes; heavy drinking; poor mental health; younger age; being male, non-Hispanic White, or single; having less than high school education or income ≤$25,000 USD; and living in the South regions of the US or urban areas). E-cigarettes were used as a quit resource by 75% of survivors reporting dual use of electronic and traditional cigarettes (95% CI 63%, 85%). CONCLUSION: More than two-thirds of survivors currently using traditional cigarettes also use e-cigarettes. Higher use rates of e-cigarettes were reported among young cancer survivors compared to older survivors. Future studies are needed to assess the impact of e-cigarettes on long-term health and improve screening of smoking behaviors. IMPLICATIONS FOR CANCER SURVIVORS: Our study provides an overview of the prevalence of e-cigarette use and sociodemographic risk factors associated with e-cigarette use among cancer survivors. The findings can assist providers in supporting attempts to quit among cancer survivors.

A systematic review with meta-analysis of the effects of smoking cessation strategies in patients with rheumatoid arthritis.

OBJECTIVE: Smoking rates among patients with rheumatoid arthritis (RA) exceed those in the general population. This study identified smoking cessation strategies used in patients with RA and synthesized data on their effects. METHODS: We conducted a systematic review of studies that reported effects of interventions for smoking cessation in patients with RA. We searched 5 electronic databases until March 2022. Screening, quality appraisal, and data collection were done independently by 2 reviewers. RESULTS: We included 18 studies reporting interventions for patients or providers: 14 evaluated strategies for patients (5 education on cardiovascular risk factors including smoking, 3 educational interventions on smoking cessation alone, 3 education with nicotine replacement and counseling, and 1 study each: education with nicotine replacement, counseling sessions alone, and a social marketing campaign). Smoking cessation rates ranged from 4% (95% CI: 2%-6%, 24 to 48 weeks) for cardiovascular risk education to 43% (95% CI: 21%-67%, 104 weeks) for counseling sessions alone. The pooled cessation rate for all interventions was 22% (95% CI: 8%-41%, 4 weeks to 104 weeks; 9 studies). Four interventions trained providers to ascertain smoking status and provide referrals for smoking cessation. The pooled rates of referrals to quit services increased from 5% in pre-implementation populations to 70% in post-implementation populations. CONCLUSION: Studies varied in patient characteristics, the interventions used, and their implementation structure. Only 3 studies were controlled clinical trials. Additional controlled studies are needed to determine best practices for smoking cessation for patients with RA.

OPTIKNEE 2022: consensus recommendations to optimise knee health after traumatic knee injury to prevent osteoarthritis.

The goal of the OPTIKNEE consensus is to improve knee and overall health, to prevent osteoarthritis (OA) after a traumatic knee injury. The consensus followed a seven-step hybrid process. Expert groups conducted 7 systematic reviews to synthesise the current evidence and inform recommendations on the burden of knee injuries; risk factors for post-traumatic knee OA; rehabilitation to prevent post-traumatic knee OA; and patient-reported outcomes, muscle function and functional performance tests to monitor people at risk of post-traumatic knee OA. Draft consensus definitions, and clinical and research recommendations were generated, iteratively refined, and discussed at 6, tri-weekly, 2-hour videoconferencing meetings. After each meeting, items were finalised before the expert group (n=36) rated the level of appropriateness for each using a 9-point Likert scale, and recorded dissenting viewpoints through an anonymous online survey. Seven definitions, and 8 clinical recommendations (who to target, what to target and when, rehabilitation approach and interventions, what outcomes to monitor and how) and 6 research recommendations (research priorities, study design considerations, what outcomes to monitor and how) were voted on. All definitions and recommendations were rated appropriate (median appropriateness scores of 7-9) except for two subcomponents of one clinical recommendation, which were rated uncertain (median appropriateness score of 4.5-5.5). Varying levels of evidence supported each recommendation. Clinicians, patients, researchers and other stakeholders may use the definitions and recommendations to advocate for, guide, develop, test and implement person-centred evidence-based rehabilitation programmes following traumatic knee injury, and facilitate data synthesis to reduce the burden of knee post-traumatic knee OA.

The time-resolved atomic, molecular and optical science instrument at the Linac Coherent Light Source.

The newly constructed time-resolved atomic, molecular and optical science instrument (TMO) is configured to take full advantage of both linear accelerators at SLAC National Accelerator Laboratory, the copper accelerator operating at a repetition rate of 120 Hz providing high per-pulse energy as well as the superconducting accelerator operating at a repetition rate of about 1 MHz providing high average intensity. Both accelerators power a soft X-ray free-electron laser with the new variable-gap undulator section. With this flexible light source, TMO supports many experimental techniques not previously available at LCLS and will have two X-ray beam focus spots in line. Thereby, TMO supports atomic, molecular and optical, strong-field and nonlinear science and will also host a designated new dynamic reaction microscope with a sub-micrometer X-ray focus spot. The flexible instrument design is optimized for studying ultrafast electronic and molecular phenomena and can take full advantage of the sub-femtosecond soft X-ray pulse generation program.

Performance, clinical utility, and cost-effectiveness of selective use of staging investigations in early breast cancers.

BACKGROUND: International guidelines do not recommend routine staging of EBCs. However, most clinicians still perform staging investigations (SI) selectively for several reasons. We examined our practice of selective use of SI to determine its performance, clinical utility, and cost-effectiveness. METHODS: We performed this retrospective study on patients who had treatment for AJCC stage I or stage II breast cancer through Eastern health Breast and cancer centre, Melbourne, for 50 months from January 2012. RESULT: Our practice of selective use resulted in SI in 41% of all EBCs (95% CI 37-46%). Overall yield was 3% (95% CI 0.4-5.4%) with a false positive rate of 22% (95% CI 1628%) and a false-negative rate of 45% (95% CI 11-79%). The sensitivity of SI is 55% (95% CI 21-89%) with a negative predictive value of 97% (95% CI 94.8-99.9%). None of the treatment components was found to be significantly changed based on findings on SI. There was no significant difference in all-cause mortality or new distant recurrence in the staged and non-staged groups. Identification of six new metastases cost at least 422 021 AUD. The approximate cost to stage one EBC is 2069 AUD. 'Number needed to scan' to detect one new metastasis is 34 at the expense of 70337AUD. CONCLUSION: Selective use of SI results in better yield. However, the clinical utility of these results is not significant. It is debatable if this level of expenditure is cost-effective. Our results point to a need for change in practice.

Targeted ordering of investigations reduces costs of treatment for surgical inpatients.

BACKGROUND: Laboratory testing forms an important part of diagnostic investigation in modern medicine; however, the overuse of 'routine blood tests' can result in significant potential harm and financial cost to the patient and the healthcare system. In 2018, a new protocol targeting the ordering of investigations was implemented within the General Surgical Teams of Wollongong Hospital in New South Wales, an Australian tertiary referral hospital, to reduce the number of 'routine blood tests' as a quality improvement initiative. OBJECTIVE: To identify whether there was a reduction in the number of 'routine blood tests' and associated costs following implementation of the new protocol. METHODS: The protocol involved regular review of the laboratory investigations being ordered for the following day with a senior team member. The medical records of all patients admitted under the general surgery service at Wollongong Hospital were retrospectively reviewed over two 10-week periods in 2017 and 2018 (control and study, respectively). The casemix was categorized into Minor, Intermediate, Major or Unscored, depending on case complexity coding. RESULTS: A total of 838 patients were identified during the control period (2017) and 805 patients were identified during the study period (2018). Ten thousand and thirty tests were included in the control period, compared to 8610 over the study period, resulting in a 16% (or greater) reduction in 'routine blood tests' per patient, per day of admission and a 6% reduction in costs in the study group (P < 0.001). CONCLUSION: Targeted ordering of investigations with personalized education and feedback to junior staff during review of clinical status of each patient as a part of normal workflow can reduce inappropriate ordering of 'routine blood tests' and associated costs to the patient and the healthcare system.

Antibodies to an Epstein Barr Virus protein that cross-react with dsDNA have pathogenic potential.

Pathogens such as the Epstein Barr virus (EBV) have long been implicated in the etiology of systemic lupus erythematosus (SLE). The Epstein Barr virus nuclear antigen I (EBNA-1) has been shown to play a role in the development of anti-nuclear antibodies characteristic of SLE. One mechanism by which EBV may play a role in SLE is molecular mimicry. We previously generated two monoclonal antibodies (mAbs) to EBNA-1 and demonstrated that they cross-react with double-stranded DNA (dsDNA). In the present study, we demonstrate that these mAbs have pathogenic potential. We show that they can bind to isolated rat glomeruli and that binding can be greatly diminished by pretreatment of glomeruli with DNase I, suggesting that these mAbs bind dsDNA in the kidney. We also demonstrate that these antibodies can deposit in the kidney when injected into mice and can induce proteinuria and elicit histopathological alterations consistent with glomerulonephritis. Finally, we show that these antibodies can cross-react with laminin and collagen IV in the extracellular matrix suggesting that direct binding to the glomerular basement membrane or mesangial matrix may also contribute to the antibody deposition in the kidney. In summary, our results indicate that EBNA-1 can elicit antibodies that cross-react with dsDNA, that can deposit in the kidney, and induce kidney damage. These results are significant because they support the role of a viral protein in SLE and lupus nephritis.

Looking for Metastasis in Early Breast Cancer: Does Bone Scan Help? A Retrospective Review.

BACKGROUND: Routine staging investigations are not recommended for early breast cancer (EBC). Staging scans and further confirmatory tests add to the cost of breast cancer treatment. Despite recommendations from international guidelines, whole body bone scan (BS) is commonly used for staging EBC. We examined our experience with BS as a staging investigation when selectively used in EBC. PATIENTS AND METHODS: All EBC patients who underwent treatment through the Eastern Health breast unit during a 50-month period from January 2012 were included in this study. All staging BS results were reviewed to evaluate yield and false-positive rate. The causes of false-positive results were analyzed. The role of BS when performed along with computed tomographic scans of chest, abdomen, and pelvis (CTCAP) was evaluated. RESULTS: Even with the selective use of BS, we could only achieve a yield of 1% (95% confidence interval, -0.6, 2.7) in EBC. When combined with CTCAP, only one additional metastasis was detected in 194 BSs. CONCLUSION: BS plays only a limited role in staging EBC. Patients who have undergone CTCAP will experience minimal benefit by undergoing additional BS.

A critical review of the chest CT scans performed to detect asymptomatic synchronous metastasis in new and recurrent breast cancers.

BACKGROUND: Chest computed tomography (CTC) has now replaced chest X-ray (CXR) as the first choice of investigation to stage breast cancers in most centers in Australia. Routine staging is not recommended in early breast cancers (EBCs). This recommendation is based largely on the use of conventional tests like CXR as staging investigations (SIs). We looked at our experience with CTC in detecting asymptomatic synchronous distant metastasis (ASM) in new and recurrent breast cancers (RBCs). MATERIALS AND METHODS: Breast cancer patients from Eastern Health Breast Unit during the period from January 2012 to March 2016 were included in the study. Cases were grouped into early, advanced, and recurrent breast cancers, and outcome of CTC was assessed in each group. Relative risk of potential risk factors (tumor size, axillary nodal status, presence of lymphovascular invasion and estrogen, and HER2 receptor status) with a positive result in CTC was determined. RESULTS: Fourteen ASMs were detected from 335 CTCs giving an overall yield of 4% (95% CI 1.89-6.47). The overall false-positive rate was 10% due to 35 indeterminate findings that were found not to be metastases after further tests or observation. Even with selective use, CTCs have a low yield of 2% (95% CI - 0.19-4.19) in EBCs. Advanced breast cancers have a 9% incidence of ASMs. None of the clinically isolated locoregionally recurrent diseases were associated with detectable distant metastasis in CTC. The most common cause of indeterminate findings was small pulmonary nodules. CONCLUSION: Even with selective use, CTC has a very low yield in EBCs. Advanced breast cancers can benefit from CTC in their initial evaluation due to the higher yield. Locoregional RBCs were not usually associated with detectable metastasis on CTC. The usefulness of CTC in all stages of breast cancer is further reduced by its high rate of false-positive results.

Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury.

Recovery from serious neurological injury requires substantial rewiring of neural circuits. Precisely-timed electrical stimulation could be used to restore corrective feedback mechanisms and promote adaptive plasticity after neurological insult, such as spinal cord injury (SCI) or stroke. This study provides the first evidence that closed-loop vagus nerve stimulation (CLV) based on the synaptic eligibility trace leads to dramatic recovery from the most common forms of SCI. The addition of CLV to rehabilitation promoted substantially more recovery of forelimb function compared to rehabilitation alone following chronic unilateral or bilateral cervical SCI in a rat model. Triggering stimulation on the most successful movements is critical to maximize recovery. CLV enhances recovery by strengthening synaptic connectivity from remaining motor networks to the grasping muscles in the forelimb. The benefits of CLV persist long after the end of stimulation because connectivity in critical neural circuits has been restored.

Time spent by patients in a pre-anaesthetic clinic and the factors affecting it: An audit from a tertiary care teaching hospital.

BACKGROUND AND AIMS: Patient satisfaction from a pre-anaesthetic clinic (PAC) visit is greatly influenced by time spent there. We aimed to determine time spent in a PAC without an appointment system and the factors affecting the same. METHODS: Four hundred and eight patients coming to PAC were tracked using a time-motion study model. Time spent in waiting and consultation was recorded. Independent variables potentially affecting time spent were documented. Patients were grouped based on independent variables, and the groups were compared for significant differences using appropriate statistical tests. Workload pending on physicians was calculated on an hourly basis by counting number of patients waiting and number of physicians in PAC. RESULTS: Non-parametric statistical tests were used for analysis because the data were not normally distributed. The median and inter-quartile range for waiting time, consultation time and total time were 60 (30-90) minutes, 17 (12-26) minutes and 79 (53-111) minutes, respectively. There was considerable variation in all three. Waiting time was significantly lower in patients posted for same-day surgery or those arriving on a stretcher or wheelchair. Consultation time was correlated with American Society of Anesthesiologists physical status and grade of surgery. Most patients arrived in the morning rather than at equal intervals. Waiting time and workload were therefore maximum in the midmorning and dropped rapidly in the afternoon. CONCLUSION: Large variability in waiting time is linked to lack of an appointment system, and to patients being seen out of turn.

Vagus Nerve Stimulation Enhances Stable Plasticity and Generalization of Stroke Recovery.

BACKGROUND AND PURPOSE: Chronic impairment of the arm and hand is a common consequence of stroke. Animal and human studies indicate that brief bursts of vagus nerve stimulation (VNS) in conjunction with rehabilitative training improve recovery of motor function after stroke. In this study, we tested whether VNS could promote generalization, long-lasting recovery, and structural plasticity in motor networks. METHODS: Rats were trained on a fully automated, quantitative task that measures forelimb supination. On task proficiency, unilateral cortical and subcortical ischemic lesions were administered. One week after ischemic lesion, rats were randomly assigned to receive 6 weeks of rehabilitative training on the supination task with or without VNS. Rats then underwent 4 weeks of testing on a task assessing forelimb strength to test generalization of recovery. Finally, the durability of VNS benefits was tested on the supination task 2 months after the cessation of VNS. After the conclusion of behavioral testing, viral tracing was performed to assess synaptic connectivity in motor networks. RESULTS: VNS enhances plasticity in corticospinal motor networks to increase synaptic connectivity to musculature of the rehabilitated forelimb. Adding VNS more than doubled the benefit of rehabilitative training, and the improvements lasted months after the end of VNS. Pairing VNS with supination training also significantly improved performance on a similar, but untrained task that emphasized volitional forelimb strength, suggesting generalization of forelimb recovery. CONCLUSIONS: This study provides the first evidence that VNS paired with rehabilitative training after stroke (1) doubles long-lasting recovery on a complex task involving forelimb supination, (2) doubles recovery on a simple motor task that was not paired with VNS, and (3) enhances structural plasticity in motor networks.