Restoration of sensory feedback from the foot and reduction of phantom limb pain via closed-loop spinal cord stimulation.

Restoring somatosensory feedback in individuals with lower-limb amputations would reduce the risk of falls and alleviate phantom limb pain. Here we show, in three individuals with transtibial amputation (one traumatic and two owing to diabetic peripheral neuropathy), that sensations from the missing foot, with control over their location and intensity, can be evoked via lateral lumbosacral spinal cord stimulation with commercially available electrodes and by modulating the intensity of stimulation in real time on the basis of signals from a wireless pressure-sensitive shoe insole. The restored somatosensation via closed-loop stimulation improved balance control (with a 19-point improvement in the composite score of the Sensory Organization Test in one individual) and gait stability (with a 5-point improvement in the Functional Gait Assessment in one individual). And over the implantation period of the stimulation leads, the three individuals experienced a clinically meaningful decrease in phantom limb pain (with an average reduction of nearly 70% on a visual analogue scale). Our findings support the further clinical assessment of lower-limb neuroprostheses providing somatosensory feedback.

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

Impact of Squamous Histology on Clinical Outcomes and Molecular Profiling in Metastatic Urothelial Carcinoma Patients Treated With Immune Checkpoint Inhibitors or Enfortumab Vedotin.

INTRODUCTION: Urothelial carcinoma with squamous differentiation (UCS) is associated with increased resistance to chemotherapy, but outcomes associated with newer therapies approved in this space over the last 5 to 10 years are less well defined. We investigated clinical outcomes and molecular profiling of patients with UCS treated with an immune checkpoint inhibitor (ICI) and/or Enfortumab vedotin (EV). PATIENTS AND METHODS: We undertook a retrospective analysis of UC patients treated with ICI and/or EV. Objective response rate (ORR), progression free survival (PFS) and overall survival (OS) were compared between pure UC (pUC) and UCS using X2 and log-rank tests, respectively. Prevalence of the most commonly detected somatic alterations were also compared between the 2 histologic subgroups. RESULTS: A total of 160 patients (40 UCS, 120 pUC) were identified for this analysis. Among 151 patients treated with ICI (38 UCS, 113 pUC), UCS patients had a shorter mPFS (1.9 vs. 4.8 months, P < 0.01) and mOS (9.2 vs. 20.7 months, P < 0.01) compared to pUC. Among 37 patients treated with EV (12 UCS, 25 pUC), UCS patients had a lower ORR (17% vs. 70%, P < 0.01) and shorter mPFS (3.4 vs. 15.8 months, P < 0.01). UCS samples were enriched for CDKN2A, CDKN2B, PIK3CA, while pUC samples were enriched for ERBB2 alterations. CONCLUSION: In this single-center retrospective analysis, patients with UCS had a distinct somatic genomic profile relative to patients with pUC. Patients with UCS also had inferior outcomes to ICIs and EV compared to patients with pUC.

Somatic alterations of TP53 and MDM2 associated with response to enfortumab vedotin in patients with advanced urothelial cancer.

Background: Enfortumab vedotin (EV) is an antibody-drug conjugate approved for patients with treatment-refractory advanced urothelial carcinoma (aUC), however data on biomarkers of response is lacking. Methods: We retrospectively identified all aUC patients at our institution who received EV monotherapy and had next-generation sequencing (NGS) data available. Patients were considered responders if they had a complete response or partial response on restaging scans during treatment. Observed response rate (ORR) was evaluated by local investigator and compared between responders and non-responders using Chi-squared test. A univariable analysis was conducted using the Cox proportional hazard test to assess for associations between baseline characteristics and most common somatic alterations (in ≥10% of patients) with patient survival outcomes [progression-free survival (PFS) and overall survival (OS)]. Somatic alterations were then individually evaluated in separate multivariate models while accounting for patient and clinical characteristics using Cox regression models. Results: Among 29 patients treated with EV monotherapy, 27 had available NGS data. Median age was 70, 24 (83%) were men, 19 (62%) were Caucasian, 15 (52%) had pure urothelial histology and 22 (76%) had primary tumor in the bladder. ORR was 41%, and PFS and OS for the overall cohort were 5.1 months and 10.2 months. Responders were enriched among patients with TP53, KDM6A and MDM2 alterations. Patients with these alterations, as well as those with composite TP53/MDM2 alterations (alterations in either TP53 or MDM2), also had increased ORR with EV treatment compared to patients without these alterations. In the univariable analysis, baseline albumin level ≥ 3.0g/dL and presence of composite TP53/MDM2 alterations were associated with a prolonged OS. Baseline ECOG 0/1, TP53 alterations and TP53/MDM2 alterations were associated with a prolonged PFS. In the multivariable analysis, TP53 and TP53/MDM2 alterations were genomic markers predictive of improved PFS after accounting for the relevant clinical characteristics. Conclusion: In this single-center retrospective analysis of aUC patients treated with EV, presence of TP53 or MDM2 somatic alterations, lower ECOG PS scores (ECOG 0 or 1) and higher albumin levels (≥3 g/dL) were associated with improved outcomes with EV treatment. Prospective and external validation of these findings in larger cohorts is warranted.

Serial stereotactic body radiation therapy for oligometastatic prostate cancer detected by novel PET-based radiotracers.

BACKGROUND: Radiopharmaceuticals, including Ga-68-prostate specific membrane antigen (PSMA)-11 and F-18-Fluciclovine, are increasingly used to inform therapies for prostate cancer (CaP). Stereotactic body radiation therapy (SBRT) to PET-detected oligometastatic CaP has been shown to improve progression free survival (PFS) and delay androgen deprivation therapy (ADT) compared to observation. For men who subsequently develop oligorecurrent CaP, outcomes following second SBRT are unknown. METHODS: A retrospective cohort study was conducted. Eligibility criteria included patients with oligometastatic (1-5 lesions) CaP detected on PSMA or Fluciclovine PET who underwent 2 consecutive SBRT courses to tracer-avid sites. Data on stage, tracer type, concurrent systemic therapy, and prostate-specific antigen (PSA) responses for first SBRT (SBRT1) and second SBRT (SBRT2) were collected. Outcomes included PSA decline ≥50% (PSA50), PFS after SBRT2, and ADT initiation or intensification-free survival after SBRT2. Factors potentially associated with PSA50 after SBRT2 was evaluated with multivariable logistic regression. Factors potentially associated with PFS and ADT initiation/intensification-free survival after SBRT2 were evaluated with separate multivariable Cox proportional-hazards models. RESULTS: Twenty-five patients were identified. At SBRT2, oligorecurrence was detected on PSMA and Fluciclovine PET in 17 (68%) and 8 (32%) patients, respectively. Fifteen (60%) patients had castration-sensitive disease and 10 (40%) had castration-resistant disease. After SBRT2, 16 (64%) achieved a PSA50 response, median PFS was 11.0mo, and median ADT initiation/intensification-free survival was 23.2mo. On multivariable analysis, maximum percent change in PSA after SBRT1 (OR 0.94, 95%CI 0.88-0.99, P = 0.046) and concurrent change in systemic therapy (OR 21.61, 95%CI 1.12-417.9, P = 0.042) were associated with PSA50 responses after SBRT2. PSA50 response after SBRT1 was associated with improved PFS (HR 0.36, 95%CI 0.00-0.42, P = 0.008) and ADT initiation/intensification-free survival (HR 0.07, 95%CI 0.01-0.68, P = 0.021) after SBRT2. From SBRT1 to last follow-up (median 48 months), 7 (28%) patients remained ADT-free. CONCLUSIONS: Serial SBRT for oligometastatic CaP detected on PSMA or Fluciclovine PET is feasible and can achieve PSA declines, with or without systemic therapy. Degree of biochemical response to first SBRT warrants further study as a potential predictor of PSA response, PFS, and ADT initiation/intensification-free survival following a subsequent SBRT course. This preliminary evidence provides rationale for larger, prospective studies of this strategy.

Sensory stimulation for upper limb amputations modulates adaptability of cortical large-scale systems and combination of somatosensory and visual inputs.

Touch-like phantom limb sensations can be elicited through targeted transcutaneous electrical nerve stimulation (tTENS) in individuals with upper limb amputation. The corresponding impact of sensory stimulation on cortical activity remains an open question. Brain network research shows that sensorimotor cortical activity is supported by dynamic changes in functional connections between relevant brain regions. These groups of interconnected regions are functional modules whose architecture enables specialized function and related neural processing supporting individual task needs. Using electroencephalographic (EEG) signals to analyze modular functional connectivity, we investigated changes in the modular architecture of cortical large-scale systems when participants with upper limb amputations performed phantom hand movements before, during, and after they received tTENS. We discovered that tTENS substantially decreased the flexibility of the default mode network (DMN). Furthermore, we found increased interconnectivity (measured by a graph theoretic integration metric) between the DMN, the somatomotor network (SMN) and the visual network (VN) in the individual with extensive tTENS experience. While for individuals with less tTENS experience, we found increased integration between DMN and the attention network. Our results provide insights into how sensory stimulation promotes cortical processing of combined somatosensory and visual inputs and help develop future tools to evaluate sensory combination for individuals with amputations.

The 5-Hydroxymethylcytosine Landscape of Prostate Cancer.

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. SIGNIFICANCE: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

Prospective Clinical Genomic Profiling of Ewing Sarcoma: ERF and FGFR1 Mutations as Recurrent Secondary Alterations of Potential Biologic and Therapeutic Relevance.

PURPOSE: Ewing sarcoma (ES) is a primitive sarcoma defined by EWSR1-ETS fusions as the primary driver alteration. To better define the landscape of cooperating secondary genetic alterations in ES, we analyzed clinical genomic profiling data of 113 patients with ES, a cohort including more adult patients (> 18 years) and more patients with advanced stage at presentation than previous genomic cohorts. METHODS: The data set consisted of patients with ES prospectively tested with the US Food and Drug Administration-cleared Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets large panel, hybrid capture-based next-generation sequencing assay. To assess the functional significance of ERF loss, we generated ES cell lines with increased expression of ERF and lines with knockdown of ERF. We assessed cell viability, clonogenic growth, and motility in these ES lines and performed transcriptomic and epigenetic analyses. Finally, we validated our findings in vivo using cell line xenografts. RESULTS: Novel subsets were defined by recurrent secondary alterations in ERF, which encodes an ETS domain transcriptional repressor, in 7% of patients (five truncating mutations, one deep deletion, and two missense mutations) and in FGFR1 in another 2.7% (one amplification and two known activating mutations). ERF alterations were nonoverlapping with STAG2 alterations. In vitro, increased expression of ERF decreased tumor cell growth, colony formation, and motility in two ES cell lines, whereas ERF loss induced cellular proliferation and clonogenic growth. Transcriptomic analysis of cell lines with ERF loss revealed an increased expression of genes and pathways associated with aggressive tumor biology, and epigenetic, chromatin-based studies revealed that ERF competes with EWSR1-FLI1 at ETS-binding sites. CONCLUSION: Our findings open avenues to new insights into ES pathobiology and to novel therapeutic approaches in a subset of patients with ES.

Distinct spatio-temporal and spectral brain patterns for different thermal stimuli perception.

Understanding the human brain's perception of different thermal sensations has sparked the interest of many neuroscientists. The identification of distinct brain patterns when processing thermal stimuli has several clinical applications, such as phantom-limb pain prediction, as well as increasing the sense of embodiment when interacting with neurorehabilitation devices. Notwithstanding the remarkable number of studies that have touched upon this research topic, understanding how the human brain processes different thermal stimuli has remained elusive. More importantly, very intense thermal stimuli perception dynamics, their related cortical activations, as well as their decoding using effective features are still not fully understood. In this study, using electroencephalography (EEG) recorded from three healthy human subjects, we identified spatial, temporal, and spectral patterns of brain responses to different thermal stimulations ranging from extremely cold and hot stimuli (very intense), moderately cold and hot stimuli (intense), to a warm stimulus (innocuous). Our results show that very intense thermal stimuli elicit a decrease in alpha power compared to intense and innocuous stimulations. Spatio-temporal analysis reveals that in the first 400 ms post-stimulus, brain activity increases in the prefrontal and central brain areas for very intense stimulations, whereas for intense stimulation, high activity of the parietal area was observed post-500 ms. Based on these identified EEG patterns, we successfully classified the different thermal stimulations with an average test accuracy of 84% across all subjects. En route to understanding the underlying cortical activity, we source localized the EEG signal for each of the five thermal stimuli conditions. Our findings reveal that very intense stimuli were anticipated and induced early activation (before 400 ms) of the anterior cingulate cortex (ACC). Moreover, activation of the pre-frontal cortex, somatosensory, central, and parietal areas, was observed in the first 400 ms post-stimulation for very intense conditions and starting 500 ms post-stimuli for intense conditions. Overall, despite the small sample size, this work presents novel findings and a first comprehensive approach to explore, analyze, and classify EEG-brain activity changes evoked by five different thermal stimuli, which could lead to a better understanding of thermal stimuli processing in the brain and could, therefore, pave the way for developing a real-time withdrawal reaction system when interacting with prosthetic limbs. We underpin this last point by benchmarking our EEG results with a demonstration of a real-time withdrawal reaction of a robotic prosthesis using a human-like artificial skin.

Mobile Audio Recording Technology to Promote Informed Decision Making in Advanced Prostate Cancer.

PURPOSE: Men with metastatic castration-resistant prostate cancer increasingly encounter complex treatment decisions. Consultation audio recordings and summaries promote patient informed decision making but are underutilized. Mobile recording software applications may increase access. Little is known regarding the feasibility of implementation in clinical encounters. METHODS: We conducted a mixed-methods pilot study in men with progressive metastatic castration-resistant prostate cancer. We instructed patients to use a mobile software application to record an oncology visit. Patients could share the recording with our patient scribing program to receive a written summary. We assessed feasibility and acceptability with postvisit surveys. We measured patient-reported helpfulness of the intervention in decision making and change in Decisional Conflict Scale-informed subscale. We conducted semistructured interviews to explore implementation and analyzed transcripts using thematic analysis. RESULTS: Across 20 patients, 18 (90%) recorded their visits. Thirteen of 18 (72%) listened to the recording, and 14 of 18 (78%) received a summary. Eighteen of 20 (90%) visits were telehealth. Fourteen patients (70% of all 20; 78% of 18 question respondents) found the application easy to use. Nine patients (50% of 18 recording patients; 90% of 10 question respondents) reported that the recording helped treatment decision making. Decisional conflict decreased from baseline to 1-week postvisit (47.4-28.5, P < .001). Interviews revealed benefits, facilitators, contextual factors, and technology and patient-related barriers to recordings and summaries. CONCLUSION: In this single-institution academic setting, a mobile application for patients to record consultations was a feasible, acceptable, and potentially valued intervention that improved decision making in the telehealth setting. Studies in larger, diverse populations are needed.

Recruitment of Primary Afferents by Dorsal Root Ganglion Stimulation using the Injectrode.

Chronic pain affects millions of people in the United States and pharmacological treatments have been ineffective. Dorsal root ganglion (DRG) stimulation is a neuromodulation method that delivers electrical stimulation to the DRG to relieve pain. DRG electrodes are rigid and cylindrical. The implantation of DRG electrodes requires a technically-challenging surgery that involves steering electrodes laterally towards the DRG. The Injectrode is an injectable conductive polymer that cures in place and is capable of delivering electrical current to stimulate neural tissue. We used the Injectrode to stimulate the L6 and L7 DRG in cats, measuring neural responses evoked in the sciatic, tibial, and common peroneal nerves to measure the thresholds for activating fibers. A cylindrical stainless-steel electrode was used for comparison. Thresholds were 38% higher with the Injectrode versus stainless-steel, likely owing to its larger contact surface area with the DRG. Both Aα and Aß sensory fibers were activated using DRG stimulation. The Injectrode has the potential to offer a new and simple method for DRG stimulation that can potentially offer more complete coverage of the DRG.

Stimulation of the dorsal root ganglion using an Injectrode®.

Objective. The goal of this work was to compare afferent fiber recruitment by dorsal root ganglion (DRG) stimulation using an injectable polymer electrode (Injectrode®) and a more traditional cylindrical metal electrode.Approach. We exposed the L6 and L7 DRG in four cats via a partial laminectomy or burr hole. We stimulated the DRG using an Injectrode or a stainless steel (SS) electrode using biphasic pulses at three different pulse widths (80, 150, 300µs) and pulse amplitudes spanning the range used for clinical DRG stimulation. We recorded antidromic evoked compound action potentials (ECAPs) in the sciatic, tibial, and common peroneal nerves using nerve cuffs. We calculated the conduction velocity of the ECAPs and determined the charge-thresholds and recruitment rates for ECAPs from Aα, Aß, and Aδfibers. We also performed electrochemical impedance spectroscopy measurements for both electrode types.Main results. The ECAP thresholds for the Injectrode did not differ from the SS electrode across all primary afferents (Aα, Aß, Aδ) and pulse widths; charge-thresholds increased with wider pulse widths. Thresholds for generating ECAPs from Aßfibers were 100.0 ± 32.3 nC using the SS electrode, and 90.9 ± 42.9 nC using the Injectrode. The ECAP thresholds from the Injectrode were consistent over several hours of stimulation. The rate of recruitment was similar between the Injectrodes and SS electrode and decreased with wider pulse widths.Significance. The Injectrode can effectively excite primary afferents when used for DRG stimulation within the range of parameters used for clinical DRG stimulation. The Injectrode can be implanted through minimally invasive techniques while achieving similar neural activation to conventional electrodes, making it an excellent candidate for future DRG stimulation and neuroprosthetic applications.

Augmenting Neuromuscular Disease Detection Using Optimally Parameterized Weighted Visibility Graph.

In this contribution, we propose a novel neuromuscular disease detection framework employing weighted visibility graph (WVG) aided analysis of electromyography signals. WVG converts a time series into an undirected graph, while preserving the signal properties. However, conventional WVG is sensitive to noise and has high computational complexity which is problematic for lengthy and noisy time series analysis. To address this issue in this article, we investigate the performance of WVG by varying two important parameters, namely penetrable distance and scale factor, both of which have shown promising results by eliminating the problem of signal adulteration and decreasing the computational complexity, respectively. We also aim to unfold the combined effect of these two aforesaid parameters on the WVG performance to discriminate between myopathy, amyotrophic lateral sclerosis (ALS) and healthy EMG signals. Using graph theory based features we demonstrated that the discriminating capability between the three classes increased significantly with the increase in both penetrable distance and scale factor values. Three binary (healthy vs. myopathy, myopathy vs. ALS and healthy vs. ALS) and one multiclass problems (healthy vs. myopathy vs. ALS) have been addressed in this study and for each problem, we obtained optimum parameter values determined on the basis of F-value computed using one way analysis of variance (ANOVA) test. Using optimal parameter values, we obtained mean accuracy of 98.57%, 98.09% and 99.45%, respectively for three binary and 99.05% for the multi-class classification problem. Additionally, the computational time was reduced by 96% with optimally selected WVG parameters compared to traditional WVG.

Neuromuscular Disease Detection Employing Deep Feature Extraction from Cross Spectrum Images of Electromyography Signals.

In this paper, a deep learning framework for detection and classification of EMG signals for diagnosis of neuromuscular disorders is proposed employing cross wavelet transform. Cross wavelet transform which is a modification of continuous wavelet transform is an important tool to analyze any non-stationary signal in time scale and in time-frequency frame. To this end, EMG signals of healthy, myopathy and Amyotrophic lateral sclerosis disorders were procured from an online existing database. A healthy EMG signal was chosen as reference and cross wavelet transform of the rest of the healthy as well as the disease EMG signals was done with the reference. From the resulting cross wavelet spectrum images of EMG signals, a convolution neural network (CNN) based automated deep feature extraction technique was implemented. The extracted deep features were further subjected to feature ranking employing one way analysis of variance (ANOVA) test. The extracted deep features with high degree of statistical significance were fed to several benchmark machine learning classifiers for the purpose of discrimination of EMG signals. Two binary classification problems are addressed in this paper and it has been observed that the highest mean classification accuracy of 100% is achieved using the statistically significant extracted deep features. The proposed method can be implemented for real-time detection of neuromuscular disorders.

Sensory Feedback in Upper Limb Amputees Impacts Cortical Activity as Revealed by Multiscale Connectivity Analysis.

Sensory feedback in upper limb amputees is crucial for improving movement decoding and also to enhance embodiment of the prosthetic limb. Recently, an increasing number of invasive and noninvasive solutions for sensory stimulation have demonstrated the capability of providing a range of sensations to upper limb amputees. However, the cortical impact of restored sensation is not clearly understood. Particularly, understanding the cortical connectivity changes at multiple scales (nodal and modular) in response to sensory stimulation, can reveal crucial information on how amputees brain process the sensory stimuli. Using Electroencephalography (EEG) signals, we compared the cortical connectivity network in response to sensory feedback provided by targeted transcutaneous electrical nerve stimulation (tTENS) in an upper limb amputee during phantom upper limb movements. We focused our cortical connectivity analysis on four functional modules comprising of 20 brain regions that are primarily associated with a visually guided motor task (visual, motor, somatosensory and multisensory integration (MI)) used in this study. At the modular level, we observed that the hubness (a graph theoretic measure quantifying the importance of brain regions in integrating brain function) of the motor module decreases whereas that of the somatosensory module increases in presence of tTENS feedback. At the nodal level, similar observations were made for the visual and MI regions. This is the first work to reveal the impact of sensory feedback at multiple scales in the cortex of amputees in response to sensory stimulation.

Sensory stimulation enhances phantom limb perception and movement decoding.

OBJECTIVE: A major challenge for controlling a prosthetic arm is communication between the device and the user's phantom limb. We show the ability to enhance phantom limb perception and improve movement decoding through targeted transcutaneous electrical nerve stimulation in individuals with an arm amputation. APPROACH: Transcutaneous nerve stimulation experiments were performed with four participants with arm amputation to map phantom limb perception. We measured myoelectric signals during phantom hand movements before and after participants received sensory stimulation. Using electroencephalogram (EEG) monitoring, we measured the neural activity in sensorimotor regions during phantom movements and stimulation. In one participant, we also tracked sensory mapping over 2 years and movement decoding performance over 1 year. MAIN RESULTS: Results show improvements in the participants' ability to perceive and move the phantom hand as a result of sensory stimulation, which leads to improved movement decoding. In the extended study with one participant, we found that sensory mapping remains stable over 2 years. Sensory stimulation improves within-day movement decoding while performance remains stable over 1 year. From the EEG, we observed cortical correlates of sensorimotor integration and increased motor-related neural activity as a result of enhanced phantom limb perception. SIGNIFICANCE: This work demonstrates that phantom limb perception influences prosthesis control and can benefit from targeted nerve stimulation. These findings have implications for improving prosthesis usability and function due to a heightened sense of the phantom hand.

Author Correction: FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The DNA methylation landscape of advanced prostate cancer.

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

Towards machine to brain interfaces: sensory stimulation enhances sensorimotor dynamic functional connectivity in upper limb amputees.

OBJECTIVE: Recent development of sensory stimulation techniques demonstrates the ability to elicit touch-like phantom sensations in upper limb amputees. The cortical processing of this phantom sensation and the corresponding influences on sensorimotor functional connectivity have not been studied. We hypothesize that sensory stimulation has a profound impact on the sensorimotor cortical functional interactions, which will be uncovered by dynamic functional connectivity (dFC) analysis of amputees' electroencephalogram (EEG) recordings. APPROACH: We investigated dFC between cortical areas associated with somatosensory, motor, visual, and multisensory processing functions using EEG signals. We applied dFC to the EEG of two amputees performing hand movements with and without sensory stimulation and compared the results with those from three able-bodied subjects. We quantified the changes due to sensory stimulation using dFC metrics, namely temporal distance, number of connection paths, temporal global and local efficiencies, and clustering coefficient. MAIN RESULTS: We show a significant effect of sensory stimulation on functional connectivity in the amputee brains, with notable facilitation on multisensory processing among the cortical systems involved in sensorimotor processing. The dFC metrics reveal that sensory stimulation enhances the speed of information transfer (shown by decreases in temporal distance) and the number of connection paths between the brain systems involved in sensorimotor processing, including primary somatosensory and motor, and higher order processing regions. SIGNIFICANCE: This is the first work to reveal dynamic communication between somatosensory, motor, and higher order processing regions in the cortex of amputees in response to sensory stimulation. We believe that our work provides crucial insights into the cortical impact of sensory stimulation in amputees, which may lead to the design of personalized brain-informed sensory feedback paradigms. This in turn may lead to building novel Machine to Brain Interfaces involving sensory feedback and the resultant enhanced motor performance.