Patients’ age explained 22% of the overall variability and positive correlations were found with Expanded Disability Status Scale and disease duration. The pooled mean difference of SSR latency showed a significant increase in patients on both upper  and lower  extremities. We tested the discriminatory value of SSR latency thresholds defined as the 95% confidence interval (CI) upper bound of the healthy controls, and validated the results on a new dataset. The lower limb threshold of 1.964 s produces the best results in terms of sensitivity 0.86, specificity 0.67, positive predicted value 0.75 and negative predicted value 0.80. Despite a considerable heterogeneity of findings, there is evidence that SSR is a useful tool in MS.The usefulness of sympathetic skin responses (SSR) in multiple sclerosis (MS) has been advocated by several studies in the last 20 years; however, due to a great heterogeneity of findings, a comprehensive meta-analysis of case-control studies is in order to pinpoint consistencies and investigate the causes of discrepancies. We searched MEDLINE, EMBASE and Cochrane databases for case-control studies comparing SSR absence frequency and latency between patients with MS and healthy controls. Thirteen eligible studies including 415 MS patients and 331 healthy controls were identified. The pooled analysis showed that SSR can be always obtained in healthy controls while 34% of patients had absent SSRs in at least one limb (95% CI 22–47%;  The sympathetic skin response (SSR) is a simple, reproducible and non-invasive test based on the modification of the skin potential elicited most frequently by electrical stimulation of peripheral nerves. It is one of the methods to assess the autonomic nervous system (ANS) as it involves peripheral pre- and post-ganglionic sympathetic sudomotor fibres as well as central structures such as the posterior hypothalamus, upper brain-stem reticular formation and spinal cord .Multiple sclerosis (MS) is an inflammatory demyelinating disease with a scattered involvement of the central nervous system that can also affect the ANS . The ANSHere, we set out to perform a comprehensive meta-analysis of case-control studies that have investigated the association of SSR with MS. We also ran a simulation study exploiting the information of previous studies to evaluate whether a suitable threshold of SSR latency may discriminate MS patients from healthy controls, and validated the results on a new dataset collected by our laboratory. Finally, we attempted to understand the variability of results across studies testing covariates which may represent meaningful sources of heterogeneity.Eligible articles reporting the prevalence of missing SSR among patients with MS and healthy controls were identified by searching MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews databases. Studies published up to December 2015 were searched using the following combination of search strings: (‘sympathetic skin response OR SSR’) AND ‘multiple sclerosis’. No language restrictions were imposed. Reference lists of all articles that met the eligibility criteria were examined to identify studies that may have been missed by the database search.Studies were eligible if they met the following criteria: (i) report of original data in a peer-reviewed publication, (ii) evaluation of patients with MS in a case-control setting against a healthy control group, (iii) use of electrical stimulation of the limbs to evoke the SSR and (iii) report of the number of patients and controls with/without the SSR response in at least one limb and, if available, the SSR latency in the two groups. Subjects with other neurological disorders in control groups were excluded from the analysis. Duplicate publications were also excluded. In the event that the full-text version of a study did not report clearly the number of patients and controls with missing SSR response as well as the SSR latency mean (SD) for both groups, the corresponding author was asked to provide the missing data in order to maximise the amount of summarized data. We removed studies whose authors did not respond. The following data were collected (when available): journal name, year of publication, number of missing SSR responses in MS patients and controls, age, sex, type of MS, disease duration, Expanded Disability Status Scale (EDSS), SSR stimulation site, SSR intensity and duration, inter-stimulus interval, skin temperature and SSR latency.Q and I2 statistics. When statistically significant heterogeneity was detected , random-effect models were employed. We referred to the I2 statistics for the qualitative interpretation of heterogeneity; values greater than 50% are usually considered as indicative of substantial heterogeneity, while values greater than 75% represent considerable heterogeneity [Because none of the controls had missing SSR responses, we used pooled proportions to evaluate the overall prevalence of missing responses within the MS patient group. The latency mean difference between patients and healthy controls was computed from studies reporting SSR latencies. The fixed-effects model (Mantel-Haenszel) or random-effects model (DerSimonian Laird) were used to compute the pooled estimates. Heterogeneity between studies was assessed by the Cochran ogeneity . PublicaIn addition to the meta-analysis study, we tested the 95% confidence interval of the controls’ pooled mean latency for both superior and inferior limbs as diagnostic thresholds. We simulated 5000 data from each study enrolled in the meta-analysis using their SSR mean and standard deviation (SD) from both upper and lower limbs and assuming normality; subsequently, we computed the overall diagnostic odds ratio (DOR) and the area under the curve (AUC) statistics for superior and inferior limbs for each repetition and extracted mean and 95% empirical CI.We recorded the SSR from SM patients and healthy controls to validate our results using the following experimental setting: we stimulated each limb with a single pulse of 10–20-mA intensity and 0.2-ms duration and recorded the first elicited ipsilateral response among 3 to 5 stimuli delivered at more than 60-s interval each. We did not attempt to control limb temperature through direct warm up of the extremities but used a wool blanket to maintain the limb temperature during the entire examination period. All recordings were conducted using XLTEK® Protector 16-channel averager and statistical analyses using R version 3.2.3  with pacIn the first step of the database search, we identified 69 studies; 16 were from the EMBASE database. After the exclusion of 23 duplicate studies, the remaining 46 were screened for eligibility. Out of 28 potentially eligible studies, 15 were excluded either because of a missing control group (8 studies) or because of missing information (7 studies) which could not be recovered but in one case, either because the studies were too old and the authors could not retrieve their data or because they did not respond to our request. Data were extracted from the remaining 13 studies  were not reported in four studies –12. We dNone of the healthy controls had a missing SSR response. The proportion of MS patients with a missing SSR response varies widely across studies Fig.  ranging p < 0.0001) with considerable heterogeneity across studies . Patients’ age explained 22% of the total heterogeneity indicating that, for instance, a 5-year increase in mean age adds another 17% to the total proportion of MS patients with an absent SSR response. Moreover, we found disease duration to be moderately correlated with the proportion of MS patients with an absent SSR response (r = 0.35) while the EDSS was weakly correlated (r = 0.25). No publication bias was evident (Egger’s test p = 0.68).The pooled analysis showed that the proportion of MS patients with an absent SSR response is significantly different from zero . The difference in mean latencies across studies was weakly correlated with EDSS and disease duration at all limbs; however, all the correlations increased  after removing just one study [Considerable heterogeneity was apparent in both arms and legs  and 1915 m (95% CI 1866–1964 ms) in the lower limbs. The results of the simulation study using the upper 95% CI of the healthy controls as a threshold showed that the diagnostic odds ratio (DOR) for the upper limbs was 5.81 (95% CI 3.80–8.66) and 6.53 (95% CI 4.1–10.1) for the lower limbs.The area under the curve was 0.77 (95% CI 0.71–0.83) for the upper limbs and 0.81 (95% CI 0.74–0.88) for the lower limbs. The validation on our dataset showed a not significant DOR for the upper limbs  and a significant DOR for the lower limbs . The SSR latency threshold of the lower limbs showed a good discrimination ability with a sensitivity of 0.86 (95% CI 0.64–0.95), a specificity of 0.67 (95% CI 0.44–0.84), a positive predicted value (PPV) of 0.75 (95% CI 0.58–0.92) and a negative predicted value (NPV) of 0.80 (95% CI 0.60–1).To our knowledge, this is the first meta-analysis of case-control studies to summarize the role of the sympathetic skin response (SSR) in multiple sclerosis (MS) patients. The pooled result of our study showed that one-third of MS patients has no SSR response at least at one limb; on the other hand, none of the 331 healthy controls in the studies considered had a missing SSR. These findings suggest that, although the presence of SSR responses at all limbs cannot rule out the disease, an absent SSR response should be considered a warning sign of a pathological condition affecting the central or peripheral sudomotor subsystem of the ANS [Moreover, an absent or altered SSR in the early phases of MS may carry additional information that standard clinical measures, such as the Expanded Disability Status Scale (EDSS), cannot capture . In addiThe pooled analysis of the SSR latency mean difference showed a significantly longer latency in the MS patients, particularly in the lower limbs. The latency of the SSR was longer for the MS patients compared to that for the controls in all the studies included in the analysis. This argues against the uselessness of SSR latency measurement suggested by some studies , 18. FurWe found a considerable heterogeneity of both proportion and mean difference pooled analyses among case-control studies included in our meta-analysis. Patients’ age explained nearly 25% of the overall variability of the proportion of patients with absent SSR across studies. Although it is possible to consider age as a proxy of disease duration in the MS framework, it is worth mentioning that in a previous work  the abseIn addition, the exploratory correlations between EDSS and both the proportion of absent SSR and SSR latency suggested that EDSS may help explain another part of the overall heterogeneity found in our meta-analysis. This agrees with some studies , 4 whereOther sources of variability may be found in the different technical setting used to record the SSR. Habituation, body temperature, stimulus intensity and selection of the evoked response are important variables to consider , 21, 22.Habituation in healthy subjects causes a progressive decrease of SSR amplitude that appears earlier if stimuli are given at a regular, predictable pace. To minimise habituation, a random stimulation with a frequency greater than one per minute is suggested . In the Skin temperature was found to be negatively related to both SSR latency and amplitude in healthy subjects , 22, andIt is known that the amplitude of the SSR depends on the stimulus strength  and thatEventually, it must be stressed that even in studies of healthy subjects, there is still no consensus on the proper way to measure the skin responses and their mathematical processing . The absTogether with a considerable heterogeneity, missing data is another limitation in our study. Several controlling factors could not be properly tested in our meta-analysis due to missing data, the main source of which is the lack of a common approach in the collection of variables across the studies with some failing to report even standard demographic and clinical information.Despite these limitations, the pooled results of this meta-analysis support SSR recording to detect ANS involvement in MS using the latency or the absence of response as a measure. Our findings suggest that SSRs yield complementary information to that of the EDSS and evoked potentials which could contribute to the understanding and monitoring of MS.


We present a rapid, simple, and scalable approach to achieve superhydrophobic (SH) substrates directly in commodity shrink wrap film utilizing Argon (Ar) plasma. Ar plasma treatment creates a stiff skin layer on the surface of the shrink film. When the film shrinks, the mismatch in stiffness between the stiff skin layer and bulk shrink film causes the formation of multiscale hierarchical wrinkles with nano-textured features. Scanning electron microscopy (SEM) images confirm the presence of these biomimetic structures. Contact angle (CA) and contact angle hysteresis (CAH) measurements, respectively, defined as values greater than 150° and less than 10°, verified the SH nature of the substrates. Furthermore, we demonstrate the ability to reliably pattern hydrophilic regions onto the SH substrates, allowing precise capture and detection of proteins in urine. Finally, we achieved self-driven microfluidics via patterning contrasting superhydrophilic microchannels on the SH Ar substrates to induce flow for biosensing. Superhydrophobic (SH) surfaces are found widely throughout nature with a variety of purposes. For example, the lotus leaf consists of micro and nano-structured features that allows for self-cleaning properties, while the Namib Desert beetle has alternating SH and hydrophilic regions to optimize water collection under extreme desert conditions ,2,3. InsSH surfaces are substrates with low surface energy, which significantly decreases the adhesion of water. Superhydrophobicity is characterized as having a water contact angle (CA) greater than 150° and a contact angle hysteresis (CAH) less than 10° ,12,13. EMethods to fabricate SH surfaces include depositing material with low surface energy onto a rough surface, roughening a hydrophobic surface via etching, creating hierarchal architectures on a substrate, or a combination of these techniques ,21,22,23In our previous work, we achieved purely structural SH surfaces by shrinking pre-stressed thermoplastic polymers with metal thin films deposited on top, resulting in multi-scale wrinkled structures. These hierarchical, biomimetic structures could subsequently be transferred to a silicone elastomer mold, which yielded a SH elastomeric substrate ,27,28. THere, we present a simple, inexpensive method to create structural SH surfaces that obviates the need for metal deposition or multiple feature transplantations. In this approach, multi-scale wrinkled SH structures were created directly in commodity shrink film by simply treating the film with Ar plasma and subsequently heating the substrate past its glass transition temperature to shrink it. We demonstrate feasibility of patterning the SH substrates with hydrophilic regions to capture protein in urine with a wide range of detectable protein concentrations. Furthermore, open-channel, self-wicking microfluidic flow can also be achieved via patterning superhydrophilic regions on the SH substrates. This drives fluid flow due to a high surface energy differential accomplished between a SH and superhydrophilic interface. A 4.5” × 4.5” polyolefin (PO) film  was cut and clamped securely onto a 5” × 5” glass slide and placed into a plasma cleaning system . The PO film was plasma treated with Ar for 1, 5, 10, 20, 30, 40, and 60 min (at 200 mTorr and 60 W). After plasma treatment, the PO films were shrunk to induce the multiscale, hierarchical wrinkling. Briefly, the PO films were sandwiched between two glass slides and two sheets of parchment paper with 1 mm rubber spacers. Four 0.5” binder clips were added to apply pressure to the sandwich. The films were then heated to 120 °C in a conventional convection oven , allowing the PO film to shrink within the constraints of the glass slides.®  [versus wavenumber. A running average of the intensity and wave number was taken, and each plot was normalized to its maximum value. The average noise summed for each wavenumber was estimated and subtracted out [The surface topology of the shrunk Ar-treated substrates were observed using a high-resolution scanning electron microscope (SEM) . Prior to imaging, 4 nm of iridium was sputtered on top of the substrates to prevent charging. For each sample, the distribution of wrinkle wavenumber, defined as the inverse wavelength, was found by applying a 2D Fast Fourier Transform (2D FFT) on the SEM images using MatlabMA, USA) ,29. The cted out ,29. i.e., cannot definitely determine submicron features). Therefore, coupled with the nanoscale FFT measurements, microscale roughness data from the laser scanning microscope was used to characterize the SH nature of our substrates.Additionally, roughness measurements were taken using a red laser scanning microscope . The root mean square (RMS) was taken to compare microscale roughness of the features on the shrunk surfaces for different treatment times. Experimentally, such optical measurements using our imaging system are limited in resolution compared to a scanning microscope and, thus, microscale rougness resolution is comparable to FFT data corresponding to 5 µm and greater (Contact angle (CA) and contact angle hysteresis (CAH) measurements were taken using a droplet shape analyzer . For the CA measurements, shrunk Ar-treated samples were cut and mounted onto standard microscope slides with double-sided tape. The samples were placed on the DSA-30, and CA values of 5 μL of water were measured via tangent analysis with ADVANCE software . The mean CA for each independent substrate was calculated by averaging the CA over three individual spots on each sample.−1 to record advancing CA. The droplet was then retracted at a constant rate of 0.16 µL·min−1 to measure receding CA. CAH was calculated by taking the difference of advancing and receding CA [CAH values were evaluated by depositing 10 µL of water at a constant rate of 0.16 µL·mineding CA ,30. The ® Laboratory Sealing Film, Bemis Co., Neenah, WI, USA) with a CO2 laser . The laser cut Parafilm mask was adhered to a non-Ar-treated substrate or a SH Ar-treated substrate by applying minimal pressure. The substrates were subsequently treated with air plasma  for 1 min at 75% power to achieve hydrophilic anchor points. Droplets of diluted green food dye  were deposited on the patterned substrates . Top view and side view images were taken with a DLSR camera  using a 100 mm lens .Non-Ar-treated PO film was shrunk in the same manner as the Ar-treated films as a control surface. The non-Ar-treated substrates and the SH Ar-treated substrates were patterned with hydrophilic regions using a negative mask and air gas plasma treatment. A mask with 2, 1, and 0.5 mm holes (with 5 mm spacing) was created by cutting the design into a paraffin film substrate  at 1 min, 75% power respectively, a 3 × 3 array of 500 µm diameter hydrophilic spots with 5 mm spacing was patterned onto the SH Ar substrates. 10 µL of adjusted urine was deposited on each spot and allowed to evaporate for 2 h. After evaporation, 10 µL of diluted protein assay dye reagent was added and incubated for 5 min. The reactants were then removed from the substrates, and the absorbance values were measured at 595 nm on the Nanodrop. Reported values are the signal minus the 0 µg·mL−1 control.A standard colorimetric Bradford protein assay (Bio-Rad Protein Assay) was used to detect protein concentrations. Urine was collected from voluntary subjects , and the baseline urine protein concentration was calculated using absorbance values from a ultraviolet-visible (UV-VIS) spectrophotometer  compared to a standard curve derived with bovine serum albumin (BSA) . Urine samples were then diluted with DI (deionized water) water or spiked with BSA to achieve final protein concentrations of 0, 20, 40, 80, 150, 200, and 250 µg·mLSimilar to the patterning and protein detection, a laser cut Parafilm mask and air plasma treatment  was used to create self-driven, open-channel microfluidic flow. The mask consisted of 400 µm wide channels. To demonstrate self-wicking, 5 µL of diluted green food dye was added to the inlet of the microchannel, and self-driven fluid flow was recorded using a high speed camera  at 120 fps and a macro lens . SEM images of the surface morphology of the non-Ar-treated and Ar plasma treated  shrunk substrates are shown in et al. [et al. reported wrinkling due to the stiff skin layer developed by argon plasma treatment on their polystyrene (PS) samples [The wrinkle formation was attributed to the stiff skin layer created on the surface of the pre-stressed PO film due to the Ar plasma treatment. During plasma treatment with the inert Ar gas, energized ions from the bulk plasma break C-H or C-C bonds on the surface to create free radicals on the surface of the PO. When the Ar-treated PO is removed from the chamber and exposed to air, the free radicals react with the molecular oxygen to form a stiff oxide layer on the PO surface ,32. Whenet al. ,34. Simi samples . The zoomed out SEM images in et al. noted that when certain polymers were exposed to Ar plasma, a dehydrogenated amphorous carbon layer formed on the surface, and the thickness remained constant once the initial layer was formed [versus the 60 min  sample, as shown in et al. where Ar plasma was used to induce nanoscale roughness on polystyrene films [To develop a better understanding of the nanoscale features observed on the multiscale wrinkles, SEM images of the PO film were captured prior to shrinking on a non-Ar-treated ne films . HoweverIn addition to wrinkle wavelength and nanoscale roughness, microscale roughness was also characterized because a combination of nanoscale and microscale features are necessary to achieve superhydrophobicity. The microscale features on the Ar-treated SH samples were observed using a red laser scanning microscrope, as shown in Samples treated with Ar for 1, 30, and 60 min result in microscale roughness of 2.2 ± 0.4 µm, 4.4 ± 0.6 µm, and 5.0 ± 0.2 µm, respectively. As plasma treatment increases, the microscale roughness increases, which could be attributed to the effective skin on our shrink film . Under hTo characterize the SH nature of the shrunk Ar-treated surfaces, CA and CAH measurements were conducted. CAH measurements are presented in As seen in The combination of having CA greater than 150° and CAH less than 10° indicates a SH surface. Therefore, PO films with Ar plasma times greater than 30 min are characterized as SH.To illustrate the contrast in fluid behavior on a hydrophobic surface compared to a SH surface, hydrophilic anchor points of various sizes  were patterned onto non-Ar-treated shrunk surfaces and SH Ar-treated surfaces. The anchor points were created by exposing the samples to air plasma through a mask. Exposure to air plasma caused molecules from the air (such as oxygen) to bombard the surface with charged particles, resulting in a chemically-modified surface with an increased surface energy. Due to the short duration of the air plasma treatment (1 min), the air plasma treatment does not add structural modifications to the surface.As shown in To demonstrate that these Ar-treated SH surfaces have the same utility as our previously fabricated SH surfaces, we applied a simple bioassay where we detected the presence of proteins in urine. A known advantage to SH surfaces is its ability to enhance detection of biomolecules in bodily fluids via simple evaporation of the fluid on the SH substrate . To condTo determine feasibility of this phenomenon on the Ar-treated SH surfaces, we evaporated urine with varying protein concentrations onto a patterned array of hydrophilic spots. Upon addition of a protein assay dye reagent to the concentrated urine pellet, we were able to reliably detect physiologically-relevant ranges of protein  that werIn line with our interest for utilizing the Ar SH surfaces for point-of-care diagnostic applications, we have tested the ability to use these substrates for creating self-driven, open-channel microfluidic flow. Open-channel microfluidic assays with self-driven flow can be beneficial because they mitigate the need for bulky, external equipment such as pumps and tubing. Furthermore, open-channels can overcome many of the problems associated with closed-channel microfluidics, such as nonspecific sidewall adsorption, loss of reagents, clogging, and bubbles ,40,41.Self-driven flow on SH surfaces can be accomplished by patterning the surface with air plasma to achieve superhydrophilic channels. As described earlier in In summary, we have demonstrated that Ar plasma can be used to etch pre-stressed PO films, thus creating a stiff layer that generates SH surfaces directly in the PO film upon shrinking. In contrast to previous studies, our method directly achieves SH surfaces without the need for post-processing and complex chemical additions. We further show that such SH surfaces can be selectively patterned by air plasma to create hydrophilic regions to capture protein in urine for molecular diagnostics. The contrast in wettability between the SH and superhydrophilic regime generated fluid flow along microchannels to achieve self-driven, open-channel microfluidics, negating the need for external equipment and eliminating the problems associated with closed-channel microfluidics. In particular, the ability to selectively pattern these SH surfaces through our method could be useful for low energy transport of fluids in molecular diagnostics, thus making our surfaces feasible for broad applications such as point-of-care diagnostics.


Augmented reality (AR), mixed reality (MR), and virtual reality devices are enabling technologies that may facilitate effective communication in healthcare between those with information and knowledge  and those seeking understanding and insight . Investigators initiated an exploratory program to enable the study of AR/MR use-cases in acute care clinical and instructional settings.Academic clinician educators, computer scientists, and diagnostic imaging specialists conducted a proof-of-concept project to 1) implement a core holoimaging pipeline infrastructure and open-access repository at the study institution, and 2) use novel AR/MR techniques on off-the-shelf devices with holoimages generated by the infrastructure to demonstrate their potential role in the instructive communication of complex medical information.The study team successfully developed a medical holoimaging infrastructure methodology to identify, retrieve, and manipulate real patients’ de-identified computed tomography and magnetic resonance imagesets for rendering, packaging, transfer, and display of modular holoimages onto AR/MR headset devices and connected displays. Holoimages containing key segmentations of cervical and thoracic anatomic structures and pathology were overlaid and registered onto physical task trainers for simulation-based “blind insertion” invasive procedural training. During the session, learners experienced and used task-relevant anatomic holoimages for central venous catheter and tube thoracostomy insertion training with enhanced visual cues and haptic feedback. Direct instructor access into the learner’s AR/MR headset view of the task trainer was achieved for visual-axis interactive instructional guidance.Investigators implemented a core holoimaging pipeline infrastructure and modular open-access repository to generate and enable access to modular holoimages during exploratory pilot stage applications for invasive procedure training that featured innovative AR/MR techniques on off-the-shelf headset devices. However, these worlds are accessible only when users wear opaque VR goggles and relinquish several essential and interactive aspects of the physical realm of reality. In contrast, augmented reality (AR) overlays a supplemental digital realm Beyond consumer-focused uses such as gaming and social media, AR/MR technologies harbor dramatic potential for meaningful scientific application due to their ability to radically shift the way individuals interact with other people, places, objects, and ideas. Specifically, the representation and sharing of informative data through sophisticated visualization approaches is likely to blossom into an explosive phenomenon. AR/MR is already catalyzing healthcare and medical education, as it embodies an innovative and accessible approach for clinicians, patients, researchers, and educators to see, discuss, study, experiment, implement, and share complex concepts. Established examples in diverse fields include anatomy education,Our goals were as follows: 1) Implement a basic holoimaging pipeline infrastructure with open-access repository to facilitate exploratory applications of AR/MR at the study institution and beyond; and 2) Use novel AR/MR techniques on off-the-shelf devices with holoimages generated by the infrastructure to demonstrate their potential role in the instructive communication of complex medical information.e.g., probe failure) and non-availability.Program investigators structured an exploratory research framework to examine AR/MR’s unique capabilities, implementation needs and barriers, and use characteristics in accessible, high-yield, best-case healthcare settings . For oneTo set up the envisioned training application, the team accessed two department-funded, off-the-shelf HoloLens headsets  at a hospital simulation center. Specifically, these devices were used to expand an existing hands-on procedural teaching curriculum in place for EM fellows, residents, advanced practice providers, and medical students. We designed a two-hour pilot session to accommodate 40 learners for the “blind insertion” procedural training using two distinct and complementary approaches: 1) modular AR/MR holoimaging overlay and registration of patient anatomic structures and pathology onto procedural task trainers; and 2) first-person view visual-axis interactive instructional guidance. The institutional review board approved the project protocol.Diagnostic imaging and computer science co-investigators collaborated with clinician educators to develop and assemble a medical holoimaging pipeline infrastructure with the following elements:Query mechanism to identify, locate, and retrieve radiographic imagesets with specified clinical findings in the hospital network’s Centricity Picture Archiving and Communication Systems  using mPower Imageset manipulation approach for de-identified, thin-slice, contrast-enhanced trauma “pan-scan” computed tomography (CT) volumetric imagesets to create modular and discrete regional segmentations of anatomic structures and pathologic findings of interest:2a. We extracted structures of interest with voxel intensity-based growing algorithms using an Advantage Workstation .2b. We converted 3D scalar fields of structures of interest into polygonal mesh isosurfaces as an .stl file  with a marching cubes algorithm, using iNtuition .2c. We managed mesh smoothness and vertex counts using open-source MeshLab  to fit within the processing capabilities of select AR/MR headset devices.Compositing, rendering, and packaging process with differentiation of mesh model layers by color and synthesis of integrating holoimages using Maya software for export in .fbx format Transfer mechanism to move holoimages onto institution-approved secure network storage, cloud storage solution, and/or an open-access repositoryRetrieval and display procedure to access holoimages on AR/MR headset devices.holocomposites that reflect patterns of pathology, e.g., combinations of multi-organ traumatic injury holoimages. At an administrative level, procedures and protocols for formalization of the infrastructure and dissemination mechanisms for institution-wide use are under development in parallel with discussions of staffing and funding arrangements. In the interim, approximately 20 of the developed holoimage .fbx files are accessibly stored on a storage cloud repository located at: https://repository.library.brown.edu/studio/collections/id_753/ .In its current implementation, the process pipeline required approximately 30 minutes for a typical head or chest CT imageset from the time of patient selection until holoimage display . One specific advantage of developing this type of infrastructure was the ever-expanding repository of modular holoimages that can be subsequently retrieved and displayed, either as originally rendered or in assembled ., sternal notch, laryngeal prominence, rib spaces. This permitted the stable overlay of task-relevant anatomy, e.g., internal jugular, carotid artery; ribcage, lung parenchyma, and pneumothorax, for training with enhanced visual cues and haptic feedback. A wirelessly networked laptop connected with the AR/MR device’s built-in webportal system to broadcast the learner’s view with superimposed holoimages for the viewer cohort.Overlaying real patients’ holoimages of key cervical and thoracic structures onto physical task trainers was essential to provide learners with the equivalent of a “visible human” for the explicit purpose of conveying the locations, shapes, sizes, and juxtapositions of internal vascular and thoracic anatomic structures with respect to surface features. This was accomplished by displaying the rendered holoimages on the HoloLens units with 3DViewer Beta (Microsoft) during the practice insertion of invasive therapeutic devices . The hol., the introduction of educator-inserted 3D visual cues such as digital pointers and arrows. By using the headset’s Skype functionality, the learner video-called an educator’s laptop Skype application with HoloLens Add-in (with screen-mirroring projection of the learner FPV). This resulted in lagless sharing of the learner’s procedural performance perspective along with the ability for both the learner and educator to “draw” into the shared view using an on-screen toolset, e.g., digital pencil tool or arrow tool. For environments without network connectivity or Skype, an alternative approach has been tested using an ad hoc device-laptop connection and Bluetooth-connected pointing device such as a wireless mouse to remotely direct the learner’s attention  between the learner’s HoloLens headset and an educator laptop with LCD projector. This arrangement was critical for accessing the learner’s AR/MR headset view of the task trainer for visual-axis interactive instructional guidance, i.ettention .Investigators successfully applied the described AR/MR holoimage visualization methodologies to a two-hour pilot session with approximately 40 learners. Four 30-minute breakout sessions (with two educators each instructing groups of 10 participants) were completed as part of a scheduled EM residency conference period; simulation and standardized patient scenarios were conducted in parallel sessions during the AR/MR-enhanced invasive procedural training. To emphasize anatomic visualization with AR/MR assistance and to review “blind insertion” techniques, the learners were intentionally not provided with ultrasound devices; standard approaches, equipment, and procedural kits were otherwise used for both procedures. All participants finished both task-training exercises without physical discomfort; formal objective metrics were not obtained during this proof-of-concept session. See Investigators successfully piloted the use of off-the-shelf AR/MR devices to integrate holoimaging-enhanced anatomic visualization with acute care invasive procedure training. We developed and implemented novel methodologies, including a core institutional holoimaging pipeline infrastructure, open-access storage repository of modular holoimage segmentations, and visual axis instruction techniques, for education and research purposes.Program researchers are continuing to explore AR/MR applications in acute care, surgical care, and medical science while concurrently working to formally study the utility and usability of the developed AR/MR methodologies in healthcare. As part of the research program’s multiphasic strategy, investigations of AR/MR devices at the live clinical bedside are being prepared in peri-procedural settings: anatomic and diagnostic imaging AR/MR visualizations will be shown to patients and family members to gauge how the intervention facilitates discussions regarding management options and whether it assists with shared decision-making. Simultaneous, shared holoimage visualization across multiple headsets/viewers has already been accomplished at the study site; automation of holoimage registration with the real world for improved user experiences is being actively pursued.., holoimage registration accuracy, stability, and usability) and longitudinal, checklist-based procedural performance assessments in simulated settings will need to be established and validated. Additional acute care procedural training that could uniquely benefit from AR/MR-enabled anatomic referencing and guidance are being reviewed, e.g., arthrocentesis, epistaxis control, lumbar puncture, orthopedic manipulations, and complex wound exploration. Well-designed trials will be necessary to ascertain the effectiveness of AR/MR-based training and treatment interventions on live-patient clinical outcomes.With respect to future directions, the program team is pursuing ongoing use of AR/MR supplementation during EM residency sessions to objectively examine its educational utility for acute care procedural training. Defined metrics such as operational quality markers  are anticipated to begin laying the foundation for meaningful and judicious use of AR/MR in healthcare.The program’s core holoimaging infrastructure was made possible by the significant in-kind efforts of co-investigators  with deep, authorized access into the institution’s clinical diagnostic imaging systems. The primary operational limitation encountered by the research team derived from the manual overlay and registration process, in that the spatial alignment between the holoimage and the task trainer was intermittently lost and required adjustments. We did not assess or compare the effects of the experimental AR/MR approach on learner training and performance against existing methods during this initial pilot application. As a novel visualization approach that has only recently become more accessible to healthcare providers and researchers, holoimaging is anticipated to progress through the “hype cycle” framework,., distortion of real-world perception,Investigators have focused on the technical aspects of core system implementation, such that continued efforts will need to address the substantial work that remains in applying human factors engineering, ensuring institutional acceptance, and conducting empirical investigations into the clinical utility of holoimaging’. Previous work has already identified a variety of emergent AR-specific adverse effects in the clinical environment, e.g


Stroke is one of the leading causes for disability worldwide. Motor function deficits due to stroke affect the patients' mobility, their limitation in daily life activities, their participation in society and their odds of returning to professional activities. All of these factors contribute to a low overall quality of life. Rehabilitation training is the most effective way to reduce motor impairments in stroke patients. This multiple systematic review focuses both on standard treatment methods and on innovating rehabilitation techniques used to promote upper extremity motor function in stroke patients. A total number of 5712 publications on stroke rehabilitation was systematically reviewed for relevance and quality with regards to upper extremity motor outcome. This procedure yielded 270 publications corresponding to the inclusion criteria of the systematic review. Recent technology-based interventions in stroke rehabilitation including non-invasive brain stimulation, robot-assisted training, and virtual reality immersion are addressed. Finally, a decisional tree based on evidence from the literature and characteristics of stroke patients is proposed. At present, the stroke rehabilitation field faces the challenge to tailor evidence-based treatment strategies to the needs of the individual stroke patient. Interventions can be combined in order to achieve the maximal motor function recovery for each patient. Though the efficacy of some interventions may be under debate, motor skill learning, and some new technological approaches give promising outcome prognosis in stroke motor rehabilitation. The World Health Organization (WHO) estimates that stroke events in EU countries are likely to increase by 30% between 2000 and 2025  after stroke are common with prevalence rates variously reported to be 11–85%  . In some cases, routine clinical treatments that have not been investigated in a randomized controlled way, are still included in the present systematic review if the trial demonstrated sufficient quality evidence. The scientific evidence of each stroke rehabilitation intervention is discussed and presented with a practical recommendation for clinicians working in the field of neurorehabilitation. A decisional tree according to the patient's characteristics is proposed based on scientific evidence available for the different interventions.lack of scientific evidence, if a total number of less than 500 subjects has been included in trials selected in the systematic review. A treatment modality is not recommended as a rehabilitation intervention because of a lack of effectiveness, if (1) it has shown non-superior (similar or inferior) efficacy compared to another rehabilitation intervention and (2) a sufficient amount of evidence is available, defined as a total number of at least 500 subjects included in trials selected in the systematic review. A treatment modality is recommended as a rehabilitation intervention, if it has shown superior efficacy compared to another rehabilitation intervention. A treatment modality is recommended as an adjuvant intervention for rehabilitation treatment, if it has shown superior efficacy in combination with another rehabilitation intervention compared to the other rehabilitation intervention alone. These recommandations as a rehabilitation intervention or as an adjuvant intervention only are issued if a sufficient amount of evidence is available, defined as a total number of at least 500 subjects included in trials selected in the systematic review.This manuscript is based on multiple systematic reviews. Twenty-six different rehabilitation treatment modalities were included and searched for with the following search terms: Bobath, Picard, Perfetti, muscle strengthening, isokinetic muscle strengthening, stretching, bilateral training, forced-use, motor skill learning, constraint induced movement, mirror therapy, motor imagery, motor imitation, movement observation, transcutaneous electrical nerve stimulation, neuromuscular electrical stimulation, positional feedback, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, deep brain stimulation, paired associative stimulation, antidepressants, botulinum toxin, robot-assisted, virtual reality, music. The 26 search terms were chosen by a panel of experts in neurorehabilitation . The systematic database search and article selection was performed by two independent investigators (SH and YB). Each of the 26 search terms was combined with the keyword “stroke” and with each of the following three keywords: “rehabilitation” or “intervention” or “recovery.” The search was performed by a hand search and by using the internet databases: medline and pubmed, retrieving articles from 1971 until May 2015, and yielded a total number of 5712 publications. Exclusion criteria at each stage of the review process are reported in a general prisma diagram. The outcome of this multiple review process includes randomized-controlled trials (RCTs), controlled trials, systematic reviews, and meta-analyses with a PEDro-score higher than or equal to 4  Neurofacilitatory approaches/multiple exercising approaches; (2) Isolated concepts; (3) Motor learning; (4) Interventions based on the hypothesis of mirror neurons and motor imagery; (5) Adjuvant therapies; and (6) Technology-supported training. For each chapter, results of the systematic review are highlighted and in the general discussion, a decisional tree is proposed for therapeutic intervention based on current scientific evidence.The systematic search yielded 5712 publications. After the systematic selection of articles following the general flowchart described in Figure Exercise therapy is a key element of stroke rehabilitation. Exercises performed after stroke may differ with regards to their objectives  or their technical characteristics . These specific elements of exercise therapy are described in a Supplementary Material The Bobath concept was developed by Berta and Karl Bobath. The Bobath treatment aims at normalizing tone and facilitate volitional movement through handling of specific points  in order to guide patients through the initiation and completion of intended tasks Bobath, . Both thn = 475) and 2 systematic reviews/meta-analyses (at least n = 209) (Supplementary Table The systematic review yielded 8 RCTs (n > 500) indicating the non-superiority of Bobath therapy, at present, there are insufficient arguments for integrating Bobath therapy into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence (n = 40) and showing no difference in motor outcomes between Perfetti's method and standard occupational therapy with regards to hand and arm impairments , at present, there are insufficient arguments for integrating Perfetti's method into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence (The systematic review with the search term “Picard” did not yield any publications matching the inclusion criteria.n < 500), at present, there are insufficient arguments for integrating Picard rehabilitation into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  have been fully described and their effects tested. These isolated rehabilitation concepts will now be discussed.Muscle strengthening techniques are progressive active exercises against resistance for the paretic arm. These exercises can be performed against a manual resistance (exerted by the therapist) or using weight-bearing apparatus. Muscle strengthening and endurance training in stroke rehabilitation for long have been decried for their supposed induction of spasticity, but now have been recovered as an essential part of the rehabilitation programs offered to brain-lesioned patients  comparing strengthening exercises of the upper limb either to strengthening exercises of the lower limb or to standard therapy. The total number of subjects in these reviews could not be retrieved. There is moderate-quality evidence indicating that strengthening exercises are useful for increasing UE impairments (strength), without or with poor improvement at the level of disabilities, in acute, subacute, and chronic stroke patients.The systematic review (Supplementary Table n > 500) indicating the superiority of muscle strengthening, muscle strengthening exercises appear to be valuable and could be integrated into stroke rehabilitation strategies with a view to improving UE motor impairments.Based on a sufficient amount of evidence , at present, there are insufficient arguments for integrating isokinetic muscle strengthening into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  and 2 systematic reviews (n = 1384). There is moderate- to high-quality evidence indicating that stretching is similar to control rehabilitation approaches for treating upper limb impairments  and disabilities in subacute and chronic stroke. No significant effects were found of stretching in comparison with control interventions with regards to passive range of motion, pain or activities of daily living. While manual passive stretching has not been proven effective, physical contentions have shown interest for the treatment of spasticity. Gains of range of motion, with an impact on spasticity and motor impairments have been observed through the use of long-term contention, , notably after injection of botulinum toxin A  indicating the non-superiority of stretching therapy, at present, there are insufficient arguments for integrating stretching into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence , 1 controlled trial (n = 23) and 7 meta-analyses/systematic reviews (at least n = 2240). There is moderate- to high-quality evidence that bilateral arm training (non-device assisted or device-assisted) is similar or inferior to unilateral arm training or to standard rehabilitation treatment. Any gains are specific for the task that is being trained (motor impairment) and do not extrapolate to upper extremity disabilities in daily life. The efficacy of bilateral arm training does not appear to be specific for a post-stroke phase. One study (n = 24) indicates that bilateral training may improve spasticity in chronic stroke  indicating the non-superiority of bilateral training, at present, there are insufficient arguments for integrating bilateral training into stroke rehabilitation with a view to improving UE motor impairments or disabilities.At present, it appears that bilateral training, though based on neurophysiological evidence, does not hold up its promise for clinical purpose. Based on a sufficient amount of evidence . However, in contrast with constraint-induced movement therapy , forced-use is not associated with specific motor skill learning techniques. Restraint of the non-paretic upper extremity is performed without specific training, or using usual care.n = 96). There is moderate-quality evidence that forced-use is similar to standard rehabilitation therapy or to bimanual training with regards to UE motor impairments or disabilities. Randomized controlled studies of forced-use of the UE after stroke are needed.The systematic review (Supplementary Table n < 500), at present, there are insufficient arguments for integrating forced-use into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence (Constraint-induced movement therapy (CIMT) is a therapeutic approach that applies motor skill learning principles to stroke rehabilitation. CIMT is a specialized task-oriented training approach. Its specific strategy is to induce motor learning  and neuroplasticity  with intensive blocks of training. In contrast with forced-used (solely based on the idea of immobilization of the non-paretic arm without specific intervention), CIMT requires both functional training of the affected arm with gradually increasing difficulty levels, and immobilization of the patient's non-affected upper extremity. The original high-intensity protocol of CIMT highlights: (1) repetitive task-oriented practice of the paretic upper limb for 6 h/day during 10 consecutive weekdays; (2) skills achieved in the clinical setting to be translated to the patient's daily real-world environment; (3) constraint of the non-paretic upper extremity to promote the use of the paretic upper extremity during 90% of the waking hours , 1 controlled trial (n = 41) and 12 systematic reviews/meta-analyses (n = 6187).The systematic review  is superior to standard rehabilitation approaches, with regards to upper extremity impairments and disabilities. CIMT appears as beneficial in acute (with a lower dosage regimen), subacute and chronic post-stroke phases. Effects of CIMT may persist till 12 months after training. CIMT can be recommended for stroke patients after 3 months, either in its original design or in modified forms, especially if hand movement is possible. In patients without active hand movement, further studies are needed to confirm the benefit of CIMT. Under 3 months after stroke, the dosage of CIMT needs to be lowered.n = 20) describes the application of motor skill learning outside the context of CIMT  indicating the superiority of constraint-induced movement therapy, at present, CIMT appears to be valuable and could be integrated into stroke rehabilitation strategies with a view to improving UE motor outcome (impairments and disabilities); taking into account the above-described recommendations.Based on a sufficient amount of evidence (n < 500), at present, there are insufficient arguments for integrating motor skill learning techniques other than CIMT, into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  networks . This trial gives moderate-quality evidence indicating that movement observation is similar to a “sham” procedure with regards to UE motor impairments and disabilities (except the box and block test which was significantly better till 5 months after exposure). More RCTs are needed to ascertain this conclusion.The systematic review (Supplementary Table n < 500), at present, there are insufficient arguments for integrating movement observation into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence . Data show that the basic brain circuitry underlying motor imitation coincides with the circuitry active during movement observation. A direct mapping of an observed action and its motor representation seems to occur through interactions in this circuitry , at present, there are insufficient arguments for integrating graded motor imitation therapies into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  and 4 systematic reviews (n = 1134). There is moderate-quality evidence that mirror therapy is superior to sham therapy, control therapy  or standard rehabilitation treatment (Supplementary Table The systematic review (Supplementary Table n > 500) indicating the superiority of mirror therapy, at present, mirror therapy appears to be valuable and could be integrated into stroke rehabilitation strategies with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence  is a training method that calls for cognitive rehearsal of activities for the explicit purpose of improving performance of those activities. The movement is not actually produced but is, instead, imagined by the individual  and 5 systematic reviews/meta-analyses (at least n = 1266). There is moderate-quality evidence that mental practice with motor imagery in combination with another rehabilitation treatment is superior to the other rehabilitation treatment alone with regards to upper extremity impairments and disabilities. Mental practice with motor imagery appears as beneficial in the subacute and chronic post-stroke phase.The systematic review (Supplementary Table n > 500) indicating the superiority of mental practice with motor imagery, at present, mental practice with motor imagery appears to be valuable and could be integrated into stroke rehabilitation strategies with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence  sensory electrical stimulation; (b) muscle (or motor) electrical stimulation.TENS corresponds to the electrical somatosensory stimulation of a peripheral nerve through the use of cutaneous electrodes. In function of the stimulation, TENS is categorized into high-frequency TENS and low-frequency TENS corresponding to respective stimulation frequencies of 80–100 and 1–5 Hz. High-frequency TENS elicits sensory responses, whereas low-frequency TENS may elicit motor contractions as well. For the latter reason, literature on low-frequency TENS will be discussed in the following section . Electroacupuncture is an electrical stimulation technique based on the application of electrical current at low frequencies (2–3 Hz) during acupuncture needling. The exact mechanisms of action of TENS on motor recovery after stroke are unknown. Most likely, a long-term potentiation-like mechanism in the excitatory glutamatergic connections between the primary sensory and motor cortices mediates the direct effects of repetitive transcutaneous electrical nerve stimulation on corticospinal excitability and motor performance  and 1 systematic review (n = 446). There is moderate-quality evidence that high-frequency TENS (100 Hz) in combination with rehabilitation treatment is superior to the rehabilitation treatment alone with regards to upper extremity impairments and disabilities. High-frequency TENS appears as beneficial in the subacute and chronic post-stroke phase. Spasticity appears to diminish with high frequency-TENS.The systematic review  in combination with rehabilitation treatment is superior to the rehabilitation treatment alone with regards to upper extremity impairment. Further RCTs are needed to ascertain this conclusion.n > 500) indicating the superiority of high-frequency TENS, at present, high-frequency TENS appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor impairments and disabilities.Based on a sufficient amount of evidence (n < 500), at present, there are insufficient arguments for integrating electroacupuncture as an adjuvant therapy into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  over a muscle (neuromuscular endplate) induces muscle contractions at stimulation frequencies of 10–50 Hz. NMES can be used to elicit simple muscle contractions as a passive technique or can be actively triggered by electromyographic activity (EMG-NMES) or by limb position (position-triggered NMES)  and 4 systematic reviews (n = 2293).The systematic review  in combination with rehabilitation treatment is superior to the rehabilitation treatment alone with regards to upper extremity impairment. There is no effect of low-frequency TENS on UE disabilities. Low-frequency TENS does not appear to influence upon spasticity. Further RCTs are needed to ascertain this conclusion.There is moderate-quality evidence that simple/passive NMES in combination with rehabilitation is superior to the rehabilitation treatment alone with regards to upper extremity impairment . There is no effect of simple/passive NMES on UE disabilities. Treatment effects have been described in acute and subacute stroke patients. Simple/passive NMES does not appear to influence upon spasticity.There is moderate quality evidence that EMG-NMES in combination with rehabilitation treatment is similar to the rehabilitation treatment alone or to passive NEMS with regards to upper extremity impairment . However, it is difficult to dissociate EMG-NMES' effects from those of the rehabilitation treatment. There is no effect of EMG- NMES on UE disabilities. Further RCTs are needed to explore the efficacy of EMG-triggered neuromuscular electrical stimulation.The systematic review with the search term “positional feedback” did not yield any publications matching the inclusion criteria.n > 500) indicating the superiority of passive neuromuscular electrical stimulation, at present, passive NMES appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor impairments.Based on a sufficient amount of evidence (n < 500), at present, there are insufficient arguments for integrating low-frequency TENS, EMG-NMES or positional feedback-NMES as an adjuvant therapy into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  and transcranial direct current stimulation (tDCS) influence the function of the corticospinal tracts by modulating the corticomotor excitability , 4 controlled trials (n = 97) and 5 systematic reviews (n = 1173).The systematic review  is superior to sham rTMS with regards to improving upper extremity impairments. There is no effect of rTMS alone on UE disabilities. Differential effects on UE impairment are obtained according to the type of rTMS that is used  indicating the superiority of repetitive transcranial magnetic stimulation, at present, rTMS appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor outcome , taking into account safety guidelines and the differential effects of stimulation protocols.Based on a sufficient amount of evidence (n < 500), at present, there are insufficient arguments for integrating theta-burst stimulation or paired associative stimulation as an adjuvant therapy into stroke rehabilitation with a view to improving UE impairments or disabilities.Based on a lack of evidence  and 4 systematic reviews/meta-analyses (at least n = 455).The systematic review  is superior to sham tDCS with regards to improving upper extremity impairment. There is no effect of tDCS alone on UE disabilities. Differential effects on UE impairments are obtained according to the type of tDCS that is used (for details: Supplementary Table n > 500) indicating the superiority of transcranial direct current stimulation, at present, tDCS appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor outcome , taking into account safety guidelines and the differential effects of stimulation protocols.Based on a sufficient amount of evidence (The systematic review with the search term “deep brain stimulation” did not yield any publications matching the inclusion criteria.n < 500), at present, there are insufficient arguments for integrating deep brain stimulation as an adjuvant therapy into stroke rehabilitation with a view to improving UE impairments or disabilities.Based on a lack of evidence  and noradrenaline reuptake inhibitors (NARI) are the best studied drugs in stroke patients. Other types of drugs have also been assessed for their effects on upper extremity paresis: stimulants (amphetamines and methylphenidate), dopaminergics (levodopa), methylphenidate, trazadone, and nortriptyline , 1 controlled study (n = 64), 1 case-control study (n = 508) and 2 systematic reviews/meta-analyses (n = 5380). There is moderate- to high-quality evidence that antidepressant therapy by SSRIs or NARIs in combination with conventional rehabilitation treatment  potentiates the effect of the rehabilitation treatment alone with regards to UE impairments or disabilities. Treatment effects have been described in acute and subacute stroke patients.The systematic review (Supplementary Table n > 500) indicating the superiority of antidepressants drugs, at present, antidepressant drug therapy appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor outcome (impairments and disabilities), in depressed as well as undepressed acute stroke patients.Based on a sufficient amount of evidence , 1 controlled study (n = 59) and 4 systematic reviews (n = 4456). There is moderate- to high-quality evidence that botulinum toxin is superior to placebo treatment with regards to UE impairment (spasticity). However, no effect is observed on UE disabilities. There is moderate- to high quality evidence that botulinum toxin in combination with rehabilitation treatment  is superior to placebo treatment in combination with rehabilitation treatment with regards to UE impairment (spasticity). Any effect on UE disabilities appears to depend on the type of concomitant rehabilitation treatment, and not on botulinum toxin itself. Short-term (1–3 months) treatment effects of botulinum toxin on spasticity have been described in acute, subacute and chronic stroke patients.The systematic review (Supplementary Table n > 500) indicating the superiority of botulinum toxin injection, at present, botulinum toxin appears to be valuable by itself with a view to improving UE motor impairment (spasticity) and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view of improving UE motor disabilities.Based on a sufficient amount of evidence , 1 controlled trial (n = 47) and 6 systematic reviews (n = 2587). There is moderate-quality evidence that robot-assisted therapy for the paretic UE is similar or inferior to standard rehabilitation treatment. Any gains that are obtained are specific to the task that is being trained (motor impairment) and do not extrapolate to upper extremity disabilities in daily life. The efficacy of robot-based therapy of the paretic upper extremity does not appear to be specific for a post-stroke phase.The systematic review (Supplementary Table n > 500) indicating the non-superiority of robot-assisted therapy, at present, there are insufficient arguments for integrating robot-assisted therapy for the paretic upper extremity into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence  frequently is based on the interaction with a two-dimensional virtual environment presented on a computer or television screen.Virtual reality immersion techniques are based on the conjunct use of a computer-generated three-dimensional graphical environments Riva,  and visuThe so-called “serious gaming” may increase patient's adherence and self-management, aid physical and psychological recovery, and enhance patient's and clinician's knowledge in a range of contexts  and 4 systematic reviews (n = 760). There is moderate-quality evidence that virtual reality is similar to standard rehabilitation treatment with regards to UE impairment and disabilities. There is moderate-quality evidence that virtual reality combined with another rehabilitation treatment  is superior to the other rehabilitation treatment alone with regards to UE impairments and activities. Treatment effects have been described in chronic stroke patients.The systematic review . There is moderate-quality evidence that serious gaming is superior to standard rehabilitation treatment or recreational therapy with regards to UE impairment (only two RCTs available). However, further RCTs are needed to ascertain treatment effects of virtual immersion and serious gaming.n < 500), at present, there are insufficient arguments for integrating virtual reality (without another rehabilitation treatment), virtual immersion or serious gaming into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence (n > 500) indicating the superiority of virtual reality as an adjuvant therapy, at present, virtual reality combined with another rehabilitation treatment appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor impairment and disabilities.Based on a sufficient amount of evidence (Neurologic music therapy (NMT) aims at improving cognitive, sensory and motor function in neurological patients through the therapeutic application of music. Passive music-supported therapy includes auditory-motor synchronization, an entrainment function with rhythmic auditory cueing of movement execution as well as motivational aspects  and 2 systematic reviews (reporting the same results on n = 41). There is moderate quality evidence that passive music-supported therapy is similar to standard rehabilitation treatment with regards to UE impairment. There is moderate quality evidence that active-music supported therapy is superior to standard rehabilitation treatment with regards to UE impairment. Further RCTs are needed to ascertain these conclusions. Treatment effects have been described in acute, subacute and chronic stroke patients.The systematic review (Supplementary Table n < 500), at present, there are insufficient arguments for integrating passive or active music-supported therapy into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence .Rehabilitation approaches recommended as a main rehabilitation intervention on the basis of current evidence for improving UE motor outcome, are: muscle strengthening exercises (impairments), constraint-induced movement therapy (impairments and disabilities), mirror therapy (impairments and disabilities), botulinum toxin (as an intervention Rehabilitation approaches recommended as an adjuvant therapy (combined with another rehabilitation treatment) on the basis of current evidence for improving UE motor outcome, are: mental practice with motor imagery (impairments and disabilities), high frequency-transcutaneous electrical nerve stimulation (impairments and disabilities), passive neuromuscular electrical stimulation (impairments), repetitive transcranial magnetic stimulation (impairments), transcranial direct current stimulation (impairments), SSRI and NARI antidepressants (impairments and disabilities), botulinum toxin (as an adjuvant intervention: disabilities), virtual reality (impairments and disabilities).Rehabilitation approaches that are not recommended on the basis of current evidence because scientific data do not show their efficacy for UE motor outcome, are: Bobath concept, manual passive stretching, bilateral training , robot-assisted therapy for the paretic upper extremity (task-oriented).Rehabilitation approaches that are not recommended on the basis of current evidence because there is insufficient scientific data available with regards to UE motor outcome, are: Perfetti method, Picard method, isokinetic muscle strengthening, device-assisted stretching , motor skill learning techniques (other than CIMT), movement observation, motor imitation, electroacupuncture, low-frequency TENS, electromyography-triggered neuromuscular electrical stimulation, position-triggered neuromuscular electrical stimulation, theta-burst stimulation, paired associative stimulation, deep brain stimulation, virtual immersion, serious gaming, passive music-supported therapy, active music-supported therapy. Large RCTs are needed to confirm preliminary data in these fields.According to the stage of stroke, some rehabilitation concepts may be more appropriate than others. In acute stroke patients, the following rehabilitation approaches have been studied and are recommended: muscle strengthening exercises, constraint-induced movement therapy (with a lower dosage regimen), mirror therapy, passive neuromuscular electrical stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, SSRI and NARI antidepressants, botulinum toxin.In subacute stroke patients, the following rehabilitation approaches have been studied and are recommended: muscle strengthening exercises, constraint-induced movement, mirror therapy, mental practice with motor imagery, high frequency-transcutaneous electrical nerve stimulation, passive neuromuscular electrical stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, SSRI and NARI antidepressants, botulinum toxin.In chronic stroke patients, the following rehabilitation approaches have been studied and are recommended: muscle strengthening exercises, constraint-induced movement therapy, mirror therapy, mental practice with motor imagery, high frequency-transcutaneous electrical nerve stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, botulinum toxin, virtual reality.For some neurorehabilitation approaches, the severity of initial motor deficit may impact upon the feasibility and effectiveness of the intervention. This is apparent for muscle strengthening exercises, constraint-induced movement therapy and virtual reality interfaces.The following neurorehabilitation approaches may modulate the degree of spasticity: botulinum toxin , and in a lesser way: repetitive transcranial magnetic stimulation, high frequency-transcutaneous electrical nerve stimulation and transcranial direct current stimulation.The following neurorehabilitation approaches that are effective upon the UE motor outcome, do not impact upon the degree of spasticity: muscle strengthening exercises, passive neuromuscular electrical stimulation, mirror therapy, constraint-induced movement therapy, virtual reality.The decisional tree proposed in this manuscript Figure  is basedThis systematic review may present some limitations. Though the investigators aimed at providing a large overview of current rehabilitation techniques for the UE, the specified choice of search terms may have excluded clinical rehabilitation strategies that are unusual in Western-European countries. This review does not include some recent technological advances making their way into clinical rehabilitation such as brain-computer interface based technologies , but subsequent improvements of motor impairment do not transfer to improving motor disabilities in activities of daily living. As an example, the lack of effectiveness of bilateral arm training  stands in contrast with the significant improvement of motor impairments and disabilities by constraint-induced movement therapy applying the premises of goal-oriented motor skill learning techniques. It can be hypothesized that a functional bimanual intensive training without constraint  as a postdoctorate clinical master specialist.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


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