Distinct patterns of cortical manifold expansion and contraction underlie human sensorimotor adaptation.

Sensorimotor learning is a dynamic, systems-level process that involves the combined action of multiple neural systems distributed across the brain. Although much is known about the specialized cortical systems that support specific components of action (such as reaching), we know less about how cortical systems function in a coordinated manner to facilitate adaptive behavior. To address this gap, our study measured human brain activity using functional MRI (fMRI) while participants performed a classic sensorimotor adaptation task and used a manifold learning approach to describe how behavioral changes during adaptation relate to changes in the landscape of cortical activity. During early adaptation, areas in the parietal and premotor cortices exhibited significant contraction along the cortical manifold, which was associated with their increased covariance with regions in the higher-order association cortex, including both the default mode and fronto-parietal networks. By contrast, during Late adaptation, when visuomotor errors had been largely reduced, a significant expansion of the visual cortex along the cortical manifold was associated with its reduced covariance with the association cortex and its increased intraconnectivity. Lastly, individuals who learned more rapidly exhibited greater covariance between regions in the sensorimotor and association cortices during early adaptation. These findings are consistent with a view that sensorimotor adaptation depends on changes in the integration and segregation of neural activity across more specialized regions of the unimodal cortex with regions in the association cortex implicated in higher-order processes. More generally, they lend support to an emerging line of evidence implicating regions of the default mode network (DMN) in task-based performance.

Effects of cognitive behavioural therapy and exposure-response prevention on brain activation in obsessive-compulsive disorder patients: systematic review and meta-analysis.

Current psychotherapeutic treatments for OCD, while effective, have complex outcomes with mixed efficacy. Previous research has observed baseline brain activation patterns in OCD patients, elucidating some of the implications of this disorder. Observing the effects of evidence-based psychotherapeutics for OCD on brain activation (through MRI) may provide a more comprehensive outline of pathology. This systematic review and meta-analysis evaluated the effects of cognitive behavioural therapy (CBT) with exposure-response prevention (ERP) on brain activation in OCD patients. Academic databases were systematically searched, and the outcomes evaluated included changes in brain activation and symptom severity between baseline and post-treatment. Patients (n = 193) had confirmed OCD diagnosis and underwent protocolized CBT with ERP programs delivered by trained therapists. Participants in the CBT with ERP programs demonstrated significant improvements in symptom severity (Cohen's d = - 1.91). In general, CBT with ERP resulted in decreased activation post-treatment in the frontal (Cohen's d = 0.40), parietal (Cohen's d = 0.79), temporal (Cohen's d = 1.02), and occipital lobe (Cohen's d = 0.76), and cerebellum (Cohen's d = - 0.78). The findings support CBT with ERP's ability to improve brain activation abnormalities in OCD patients. By identifying regions that improved activation levels, psychotherapy programs may benefit from the addition of function-specific features that could improve treatment outcomes.

Whole-brain dynamics of human sensorimotor adaptation.

Humans vary greatly in their motor learning abilities, yet little is known about the neural processes that underlie this variability. We identified distinct profiles of human sensorimotor adaptation that emerged across 2 days of learning, linking these profiles to the dynamics of whole-brain functional networks early on the first day when cognitive strategies toward sensorimotor adaptation are believed to be most prominent. During early learning, greater recruitment of a network of higher-order brain regions, involving prefrontal and anterior temporal cortex, was associated with faster learning. At the same time, greater integration of this "cognitive network" with a sensorimotor network was associated with slower learning, consistent with the notion that cognitive strategies toward adaptation operate in parallel with implicit learning processes of the sensorimotor system. On the second day, greater recruitment of a network that included the hippocampus was associated with faster learning, consistent with the notion that declarative memory systems are involved with fast relearning of sensorimotor mappings. Together, these findings provide novel evidence for the role of higher-order brain systems in driving variability in adaptation.

A Novel Cooling Device for Kidney Transplant Surgery.

Background: Prolonged warm ischemia time (WIT) in kidney transplantation is associated with numerous adverse outcomes including delayed graft function and decreased patient and graft survival. Circumventing WIT lies in maintaining renal hypothermia and efficiently performing the vascular anastomosis during this portion of the procedure. Although numerous methods of intra-operative renal cooling have been proposed, most suffer from practical limitations, and none have been widely adopted. Herein we describe a novel device specifically designed to maintain renal hypothermia during kidney transplant surgery.Methods: Aluminum tubing was organized in a serpentine pattern to create a malleable, form-fitting cooling jacket to manipulate renal allografts during transplant surgery. Adult porcine kidneys were used to test the device with 4°C saline as coolant. Kidneys were placed at 24°C; surface and core temperatures were monitored using implanted thermocouples. Anastomosis of porcine kidney vessels to GORE-TEX® vascular grafts in an ex-vivo operative field was performed to assess the functionality of the device.Results: The device maintained surface and core graft temperatures of ≤5°C after 60 minutes of WIT. Furthermore, the device provided hands-free retraction and support for the allograft. We found that ex-vivo anastomosis testing was enhanced by the presence of the cooling jacket.Conclusions: This proof-of-concept study demonstrated that our novel device is a practical tool for renal transplantation and can maintain sufficiently cool graft temperatures to mitigate WIT in an ex-vivo setting. This device is the first of its kind and has the potential to improve kidney transplant outcomes by eliminating WIT during graft implantation.

Muting, not fragmentation, of functional brain networks under general anesthesia.

Changes in resting-state functional connectivity (rs-FC) under general anesthesia have been widely studied with the goal of identifying neural signatures of consciousness. This work has commonly revealed an apparent fragmentation of whole-brain network structure during unconsciousness, which has been interpreted as reflecting a break-down in connectivity and a disruption of the brain's ability to integrate information. Here we show, by studying rs-FC under varying depths of isoflurane-induced anesthesia in nonhuman primates, that this apparent fragmentation, rather than reflecting an actual change in network structure, can be simply explained as the result of a global reduction in FC. Specifically, by comparing the actual FC data to surrogate data sets that we derived to test competing hypotheses of how FC changes as a function of dose, we found that increases in whole-brain modularity and the number of network communities - considered hallmarks of fragmentation - are artifacts of constructing FC networks by thresholding based on correlation magnitude. Taken together, our findings suggest that deepening levels of unconsciousness are instead associated with the increasingly muted expression of functional networks, an observation that constrains current interpretations as to how anesthesia-induced FC changes map onto existing neurobiological theories of consciousness.

Dynamic Reconfiguration, Fragmentation, and Integration of Whole-Brain Modular Structure across Depths of Unconsciousness.

General anesthetics are routinely used to induce unconsciousness, and much is known about their effects on receptor function and single neuron activity. Much less is known about how these local effects are manifest at the whole-brain level nor how they influence network dynamics, especially past the point of induced unconsciousness. Using resting-state functional magnetic resonance imaging (fMRI) with nonhuman primates, we investigated the dose-dependent effects of anesthesia on whole-brain temporal modular structure, following loss of consciousness. We found that higher isoflurane dose was associated with an increase in both the number and isolation of whole-brain modules, as well as an increase in the uncoordinated movement of brain regions between those modules. Conversely, we found that higher dose was associated with a decrease in the cohesive movement of brain regions between modules, as well as a decrease in the proportion of modules in which brain regions participated. Moreover, higher dose was associated with a decrease in the overall integrity of networks derived from the temporal modules, with the exception of a single, sensory-motor network. Together, these findings suggest that anesthesia-induced unconsciousness results from the hierarchical fragmentation of dynamic whole-brain network structure, leading to the discoordination of temporal interactions between cortical modules.

Rapid and flexible whole body postural responses are evoked from perturbations to the upper limb during goal-directed reaching.

An important aspect of motor control is the ability to perform tasks with the upper limbs while maintaining whole body balance. However, little is known about the coordination of upper limb voluntary and whole body postural control after mechanical disturbances that require both upper limb motor corrections to attain a behavioral goal and lower limb motor responses to maintain whole body balance. The present study identified the temporal organization of muscle responses and center of pressure (COP) changes following mechanical perturbations during reaching. Our results demonstrate that muscle responses in the upper limb are evoked first (∼50 ms), with lower limb muscle activity occurring immediately after, in as little as ∼60 ms after perturbation. Hand motion was immediately altered by the load, while COP changes occurred after ∼100 ms, when lower limb muscle activity was already present. Our secondary findings showed that both muscle activity and COP changes were influenced by behavioral context (by altering target shape, circle vs. rectangle). Voluntary and postural actions initially directed the hand toward the center of both target types, but after the perturbation upper limb and postural responses redirected the hand toward different spatial locations along the rectangle. Muscle activity was increased for both upper and lower limbs when correcting to the circle vs. the rectangle, and these differences emerged as early as the long-latency epoch (∼75-120 ms). Our results demonstrate that postural responses are rapidly and flexibly altered to consider the behavioral goal of the upper limb.NEW & NOTEWORTHY The present work establishes that, when reaching to a target while standing, perturbations applied to the upper limb elicit a rapid response in lower limb muscles. Unlike voluntary movements, postural responses do not occur before corrections of the upper limb. We show the first evidence that corrective postural adjustments are modulated by upper limb behavioral context (target shape). Importantly, this indicates that postural responses take into account upper limb feedback for online control.

Primary motor cortex underlies multi-joint integration for fast feedback control.

A basic difficulty for the nervous system is integrating locally ambiguous sensory information to form accurate perceptions about the outside world. This local-to-global problem is also fundamental to motor control of the arm, because complex mechanical interactions between shoulder and elbow allow a particular amount of motion at one joint to arise from an infinite combination of shoulder and elbow torques. Here we show, in humans and rhesus monkeys, that a transcortical pathway through primary motor cortex (M1) resolves this ambiguity during fast feedback control. We demonstrate that single M1 neurons of behaving monkeys can integrate shoulder and elbow motion information into motor commands that appropriately counter the underlying torque within about 50 milliseconds of a mechanical perturbation. Moreover, we reveal a causal link between M1 processing and multi-joint integration in humans by showing that shoulder muscle responses occurring ∼50 milliseconds after pure elbow displacement can be potentiated by transcranial magnetic stimulation. Taken together, our results show that transcortical processing through M1 permits feedback responses to express a level of sophistication that rivals voluntary control; this provides neurophysiological support for influential theories positing that voluntary movement is generated by the intelligent manipulation of sensory feedback.

Rapid Visuomotor Corrective Responses during Transport of Hand-Held Objects Incorporate Novel Object Dynamics.

Numerous studies have shown that people are adept at learning novel object dynamics, linking applied force and motion, when performing reaching movements with hand-held objects. Here we investigated whether the control of rapid corrective arm responses, elicited in response to visual perturbations, has access to such newly acquired knowledge of object dynamics. Participants first learned to make reaching movements while grasping an object subjected to complex load forces that depended on the distance and angle of the hand from the start position. During a subsequent test phase, we examined grip and load force coordination during corrective arm movements elicited (within ∼150 ms) in response to viewed sudden lateral shifts (1.5 cm) in target or object position. We hypothesized that, if knowledge of object dynamics is incorporated in the control of the corrective responses, grip force changes would anticipate the unusual load force changes associated with the corrective arm movements so as to support grasp stability. Indeed, we found that the participants generated grip force adjustments tightly coupled, both spatially and temporally, to the load force changes associated with the arm movement corrections. We submit that recently learned novel object dynamics are effectively integrated into sensorimotor control policies that support rapid visually driven arm corrective actions during transport of hand held objects. Significance statement: Previous studies have demonstrated that the motor system can learn, and make use of, internal models of object dynamics to generate feedforward motor commands. However, it is not known whether such internal models are incorporated into rapid, automatic arm movement corrections that compensate for errors that arise during movement. Here we demonstrate, for the first time, that internal models of novel object dynamics are integrated into rapid corrective arm movements made in response to visuomotor perturbations that, importantly, do not directly perturb the object.

Rapid online selection between multiple motor plans.

Recent theories of voluntary control predict that multiple motor strategies can be precomputed and expressed throughout movement. We examined online decisional processing in humans by asking them to make reaching movements with obstacles located just to the sides of a direct path between start and end targets. On random trials, the limb was perturbed with one of four mechanical loads that varied in direction and amplitude. Notably, we observed two different strategies when we applied a perturbation (left medium-sized) that deviated the participants' hand directly toward an obstacle. In some trials, subjects directed their hand between the obstacles and in other trials to the left of the obstacles. Importantly, changes in the muscle stretch response between these two strategies were observed in <60 ms after perturbation, during the R2 long-latency epoch (~45-75 ms). As predicted, the selected strategy depended on the estimated position of the limb when it was perturbed. In our second experiment, we presented either one or three potential goal targets. Movements initially directed to the closest target could be quickly redirected to other potential targets after a perturbation. Differences in muscle stretch responses for redirected movements were observed ~75 ms after perturbation during the R3 long-latency epoch (~75-105 ms). The results show that decisional processes are rapidly implemented during movement execution. In addition, our data suggest a hierarchical process with corrective responses on "how" to attain a behavioral goal expressed during the R2 epoch and responses on "what" goal to attain during the R3 epoch.

Context-dependent inhibition of unloaded muscles during the long-latency epoch.

A number of studies have highlighted the sophistication of corrective responses in lengthened muscles during the long-latency epoch. However, in various contexts, unloading can occur, which requires corrective actions from a shortened muscle. Here, we investigate the sophistication of inhibitory responses in shortened muscles due to unloading. Our first experiment quantified the inhibitory responses following an unloading torque that displaced the hand either into or away from a peripheral target. We observed larger long-latency inhibitory responses when perturbed into the peripheral target compared with away from the target. In our second experiment, we characterized the degree of inhibition following unloading with respect to different levels of preperturbation muscle activity. We initially observed that the inhibitory activity during the short-latency epoch scaled with increased levels of preperturbation muscle activity. However, this scaling peaked early in the R2 epoch (∼ 50 ms) but then quickly diminished through the rest of the long-latency epoch. Finally, in experiment 3, we investigated whether inhibitory perturbation responses consider intersegmental dynamics of the limb. We quantified unloading responses for either pure shoulder or pure elbow torques that evoked similar motion at the shoulder but different elbow motion. The long-latency inhibitory response in the shoulder, unlike the short-latency, was greater for the shoulder torque compared with the response following an elbow torque, as previously observed for a loading response. Taken together, these results illustrate that the long-latency unloading response is capable of a similar level of complexity as observed when loads are applied to the limb.

Virtual OSCE examinations during COVID-19 A 360 satisfaction assessment from examiners and candidates.

INTRODUCTION: We sought to determine the satisfaction rates of examiners and candidates in a virtual Objective Structured Clinical Exam (OSCE) of graduating Canadian urology residents. METHODS: An annual mock exam, aimed at simulating the licencing urology exam for Canadian graduates, was moved to an online format for the 2020 cohort. This exam consists of an OSCE, and a written multiple-choice exam. The Telemedicine Satisfaction Questionnaire (TSQ), a previously validated tool for clinical encounters with three sub-domains (quality of care provided, similarity to face-to-face encounter, and perception of the interaction) was modified for the purposes of evaluating the OSCE encounter. The TSQ was sent electronically to all examiners and candidates after the exam. RESULTS: There were 14/16 responses from examiners (87.5%) and 24/39 responses from candidates (61.5%). Overall, the format was judged to be a good experience by 13/14 (92.9%) of examiners and 21/24 (87.5%) of candidates; however, when asked specifically if the virtual OSCE was an acceptable way to determine a candidate's competency to practice urology independently, only 8/14 (57.1%) of examiners and 15/24 (62.5%) of candidates agreed. CONCLUSIONS: This study demonstrates an overall good satisfaction rate among both examiners and candidates when using a teleconference format for a mock OSCE.

Using electronically delivered therapy and brain imaging to understand OCD pathology: A pilot feasibility study.

Background: Obsessive-compulsive disorder (OCD) is a debilitating mental health disorder with current psychotherapeutic treatments, while somewhat effective, yielding low accessibility and scalability. A lack of knowledge regarding the neural pathology of OCD may be hindering the development of innovative treatments. Previous research has observed baseline brain activation patterns in OCD patients, elucidating some understanding of the implications. However, by using neuroimaging to observe the effects of treatment on brain activation, a more complete picture of OCD can be drawn. Currently, the gold standard treatment is cognitive behavioral therapy (CBT). However, CBT is often inaccessible, time-consuming, and costly. Fortunately, it can be effectively delivered electronically (e-CBT). Objectives: This pilot study implemented an e-CBT program for OCD and observed its effects on cortical activation levels during a symptom provocation task. It was hypothesized that abnormal activations could be attenuated following treatment. Methods: OCD patients completed a 16-week e-CBT program administered through an online platform, mirroring in-person content. Treatment efficacy was evaluated using behavioral questionnaires and neuroimaging. Activation levels were assessed at the resting state and during the symptom provocation task. Results: In this pilot, seven participants completed the program, with significant improvements (p < 0.05) observed between baseline and post-treatment for symptom severity and levels of functioning. No statistically significant (p = 0.07) improvement was observed in the quality of life. Participants had mostly positive qualitative feedback, citing accessibility benefits, comprehensive formatting, and relatable content. No significant changes in cortical activation were observed between baseline and post-treatment. Conclusion: This project sheds light on the application of e-CBT as a tool to evaluate the effects of treatment on cortical activation, setting the stage for a larger-scale study. The program showed great promise in feasibility and effectiveness. While there were no significant findings regarding changes in cortical activation, the trends were in agreeance with previous literature, suggesting future work could provide insight into whether e-CBT offers comparable cortical effects to in-person psychotherapy. Applying a greater knowledge of the neural mechanisms of action in OCD can help develop novel treatment plans in the future.

Influence of the behavioral goal and environmental obstacles on rapid feedback responses.

The motor system must consider a variety of environmental factors when executing voluntary motor actions, such as the shape of the goal or the possible presence of intervening obstacles. It remains unknown whether rapid feedback responses to mechanical perturbations also consider these factors. Our first experiment quantified how feedback corrections were altered by target shape, which was either a circular dot or a bar. Unperturbed movements to each target were qualitatively similar on average but with greater dispersion of end point positions when reaching to the bar. On random trials, multijoint torque perturbations deviated the hand left or right. When reaching to a circular target, perturbations elicited corrective movements that were directed straight to the location of the target. In contrast, corrective movements when reaching to a bar were redirected to other locations along the bar axis. Our second experiment quantified whether the presence of obstacles could interfere with feedback corrections. We found that hand trajectories after the perturbations were altered to avoid obstacles in the environment. Importantly, changes in muscle activity reflecting the different target shapes (bar vs. dot) or the presence of obstacles were observed in as little as 70 ms. Such changes in motor responses were qualitatively consistent with simulations based on optimal feedback control. Taken together, these results highlight that long-latency motor responses consider spatial properties of the goal and environment.

Neural excursions from manifold structure explain patterns of learning during human sensorimotor adaptation.

Humans vary greatly in their motor learning abilities, yet little is known about the neural mechanisms that underlie this variability. Recent neuroimaging and electrophysiological studies demonstrate that large-scale neural dynamics inhabit a low-dimensional subspace or manifold, and that learning is constrained by this intrinsic manifold architecture. Here, we asked, using functional MRI, whether subject-level differences in neural excursion from manifold structure can explain differences in learning across participants. We had subjects perform a sensorimotor adaptation task in the MRI scanner on 2 consecutive days, allowing us to assess their learning performance across days, as well as continuously measure brain activity. We find that the overall neural excursion from manifold activity in both cognitive and sensorimotor brain networks is associated with differences in subjects' patterns of learning and relearning across days. These findings suggest that off-manifold activity provides an index of the relative engagement of different neural systems during learning, and that subject differences in patterns of learning and relearning are related to reconfiguration processes occurring in cognitive and sensorimotor networks.

Spontaneous Behavioural Recovery Following Stroke Relates to the Integrity of Parietal and Temporal Regions.

Stroke is a devastating disease that results in neurological deficits and represents a leading cause of death and disability worldwide. Following a stroke, there is a degree of spontaneous recovery of function, the neural basis of which is of great interest among clinicians in their efforts to reduce disability following stroke and enhance rehabilitation. Conventionally, work on spontaneous recovery has tended to focus on the neural reorganization of motor cortical regions, with comparably little attention being paid to changes in non-motor regions and how these relate to recovery. Here we show, using structural neuroimaging in a macaque stroke model (N = 31) and by exploiting individual differences in spontaneous behavioural recovery, that the preservation of regions in the parietal and temporal cortices predict animal recovery. To characterize recovery, we performed a clustering analysis using Non-Human Primate Stroke Scale (NHPSS) scores and identified a good versus poor recovery group. By comparing the preservation of brain volumes in the two groups, we found that brain areas in integrity of brain areas in parietal, temporal and somatosensory cortex were associated with better recovery. In addition, a decoding approach performed across all subjects revealed that the preservation of specific brain regions in the parietal, somatosensory and medial frontal cortex predicted recovery. Together, these findings highlight the importance of parietal and temporal regions in spontaneous behavioural recovery.

Head roll influences perceived hand position.

Visual and proprioceptive sensory inputs are naturally coded in different reference frames, i.e., eye-centered and body-centered, respectively. To use these signals in conjunction for motor planning or perception ultimately requires converting them into a common frame of reference using estimates of the relative orientation of the eyes, head, and body. Here, we examine whether extraretinal signals-specifically head roll-alter multisensory perception through noisy reference frame transformations. To do so, we examine the accuracy of visual localization relative to proprioceptive hand position for different head roll orientations. Subjects were required to judge whether a visual target was located closer or further and left or right (4-alternative forced-choice task) from their unseen hand. This was done for three different head roll rotations (-30, 0, and 30 deg). We show that eccentric head roll increased the variability in the subjects' ability to discriminate target location relative to the fingertip. We conclude that sensory perception is sensitive to body-geometry-dependent noise affecting the coordinate matching transformations of sensory data.

Using Electronically Delivered Therapy and Brain Imaging to Understand Obsessive-Compulsive Disorder Pathophysiology: Protocol for a Pilot Study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating and prevalent anxiety disorder. Although the basal ganglia and frontal cortex are the brain regions that are most commonly hypothesized to be involved in OCD, the exact pathophysiology is unknown. By observing the effects of proven treatments on brain activation levels, the cause of OCD can be better understood. Currently, the gold standard treatment for OCD is cognitive behavioral therapy (CBT) with exposure and response prevention. However, this is often temporally and geographically inaccessible, time consuming, and costly. Fortunately, CBT can be effectively delivered using the internet (electronically delivered CBT [e-CBT]) because of its structured nature, thus addressing these barriers. OBJECTIVE: The aims of this study are to implement an e-CBT program for OCD and to observe its effects on brain activation levels using functional magnetic resonance imaging (MRI). It is hypothesized that brain activation levels in the basal ganglia and frontal cortex will decrease after treatment. METHODS: Individuals with OCD will be offered a 16-week e-CBT program with exposure and response prevention mirroring in-person CBT content and administered through a secure web-based platform. The efficacy of the treatment will be evaluated using clinically validated symptomology questionnaires at baseline, at week 8, and after treatment (week 16). Using functional MRI at baseline and after treatment, brain activation levels will be assessed in the resting state and while exposed to anxiety-inducing images (eg, dirty dishes if cleanliness is an obsession). The effects of treatment on brain activation levels and the correlation between symptom changes and activation levels will be analyzed. RESULTS: The study received initial ethics approval in December 2020, and participant recruitment began in January 2021. Participant recruitment has been conducted through social media advertisements, physical advertisements, and physician referrals. To date, 5 participants have been recruited. Data collection is expected to conclude by January 2022, and data analysis is expected to be completed by February 2022. CONCLUSIONS: The findings from this study can further our understanding of the causation of OCD and help develop more effective treatments for this disorder. TRIAL REGISTRATION: ClinicalTrials.gov NCT04630197; https://clinicaltrials.gov/ct2/show/NCT04630197. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/30726.

Robotic Assessment of Upper Limb Function in a Nonhuman Primate Model of Chronic Stroke.

Stroke is a leading cause of death and disability worldwide and survivors are frequently left with long-term disabilities that diminish their autonomy and result in the need for chronic care. There is an urgent need for the development of therapies that improve stroke recovery, as well as accurate and quantitative tools to measure function. Nonhuman primates closely resemble humans in neuroanatomy and upper limb function and may be crucial in randomized pre-clinical trials for testing the efficacy of stroke therapies. To test the feasibility of robotic assessment of motor function in a NHP model of stroke, two cynomolgus macaques were trained to perform a visually guided reaching task and were also assessed in a passive stretch task using the Kinarm robot. Strokes were then induced in these animals by transiently occluding the middle cerebral artery, and their motor performance on the same tasks was assessed after recovery. Relative to pre-stroke performance, post-stroke hand movements of the affected limb became slower and less accurate. Regression analyses revealed both recovered and compensatory movements to complete movements in different spatial directions. Lastly, we noted decreased range of motion in the elbow joint of the affected limb post-stroke associated with spasticity during passive stretch. Taken together, these studies highlight that sensorimotor deficits in reaching movements following stroke in cynomolgus macaques resemble those in human patients and validate the use of robotic assessment tools in a nonhuman primate model of stroke for identifying and characterizing such deficits.

Poly-Arginine Peptide-18 (R18) Reduces Brain Injury and Improves Functional Outcomes in a Nonhuman Primate Stroke Model.

Poly-arginine peptide-18 (R18) is neuroprotective in different rodent middle cerebral artery occlusion (MCAO) stroke models. In this study, we examined whether R18 treatment could reduce ischemic brain injury and improve functional outcome in a nonhuman primate (NHP) stroke model. A stroke was induced in male cynomolgus macaques by MCAO distal to the orbitofrontal branch of the MCA through a right pterional craniotomy, using a 5-mm titanium aneurysm clip for 90 min. R18 (1000 nmol/kg) or saline vehicle was administered intravenously 60 min after the onset of MCAO. Magnetic resonance imaging (MRI; perfusion-weighted imaging, diffusion-weighted imaging, or T2-weighted imaging) of the brain was performed 15 min, 24 h, and 28 days post-MCAO, and neurological outcome was assessed using the NHP stroke scale (NHPSS). Experimental endpoint was 28 days post-MCAO, treatments were randomized, and all procedures were performed blinded to treatment status. R18 treatment reduced infarct lesion volume by up to 65.2% and 69.7% at 24 h and 28 days poststroke, respectively. Based on NHPSS scores, R18-treated animals displayed reduced functional deficits. This study confirms the effectiveness of R18 in reducing the severity of ischemic brain injury and improving functional outcomes after stroke in a NHP model, and provides further support for its clinical development as a stroke neuroprotective therapeutic.