Characterization and Optimization of the Tumor Microenvironment in Patient-Derived Organotypic Slices and Organoid Models of Glioblastoma.

While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future.

War-related traumatic brain injuries during the Syrian armed conflict in Damascus 2014-2017: a cohort study and a literature review.

BACKGROUND: The decade-long Syrian armed conflict killed or injured more than 11% of the Syrian population. Head and neck injuries are the most frequent cause of war-related trauma, about half of which are brain injuries. Reports about Syrian brain trauma victims were published from neighboring countries; However, none are available from Syrian hospitals. This study aims to report war-related traumatic brain injuries from the Syrian capital. METHODS: We conducted a retrospective cohort study between 2014 and 2017 at Damascus Hospital, the largest public hospital in Damascus, Syria. Target patients were the victims of combat-related traumatic brain injuries who arrived alive and were admitted to the neurosurgery department or to another department but followed by the neurosurgery team. The collected data included the mechanism, type, and site of injury based on imaging findings; types of invasive interventions; intensive-care unit (ICU) admissions; as well as neurological status at admission and discharge including several severity scales. RESULTS: Our sample consisted of 195 patients; Ninety-six of them were male young adults, in addition to 40 females and 61 children. Injuries were caused by shrapnel in 127 (65%) cases, and by gunshots in the rest, and most of them (91%) were penetrating. Sixty-eight patients (35%) were admitted to the ICU, and 56 (29%) underwent surgery. Neurological impairment was reported in 49 patients (25%) at discharge, and the mortality rate during hospitalization was 33%. Mortality and neurological impairment associated significantly with higher values on clinical and imaging severity scores. CONCLUSIONS: This study captured the full spectrum of war-related brain injuries of civilians and armed personnel in Syria without the delay required to transport patients to neighboring countries. Although the clinical presentation of injuries at admission was not as severe as that in previous reports, the inadequate resources (i.e., ventilators and operation rooms) and the lack of previous experience with similar injuries might have resulted in the higher mortality rate. Clinical and imaging severity scales can provide a handy tool in identifying cases with low probability of survival especially with the shortage of personal and physical resources.

Malignant transformation of a cerebral dermoid cyst into a squamous cell carcinoma with malignant intraperitoneal spreading along a ventriculoperitoneal shunt: illustrative case.

BACKGROUND: Malignant progression of intracranial dermoid cysts into squamous cell carcinoma is extremely rare with only three reports published so far. Intracranial dermoid cysts are uncommon benign tumors lined by stratified squamous epithelium of embryonic ectodermal origin. OBSERVATIONS: Here, the authors present the case of a 64-year-old female with a recurrent temporal dermoid cyst. After surgery for the recurrent dermoid cyst, once in the early 1990s and another 16 years later, the patient presented with headache and nausea due to hydrocephalus. After implantation of a ventriculoperitoneal shunt, she deteriorated rapidly and died only 60 days after admission. Autopsy revealed malignant transformation of the epithelial lining of the dermoid cyst into a squamous cell carcinoma resulting in neoplastic meningiosis and intraperitoneal tumor spread along a previously implanted ventriculoperitoneal shunt. LESSONS: Malignant transformation should be considered in patients with dermoid cyst who show new leptomeningeal contrast enhancement. In the case of hydrocephalus, alternatives to peritoneal shunting should be considered.

Shared Control of Bimanual Robotic Limbs With a Brain-Machine Interface for Self-Feeding.

Advances in intelligent robotic systems and brain-machine interfaces (BMI) have helped restore functionality and independence to individuals living with sensorimotor deficits; however, tasks requiring bimanual coordination and fine manipulation continue to remain unsolved given the technical complexity of controlling multiple degrees of freedom (DOF) across multiple limbs in a coordinated way through a user input. To address this challenge, we implemented a collaborative shared control strategy to manipulate and coordinate two Modular Prosthetic Limbs (MPL) for performing a bimanual self-feeding task. A human participant with microelectrode arrays in sensorimotor brain regions provided commands to both MPLs to perform the self-feeding task, which included bimanual cutting. Motor commands were decoded from bilateral neural signals to control up to two DOFs on each MPL at a time. The shared control strategy enabled the participant to map his four-DOF control inputs, two per hand, to as many as 12 DOFs for specifying robot end effector position and orientation. Using neurally-driven shared control, the participant successfully and simultaneously controlled movements of both robotic limbs to cut and eat food in a complex bimanual self-feeding task. This demonstration of bimanual robotic system control via a BMI in collaboration with intelligent robot behavior has major implications for restoring complex movement behaviors for those living with sensorimotor deficits.

Characteristics and stability of sensorimotor activity driven by isolated-muscle group activation in a human with tetraplegia.

Understanding the cortical representations of movements and their stability can shed light on improved brain-machine interface (BMI) approaches to decode these representations without frequent recalibration. Here, we characterize the spatial organization (somatotopy) and stability of the bilateral sensorimotor map of forearm muscles in an incomplete-high spinal-cord injury study participant implanted bilaterally in the primary motor and sensory cortices with Utah microelectrode arrays (MEAs). We built representation maps by recording bilateral multiunit activity (MUA) and surface electromyography (EMG) as the participant executed voluntary contractions of the extensor carpi radialis (ECR), and attempted motions in the flexor carpi radialis (FCR), which was paralytic. To assess stability, we repeatedly mapped and compared left- and right-wrist-extensor-related activity throughout several sessions, comparing somatotopy of active electrodes, as well as neural signals both at the within-electrode (multiunit) and cross-electrode (network) levels. Wrist motions showed significant activation in motor and sensory cortical electrodes. Within electrodes, firing strength stability diminished as the time increased between consecutive measurements (hours within a session, or days across sessions), with higher stability observed in sensory cortex than in motor, and in the contralateral hemisphere than in the ipsilateral. However, we observed no differences at network level, and no evidence of decoding instabilities for wrist EMG, either across timespans of hours or days, or across recording area. While map stability differs between brain area and hemisphere at multiunit/electrode level, these differences are nullified at ensemble level.

Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia.

Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.

A brain network for deep brain stimulation induced cognitive decline in Parkinson's disease.

Deep brain stimulation is an effective treatment for Parkinson's disease but can be complicated by side-effects such as cognitive decline. There is often a delay before this side-effect is apparent and the mechanism is unknown, making it difficult to identify patients at risk or select appropriate deep brain stimulation settings. Here, we test whether connectivity between the stimulation site and other brain regions is associated with cognitive decline following deep brain stimulation. First, we studied a unique patient cohort with cognitive decline following subthalamic deep brain stimulation for Parkinson's disease (n = 10) where reprogramming relieved the side-effect without loss of motor benefit. Using resting state functional connectivity data from a large normative cohort (n = 1000), we computed connectivity between each stimulation site and the subiculum, an a priori brain region functionally connected to brain lesions causing memory impairment. Connectivity between deep brain stimulation sites and this same subiculum region was significantly associated with deep brain stimulation induced cognitive decline (P < 0.02). We next performed a data-driven analysis to identify connections most associated with deep brain stimulation induced cognitive decline. Deep brain stimulation sites causing cognitive decline (versus those that did not) were more connected to the anterior cingulate, caudate nucleus, hippocampus, and cognitive regions of the cerebellum (PFWE < 0.05). The spatial topography of this deep brain stimulation-based circuit for cognitive decline aligned with an a priori lesion-based circuit for memory impairment (P = 0.017). To begin translating these results into a clinical tool that might be used for deep brain stimulation programming, we generated a 'heat map' in which the intensity of each voxel reflects the connectivity to our cognitive decline circuit. We then validated this heat map using an independent dataset of Parkinson's disease patients in which cognitive performance was measured following subthalamic deep brain stimulation (n = 33). Intersection of deep brain stimulation sites with our heat map was correlated with changes in the Mattis dementia rating scale 1 year after lead implantation (r = 0.39; P = 0.028). Finally, to illustrate how this heat map might be used in clinical practice, we present a case that was flagged as 'high risk' for cognitive decline based on intersection of the patient's deep brain stimulation site with our heat map. This patient had indeed experienced cognitive decline and our heat map was used to select alternative deep brain stimulation parameters. At 14 days follow-up the patient's cognition improved without loss of motor benefit. These results lend insight into the mechanism of deep brain stimulation induced cognitive decline and suggest that connectivity-based heat maps may help identify patients at risk and who might benefit from deep brain stimulation reprogramming.

Intracortical Somatosensory Stimulation to Elicit Fingertip Sensations in an Individual With Spinal Cord Injury.

BACKGROUND AND OBJECTIVES: The restoration of touch to fingers and fingertips is critical to achieving dexterous neuroprosthetic control for individuals with sensorimotor dysfunction. However, localized fingertip sensations have not been evoked via intracortical microstimulation (ICMS). METHODS: Using a novel intraoperative mapping approach, we implanted electrode arrays in the finger areas of left and right somatosensory cortex and delivered ICMS over a 2-year period in a human participant with spinal cord injury. RESULTS: Stimulation evoked tactile sensations in 8 fingers, including fingertips, spanning both hands. Evoked percepts followed expected somatotopic arrangements. The subject was able to reliably identify up to 7 finger-specific sites spanning both hands in a finger discrimination task. The size of the evoked percepts was on average 33% larger than a finger pad, as assessed via manual markings of a hand image. The size of the evoked percepts increased modestly with increased stimulation intensity, growing 21% as pulse amplitude increased from 20 to 80 µA. Detection thresholds were estimated on a subset of electrodes, with estimates of 9.2 to 35 µA observed, roughly consistent with prior studies. DISCUSSION: These results suggest that ICMS can enable the delivery of consistent and localized fingertip sensations during object manipulation by neuroprostheses for individuals with somatosensory deficits. CLINICALTRIALSGOV IDENTIFIER: NCT03161067.

Intracortical microstimulation of somatosensory cortex enables object identification through perceived sensations.

Advances in brain-machine interfaces have helped restore function and independence for individuals with sensorimotor deficits; however, providing efficient and effective sensory feedback remains challenging. Intracortical microstimulation (ICMS) of sensorimotor brain regions is a promising technique for providing bioinspired sensory feedback. In a human participant with chronically-implanted microelectrode arrays, we provided ICMS to the primary somatosensory cortex to generate tactile percepts in his hand. In a 3-choice object identification task, the participant identified virtual objects using tactile sensory feedback and no visual information. We evaluated three different stimulation paradigms, each with a different weighting of the grip force and its derivative, to explore the potential benefits of a more bioinspired stimulation strategy. In all paradigms, the participant's ability to identify the objects was above-chance, with object identification accuracy reaching 80% correct when using only sustained grip force feedback and 76.7% when using equal weighting of both sustained grip force and its derivative. These results demonstrate that bioinspired ICMS can provide sensory feedback that is functionally beneficial in sensorimotor tasks. Designing more efficient stimulation paradigms is important because it will allow us to 1) provide safer stimulation delivery methods that reduce overall injected charge without sacrificing function and 2) more effectively transmit sensory information to promote intuitive integration and usage by the human body.

Combined frameless stereotactical biopsy and intraoperative cerebral angiography by 3D-rotational fluoroscopy with intravenous contrast administration: a feasibility study.

BACKGROUND: Mobile 3-dimensional fluoroscopes are an integral part of modern neurosurgical operating theatres and can also be used in combination with free available image post processing to depict cerebral vessels. In preparation of stereotactic surgery, preoperative Computed Tomography (CT) may be required for image fusion. Contrast CT may be of further advantage for image fusion as it regards the vessel anatomy in trajectory planning. Time-consuming in-hospital transports are necessary for this purpose. Mobile 3D-fluoroscopes may be used to generate a CT equal preoperative data set without an in-hospital transport. This study was performed to determine the feasibility and image quality of intraoperative 3-dimensional fluoroscopy with intravenous contrast administration in combination with stereotactical procedures. METHODS: 6 patients were included in this feasibility study. After fixation in a radiolucent Mayfield clamp a rotational fluoroscopy scan was performed with 50 mL iodine contrast agent. The image data sets were merged with the existing MRI images at a planning station and visually evaluated by two observer. The operation times were compared between the frame-based and frameless systems ("skin-to-skin" and "OR entry to exit"). RESULTS: The procedure proves to be safe. The entire procedure from fluoroscope positioning to the transfer to the planning station took 5-6 min with an image acquisition time of 24 s. In 5 of 6 cases, the fused imaging was able to reproduce the vascular anatomy accurately and in good quality. Both time end-points were significantly shorter compared to frame-based interventions. CONCLUSION: The images could easily be transferred to the planning and navigation system and were successfully merged with the MRI data set. The procedure can be completely integrated into the surgical workflow. Preoperative CT imaging or transport under anaesthesia may even be replaced by this technique in the future. Furthermore, hemorrhages can be successfully visualized intraoperatively and might prevent time delays in emergencies.

Novel intraoperative online functional mapping of somatosensory finger representations for targeted stimulating electrode placement: technical note.

Defining eloquent cortex intraoperatively, traditionally performed by neurosurgeons to preserve patient function, can now help target electrode implantation for restoring function. Brain-machine interfaces (BMIs) have the potential to restore upper-limb motor control to paralyzed patients but require accurate placement of recording and stimulating electrodes to enable functional control of a prosthetic limb. Beyond motor decoding from recording arrays, precise placement of stimulating electrodes in cortical areas associated with finger and fingertip sensations allows for the delivery of sensory feedback that could improve dexterous control of prosthetic hands. In this study, the authors demonstrated the use of a novel intraoperative online functional mapping (OFM) technique with high-density electrocorticography to localize finger representations in human primary somatosensory cortex. In conjunction with traditional pre- and intraoperative targeting approaches, this technique enabled accurate implantation of stimulating microelectrodes, which was confirmed by postimplantation intracortical stimulation of finger and fingertip sensations. This work demonstrates the utility of intraoperative OFM and will inform future studies of closed-loop BMIs in humans.

Directional Leads for Deep Brain Stimulation: Technical Notes and Experiences.

OBJECTIVE: Deep brain stimulation (DBS) is an approved treatment for movement disorders. Despite high precision in electrode placement, side effects do occur by current spread to adjacent fibers or nuclei. Directional leads (D-leads) are designed to adapt the volume of stimulation relative to the position within the target by horizontal and vertical current steering directions. The feasibility of implanting these new leads, possible difficulties, and complications were the focus of this study. MATERIAL AND METHODS: This analysis is based on 31 patients who underwent a DBS procedure with D-leads and an implantable pulse generator (IPG) capable of multiple independent current control and 31 patients who received non-D-leads with a similar IPG. While trajectory planning and most steps of the surgical procedure were identical to conventional DBS lead implantation, differences in indication, electrode handling, lead control, and complications were documented and analyzed in comparison to a control group with ring electrodes. RESULTS: During a consecutive series of 51 patients implanted with a DBS system, 31 patients (60.1%) were selected for implantation of D-leads and received 59 D-leads, 28 bilateral, and 3 unilateral implantations. The control group consisted of a consecutive series of a comparable time period, with 31 patients who received conventional ring electrodes. Indication of D-lead implantation was based on the anatomic conditions of the trajectory and target regions and the results of intraoperative test stimulations. In 1 patient, primary D-lead implantation on both sides was performed without any microelectrode implantation to minimize risk for hemorrhage. In the absence of an externally visible marker, the control of implant depth and of the orientation of the D-lead needs to be controlled by X-ray resulting in a longer fluoroscopy time and, therefore, higher X-ray dose compared to conventional lead implantations (415.53 vs. 328.96 Gy cm2; p = 0.09). Mean procedure duration for complete system implantation did not differ between either type of leads (ring electrodes vs. D-leads, 08:55 vs. 09:02 h:min). Surgical complications were unrelated to the type of electrode: surgical revision was necessary and successfully performed in 1 subcutaneous hematoma and 1 unilateral electrode dislocation. A rather rare complication, symptomatic idiopathic delayed-onset edema, was observed in 4 patients with D-leads. They recovered completely within 1-3 weeks, spontaneously or after short-term cortisone medication. In the control group, in a series of 31 patients (20 implanted with Medtronic 3389 lead and 11 with Boston Scientific Vercise lead), not a single problem of this kind was encountered at any time. CONCLUSION: Precise positioning of D-leads is more challenging than that of conventional DBS leads. By adding an external lead marker, control of optimal lead position and orientation is enhanced. In case of supposed increased risk for hemorrhage because of vessels crossing all possible trajectories in the pre-surgical navigated simulation program, primary D-lead implantation instead of the sharper microelectrodes may be a feasible alternative and it may offer more options than ring electrodes especially in these cases. Prospective studies comparing ring-mode stimulation to directional stimulation to examine the differences of the clinical effects have been started.

Vestibular Schwannoma Resection in a Consecutive Series of 502 Cases via the Retrosigmoid Approach: Technical Aspects, Complications, and Functional Outcome.

OBJECTIVE: Outcome in vestibular schwannoma (VS) surgery has improved enormously over the last decades. Surgical positioning remains a matter of discussion. A standardized protocol for diagnostics and management has been applied and evaluated for complications and functional outcome. METHODS: We examined 502 VS tumors in 483 patients (227 men and 256 women) between 2005 and 2016. According to our patient selection and treatment algorithm, 488 operations (97%) were performed in the semi-sitting position, and 14 (3%) were in the supine position. Auditory and facial functions were analyzed before and after surgery as were perioperative complications. RESULTS: There were 182 patients (36%) with small tumors (Hannover classification T1-T3A) and 320 (64%) large tumors (T3B or T4). Of the patients, 14% were neurofibromatosis type 2 cases. Complete tumor resection was achieved in 96.4%. Hearing preservation occurred in 44% of patients with small tumors and 23% of those with large tumors (Hannover classification), and correlated significantly with tumor size (P < 0.001). Facial palsy (House Brackmann grades II-VI) was present in 63 patients before and in 185 patients after surgery. Useful facial function (House Brackmann grades I-III) early after surgery was maintained in 86% of patients with small tumors and in 77% of patients with large tumors. Intraoperative complications included air embolism in 45 cases (9%), sinus injury in 3 cases, cerebrospinal fluid leakage in 46 cases (9%), and local hemorrhage in 19 cases (4%). Surgical revision was indicated in 31 cases (6%). CONCLUSIONS: In a standardized setting, the semi-sitting position allowed a safe approach. This setting offers the advantage of bimanual tumor nerve handling by the surgeon and an optimal visualization of important functional structures.

Rescuing Suboptimal Outcomes of Subthalamic Deep Brain Stimulation in Parkinson Disease by Surgical Lead Revision.

BACKGROUND: Clinical trials have established subthalamic deep-brain-stimulation (STN-DBS) as a highly effective treatment for motor symptoms of Parkinson disease (PD), but in clinical practice outcomes are variable. Experienced centers are confronted with an increasing number of patients with partially "failed" STN-DBS, in whom motor benefit doesn't meet expectations. These patients require a complex multidisciplinary and standardized workup to identify the likely cause. OBJECTIVE: To describe outcomes in a series of PD patients undergoing lead revision for suboptimal motor benefit after STN-DBS surgery and characterize selection criteria for surgical revision. METHODS: We investigated 9 PD patients with STN-DBS, who had unsatisfactory outcomes despite intensive neurological management. Surgical revision was considered if the ratio of DBS vs levodopa-induced improvement of UPDRS-III (DBS-rr) was below 75% and the electrodes were found outside the dorsolateral STN. RESULTS: Fifteen electrodes were replaced via stereotactic revision surgery into the dorsolateral STN without any adverse effects. Median displacement distance was 4.1 mm (range 1.6-8.42 mm). Motor symptoms significantly improved (38.2 ± 6.6 to 15.5 ± 7.9 points, P < .001); DBS-rr increased from 64% to 190%. CONCLUSION: Patients with persistent OFFmotor symptoms after STN-DBS should be screened for levodopa-responsiveness, which can serve as a benchmark for best achievable motor benefit. Even small horizontal deviations of the lead from the optimal position within the dorsolateral STN can cause stimulation responses, which are markedly inferior to the levodopa response. Patients with an image confirmed lead displacement and preserved levodopa response are candidates for lead revision and can expect significant motor improvement from appropriate lead replacement.

Probabilistic mapping of the antidystonic effect of pallidal neurostimulation: a multicentre imaging study.

Deep brain stimulation of the internal globus pallidus is a highly effective and established therapy for primary generalized and cervical dystonia, but therapeutic success is compromised by a non-responder rate of up to 25%, even in carefully-selected groups. Variability in electrode placement and inappropriate stimulation settings may account for a large proportion of this outcome variability. Here, we present probabilistic mapping data on a large cohort of patients collected from several European centres to resolve the optimal stimulation volume within the pallidal region. A total of 105 dystonia patients with pallidal deep brain stimulation were enrolled and 87 datasets (43 with cervical dystonia and 44 with generalized dystonia) were included into the subsequent 'normative brain' analysis. The average improvement of dystonia motor score was 50.5 ± 30.9% in cervical and 58.2 ± 48.8% in generalized dystonia, while 19.5% of patients did not respond to treatment (<25% benefit). We defined probabilistic maps of anti-dystonic effects by aggregating individual electrode locations and volumes of tissue activated (VTA) in normative atlas space and ranking voxel-wise for outcome distribution. We found a significant relation between motor outcome and the stimulation volume, but not the electrode location per se. The highest probability of stimulation induced motor benefit was found in a small volume covering the ventroposterior globus pallidus internus and adjacent subpallidal white matter. We then used the aggregated VTA-based outcome maps to rate patient individual VTAs and trained a linear regression model to predict individual outcomes. The prediction model showed robustness between the predicted and observed clinical improvement, with an r2 of 0.294 (P < 0.0001). The predictions deviated on average by 16.9 ± 11.6 % from observed dystonia improvements. For example, if a patient improved by 65%, the model would predict an improvement between 49% and 81%. Results were validated in an independent cohort of 10 dystonia patients, where prediction and observed benefit had a correlation of r2 = 0.52 (P = 0.02) and a mean prediction error of 10.3% (±8.9). These results emphasize the potential of probabilistic outcome brain mapping in refining the optimal therapeutic volume for pallidal neurostimulation and advancing computer-assisted planning and programming of deep brain stimulation.

Complementary spatial and timing control in rhythmic arm movements.

Volitional rhythmic motor behaviors such as limb cycling and locomotion exhibit spatial and timing regularity. Such rhythmic movements are executed in the presence of exogenous visual and nonvisual cues, and previous studies have shown the pivotal role that vision plays in guiding spatial and temporal regulation. However, the influence of nonvisual information conveyed through auditory or touch sensory pathways, and its effect on control, remains poorly understood. To characterize the function of nonvisual feedback in rhythmic arm control, we designed a paddle juggling task in which volunteers bounced a ball off a rigid elastic surface to a target height in virtual reality by moving a physical handle with the right hand. Feedback was delivered at two key phases of movement: visual feedback at ball peaks only and simultaneous audio and haptic feedback at ball-paddle collisions. In contrast to previous work, we limited visual feedback to the minimum required for jugglers to assess spatial accuracy, and we independently perturbed the spatial dimensions and the timing of feedback. By separately perturbing this information, we evoked dissociable effects on spatial accuracy and timing, confirming that juggling, and potentially other rhythmic tasks, involves two complementary processes with distinct dynamics: spatial error correction and feedback timing synchronization. Moreover, we show evidence that audio and haptic feedback provide sufficient information for the brain to control the timing synchronization process by acting as a metronome-like cue that triggers hand movement. NEW & NOTEWORTHY Vision contains rich information for control of rhythmic arm movements; less is known, however, about the role of nonvisual feedback (touch and sound). Using a virtual ball bouncing task allowing independent real-time manipulation of spatial location and timing of cues, we show their dissociable roles in regulating motor behavior. We confirm that visual feedback is used to correct spatial error and provide new evidence that nonvisual event cues act to reset the timing of arm movements.

Connectivity Predicts deep brain stimulation outcome in Parkinson disease.

OBJECTIVE: The benefit of deep brain stimulation (DBS) for Parkinson disease (PD) may depend on connectivity between the stimulation site and other brain regions, but which regions and whether connectivity can predict outcome in patients remain unknown. Here, we identify the structural and functional connectivity profile of effective DBS to the subthalamic nucleus (STN) and test its ability to predict outcome in an independent cohort. METHODS: A training dataset of 51 PD patients with STN DBS was combined with publicly available human connectome data (diffusion tractography and resting state functional connectivity) to identify connections reliably associated with clinical improvement (motor score of the Unified Parkinson Disease Rating Scale [UPDRS]). This connectivity profile was then used to predict outcome in an independent cohort of 44 patients from a different center. RESULTS: In the training dataset, connectivity between the DBS electrode and a distributed network of brain regions correlated with clinical response including structural connectivity to supplementary motor area and functional anticorrelation to primary motor cortex (p < 0.001). This same connectivity profile predicted response in an independent patient cohort (p < 0.01). Structural and functional connectivity were independent predictors of clinical improvement (p < 0.001) and estimated response in individual patients with an average error of 15% UPDRS improvement. Results were similar using connectome data from normal subjects or a connectome age, sex, and disease matched to our DBS patients. INTERPRETATION: Effective STN DBS for PD is associated with a specific connectivity profile that can predict clinical outcome across independent cohorts. This prediction does not require specialized imaging in PD patients themselves. Ann Neurol 2017;82:67-78.

Selective Brain Cooling after Traumatic Brain Injury: Effects of Three Different Cooling Methods-Case Report.

Background In experimental models of neuronal damage, therapeutic hypothermia proved to be a powerful neuroprotective method. In clinical studies of traumatic brain injury (TBI), this very distinct effect was not reproducible. Several meta-analyses draw different conclusions about whether therapeutic hypothermia can improve outcome after TBI. Adverse side effects of systemic hypothermia, such as severe pneumonia, have been held responsible by some authors to counteract the neuroprotective effect. Selective brain cooling (SBC) attempts to take advantage of the protective effects of therapeutic hypothermia without the adverse side effects of systemic hypothermia. Methods Three different methods of SBC were applied in a patient who had severe TBI with recurrent increases of intracranial pressure (ICP) refractory to conventional forms of treatment: (1) external cooling of the scalp and neck using ice packs prior to hemicraniectomy, (2) external cooling of the craniectomy defect using ice packs after hemicraniectomy, and (3) cooling by epidural irrigation with cold Ringer solution after hemicraniectomy. Results External scalp cooling before hemicraniectomy, external cooling of the craniectomy defect, and epidural irrigation with cold fluid resulted in temperature differences (brain temperature to body temperature) of - 0.2°, - 0.7°, and - 3.6°C, respectively. ICP declined with decreasing brain temperature. Conclusion Previous external cooling attempts for SBC faced the problem that brain temperature could not be lowered without a simultaneous decrease of systemic temperature. After hemicraniectomy, epidural irrigation with cold fluid may be a simple and effective way to lower ICP and apply one of the most powerful methods of cerebroprotection after severe TBI.

Distinctive neuronal firing patterns in subterritories of the subthalamic nucleus.

OBJECTIVE: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established treatment for Parkinson's disease (PD). Anatomical connectivity analyses and task-related physiological studies have divided the STN into different functional domains: sensorimotor, limbic, and associative - located in its dorsolateral (dSTN), anteroventral (vSTN) and medial territories, respectively. Targeting sensorimotor STN is essential for stimulation efficacy and is supported by intraoperative micro-electrode recordings. A different neuronal signature in microelectrode recordings across STN subterritories was explored in this study. METHODS: Stable recordings from 30 PD patients were assigned to dSTN or vSTN by means of an anatomical method (based on fused computed tomography/magnetic resonance images) and through a priori tri-segmented partition of the recording itself. We computed the inter-spike interval (ISI) and ISI-characteristics, mean firing rate (MFR), discharge patterns and mean burst rate (MBR) of each detected single unit activity. RESULTS: We showed a different MBR between dSTN and vSTN (1.51±0.18 vs. 1.76±0.22events/minute, Wilcoxon rank sum test, p<0.05) and a trend in the difference between their MFR (12.78 vs. 15.05Hz, Wilcoxon rank sum test, p=0.053) only with the anatomically based method. CONCLUSION: Burst firing differs across STN subterritories. SIGNIFICANCE: Different functions of subthalamic domains might be reflected by distinctive burst signalling of its subterritories.