Self-directed arm therapy at home after stroke with a sensor-based virtual reality training system.

BACKGROUND: The effect of rehabilitative training after stroke is dose-dependent. Out-patient rehabilitation training is often limited by transport logistics, financial resources and a lack of motivation/compliance. We studied the feasibility of an unsupervised arm therapy for self-directed rehabilitation therapy in patients' homes. METHODS: An open-label, single group study involving eleven patients with hemiparesis due to stroke (27 ± 31.5 months post-stroke) was conducted. The patients trained with an inertial measurement unit (IMU)-based virtual reality system (ArmeoSenso) in their homes for six weeks. The self-selected dose of training with ArmeoSenso was the principal outcome measure whereas the Fugl-Meyer Assessment of the upper extremity (FMA-UE), the Wolf Motor Function Test (WMFT) and IMU-derived kinematic metrics were used to assess arm function, training intensity and trunk movement. Repeated measures one-way ANOVAs were used to assess differences in training duration and clinical scores over time. RESULTS: All subjects were able to use the system independently in their homes and no safety issues were reported. Patients trained on 26.5 ± 11.5 days out of 42 days for a duration of 137 ± 120 min per week. The weekly training duration did not change over the course of six weeks (p = 0.146). The arm function of these patients improved significantly by 4.1 points (p = 0.003) in the FMA-UE. Changes in the WMFT were not significant (p = 0.552). ArmeoSenso based metrics showed an improvement in arm function, a high number of reaching movements (387 per session), and minimal compensatory movements of the trunk while training. CONCLUSIONS: Self-directed home therapy with an IMU-based home therapy system is safe and can provide a high dose of rehabilitative therapy. The assessments integrated into the system allow daily therapy monitoring, difficulty adaptation and detection of maladaptive motor patterns such as trunk movements during reaching. TRIAL REGISTRATION: Unique identifier: NCT02098135 .

Chasing central nervous system plasticity: the brainstem's contribution to locomotor recovery in rats with spinal cord injury.

Anatomical plasticity such as fibre growth and the formation of new connections in the cortex and spinal cord is one known mechanism mediating functional recovery after damage to the central nervous system. Little is known about anatomical plasticity in the brainstem, which contains key locomotor regions. We compared changes of the spinal projection pattern of the major descending systems following a cervical unilateral spinal cord hemisection in adult rats. As in humans (Brown-Séquard syndrome), this type of injury resulted in a permanent loss of fine motor control of the ipsilesional fore- and hindlimb, but for basic locomotor functions substantial recovery was observed. Antero- and retrograde tracings revealed spontaneous changes in spinal projections originating from the reticular formation, in particular from the contralesional gigantocellular reticular nucleus: more reticulospinal fibres from the intact hemicord crossed the spinal midline at cervical and lumbar levels. The intact-side rubrospinal tract showed a statistically not significant tendency towards an increased number of midline crossings after injury. In contrast, the corticospinal and the vestibulospinal tract, as well as serotonergic projections, showed little or no side-switching in this lesion paradigm. Spinal adaptations were accompanied by modifications at higher levels of control including side-switching of the input to the gigantocellular reticular nuclei from the mesencephalic locomotor region. Electrolytic microlesioning of one or both gigantocellular reticular nuclei in behaviourally recovered rats led to the reappearance of the impairments observed acutely after the initial injury showing that anatomical plasticity in defined brainstem motor networks contributes significantly to functional recovery after injury of the central nervous system.

Improving activity recognition using a wearable barometric pressure sensor in mobility-impaired stroke patients.

BACKGROUND: Stroke survivors often suffer from mobility deficits. Current clinical evaluation methods, including questionnaires and motor function tests, cannot provide an objective measure of the patients' mobility in daily life. Physical activity performance in daily-life can be assessed using unobtrusive monitoring, for example with a single sensor module fixed on the trunk. Existing approaches based on inertial sensors have limited performance, particularly in detecting transitions between different activities and postures, due to the inherent inter-patient variability of kinematic patterns. To overcome these limitations, one possibility is to use additional information from a barometric pressure (BP) sensor. METHODS: Our study aims at integrating BP and inertial sensor data into an activity classifier in order to improve the activity (sitting, standing, walking, lying) recognition and the corresponding body elevation (during climbing stairs or when taking an elevator). Taking into account the trunk elevation changes during postural transitions (sit-to-stand, stand-to-sit), we devised an event-driven activity classifier based on fuzzy-logic. Data were acquired from 12 stroke patients with impaired mobility, using a trunk-worn inertial and BP sensor. Events, including walking and lying periods and potential postural transitions, were first extracted. These events were then fed into a double-stage hierarchical Fuzzy Inference System (H-FIS). The first stage processed the events to infer activities and the second stage improved activity recognition by applying behavioral constraints. Finally, the body elevation was estimated using a pattern-enhancing algorithm applied on BP. The patients were videotaped for reference. The performance of the algorithm was estimated using the Correct Classification Rate (CCR) and F-score. The BP-based classification approach was benchmarked against a previously-published fuzzy-logic classifier (FIS-IMU) and a conventional epoch-based classifier (EPOCH). RESULTS: The algorithm performance for posture/activity detection, in terms of CCR was 90.4 %, with 3.3 % and 5.6 % improvements against FIS-IMU and EPOCH, respectively. The proposed classifier essentially benefits from a better recognition of standing activity (70.3 % versus 61.5 % [FIS-IMU] and 42.5 % [EPOCH]) with 98.2 % CCR for body elevation estimation. CONCLUSION: The monitoring and recognition of daily activities in mobility-impaired stoke patients can be significantly improved using a trunk-fixed sensor that integrates BP, inertial sensors, and an event-based activity classifier.

Comparative evaluation of the drug interaction screening programs MediQ and ID PHARMA CHECK in neurological inpatients.

PURPOSE: The comparative evaluation of clinical decision support software (CDSS) programs regarding their sensitivity and positive predictive value for the identification of clinically relevant drug interactions. METHODS: In this research, we used a cross-sectional study that identified potential drug interactions using the CDSS MediQ and the ID PHARMA CHECK in 484 neurological inpatients. Interactions were reclassified according to the Zurich Interaction System, a multidimensional classification that incorporates the Operational Classification of Drug Interactions. RESULTS: In 484 patients with 2812 prescriptions, MediQ and ID PHARMA CHECK generated a total of 1759 and 1082 alerts, respectively. MediQ identified 658 unique potentially interacting combinations, 8 classified as "high danger," 164 as "average danger," and 486 as "low danger." ID PHARMA CHECK detected 336 combinations assigned to one or several of 12 risk and management categories. Altogether, both CDSS issued alerts relating to 808 unique potentially interacting combinations. According to the Zurich Interaction System, 6 of these were contraindicated, 25 were provisionally contraindicated, 190 carried a conditional risk, and 587 had a minimal risk of adverse events. The positive predictive value for alerts having at least a conditional risk was 0.24 for MediQ and 0.48 for ID PHARMA CHECK. CONCLUSIONS: CDSS showed major differences in the identification and grading of interactions, and many interactions were only identified by one of the two CDSS. For both programs, only a small proportion of all identified interactions appeared clinically relevant, and the selected display of alerts that imply management changes is a key issue in the further development and local setup of such programs.

Nogo-A antibodies and training reduce muscle spasms in spinal cord-injured rats.

OBJECTIVE: Spinal cord injury (SCI) leads to permanent motor and sensory deficits due to the damage of ascending and descending fiber tracts. In addition, malfunctions such as neuropathic pain or muscle spasms develop in many patients, possibly caused by injury-induced plastic changes of neuronal circuits above and below the lesion. New treatment strategies for spinal cord injury aim at enhancing plasticity and neurite growth, for example, by blocking the key neurite growth inhibitor Nogo-A or its downstream effectors. It is therefore crucial to investigate potential effects of such treatments on malfunctions such as muscle spasms. In addition, locomotor training, now a standard therapeutic tool to improve walking ability in incomplete SCI subjects, can be expected to influence the rearrangement of spinal cord circuits and the development of muscle spasms and other malfunctions. METHODS AND RESULTS: Here we present and validate a new rat model for muscle spasms after incomplete SCI and show that both intrathecal anti-Nogo-A antibody treatment and locomotor training, started early after injury, permanently reduce the development of muscle spasms. INTERPRETATION: The results show that an antibody-mediated suppression of the growth inhibitory protein Nogo-A leads to functional recovery and a lower level of malfunctions, suggesting the formation of functionally meaningful connections in the damaged spinal cord. Treadmill training early after SCI also has a beneficial effect.

Evaluation of drug interactions and dosing in 484 neurological inpatients using clinical decision support software and an extended operational interaction classification system (Zurich Interaction System).

PURPOSE: The current study aimed at identifying and quantifying critical drug interactions in neurological inpatients using clinical decision support software (CDSS). Reclassification of interactions with a focus on clinical management aimed to support the development of CDSS with higher efficacy to reduce overalerting and improve medication safety in clinical practice. METHODS: We conducted a cross-sectional study in consecutive patients admitted to the neurology ward of a tertiary care hospital. We developed a customized interface for mass analysis with the CDSS MediQ, which we used for automated retrospective identification of drug interactions during the first day of hospitalization. Interactions were reclassified according to the Zurich Interaction System (ZHIAS), which incorporates the Operational Classification of Drug Interactions (ORCA). Dose adjustments for renal impairment were also evaluated. RESULTS: In 484 patients with 2812 prescriptions, MediQ generated 8 "high danger," 518 "average danger," and 1233 "low danger" interaction alerts. According to ZHIAS, 6 alerts involved contraindicated and 33 alerts involved provisionally contraindicated combinations, and 327 alerts involved a conditional and 1393 alerts involved a minimal risk of adverse outcomes. Thirty-five patients (6.2%) had at least one combination that was at least provisionally contraindicated. ZHIAS also provides categorical information on expected adverse outcomes and management recommendations, which are presented in detail. We identified 13 prescriptions without recommended dose adjustment for impaired renal function. CONCLUSIONS: MediQ detected a large number of drug interactions with variable clinical relevance in neurological inpatients. ZHIAS supports the selection of those interactions that require active management, and the effects of its implementation into CDSS on medication safety should be evaluated in future prospective studies.

Lamina-specific restoration of serotonergic projections after Nogo-A antibody treatment of spinal cord injury in rats.

Blocking the neurite growth inhibitor Nogo-A by neutralizing antibodies improves functional recovery after partial spinal cord injury. In parallel, regeneration and sprouting of cortico- and rubrospinal projections are increased and may partially explain the enhanced functional recovery. The serotonergic raphe-spinal tract, which plays a key regulatory role for spinal motor circuits, has not been analysed in detail with regard to its response to Nogo-A function blocking antibody treatment after spinal cord injury. We studied the effect of 2 weeks of intrathecal Nogo-A antibody application after partial thoracic spinal cord injury on the lamina-specific restitution of the serotonergic (5-HT) raphe-spinal projections to the mid-lumbar grey matter. Nine weeks after the lesion, the number of 5-HT fibres in Rexed's laminae 4 and 7 and the number of 5-HT-positive varicosities on motoneurons in lamina 9 returned to their lamina-specific preinjury levels in Nogo-A antibody-treated rats. By contrast, control antibody-treated animals showed only a moderate increase in 5-HT fibre density in the respective laminae, and the number of 5-HT-positive varicosities on motoneurons remained low. Our results suggest that the Nogo-A antibody-induced recovery of descending serotonergic projections to the grey matter is lamina-specific and molecular cues must be present to guide the growing axons to the correct target areas. This appropriate restitution of the serotonergic innervation below the lesion site probably contributes to the impressive recovery of motor function.

Infusion of anti-Nogo-A antibodies in adult rats increases growth and synapse related proteins in the absence of behavioral alterations.

Restricted structural re-growth in the adult CNS is a major limitation to fully functional recovery following extensive CNS trauma. This limitation is partly due to the presence of growth inhibitory proteins, in particular, Nogo-A. Pre-clinical studies have demonstrated that intrathecally infused anti-Nogo-A antibodies are readily distributed via the cerebrospinal fluid penetrating throughout the spinal cord and brain, where they promote sprouting, axonal regeneration and improved functional recovery after CNS injury. Whether anti-Nogo-A treatments of intact animals might induce behavioral alterations has not been systematically tested. This is addressed here in an adult rat model of chronic intrathecal infusion of function-blocking anti-Nogo-A antibodies for 2 to 4weeks. We observed by proteomic and immunohistochemical techniques that chronic Nogo-A neutralization in the intact CNS increased expression of cytoskeletal, fiber-growth-related, and synaptic proteins in the hippocampus, a brain region which might be particularly sensitive to Nogo-A depletion due to the high expression level of Nogo-A. Despite such molecular and proteomic changes, Nogo-A blockade was not associated with any pronounced cognitive-behavioral changes indicative of hippocampal functional deficiency across several critical tests. Our results suggest that the plastic changes induced by Nogo-A blockade in the adult hippocampus are counter-balanced by homeostatic mechanisms in the intact and the injured CNS. The data indicate that anti-Nogo-A therapy appears safe in the adult CNS over 4weeks of continuous administration.

Delayed anti-nogo-a antibody application after spinal cord injury shows progressive loss of responsiveness.

Blocking the function of the myelin protein Nogo-A or its signaling pathway is a promising method to overcome an important neurite growth inhibitory factor of the adult central nervous system (CNS), and to enhance axonal regeneration and plasticity after brain or spinal cord injuries. Several studies have shown increased axonal regeneration and enhanced compensatory sprouting, along with substantially improved functional recovery after treatment with anti-Nogo-A antibodies, Nogo-receptor antagonists, or inhibition of the downstream mediator RhoA/ROCK in adult rodents. Proof-of-concept studies in spinal cord-injured macaque monkeys with anti-Nogo-A antibodies have replicated these findings; recently, clinical trials in spinal cord-injured patients have begun. However, the optimal time window for successful Nogo-A function blocking treatments has not yet been determined. We studied the effect of acute as well as 1- or 2-weeks delayed intrathecal anti-Nogo-A antibody infusions on the regeneration of corticospinal tract (CST) axons and the recovery of motor function after large but anatomically incomplete thoracic spinal cord injuries in adult rats. We found that lesioned CST fibers regenerated over several millimeters after acute or 1-week-delayed treatments, but not when the antibody treatment was started with a delay of 2 weeks. Swimming and narrow beam crossing recovered well in rats treated acutely or with a 1-week delay with anti-Nogo-A antibodies, but not in the 2-week-delayed group. These results show that the time frame for treatment of spinal cord lesions with anti-Nogo-A antibodies is restricted to less than 2 weeks in adult rodents.