Combining Repetitive Transcranial Magnetic Stimulation and Video Game-Based Training to Improve Dexterity in Parkinson's Disease: Study Protocol of a Randomized Controlled Trial

Introduction: Patients with Parkinson’s disease (PD) often exhibit difficulties with dexterity during the performance of activities of daily living (ADL) due to dysfunctional supplementary motor area (SMA). The aim of this clinical trial protocol work is to describe how the effectiveness of a combined repetitive transcranial magnetic stimulation (rTMS) over SMA and video-game-based skill training (VBT) in PD will be evaluated. The short and long-term benefits are assessed. Methods and analysis: A single-blind (patients) stratified (based on Hoehn & Yahr) parallel randomized sham-controlled rTMS-VBT study with a baseline and two follow-up measurements (3 and 12 weeks) is being conducted. These measurements include the dexterity questionnaire 24 (DextQ-24) as a primary outcome, and nine hole peg test and coin rotation task as main secondary dexterity outcomes. Further secondary outcomes will be the subscale II of the movement disorders society unified PD rating scale (MDS-UPDRS) to assess improvements on overall ADL and the Parkinson’s Disease Questionnaire-39 to assess quality of life. Thirty-six outpatients (from one neurorehabilitation center) with PD (diagnosis based on brain bank criteria) will be recruited who report difficulties with dexterity in performing ADL. All PD patients will receive a 45-min VBT three times a week for 3 weeks. The PD patients randomized in the experimental group will receive VBT preceded by real rTMS, being intermittent theta burst (iTBS) stimulation sessions. The PD patients randomized to the control group receive a VBT with sham rTMS. Discussion: The study will provide evidence to determine whether a combined iTBS and VBT skill intervention is more effective than a VBT intervention alone to improve dexterity in PD. Ethics and dissemination: The study was approved by the Ethics Committee for Northwest and Central Switzerland (EKNZ), Switzerland 2019–00433. The study will be conducted in accordance with the Helsinki Declaration and the Guidelines of Good Clinical Practice. Informed consent will be signed prior to subject enrolment. Dissemination will include submission to international peer-reviewed professional journals and presentation at international congresses. The study protocol has been registered in the clinicaltrials.gov registry with the identification code: NCT04699149

Distinguishing transient from persistent tactile agnosia after partial anterior circulation infarcts - Behavioral and neuroimaging evidence for white matter disconnection.

From a cohort of 36 patients presenting apperceptive tactile agnosia after first cortical ischemic stroke, 14 showed temporary impairment at admission. A previous multi-voxel analysis of the cortical lesions, using as explanatory variable the course of tactile object recognition performance over the recovery period of 9 months, partitioned the cohort into three subgroups. Of the 14 patients constituting two of the subgroups, 7 recovered from their impairment whereas 7 did not. These two subgroups could not be distinguished at admission. The primary aim of the present study is to present two assessments that can do so. The first assessment comprises a pattern of behavioral measures, determined via principal component analysis, encoded in three tests: picking small objects, macrogeometrical discrimination and tactile object recognition. The receiver operating characteristic curve derived from permutation of the behavioral test scores yielded an 80% probability of correct identification of the patient subgroup and an 8% probability for false identification. As done with the permuted scores, the pattern could predict the persistence of affliction of new stroke patients with tactile agnosia. The second predictive assessment extends our previous evaluation of cortical MRI lesion maps to include subcortical regions. Confirming our previous study, the lesions of the persistently impaired subgroup disrupted significantly the anterior arcuatus fasciculus and associated superior longitudinal fasciculus III in the ipsilesional hemisphere, impeding reciprocal information transfer between supramarginal gyrus and both the ventral premotor cortex and Brodmann area 44. Due to the importance of interhemispheric information transfer in tactile agnosia, we performed a supplementary analysis of tactile object recognition scores. It showed that haptic information transfer from the non-affected to the affected hands in the persistent cases partly restored function during the nine months, possibly following restoration of functional interhemispheric haptic information transfer at the border of posterior corpus callosum and splenium. In conclusion, the combined findings of the cortical lesion at subarea PFt of the inferior parietal lobule and the associated subcortical tract lesions permit almost perfect prediction of persistent impairment of tactile object recognition. The study substantiates the need for combined analysis of both cortical lesions and white matter tract disconnections

Usability of Two New Interactive Game Sensor-Based Hand Training Devices in Parkinson's Disease.

This pilot cross-sectional study aimed to evaluate the usability of two new interactive game sensor-based hand devices (GripAble and Smart Sensor Egg) in both healthy adults as well as in persons with Parkinson's Disease (PD). Eight healthy adults and eight persons with PD participated in this study. Besides a standardised usability measure, the state of flow after one training session and the effect of cognitive abilities on flow were evaluated. High system usability scores (SUS) were obtained both in healthy participants (72.5, IQR = 64.375-90, GripAble) as well as persons with PD (77.5, IQR = 70-80.625, GripAble; 77.5, IQR = 75-82.5, Smart Sensor Egg). Similarly, high FSSOT scores were achieved after one training session (42.5, IQR = 39.75-50, GripAble; 50, IQR = 47-50, Smart Sensor Egg; maximum score 55). Across both groups, FSSOT scores correlated significantly with SUS scores (r = 0.52, p = 0.039). Finally, MoCA did not correlate significantly with FSSOT scores (r = 0.02, p = 0.9). The present study shows high usability for both interactive game sensor-based hand training devices, for persons with PD and healthy participants

Distended Seminal Vesicles Are Involved in Specific Cerebral Sexual Arousal: A Pilot Study Using Functional Brain Imaging in Young Healthy Men.

Background Whether seminal vesicles play a role in sexual activity in men is unknown. No study so far has compared the neural processing of visual sexual stimuli in men depending on the filling state of the seminal vesicles. Objective To evaluate potential specific cortical activation by visual sexual stimuli with distended and empty seminal vesicles. Design setting and participants A prospective case-control trial was conducted. Six male individuals underwent two visits on 2 consecutive days for hormone analyses; Derogatis Interview for Sexual Functioning (DISF) questionnaire; functional magnetic resonance imaging (fMRI) with passively viewing sexual, neutral, positive, and negative emotional pictures; and structural pelvic MRI. After the first visit, the participants had to empty seminal vesicles by masturbation. During fMRI, every participant viewed alternating blocks of sexual, neutral, positive, and negative emotional pictures. Outcome measurements and statistical analysis Comparisons between days 1 and 2 were evaluated using paired t tests. Results and limitations No significant differences were observed regarding hormone analyses, DISF questionnaire score, and arousal scoring between days 1 and 2. Seminal vesicle volume was significantly lower on day 2 (p = 0.003). Significantly higher activation was observed in the right precentral gyrus, middle frontal gyrus, and right superior temporal sulcus when contrasted for sexual over neutral (p < 0.05). Conclusions In response to pictures with sexual emotional content, significantly higher activation was detected in brain areas involved in motor preparation (arousal) and coding of desirability of visual sexual stimuli in men with distended seminal vesicles than in the same men with emptied seminal vesicles. This suggests that the filling state of the seminal vesicles may influence sexual desire in men. Patient summary We compared brain activity of men with filled and emptied seminal vesicles by functional magnetic resonance imaging. We found that men with filled seminal vesicles had higher activation of brain areas involved in arousal and sexual desire

Signal Alteration of the Inner Ear on High-Resolution Three-Dimensional Constructive Interference in Steady State Sequence in Patients with Ménière's Disease and Labyrinthitis.

INTRODUCTION The aim of this study is to evaluate signal alteration in the inner ear using three-dimensional (3D)-constructive interference in steady state (CISS) sequence in patients with Ménière's disease and labyrinthitis and its correlation with clinical and audiological parameters. METHODS The medical records of the department of otorhinolaryngology were searched for patients with Ménière's disease or labyrinthitis who underwent MRI with 3D-CISS sequence. Blinded analysis of these patients and of MRI from control subjects without middle or inner ear symptoms was performed to detect any signal asymmetry of the inner ear structures. The results were correlated with clinical symptoms and results of audiological and vestibular tests. RESULTS Fifty-eight patients with definite Ménière's disease and 5 patients with labyrinthitis as well as 41 control exams were included. A separate analysis was performed for patients with probable Ménière's disease (n = 68). A total of 172 3D-CISS sequences were analyzed by 2 blinded independent neuroradiologists. A CISS-hypointense signal of the inner ear structures was found in 3 patients with definite Ménière's disease (5.2%), in 4 patients with probable Ménière's disease (5.9%), and 2 patients with labyrinthitis (40%). No CISS hypointensity was found in the control group. Although no significant difference in symptoms or audiological test results was found between patients with and without this signal change, the side of hypointensity was frequently correlated with the symptomatic side and with hearing impairment. DISCUSSION/CONCLUSION CISS hypointensity of the inner ear structures was evident in patients with clinical conditions other than vestibular schwannoma - more frequently in labyrinthitis than in Ménière's disease. This signal alteration was frequently encountered on the same symptomatic side as that of the pathological audiology tests, but it is not a predictor for hearing or vestibular impairment

Joint impact on attention, alertness and inhibition of lesions at a frontal white matter crossroad.

In everyday life, information from different cognitive domains - such as visuospatial attention, alertness, and inhibition - needs to be integrated between different brain regions. Early models suggested that completely segregated brain networks control these three cognitive domains. However, more recent accounts, mainly based on neuroimaging data in healthy participants, indicate that different tasks lead to specific patterns of activation within the same, higher-order and "multiple-demand" network. If so, then a lesion to critical substrates of this common network should determine a concomitant impairment in all three cognitive domains. The aim of the present study was to critically investigate this hypothesis, i.e., to identify focal stroke lesions within the network that can concomitantly impact visuospatial attention, alertness and inhibition. We studied an unselected sample of 60 first-ever right-hemispheric, subacute stroke patients using a data-driven, bottom-up approach. Patients performed 12 standardized neuropsychological and oculomotor tests, four per cognitive domain. Principal component analyses revealed a strong relationship between all three cognitive domains: 10 of 12 tests loaded on a first, Common Component. Analysis of the neuroanatomical lesion correlates using different approaches (i.e., Voxel-Based and Tractwise Lesion-Symptom Mapping, Disconnectome maps) provided convergent evidence on the association between severe impairment of this Common Component and lesions at the intersection of Superior Longitudinal Fasciculus II and III, Frontal Aslant Tract and, to a lesser extent, the Putamen and Inferior Fronto-Occipital Fasciculus. Moreover, patients with a lesion involving this region were significantly more impaired in daily living cognition, which provides an ecological validation of our results. A probabilistic functional atlas of the multiple-demand network was performed to confirm the potential relationship between patients' lesion substrates and observed cognitive impairments as a function of the MD-network connectivity disruption. These findings show, for the first time, that a lesion to a specific white matter crossroad can determine a concurrent breakdown in all three considered cognitive domains. Our results support the multiple-demand network model, proposing that different cognitive operations depend on specific collaborators and their interaction, within the same underlying neural network. Our findings also extend this hypothesis by showing (1) the contribution of SLF and FAT to the multiple-demand network, and (2) a critical neuroanatomical intersection, crossed by a vast amount of long-range white matter tracts, many of which interconnect cortical areas of the multiple-demand network. The vulnerability of this crossroad to stroke has specific cognitive and clinical consequences; this has the potential to influence future rehabilitative approaches

Improved gesturing in left-hemispheric stroke by right inferior parietal theta burst stimulation.

OBJECTIVES Apraxia is a common syndrome of left hemispheric stroke. A parieto-premotor-prefrontal network has been associated with apraxia, in which the left inferior parietal lobe (IPL-L) plays a major role. We hypothesized that transcranial continuous theta burst stimulation (cTBS) over the right inferior parietal lobe (IPL-R) improves gesturing by reducing its inhibition on the contralateral IPL in left hemispheric stroke patients. It was assumed that this effect is independent of lesion volume and that transcallosal connectivity is predictive for gestural effect after stimulation. MATERIALS AND METHODS Nineteen stroke patients were recruited. Lesion volume and fractional anisotropy of the corpus callosum were acquired with structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Each patient had pseudorandomised sessions with sham or with stimulation over the IPL-R or over the right inferior frontal gyrus IFG-R. Gesturing was assessed in a double-blinded manner before and after each session. We tested the effects of stimulation on gesture performance using a linear mixed-effects model. RESULTS Pairwise treatment contrasts showed, that, compared to sham, the behavioral effect was higher after stimulation over IPL-R (12.08, 95% CI 6.04 - 18.13, p < 0.001). This treatment effect was approximately twice as high as the contrasts for IFG-R vs. sham (6.25, 95% CI -0.20 - 12.70, p = 0.058) and IPL-R vs. IFG-R vs. sham (5.83, 95% CI -0.49 - 12.15, p = 0.071). Furthermore, higher fractional anisotropy in the splenium (connecting the left and right IPL) were associated with higher behavioral effect. Relative lesion volume did not affect the changes after sham or stimulation over IPL-R or IFG-R. CONCLUSION One single session of cTBS over the IPL-R improved gesturing after left hemispheric stroke. Denser microstructure in the corpus callosum correlated with favorable gestural response. We therefore propose the indirect transcallosal modulation of the IPL-L as a promising model of restoring interhemispheric balance, which may be useful in rehabilitation of apraxia

An Overview of Wearable Haptic Technologies and Their Performance in Virtual Object Exploration.

We often interact with our environment through manual handling of objects and exploration of their properties. Object properties (OP), such as texture, stiffness, size, shape, temperature, weight, and orientation provide necessary information to successfully perform interactions. The human haptic perception system plays a key role in this. As virtual reality (VR) has been a growing field of interest with many applications, adding haptic feedback to virtual experiences is another step towards more realistic virtual interactions. However, integrating haptics in a realistic manner, requires complex technological solutions and actual user-testing in virtual environments (VEs) for verification. This review provides a comprehensive overview of recent wearable haptic devices (HDs) categorized by the OP exploration for which they have been verified in a VE. We found 13 studies which specifically addressed user-testing of wearable HDs in healthy subjects. We map and discuss the different technological solutions for different OP exploration which are useful for the design of future haptic object interactions in VR, and provide future recommendations

Theta burst stimulation over premotor cortex in Parkinson's disease: an explorative study on manual dexterity.

Dorsal pre-motor cortex (PMd) is thought to play a role in fine motor control. The aim of the present study was to investigate whether inhibitory or excitatory stimulation of PMd would have an impact on manual dexterity in Parkinson's disease (PD). Fifteen patients with PD participated in this study. High resolution structural MRI was used for neuro-navigated TBS. Participants were targeted with one train of TBS in three experimental sessions: sham stimulation over vertex, continuous TBS (cTBS) over PMd and intermittent TBS (iTBS) over PMd, respectively. Dexterity was measured by a coin rotation task (CRT), which is a valid measure to detect limb kinetic apraxia (LKA). Neither cTBS or iTBS significantly interfered with CRT. Post hoc sub-analysis in a group of PD patients (n = 5) with stronger baseline impairment, indicating LKA, revealed further deterioration of dexterous performance for the cTBS condition (p = 0.04). This sham controlled pilot study demonstrates that TBS over PMd does not significantly interfere with dexterity in PD. However, patients with dexterous impairment qualifying for LKA may be more susceptible to TBS

Improved gesturing in left-hemispheric stroke by right inferior parietal theta burst stimulation

ObjectivesApraxia is a common syndrome of left hemispheric stroke. A parieto-premotor-prefrontal network has been associated with apraxia, in which the left inferior parietal lobe (IPL-L) plays a major role. We hypothesized that transcranial continuous theta burst stimulation (cTBS) over the right inferior parietal lobe (IPL-R) improves gesturing by reducing its inhibition on the contralateral IPL in left hemispheric stroke patients. It was assumed that this effect is independent of lesion volume and that transcallosal connectivity is predictive for gestural effect after stimulation.Materials and methodsNineteen stroke patients were recruited. Lesion volume and fractional anisotropy of the corpus callosum were acquired with structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Each patient had pseudorandomised sessions with sham or with stimulation over the IPL-R or over the right inferior frontal gyrus IFG-R. Gesturing was assessed in a double-blinded manner before and after each session. We tested the effects of stimulation on gesture performance using a linear mixed-effects model.ResultsPairwise treatment contrasts showed, that, compared to sham, the behavioral effect was higher after stimulation over IPL-R (12.08, 95% CI 6.04 – 18.13, p &lt; 0.001). This treatment effect was approximately twice as high as the contrasts for IFG-R vs. sham (6.25, 95% CI –0.20 – 12.70, p = 0.058) and IPL-R vs. IFG-R vs. sham (5.83, 95% CI –0.49 – 12.15, p = 0.071). Furthermore, higher fractional anisotropy in the splenium (connecting the left and right IPL) were associated with higher behavioral effect. Relative lesion volume did not affect the changes after sham or stimulation over IPL-R or IFG-R.ConclusionOne single session of cTBS over the IPL-R improved gesturing after left hemispheric stroke. Denser microstructure in the corpus callosum correlated with favorable gestural response. We therefore propose the indirect transcallosal modulation of the IPL-L as a promising model of restoring interhemispheric balance, which may be useful in rehabilitation of apraxia