Relief of post-stroke spasticity with acute vibrotactile stimulation: controlled crossover study of muscle and skin stimulus methods.

Background: Prior work suggests that vibratory stimulation can reduce spasticity and hypertonia. It is unknown which of three predominant approaches (stimulation of the spastic muscle, antagonist muscle, or cutaneous regions) most reduces these symptoms. Objective: Determine which vibrotactile stimulation approach is most effective at reducing spastic hypertonia among post-stroke patients. Methods: Sham-controlled crossover study with random assignment of condition order in fourteen patients with post-stroke hand spasticity. All patients were studied in four conditions over four visits: three stimulation conditions and a sham control. The primary outcome measure was the Modified Ashworth Scale, and the secondary outcome measure was the Modified Tardieu Scale measured manually and using 3D motion capture. For each condition, measures of spastic hypertonia were taken at four time points: baseline, during stimulation, after stimulation was removed, and after a gripping exercise. Results: A clinically meaningful difference in spastic hypertonia was found during and after cutaneous stimulation of the hand. Modified Ashworth and Modified Tardieu scores were reduced by a median of 1.1 (SD = 0.84, p = 0.001) and 0.75 (SD = 0.65, p = 0.003), respectively, during cutaneous stimulation, and by 1.25 (SD = 0.94, p = 0.001) and 0.71 (SD = 0.67, p = 0.003), respectively, at 15 min after cutaneous stimulation. Symptom reductions with spastic muscle stimulation and antagonist muscle stimulation were non-zero but not significant. There was no change with sham stimulation. Conclusions: Cutaneous vibrotactile stimulation of the hand provides significant reductions in spastic hypertonia, compared to muscle stimulation. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT03814889.

Between-Tactor Display Using Dynamic Tactile Stimuli for Directional Cueing in Vibrating Environments.

Torso-worn vibrotactile devices have been used in many studies on directional cueing and navigation in environments where visual feedback is limited. These devices aim to indicate directions with high resolution while using the smallest possible number of vibration motors (tactors). Resolution can be increased using between-tactor displays, but their performance in vibrating environments (e.g., a helicopter) are unknown. This study proposes a between-tactor display using dynamic stimuli and verifies its effectiveness when the user sits in a vibrating chair. We developed a waist belt device that displays 12 directions using 6 tactors. Static stimuli display virtual (between-tactor) locations by constantly vibrating two adjacent tactors equally, whereas dynamic stimuli move the virtual vibration position back and forth between tactors. We performed two studies in which participants felt tactile stimuli and used a joystick to move a cursor on a screen to a target in the perceived direction. Direction recognition accuracy and task completion time were measured under combined conditions of two belt orientations (tactor alignments), with and without chair vibration, and with and without audio white noise to mask tactor sound. In all conditions, dynamic stimuli increased recognition accuracy while maintaining task completion time compared to static stimuli.

Daily Vibrotactile Stimulation Exhibits Equal or Greater Spasticity Relief Than Botulinum Toxin in Stroke.

OBJECTIVE: To test the feasibility and efficacy of the VibroTactile Stimulation (VTS) Glove, a wearable device that provides VTS to the impaired limb to reduce spastic hypertonia. DESIGN: Prospective 2-arm intervention study-including 1 group of patients who use Botulinum toxin (BTX-A) for spasticity and 1 group of patients who do not use BTX-A. SETTING: Participants were recruited through rehabilitation and neurology clinics. PARTICIPANTS: Patients with chronic stroke (N=20; mean age=54 years, mean time since stroke=6.9 years). Patients who were previously receiving the standard of care (BTX-A injection) were eligible to participate and started the intervention 12 weeks after their last injection. INTERVENTION: Participants were instructed to use the VTS Glove for 3 hours daily, at home or during everyday activities, for 8 weeks. MAIN OUTCOME MEASURES: Spasticity was assessed with the Modified Ashworth Scale and the Modified Tardieu Scale at baseline and then at 2-week intervals for 12 weeks. Primary outcomes were the difference from baseline and at week 8 (end of VTS Glove use) and week 12 (4 weeks after stopping VTS Glove use). Patients who were receiving BTX-A were also assessed during the 12 weeks preceding the start of VTS Glove use to monitor the effect of BTX-A on spastic hypertonia. Range of motion and participant feedback were also studied. RESULTS: A clinically meaningful difference in spastic hypertonia was found during and after daily VTS Glove use. Modified Ashworth and Modified Tardieu scores were reduced by an average of 0.9 (P=.0014) and 0.7 (P=.0003), respectively, at week 8 of daily VTS Glove use, and by 1.1 (P=.00025) and 0.9 (P=.0001), respectively, 1 month after stopping VTS Glove use. For participants who used BTX-A, 6 out of 11 showed greater change in Modified Ashworth ratings during VTS Glove use (mean=-1.8 vs mean=-1.6 with BTX-A) and 8 out of 11 showed their lowest level of symptoms during VTS Glove use (vs BTX-A). CONCLUSIONS: Daily stimulation from the VTS Glove provides relief of spasticity and hypertonia. For more than half of the participants who had regularly used BTX-A, the VTS Glove provided equal or greater symptom relief.

Single-cell transcriptomes of developing and adult olfactory receptor neurons in Drosophila.

Recognition of environmental cues is essential for the survival of all organisms. Transcriptional changes occur to enable the generation and function of the neural circuits underlying sensory perception. To gain insight into these changes, we generated single-cell transcriptomes of Drosophila olfactory- (ORNs), thermo-, and hygro-sensory neurons at an early developmental and adult stage using single-cell and single-nucleus RNA sequencing. We discovered that ORNs maintain expression of the same olfactory receptors across development. Using receptor expression and computational approaches, we matched transcriptomic clusters corresponding to anatomically and physiologically defined neuron types across multiple developmental stages. We found that cell-type-specific transcriptomes partly reflected axon trajectory choices in development and sensory modality in adults. We uncovered stage-specific genes that could regulate the wiring and sensory responses of distinct ORN types. Collectively, our data reveal transcriptomic features of sensory neuron biology and provide a resource for future studies of their development and physiology.

Temporal evolution of single-cell transcriptomes of Drosophila olfactory projection neurons.

Neurons undergo substantial morphological and functional changes during development to form precise synaptic connections and acquire specific physiological properties. What are the underlying transcriptomic bases? Here, we obtained the single-cell transcriptomes of Drosophila olfactory projection neurons (PNs) at four developmental stages. We decoded the identity of 21 transcriptomic clusters corresponding to 20 PN types and developed methods to match transcriptomic clusters representing the same PN type across development. We discovered that PN transcriptomes reflect unique biological processes unfolding at each stage-neurite growth and pruning during metamorphosis at an early pupal stage; peaked transcriptomic diversity during olfactory circuit assembly at mid-pupal stages; and neuronal signaling in adults. At early developmental stages, PN types with adjacent birth order share similar transcriptomes. Together, our work reveals principles of cellular diversity during brain development and provides a resource for future studies of neural development in PNs and other neuronal types.

Single-Cell Transcriptomes Reveal Diverse Regulatory Strategies for Olfactory Receptor Expression and Axon Targeting.

The regulatory mechanisms by which neurons coordinate their physiology and connectivity are not well understood. The Drosophila olfactory receptor neurons (ORNs) provide an excellent system to investigate this question. Each ORN type expresses a unique olfactory receptor, or a combination thereof, and sends their axons to a stereotyped glomerulus. Using single-cell RNA sequencing, we identified 33 transcriptomic clusters for ORNs and mapped 20 to their glomerular types, demonstrating that transcriptomic clusters correspond well with anatomically and physiologically defined ORN types. Each ORN type expresses hundreds of transcription factors. Transcriptome-instructed genetic analyses revealed that (1) one broadly expressed transcription factor (Acj6) only regulates olfactory receptor expression in one ORN type and only wiring specificity in another type, (2) one type-restricted transcription factor (Forkhead) only regulates receptor expression, and (3) another type-restricted transcription factor (Unplugged) regulates both events. Thus, ORNs utilize diverse strategies and complex regulatory networks to coordinate their physiology and connectivity.