Dosage Frequency Effects on Treatment Outcomes Following Self-managed Digital Therapy: Retrospective Cohort Study.

BACKGROUND: Although the efficacy of high-dose speech-language therapy (SLT) for individuals with poststroke aphasia has been established in the literature, there is a gap in translating these research findings to clinical practice. Therefore, patients continue to receive suboptimal amounts of SLT, with negative consequences for their functional communication recovery. Recent research has identified self-managed digital health technology as one way to close the dosage gap by enabling high-intensity therapy unrestricted by clinician availability or other practical constraints. However, there is limited empirical evidence available to rehabilitation professionals to guide dose prescriptions for self-managed SLT despite their increasing use in the COVID-19 era and likely beyond. OBJECTIVE: This study aims to leverage real-world mobile health data to investigate the effects of varied dosage frequency on performance outcomes for individuals with poststroke speech, language, and cognitive deficits following a 10-week period of self-managed treatment via a commercially available digital health platform. METHODS: Anonymized data from 2249 poststroke survivors who used the Constant Therapy app between late 2016 and 2019 were analyzed. The data included therapy tasks spanning 13 different language and cognitive skill domains. For each patient, the weekly therapy dosage was calculated based on the median number of days per week of app use over the 10-week therapy period, binned into groups of 1, 2, 3, 4, or ≥5 days per week. Linear mixed-effects models were run to examine change in performance over time as a function of dosage group, with post hoc comparisons of slopes to evaluate the performance gain associated with each additional day of practice. RESULTS: Across all skill domains, linear mixed-effects model results showed that performance improvement was significantly greater for patients who practiced 2 (ß=.001; t15,355=2.37; P=.02), 3 (ß=.003; t9738=5.21; P<.001), 4 (ß=.005; t9289=7.82; P<.001), or ≥5 (ß=.005; t6343=8.14; P<.001) days per week compared with those who only practiced for 1 day per week. Post hoc comparisons confirmed an incremental dosage effect accumulating with each day of practice (ie, 1 day vs 2 days, 2 days vs 3 days, and 3 days vs 4 days), apart from 4 days versus ≥5 days of practice per week. The result of greater improvement for higher versus lower dosage frequency groups was true not only across all domains but also within a majority of individual subdomains. CONCLUSIONS: The findings from this study demonstrated that increased dosage frequency is associated with greater therapy gains over a 10-week treatment period of self-managed digital therapy. The use of real-world data maximizes the ecological validity of study results and makes the findings more generalizable to clinical settings. This study represents an important step toward the development of optimal dose recommendations for self-managed SLT.

Closing the Digital Divide in Speech, Language, and Cognitive Therapy: Cohort Study of the Factors Associated With Technology Usage for Rehabilitation.

BACKGROUND: For stroke, traumatic brain injury (TBI), and other neurologic conditions associated with speech-language disorders, speech and language therapy is the standard of care for promoting recovery. However, barriers such as clinician time constraints and insurance reimbursement can inhibit a patient's ability to receive the support needed to optimize functional gain. Although digital rehabilitation has the potential to increase access to therapy by allowing patients to practice at home, the clinical and demographic characteristics that impact a patient's level of engagement with technology-based therapy are currently unknown. OBJECTIVE: This study aimed to evaluate whether the level of engagement with digital therapy differs by various patient characteristics, including age, gender, diagnosis, time from disease onset, and geographic location (urban vs rural). METHODS: Data for patients with stroke or TBI that initiated the use of Constant Therapy, a remotely delivered, cloud-based rehabilitation program for patients with speech-language disorders, were retrospectively analyzed. Only data from therapeutic sessions completed at home were included. The following three activity metrics were evaluated: (1) the number of active weeks of therapy, (2) the average number of active therapy days per week, and (3) the total number of therapeutic sessions completed during the first 20 weeks of program access. An active day or week was defined as having at least one completed therapeutic session. Separate multiple linear regression models were performed with each activity measure as the dependent variable and all available patient demographics as model covariates. RESULTS: Data for 2850 patients with stroke or TBI were analyzed, with the average patient completing 8.6 weeks of therapy at a frequency of 1.5 days per week. Contrary to known barriers to technological adoption, older patients were more active during their first 20 weeks of program access, with those aged 51 to 70 years completing 5.01 more sessions than patients aged 50 years or younger (P=.04). Similarly, patients living in a rural area, who face greater barriers to clinic access, were more digitally engaged than their urban counterparts, with rural patients completing 11.54 more (P=.001) sessions during their first 20 weeks of access, after controlling for other model covariates. CONCLUSIONS: An evaluation of real-world data demonstrated that patients with stroke and TBI use digital therapy frequently for cognitive and language rehabilitation at home. Usage was higher in areas with limited access to clinical services and was unaffected by typical barriers to technological adoption, such as age. These findings will help guide the direction of future research in digital rehabilitation therapy, including the impact of demographics on recovery outcomes and the design of large, randomized controlled trials.

Comparison of Therapy Practice at Home and in the Clinic: A Retrospective Analysis of the Constant Therapy Platform Data Set.

Background: Computer-based therapies can provide an affordable and practical alternative by providing frequent intervention for stroke survivors with chronic aphasia by allowing the opportunity for home exercise practice, however more evidence is needed. The goal of this retrospective analysis was to compare the time course of therapy engagement when therapy was targeted in the clinic or at home by post-stroke individuals. We examined if home users of the therapy were compliant in therapy and if this documented practice time was associated with improved outcomes similar to clinic patients who practiced under the guidance of a clinician. Methods: A retrospective analysis of anonymously aggregated data collected for 3,686 patients with post-stroke aphasia over the course of four years (2013-2017) was conducted. Participants either received therapy delivered through Constant Therapy only at home (N = 2,100) or only in the clinic (N = 1,577). Constant Therapy includes over 70 evidence-based therapies for language and cognitive skills. This program was individualized for each patient with targeted tasks that dynamically adapted to each individual's progress. Results: Patients with <60% accuracy were analyzed to determine how long it took them to reach >90% accuracy. Results showed that both home-therapy and clinic patients reached 90% accuracy on their tasks similarly (Median = 3 sessions), but the frequency of therapy was significantly different with 50% of home users receiving therapy at least every 2 days while 50% of clinic patients only had therapy once every 5 days (p < 0.001). Thus, home-therapy users were able to master tasks in a shorter time (median of 6 days) than clinic patients (median of 12 days) (p < 0.001). Conclusion: Outcomes of treatment are similar for home users and clinic patients indicating the potential usability of a home-based treatment program for rehabilitation for post-stroke aphasia.

Effects of somatosensory electrical stimulation on motor function and cortical oscillations.

BACKGROUND: Few patients recover full hand dexterity after an acquired brain injury such as stroke. Repetitive somatosensory electrical stimulation (SES) is a promising method to promote recovery of hand function. However, studies using SES have largely focused on gross motor function; it remains unclear if it can modulate distal hand functions such as finger individuation. OBJECTIVE: The specific goal of this study was to monitor the effects of SES on individuation as well as on cortical oscillations measured using EEG, with the additional goal of identifying neurophysiological biomarkers. METHODS: Eight participants with a history of acquired brain injury and distal upper limb motor impairments received a single two-hour session of SES using transcutaneous electrical nerve stimulation. Pre- and post-intervention assessments consisted of the Action Research Arm Test (ARAT), finger fractionation, pinch force, and the modified Ashworth scale (MAS), along with resting-state EEG monitoring. RESULTS: SES was associated with significant improvements in ARAT, MAS and finger fractionation. Moreover, SES was associated with a decrease in low frequency (0.9-4 Hz delta) ipsilesional parietomotor EEG power. Interestingly, changes in ipsilesional motor theta (4.8-7.9 Hz) and alpha (8.8-11.7 Hz) power were significantly correlated with finger fractionation improvements when using a multivariate model. CONCLUSIONS: We show the positive effects of SES on finger individuation and identify cortical oscillations that may be important electrophysiological biomarkers of individual responsiveness to SES. These biomarkers can be potential targets when customizing SES parameters to individuals with hand dexterity deficits. TRIAL REGISTRATION: NCT03176550; retrospectively registered.

Muscle synergies after stroke are correlated with perilesional high gamma.

Movements can be factored into modules termed "muscle synergies". After stroke, abnormal synergies are linked to impaired movements; however, their neural basis is not understood. In a single subject, we examined how electrocorticography signals from the perilesional cortex were associated with synergies. The measured synergies contained a mix of both normal and abnormal patterns and were remarkably similar to those described in past work. Interestingly, we found that both normal and abnormal synergies were correlated with perilesional high gamma. Given the link between high gamma and cortical spiking, our results suggest that perilesional spiking may organize synergies after stroke.

Cortical neuroprosthetics from a clinical perspective.

Recent pilot clinical studies have demonstrated that subjects with severe disorders of movement and communication can exert direct neural control over assistive devices using invasive Brain-Machine Interface (BMI) technology, also referred to as 'cortical neuroprosthetics'. These important proof-of-principle studies have generated great interest among those with disability and clinicians who provide general medical, neurological and/or rehabilitative care. Taking into account the perspective of providers who may be unfamiliar with the field, we first review the clinical goals and fundamentals of invasive BMI technology, and then briefly summarize the vast body of basic science research demonstrating its feasibility. We emphasize recent translational progress in the target clinical populations and discuss translational challenges and future directions.

Comparing temporal aspects of visual, tactile, and microstimulation feedback for motor control.

OBJECTIVES: Current brain-computer interfaces (BCIs) rely on visual feedback, requiring sustained visual attention to use the device. Improvements to BCIs may stem from the development of an effective way to provide quick feedback independent of vision. Tactile stimuli, either delivered on the skin surface, or directly to the brain via microstimulation in somatosensory cortex, could serve that purpose. We examined the effectiveness of vibrotactile stimuli and microstimulation as a means of non-visual feedback by using a fundamental element of feedback: the ability to react to a stimulus while already in motion. APPROACH: Human and monkey subjects performed a center-out reach task which was, on occasion, interrupted with a stimulus cue that instructed a change in reach target. MAIN RESULTS: Subjects generally responded faster to tactile cues than to visual cues. However, when we delivered cues via microstimuation in a monkey, its response was slower on average than for both tactile and visual cues. SIGNIFICANCE: Tactile and microstimulation feedback can be used to rapidly adjust movements mid-flight. The relatively slow speed of microstimulation is surprising and warrants further investigation. Overall, these results highlight the importance of considering temporal aspects of feedback when designing alternative forms of feedback for BCIs.

Direction and speed tuning of motor-cortex multi-unit activity and local field potentials during reaching movements.

Primary motor-cortex multi-unit activity (MUA) and local-field potentials (LFPs) have both been suggested as potential control signals for brain-computer interfaces (BCIs) aimed at movement restoration. Some studies report that LFP-based decoding is comparable to spiking-based decoding, while others offer contradicting evidence. Differences in experimental paradigms, tuning models and decoding techniques make it hard to directly compare these results. Here, we use regression and mutual information analyses to study how MUA and LFP encode various kinematic parameters during reaching movements. We find that in addition to previously reported directional tuning, MUA also contains prominent speed tuning. LFP activity in low-frequency bands (15-40Hz, LFPL) is primarily speed tuned, and contains more speed information than both high-frequency LFP (100-300Hz, LFPH) and MUA. LFPH contains more directional information compared to LFPL, but less information when compared with MUA. Our results suggest that a velocity and speed encoding model is most appropriate for both MUA and LFPH, whereas a speed only encoding model is adequate for LFPL.

Gene expression and generation of CD28-CD8 T cells mediated by interleukin 15.

Accumulation of CD28(-)CD8 T cells that are defective in response to antigenic stimulation is a hallmark of age-associated decline in T cell function. However, the underlying mechanism of this age-associated change is not fully understood. We recently analyzed the global gene expression profiles of CD8 T cell subsets from nai ve to memory (CD28(+) to CD28(-)) cells and the growth of CD28(+) and CD28(-)CD8 memory T cells in response to homeostatic cytokine interleukin 15 (IL-15). At the gene expression level, one of the most striking changes is the altered expression of some co-stimulatory receptors and various NK cell receptors in CD28(-)CD8 T cells. Furthermore, CD28(-)CD8 T cells appear to have a normal proliferation response to IL-15 in vitro. Interestingly, IL-15 is also capable of inducing stable loss of CD28 expression in actively dividing CD28(+)CD8 memory T cells. Together, these findings provide the gene expression features of CD28(-)CD8 T cells that differ from their CD28(+) counterparts and suggest a possible role of IL-15 in the increase of CD28(-)CD8 T cells that occurs with aging.

Histone acetylation is associated with differential gene expression in the rapid and robust memory CD8(+) T-cell response.

To understand the molecular basis for the rapid and robust memory T-cell responses, we examined gene expression and chromatin modification by histone H3 lysine 9 (H3K9) acetylation in resting and activated human naive and memory CD8(+) T cells. We found that, although overall gene expression patterns were similar, a number of genes are differentially expressed in either memory or naive cells in their resting and activated states. To further elucidate the basis for differential gene expression, we assessed the role of histone H3K9 acetylation in differential gene expression. Strikingly, higher H3K9 acetylation levels were detected in resting memory cells, prior to their activation, for those genes that were differentially expressed following activation, indicating that hyperacetylation of histone H3K9 may play a role in selective and rapid gene expression of memory CD8(+) T cells. Consistent with this model, we showed that inducing high levels of H3K9 acetylation resulted in an increased expression in naive cells of those genes that are normally expressed differentially in memory cells. Together, these findings suggest that differential gene expression mediated at least in part by histone H3K9 hyperacetylation may be responsible for the rapid and robust memory CD8(+) T-cell response.