Monitoring medication optimization in patients with Parkinson's disease.

Medication optimization is a common component of the treatment strategy in patients with Parkinson's disease. As the disease progresses, it is essential to compensate for the movement deterioration in patients. Conventionally, examining motor deterioration and prescribing medication requires the patient's onsite presence in hospitals or practices. Home-monitoring technologies can remotely deliver essential information to physicians and help them devise a treatment decision according to the patient's need. Additionally, they help to observe the patient's response to these changes. In this regard, we conducted a longitudinal study to collect gait data of patients with Parkinson's disease while they received medication changes. Using logistic regression classifier, we could detect the annotated motor deterioration during medication optimization with an accuracy of 92%. Moreover, an in-depth examination of the best features illustrated a decline in gait speed and swing phase duration in the deterioration phases due to suboptimal medication.Clinical relevance- Our proposed gait analysis method in this study provides objective, detailed, and punctual information to physicians. Revealing clinically relevant time points related to the patient's need for medical adaption alleviates therapy optimization for physicians and reduces the duration of suboptimal treatment for patients. As the home-monitoring system acts remotely, embedding it in the medical care pathways could improve patients' quality of life.

The effects of an individualized smartphone-based exercise program on self-defined motor tasks in Parkinson's disease: a long-term feasibility study.

BACKGROUND: Exercise therapy is considered effective for the treatment of motor impairment in patients with Parkinson's disease (PD). During the COVID-19 pandemic, training sessions were cancelled and the implementation of telerehabilitation concepts became a promising solution. The aim of this controlled interventional feasibility study was to evaluate the long-term acceptance and to explore initial effectiveness of a digital, home-based, high-frequency exercise program for PD patients. Training effects were assessed using patient-reported outcome measures combined with sensor-based and clinical scores. METHODS: 16 PD patients (smartphone group, SG) completed a home-based, individualized training program over 6-8 months using a smartphone app, remotely supervised by a therapist, and tailored to the patient's motor impairments and capacity. A control group (CG, n = 16) received medical treatment without participating in digital exercise training. The usability of the app was validated using System Usability Scale (SUS) and User Version of the Mobile Application Rating Scale (uMARS). Outcome measures included among others Unified Parkinson Disease Rating Scale, part III (UPDRS-III), sensor-based gait parameters derived from standardized gait tests, Parkinson's Disease Questionnaire (PDQ-39), and patient-defined motor activities of daily life (M-ADL). RESULTS: Exercise frequency of 74.5% demonstrated high adherence in this cohort. The application obtained 84% in SUS and more than 3.5/5 points in each subcategory of uMARS, indicating excellent usability. The individually assessed additional benefit showed at least 6 out of 10 points (Mean = 8.2 ± 1.3). From a clinical perspective, patient-defined M-ADL improved for 10 out of 16 patients by 15.5% after the training period. The results of the UPDRS-III remained stable in the SG while worsening in the CG by 3.1 points (24%). The PDQ-39 score worsened over 6-8 months by 83% (SG) and 59% (CG) but the subsection mobility showed a smaller decline in the SG (3%) compared to the CG (77%) without reaching significance level for all outcomes. Sensor-based gait parameters remained constant in both groups. CONCLUSIONS: Long-term training over 6-8 months with the app is considered feasible and acceptable, representing a cost-effective, individualized approach to complement dopaminergic treatment. This study indicates that personalized, digital, high-frequency training leads to benefits in motor sections of ADL and Quality of Life.

The Effects of an Individualized Smartphone-Based Exercise Program on Self-defined Motor Tasks in Parkinson Disease: Pilot Interventional Study.

BACKGROUND: Bradykinesia and rigidity are prototypical motor impairments of Parkinson disease (PD) highly influencing everyday life. Exercise training is an effective treatment alternative for motor symptoms, complementing dopaminergic medication. High frequency training is necessary to yield clinically relevant improvements. Exercise programs need to be tailored to individual symptoms and integrated in patients' everyday life. Due to the COVID-19 pandemic, exercise groups in outpatient setting were largely reduced. Developing remotely supervised solutions is therefore of significant importance. OBJECTIVE: This pilot study aimed to evaluate the feasibility of a digital, home-based, high-frequency exercise program for patients with PD. METHODS: In this pilot interventional study, patients diagnosed with PD received 4 weeks of personalized exercise at home using a smartphone app, remotely supervised by specialized therapists. Exercises were chosen based on the patient-defined motor impairment and depending on the patients' individual capacity (therapists defined 3-5 short training sequences for each participant). In a first education session, the tailored exercise program was explained and demonstrated to each participant and they were thoroughly introduced to the smartphone app. Intervention effects were evaluated using the Unified Parkinson Disease Rating Scale, part III; standardized sensor-based gait analysis; Timed Up and Go Test; 2-minute walk test; quality of life assessed by the Parkinson Disease Questionnaire; and patient-defined motor tasks of daily living. Usability of the smartphone app was assessed by the System Usability Scale. All participants gave written informed consent before initiation of the study. RESULTS: In total, 15 individuals with PD completed the intervention phase without any withdrawals or dropouts. The System Usability Scale reached an average score of 72.2 (SD 6.5) indicating good usability of the smartphone app. Patient-defined motor tasks of daily living significantly improved by 40% on average in 87% (13/15) of the patients. There was no significant impact on the quality of life as assessed by the Parkinson Disease Questionnaire (but the subsections regarding mobility and social support improved by 14% from 25 to 21 and 19% from 15 to 13, respectively). Motor symptoms rated by Unified Parkinson Disease Rating Scale, part III, did not improve significantly but a descriptive improvement of 14% from 18 to 16 could be observed. Clinically relevant changes in Timed Up and Go test, 2-minute walk test, and sensor-based gait parameters or functional gait tests were not observed. CONCLUSIONS: This pilot interventional study presented that a tailored, digital, home-based, and high-frequency exercise program over 4 weeks was feasible and improved patient-defined motor activities of daily life based on a self-developed patient-defined impairment score indicating that digital exercise concepts may have the potential to beneficially impact motor symptoms of daily living. Future studies should investigate sustainability effects in controlled study designs conducted over a longer period.

Walking on common ground: a cross-disciplinary scoping review on the clinical utility of digital mobility outcomes.

Physical mobility is essential to health, and patients often rate it as a high-priority clinical outcome. Digital mobility outcomes (DMOs), such as real-world gait speed or step count, show promise as clinical measures in many medical conditions. However, current research is nascent and fragmented by discipline. This scoping review maps existing evidence on the clinical utility of DMOs, identifying commonalities across traditional disciplinary divides. In November 2019, 11 databases were searched for records investigating the validity and responsiveness of 34 DMOs in four diverse medical conditions (Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, hip fracture). Searches yielded 19,672 unique records. After screening, 855 records representing 775 studies were included and charted in systematic maps. Studies frequently investigated gait speed (70.4% of studies), step length (30.7%), cadence (21.4%), and daily step count (20.7%). They studied differences between healthy and pathological gait (36.4%), associations between DMOs and clinical measures (48.8%) or outcomes (4.3%), and responsiveness to interventions (26.8%). Gait speed, step length, cadence, step time and step count exhibited consistent evidence of validity and responsiveness in multiple conditions, although the evidence was inconsistent or lacking for other DMOs. If DMOs are to be adopted as mainstream tools, further work is needed to establish their predictive validity, responsiveness, and ecological validity. Cross-disciplinary efforts to align methodology and validate DMOs may facilitate their adoption into clinical practice.

Deep brain stimulation of the pedunculopontine nucleus for treatment of gait and balance disorder in progressive supranuclear palsy: Effects of frequency modulations and clinical outcome.

BACKGROUND: The pedunculopontine nucleus has been suggested as a potential deep brain stimulation target for axial symptoms such as gait and balance impairment in idiopathic Parkinson's disease as well as atypical Parkinsonian disorders. METHODS: Seven consecutive patients with progressive supranuclear palsy received bilateral pedunculopontine nucleus deep brain stimulation. Inclusion criteria comprised of the clinical diagnosis of progressive supranuclear palsy, a levodopa-resistant gait and balance disorder, age <75 years, and absence of dementia or major psychiatric co-morbidities. Effects of stimulation frequencies at 8, 20, 60 and 130 Hz on motor scores and gait were assessed. Motor scores were followed up for two years postoperatively. Activities of daily living, frequency of falls, health-related quality of life, cognition and mood at 12 months were compared to baseline parameters. Surgical and stimulation related adverse events were assessed. RESULTS: Bilateral pedunculopontine nucleus deep brain stimulation at 8 Hz significantly improved axial motor symptoms and cyclic gait parameters, while high frequency stimulation did not ameliorate gait and balance but improved hypokinesia. This improvement however did not translate into clinically relevant benefits. Frequency of falls was not reduced. Activities of daily living, quality of life and frontal cognitive functions declined, while mood remained unchanged. CONCLUSION: Bilateral pedunculopontine nucleus deep brain stimulation in progressive supranuclear palsy generates frequency-dependent effects with improvement of cyclic gait parameters at low frequency and amelioration of hypokinesia at high frequency stimulation. However, these effects do not translate into a clinically important improvement.

Neural generators of sustained activity differ for stimulus-encoding and delay maintenance.

The ability to maintain information online beyond sensory stimulation is regarded as a key contribution of working memory to goal-directed behaviour. It is widely accepted that sustained neural activity is a key mechanism of stimulus maintenance, but it is unclear to what extent the neural generators of sustained activity change from stimulus-encoding to maintenance. Using event-related potentials in humans, we show that, in a delayed match-to-sample task, slow shifts over parieto-occipital electrode sites had a different topography and polarity during encoding and delay maintenance of images depicting scenes. This clearly demonstrates that neural generators of sustained activity associated with stimulus-encoding and delay maintenance differed, and that the change between these generators occurred time-locked to the onset of the delay period. We also investigated how monetary reward incentives modulated the amplitude and topography of sustained delay activity and the ability to suppress irrelevant distracting information during the delay. Reward incentives improved maintenance performance and this was correlated with an expansion of the parieto-occipital electrode sites that were entrained into sustained delay activity (rather than improved distractor suppression), suggesting that under the influence of reward, the parieto-occipital regions that contributed to delay maintenance expanded in size.

A close relationship between verbal memory and SN/VTA integrity in young and older adults.

Age-related dysfunction in dopaminergic neuromodulation is assumed to contribute to age-associated memory impairment. However, to date there are no in vivo data on how structural parameters of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic projections, relate to memory performance in healthy young and older adults. We investigated this relationship in a cross-sectional study including data from the hippocampus and frontal white matter (FWM) and also assessing working memory span and attention. In groups of young and older adults matched for the variance of their age distribution, gender and body mass index, we observed a robust positive correlation between Magnetization Transfer Ratio (MTR)--a measure of structural integrity--of the SN/VTA and FWM with verbal learning and memory performance among older adults, while there was a negative correlation in the young. Two additional imaging parameters, anisotropy of diffusion and diffusion coefficient, suggested that in older adults FWM changes reflected vascular pathology while SN/VTA changes pointed towards neuronal loss and loss of water content. The negative correlation in the young possibly reflected maturational changes. Multiple regression analyses indicated that in both young and older adults, SN/VTA MTR explained more variance of verbal learning and memory than FWM MTR or hippocampal MTR, and contributed less to explaining variance of working memory span. Together these findings indicate that structural integrity in the SN/VTA has a relatively selective impact on verbal learning and memory and undergoes specific changes from young adulthood to older age that qualitatively differ from changes in the FWM and hippocampus.

Mesolimbic novelty processing in older adults.

Normal aging is associated with neuronal loss in the dopaminergic midbrain (substantia nigra/ventral tegmental area, SN/VTA), a region that has recently been implicated in processing novel stimuli as part of a mesolimbic network including the hippocampus. Here, we quantified age-related structural degeneration of the mesolimbic system using magnetization transfer ratio (MTR) and correlated it with mesolimbic hemodynamic responses (HRs) to stimulus novelty. Twenty-one healthy older adults between 55 and 77 years performed a visual oddball paradigm allowing to distinguish mesolimbic HRs to novelty from rareness, negative emotional valence, and targetness using functional magnetic resonance imaging. The HRs in the right SN/VTA and the right hippocampus to novelty were positively correlated both with the SN/VTA MTR and hippocampus MTR but not amygdala MTR. However, the HR of the amygdala to negative emotional valence correlated with the amygdala MTR but not with the MTR in SN/VTA or the hippocampus. The results establish a structure-function relationship in support of a hippocampal-SN/VTA loop of mesolimbic novelty processing by showing that the hemodynamic activation in SN/VTA and hippocampus for novelty is selectively affected by age-related degeneration of these structures.

Altered pain behavior and regeneration after nerve injury in TNF receptor deficient mice.

The pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha is an important mediator in hyperalgesia, nerve injury, and regeneration. Here, we used mice deficient of TNF receptor (TNFR) 1 or 2 to investigate the role of TNF signaling via receptor in each pain behavior and nerve de- and regeneration after chronic constriction injury (CCI) of the sciatic nerve. We found an absence of thermal hyperalgesia in mice deficient of TNFR1 and a reduction in mechanical and cold allodynia in mice deficient of TNFR1 or TNFR2 compared with wild-type mice. Nerve conduction studies and nerve pathology did not reveal major differences between genotypes in the temporal course of de- and regeneration of the nerve. We propose that the functional effects of the TNFRs on pain symptoms are independent of effects on nerve regeneration. Furthermore, the differential action of TNF via each of its receptors should be taken into account when considering clinical trials with TNF inhibitors for pain.