Multidomain cognitive training increases physical activity in people with Parkinson's disease with mild cognitive impairment.

INTRODUCTION: Cognitive impairment in Parkinson's disease (PD), especially in patients with mild cognitive impairment (PD-MCI), coincides with less physical activity. Cognitive trainings (CT) have been found to promote laboratory environment-based movement. Knowledge about their effect in natural home-based environment, reflecting everyday function, is sparse. This explorative study investigated short-term effects of CT on physical activity assessed by home-based accelerometry, and its relation to change of cognitive function over time and non-cognitive outcomes in patients with PD-MCI. Cognitive and non-cognitive correlates of movement parameters at pretest were evaluated as well. METHODS: Eighteen patients with PD-MCI of the TrainParC study were analyzed. Those patients received either a 6-week multidomain group CT or physical training (PT). Physical activity and sedentary behavior were assessed with wearable accelerometers worn up to seven days pre- and post-training. RESULTS: Patients in the CT group displayed significantly greater increases in active periods after training than patients assigned to PT. In the CT group, increases in executive functioning were associated with increases in active periods and decreases in active mean bout length after training. At pretest, reduced working memory correlated with longer sedentary mean bout length, and impairment in activities of daily living (ADL) correlated with a higher number of sedentary periods. CONCLUSION: Study data revealed that CT can increase physical activity in patients with PD-MCI, possibly due to effects on executive functions, which needs further investigation in larger sample sizes. Lower working memory performance and ADL impairment might be associated with a more inactive lifestyle in patients with PD-MCI.

No effect of subthalamic deep brain stimulation on metacognition in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a powerful treatment in Parkinson's disease (PD), which provides a positive effect on motor symptoms although the way it operates on high cognitive processes such as metacognition remains unclear. To address this issue, we recorded electroencephalogram (EEG) of PD patients treated with STN-DBS that performed a reversal learning (RL) paradigm endowed with metacognitive self-assessment. We considered two stimulation conditions, namely DBS-ON (stimulation on) and DBS-OFF (stimulation off), and focused our EEG-analysis on the frontal brain region due to its involvement on high cognitive processes. We found a trend towards a significant difference in RL ability between stimulation conditions. STN-DBS showed no effect on metacognition, although a significant association between accuracy and decision confidence level held for DBS OFF, but not in the case of DBS ON. In summary, our study revealed no significant effect of STN-DBS on RL or metacognition.

Results of a Randomized Clinical Trial of Speech after Early Neurostimulation in Parkinson's Disease.

BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Safety of Deep Repetitive Transcranial Magnetic Stimulation (drTMS) against Medical Refractory Symptoms in Parkinson Syndromes: First German Real-World Data with a Specific H5 Coil.

So far, deep repetitive transcranial magnetic stimulation (drTMS) has shown promising results as an add-on treatment for Parkinson's disease (PD) but not for non-idiopathic Parkinson Syndromes (PS). We aimed to investigate the safety and feasibility of drTMS application in patients with different Parkinson Syndromes and medical refractory symptoms. Multifaceted real-world data (n = 21) were retrospectively analyzed regarding adverse effects as well as short-term effects of the drTMS treatment on patients' self-rated symptom severity and motor, cognitive, and emotional functions. The drTMS treatment with H5 coil included a sequential 1 Hz primary motor cortex stimulation contralateral to the more-affected body side and a bilateral 10 Hz stimulation of the prefrontal cortex. Overall, drTMS could be safely administered to patients with different PSs and medical refractory symptoms, but large variation was apparent in the rate and severity ratings of the reported adverse event/adverse device effect. The treatment significantly decreased the subjective main symptom severity. This effect was more pronounced in older patients with PD. Furthermore, analysis showed an improvement in depression, but no effect could be established in terms of cognitive performance. drTMS can be safely administered to patients with PS and medical refractory symptoms and can decrease the subjective motor symptom severity and depression.

Retrospective real-world pilot data on transcranial pulse stimulation in mild to severe Alzheimer's patients.

Introduction: Transcranial pulse stimulation (TPS) is a non-invasive neuromodulation therapy that uses short, repetitive shockwaves through a neuro-navigated device. Current research suggests that these pulses lead to a wide range of vascular, metabolic, and neurotrophic changes. This relatively new CE-marked treatment provided first promising results in a clinical pilot study for improving cognition in mild-to-moderate Alzheimer's. Data from other centers is lacking, so here we analyzed safety and pilot real-world short-term results of TPS from the first center in Germany. To gain information about effects in different stages, patients with not only mild but also moderate-to-severe Alzheimer's were analyzed. Methods: A total of 11 patients were retrospectively examined for cognitive and emotional function before and after the first stimulation series. The effect was assessed using several neuropsychological tests [Alzheimer's Disease Assessment Scale (ADAS), including the ADAS cognitive score (ADAS Cog) and ADAS affective scores, Mini-Mental Status Examination (MMSE), and Montreal Cognitive Assessment (MoCA)] including in comparison between the groups of mild-to-severe patients. Moreover, subjective improvement of symptom severity, potential effects on depressive symptoms, and side effects were analyzed using Numeric Rating Scales (NRS). Results: Side effects were rare (in 4% of sessions) with moderate subjective severity and only transient. Patients significantly improved in the ADAS and ADAS Cog, while there was no significant effect in MMSE and MoCA. Patients' self-reported symptom severity improved significantly. The depressive symptoms measured in an ADAS subscale also improved significantly. Statistical data analyses revealed no significant correlation of clinical improvement with baseline symptom severity. Conclusion: TPS might be a safe and promising add-on therapy for Alzheimer's, even for moderate-to-severe patients. More research on long-term effects in patients as well as studies with sham control groups is needed. Moreover, translational research on the mechanisms of action and effects on cerebral network physiology will be needed to understand this new neuromodulation technique.

Genetic stratification of motor and QoL outcomes in Parkinson's disease in the EARLYSTIM study.

PURPOSE: The decision for subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD) relies on clinical predictors. Whether genetic variables could predict favourable or unfavourable decisions is under investigation. OBJECTIVE: First, we aimed to reproduce the previous observation that SNCA rs356220 was associated with favourable STN-DBS motor response. In additional exploratory analyses, we studied if other PD risk and progression variants from the latest GWAS are associated with therapeutic outcome. Further, we evaluated the predictive value of polygenic risk scores. METHODS: We comprehensively genotyped patients from the EarlyStim cohort using NeuroChip, and assessed the clinico-genetic associations with longitudinal outcome parameters. RESULTS: The SNCA rs356220 variant did not predict UPDRS III outcomes. However, it was associated with quality of life improvement in secondary analyses. Several polymorphisms from previously identified GWAS hits predicted motor or quality of life outcomes in DBS patients. Polygenic risk scores did not predict any outcome parameter. CONCLUSIONS: Our findings support the hypothesis that different common genetic markers are associated with favourable quality of life outcomes of STN-DBS in PD. These findings can be the basis for further validation in larger and independent cohorts.

The Deep Brain Stimulation Impairment Scale: A useful complement in assessment of well-being and functioning in DBS-patients - Results from a large multicentre survey in patients with Parkinson's disease.

BACKGROUND: Deep Brain Stimulation (DBS) has been proven to alleviate motor symptoms in Parkinson's Disease (PD). Regarding non-motor symptoms, however, inconsistencies have been reported, on whether DBS causes reductions in well-being and functioning. To assess motor and non-motor impairment in DBS-patients, the Deep Brain Stimulation Impairment Scale (DBS-IS) has been developed. Yet, the extent to which the DBS-IS detects impairment in DBS-patients and thus could serve as a useful tool that complements the PDQ-39 (gold standard) in assessment of well-being and functioning in PD-patients has not been shown. OBJECTIVES: By comparing DBS and non-DBS-patients we aimed to identify DBS-specific symptoms. We thereby aimed to show in how far the DBS-IS complements the PDQ-39 in assessing well-being and functioning in PD patients under DBS. METHODS: In a cross-sectional study, 186 DBS-patients were matched (for age, disease duration and sex) to 186 non-DBS-patients (N = 372) and the two groups were compared regarding well-being and functioning: Impairment was assessed via DBS-IS and overall Quality of Life (QoL) was assessed via PDQ-39. Additionally, we analyzed differences in impairment between age and disease duration clusters. RESULTS: DBS-patients showed significantly higher total impairment (DBS-IS) and significantly higher impairment on the subscales Postural Instability and Gait difficulties and speaking difficulties than non-DBS-patients. Impairment increased with age and disease duration and, overall, differences in impairment rose by age. Overall QoL (PDQ-39) was non-significantly lower in DBS-patients. CONCLUSION: Since there is evidence that the PDQ-39 misses some DBS-specific symptoms, the DBS-IS is recommended to complement the PDQ-39 when assessing DBS-patients.

Myelitis with flaccid paralysis due to Japanese encephalitis: case report and review of the literature.

BACKGROUND: Japanese encephalitis is an arthropod-borne zoonotic flavivirus infection endemic to tropical and subtropical Asia. A minority of infections leads to a symptomatic course, but affected patients often develop life-threatening encephalitis with severe sequelae. LITERATURE REVIEW: Myelitis with flaccid paralysis is a rare complication of Japanese Encephalitis, which-according to our literature search-was reported in 27 cases, some of which were published as case reports and others as case series. Overall, there is a broad clinical spectrum with typically asymmetric manifestation and partly severe motor sequelae and partly mild courses. Lower limb paralysis appears to be more frequent than upper limb paralysis. An encephalitic component is not apparent in all cases CASE PRESENTATION: We herein add the case of a 29 year-old female who developed encephalitis and myelitis with flaccid paralysis during a long-time stay in Indonesia. Diagnostic workup in Indonesia did not clearly reveal an underlying cause. Upon clinical stabilization, the patient was evacuated to her home country Germany, where further diagnostics confirmed Japanese encephalitis virus as the causative agent. The patient has partly recovered, but still suffers from residual paralysis of the upper limb. CONCLUSION: Flaccid paralysis is a rare, and likely underdiagnosed complication of Japanese encephalitis, which, to the best of our knowledge, has never been diagnosed outside endemic areas before.

The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. OBJECTIVES: The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. METHODS: Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. RESULTS: Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. CONCLUSIONS: The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Memory enhancement by multidomain group cognitive training in patients with Parkinson's disease and mild cognitive impairment: long-term effects of a multicenter randomized controlled trial.

BACKGROUND: Meta-analyses indicate positive effects of cognitive training (CT) in patients with Parkinson's disease (PD), however, most previous studies had small sample sizes and did not evaluate long-term follow-up. Therefore, a multicenter randomized controlled, single-blinded trial (Train-ParC study) was conducted to examine CT effects in PD patients with mild cognitive impairment (PD-MCI). Immediately after CT, an enhancement of executive functions was demonstrated. Here, we present the long-term results 6 and 12 months after CT. METHODS: At baseline, 64 PD-MCI patients were randomized to a multidomain CT group (n = 33) or to a low-intensity physical activity training control group (PT) (n = 31). Both interventions included 90 min training sessions twice a week for 6 weeks. 54 patients completed the 6 months (CT: n = 28, PT: n = 26) and 49 patients the 12 months follow-up assessment (CT: n = 25, PT: n = 24). Primary study outcomes were memory and executive functioning composite scores. Mixed repeated measures ANOVAs, post-hoc t tests and multiple regression analyses were conducted. RESULTS: We found a significant time x group interaction effect for the memory composite score (p = 0.006, η2 = 0.214), but not for the executive composite score (p = 0.967, η2 = 0.002). Post-hoc t tests revealed significant verbal and nonverbal memory improvements from pre-intervention to 6 months, but not to 12 months follow-up assessment in the CT group. No significant predictors were found for predicting memory improvement after CT. CONCLUSIONS: This study provides Class 1 evidence that multidomain CT enhances memory functioning in PD-MCI after 6 months but not after 12 months, whereas executive functioning did not change in the long-term. CLINICAL TRIAL REGISTRATION: German Clinical Trials Register (ID: DRKS00010186), 21.3.2016 (The study registration is outlined as retrospective due to an administrative delay. The first patient was enrolled three months after the registration process was started. A formal confirmation of this process from the German Clinical Trials Register can be obtained from the authors.).

Screen Fast, Screen Faster: A Pilot Study to Screen for Depressive Symptoms Using the Beck Depression Inventory Fast Screen in Parkinson's Disease With Mild Cognitive Impairment.

Objective: Depressive symptoms have a high prevalence in patients with Parkinson's disease (PD) and are associated with cognitive dysfunction. Especially in PD with mild cognitive impairment (MCI), a time-efficient and valid instrument for the assessment of depression primarily focusing on psychological symptoms and disregarding confounding somatic symptoms is needed. We performed an examination of the psychometric properties of the Beck Depression Inventory II (BDI-II) and the Beck Depression Inventory Fast Screen (BDI-FS). Methods: The sample consisted of 64 patients [22 females and 42 males, mean age: 67.27 years (SD = 7.32)]. Depressive symptoms were measured in a cohort of PD patients with MCI. For the BDI-II and BDI-FS the psychometric concepts of internal consistency, convergent validity and diagnostic agreement were assessed. Results: Patients gave higher ratings on test items addressing somatic symptoms than those addressing non-somatic ones. The correlation between the absolute total scores of the BDI-II and the BDI-FS was significant (r = 0.91, p < 0.001), which indicated convergent validity. The Cronbach's alpha values indicated adequate internal consistencies for both measures (BDI-II: 0.84; BDI-FS: 0.78). There was a higher than chance level agreement of diagnoses of the two questionnaires, measured by Cohen's kappa (0.58, p < 0.001). The agreements between previous diagnosis of depression and the diagnoses of the BDI-II/BDI-FS were also significantly higher than chance level (BDI-II: 0.34, p = 0.007, BDI-FS: 0.39, p = 0.002). Additional AUC analysis across different cutoffs showed that performance of BDI-FS was better than BDI-II, supporting the observation of an equivalent or better performance of BDI-FS than BDI-II. Importantly, AUC analysis confirmed that a cutoff = 4 for BDI-FS was suitable in the considered sample of patients with PD-MCI. Discussion: In a cohort of PD-MCI, the BDI-FS demonstrates adequate psychometric properties in comparison to the BDI-II and can be used as a screening measure for assessing depression in cognitively impaired PD patients, focusing solely on psychological symptoms. Still, further research is needed to validate this instrument.

Enhancement of Executive Functions but Not Memory by Multidomain Group Cognitive Training in Patients with Parkinson's Disease and Mild Cognitive Impairment: A Multicenter Randomized Controlled Trial.

BACKGROUND: Meta-analyses have demonstrated cognitive training (CT) benefits in Parkinson's disease (PD) patients. However, the patients' cognitive status has only rarely been based on established criteria. Also, prediction analyses of CT success have only sparsely been conducted. OBJECTIVE: To determine CT effects in PD patients with mild cognitive impairment (PD-MCI) on cognitive and noncognitive outcomes compared to an active control group (CG) and to analyze CT success predictors. METHODS: Sixty-four PD-MCI patients (age: 67.61 ± 7.70; UPDRS-III: 26.58 ± 13.54; MoCA: 24.47 ± 2.78) were randomized to either a CT group or a low-intensity physical activity CG for six weeks (twice weekly, 90 minutes). Outcomes were assessed before and after training. MANOVAs with follow-up ANOVAs and multiple regression analyses were computed. RESULTS: Both interventions were highly feasible (participation, motivation, and evaluation); the overall dropout rate was 4.7%. Time × group interaction effects favoring CT were observed for phonemic fluency as a specific executive test (p=0.018, η p 2=0.092) and a statistical trend for overall executive functions (p=0.095, η p 2=0.132). A statistical trend for a time × group interaction effect favoring CG was shown for the digit span backward as a working memory test (p=0.098, η p 2=0.043). Regression analyses revealed cognitive baseline levels, education, levodopa equivalent daily dose, motor scores, and ApoE status as significant predictors for CT success. CONCLUSIONS: CT is a safe and feasible therapy option in PD-MCI, yielding executive functions improvement. Data indicate that vulnerable individuals may show the largest cognitive gains. Longitudinal studies are required to determine whether CT may also attenuate cognitive decline in the long term. This trial is registered with DRKS00010186.

Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease With Early Motor Complications.

BACKGROUND: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. OBJECTIVE: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial). METHODS: One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions. RESULTS: Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions. CONCLUSIONS: Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. © 2019 International Parkinson and Movement Disorder Society.

Beyond Emotions: Oscillations of the Amygdala and Their Implications for Electrical Neuromodulation.

The amygdala is a structure involved in emotions, fear, learning and memory and is highly interconnected with other brain regions, for example the motor cortex and the basal ganglia that are often targets of treatments involving electrical stimulation. Deep brain stimulation of the basal ganglia is successfully used to treat movement disorders, but can carry along non-motor side effects. The origin of these non-motor side effects is not fully understood yet, but might be altered oscillatory communication between specific motor areas and the amygdala. Oscillations in various frequency bands have been detected in the amygdala during cognitive and emotional tasks, which can couple with oscillations in cortical regions or the hippocampus. However, data on oscillatory coupling between the amygdala and motor areas are still lacking. This review provides a summary of oscillation frequencies measured in the amygdala and their possible functional relevance in different species, followed by evidence for connectivity between the amygdala and motor areas, such as the basal ganglia and the motor cortex. We hypothesize that the amygdala could communicate with motor areas through coherence of low frequency bands in the theta-alpha range. Furthermore, we discuss a potential role of the amygdala in therapeutic approaches based on electrical stimulation.

An update on best practice of deep brain stimulation in Parkinson's disease.

During the last 30 years, deep brain stimulation (DBS) has evolved into the clinical standard of care as a highly effective treatment for advanced Parkinson's disease. Careful patient selection, an individualized anatomical target localization and meticulous evaluation of stimulation parameters for chronic DBS are crucial requirements to achieve optimal results. Current hardware-related advances allow for a more focused, individualized stimulation and hence may help to achieve optimal clinical results. However, current advances also increase the degrees of freedom for DBS programming and therefore challenge the skills of healthcare providers. This review gives an overview of the clinical effects of DBS, the criteria for patient, target, and device selection, and finally, offers strategies for a structured programming approach.

Longitudinal Recordings Reveal Transient Increase of Alpha/Low-Beta Power in the Subthalamic Nucleus Associated With the Onset of Parkinsonian Rest Tremor.

Functional magnetic resonance imaging studies suggest that different subcortico-cortical circuits control different aspects of Parkinsonian rest tremor. The basal ganglia were proposed to drive tremor onset, and the cerebellum was suggested to be responsible for tremor maintenance ("dimmer-switch" hypothesis). Although several electrophysiological correlates of tremor have been described, it is currently unclear whether any of these is specific to tremor onset or maintenance. In this study, we present data from a single patient measured repeatedly within 2 years after implantation of a deep brain stimulation (DBS) system capable of recording brain activity from the target. Local field potentials (LFPs) from the subthalamic nucleus and the scalp electroencephalogram were recorded 1 week, 3 months, 6 months, 1 year, and 2 years after surgery. Importantly, the patient suffered from severe rest tremor of the lower limbs, which could be interrupted voluntarily by repositioning the feet. This provided the unique opportunity to record many tremor onsets in succession. We found that tremor onset and tremor maintenance were characterized by distinct modulations of subthalamic oscillations. Alpha/low-beta power increased transiently immediately after tremor onset. In contrast, beta power was continuously suppressed during tremor maintenance. Tremor maintenance was additionally associated with subthalamic and cortical power increases around individual tremor frequency. To our knowledge, this is the first evidence of distinct subthalamic LFP modulations in tremor onset and tremor maintenance. Our observations suggest the existence of an acceleration signal for Parkinsonian rest tremor in the basal ganglia, in line with the "dimmer-switch" hypothesis.