Targeting thalamic circuits rescues motor and mood deficits in PD mice.

Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PF→CPu and PF→STN circuits are critical for locomotion and motor learning, respectively, inhibition of the PF→NAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PF→STN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

Undermatching Is a Consequence of Policy Compression.

The matching law describes the tendency of agents to match the ratio of choices allocated to the ratio of rewards received when choosing among multiple options (Herrnstein, 1961). Perfect matching, however, is infrequently observed. Instead, agents tend to undermatch or bias choices toward the poorer option. Overmatching, or the tendency to bias choices toward the richer option, is rarely observed. Despite the ubiquity of undermatching, it has received an inadequate normative justification. Here, we assume agents not only seek to maximize reward, but also seek to minimize cognitive cost, which we formalize as policy complexity (the mutual information between actions and states of the environment). Policy complexity measures the extent to which the policy of an agent is state dependent. Our theory states that capacity-constrained agents (i.e., agents that must compress their policies to reduce complexity) can only undermatch or perfectly match, but not overmatch, consistent with the empirical evidence. Moreover, using mouse behavioral data (male), we validate a novel prediction about which task conditions exaggerate undermatching. Finally, in patients with Parkinson's disease (male and female), we argue that a reduction in undermatching with higher dopamine levels is consistent with an increased policy complexity.SIGNIFICANCE STATEMENT The matching law describes the tendency of agents to match the ratio of choices allocated to different options to the ratio of reward received. For example, if option a yields twice as much reward as option b, matching states that agents will choose option a twice as much. However, agents typically undermatch: they choose the poorer option more frequently than expected. Here, we assume that agents seek to simultaneously maximize reward and minimize the complexity of their action policies. We show that this theory explains when and why undermatching occurs. Neurally, we show that policy complexity, and by extension undermatching, is controlled by tonic dopamine, consistent with other evidence that dopamine plays an important role in cognitive resource allocation.

Dopamine dysregulation in Parkinson's disease flattens the pleasurable urge to move to musical rhythms.

The pleasurable urge to move to music (PLUMM) activates motor and reward areas of the brain and is thought to be driven by predictive processes. Dopamine in motor and limbic networks is implicated in beat-based timing and music-induced pleasure, suggesting a central role of basal ganglia (BG) dopaminergic systems in PLUMM. This study tested this hypothesis by comparing PLUMM in participants with Parkinson's disease (PD), age-matched controls, and young controls. Participants listened to musical sequences with varying rhythmic and harmonic complexity (low, medium and high), and rated their experienced pleasure and urge to move to the rhythm. In line with previous results, healthy younger participants showed an inverted U-shaped relationship between rhythmic complexity and ratings, with preference for medium complexity rhythms, while age-matched controls showed a similar, but weaker, inverted U-shaped response. Conversely, PD showed a significantly flattened response for both the urge to move and pleasure. Crucially, this flattened response could not be attributed to differences in rhythm discrimination and did not reflect an overall decrease in ratings. For harmonic complexity, PD showed a negative linear pattern for both the urge to move and pleasure while healthy age-matched controls showed the same pattern for pleasure and an inverted U for the urge to move. This contrasts with the pattern observed in young healthy controls in previous studies, suggesting that both healthy aging and PD also influence affective responses to harmonic complexity. Together, these results support the role of dopamine within cortico-striatal circuits in the predictive processes that form the link between the perceptual processing of rhythmic patterns and the affective and motor responses to rhythmic music.

Trial of Pimavanserin in Dementia-Related Psychosis.

BACKGROUND: Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT2A inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis. RESULTS: Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin. CONCLUSIONS: In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.).

Theory of mind in mild cognitive impairment and Parkinson's disease: The role of memory impairment.

BACKGROUND: Social cognition is impaired in Parkinson's disease (PD). Whether social cognitive impairment (iSC) is a by-product of the underlying cognitive deficits in PD or a process independent of cognitive status is unknown. To this end, the present study was designed to investigate the weight of specific cognitive deficits in social cognition, considering different mild cognitive impairment subtypes of PD (PD-MCI). METHODS: Fifty-eight PD patients underwent a neuropsychological battery assessing executive functions, memory, language, and visuospatial domains, together with social cognitive tests focused on theory of mind (ToM). Patients were divided into subgroups according to their clinical cognitive status: amnestic PD-MCI (PD-aMCI, n = 18), non-amnestic PD-MCI (PD-naMCI, n = 16), and cognitively unimpaired (PD-CU, n = 24). Composite scores for cognitive and social domains were computed to perform mediation analyses. RESULTS: Memory and language impairments mediated the effect of executive functioning in social cognitive deficits in PD patients. Dividing by MCI subgroups, iSC occurred more frequently in PD-aMCI (77.8%) than in PD-naMCI (18.8%) and PD-CU (8.3%). Moreover, PD-aMCI performed worse than PD-CU in all social cognitive measures, whereas PD-naMCI performed worse than PD-CU in only one subtype of the affective and cognitive ToM tests. CONCLUSIONS: Our findings suggest that ToM impairment in PD can be explained by memory dysfunction that mediates executive control. ToM downsides in the amnesic forms of PD-MCI may suggest that subtle changes in social cognition could partly explain future transitions into dementia. Hence, the evaluation of social cognition in PD is critical to characterize a possible behavioral marker of cognitive decline.

Cognitive and psychiatric outcomes in the GALAXY trial: effect of anaesthesia in deep brain stimulation.

BACKGROUND: This study aims: (1) To compare cognitive and psychiatric outcomes after bilateral awake versus asleep subthalamic nucleus (STN) deep brain stimulation (DBS) surgery for Parkinson's disease (PD). (2) To explore the occurrence of psychiatric diagnoses, cognitive impairment and quality of life after surgery in our whole sample. (3) To validate whether we can predict postoperative cognitive decline. METHODS: 110 patients with PD were randomised to receive awake (n=56) or asleep (n=54) STN DBS surgery. At baseline and 6-month follow-up, all patients underwent standardised assessments testing several cognitive domains, psychiatric symptoms and quality of life. RESULTS: There were no differences on neuropsychological composite scores and psychiatric symptoms between the groups, but we found small differences on individual tests and cognitive domains. The asleep group performed better on the Rey Auditory Verbal Learning Test delayed memory test (f=4.2, p=0.04), while the awake group improved on the Rivermead Behavioural Memory Test delayed memory test. (f=4.4, p=0.04). The Stroop III score was worse for the awake group (f=5.5, p=0.02). Worse scores were present for Stroop I (Stroop word card) (f=6.3, p=0.01), Stroop II (Stroop color card) (f=46.4, p<0.001), Stroop III (Stroop color-word card) (f=10.8, p=0.001) and Trailmaking B/A (f=4.5, p=0.04). Improvements were seen on quality of life: Parkinson's Disease Questionnaire-39 (f=24.8, p<0.001), and psychiatric scales: Hamilton Depression Rating Scale (f=6.2, p=0.01), and Hamilton Anxiety Rating Scale (f=5.5, p=0.02). CONCLUSIONS: This study suggests that the choice between awake and asleep STN DBS does not affect cognitive, mood and behavioural adverse effects, despite a minor difference in memory. STN DBS has a beneficial effect on quality of life, mood and anxiety symptoms. TRIAL REGISTRATION NUMBER: NTR5809.

Cognitive and executive impairments in Parkinson's disease psychosis: a Bayesian meta-analysis.

BACKGROUND: Cognitive and executive deficits lead to worsening of quality of life and are a risk factor for developing dementia in people with Parkinson's disease (PD) with psychosis (PDP). However, which key cognitive domains are differentially affected in PDP compared with those without (PDnP), remains unclear. Here, we examined this using a Bayesian meta-analytical approach. METHODS: Searches were conducted on PubMed, Web of Science, SCOPUS, Medline and PsycINFO. Hedges' g effect-size estimates were extracted from eligible studies as a measure of standard mean differences between PDP and PDnP participants. Meta-analyses were conducted separately for each cognitive domain and subdomain, we examined the effect of age, PD medications, PD duration and severity, depression and psychosis severity for all major domains with meta-regressions. RESULTS: Effect-size estimates suggest worse performance on all major domains (k=105 studies) in PDP compared with PDnP participants, with global cognition (k=103 studies, g=-0.57), processing speed (k=29 studies, g=-0.58), executive functions (k=33, g=-0.56), episodic memory (k=30 studies, g=-0.58) and perception (k=34 studies, g=-0.55) as the most likely affected domains. Age, depression and PD duration had moderating effects on task-related performance across most of the major nine domains. CONCLUSIONS: We report extensive deficits across nine domains as well as subdomains in PD psychosis, with global cognition, processing speed and executive functions as the most likely impaired. The presence of depression may influence task-related performance in PDP, alongside age and PD duration, but not dose of dopamine replacement treatments.

Bodily Maps of Symptoms and Emotions in Parkinson's Disease.

BACKGROUND: Emotions are reflected in bodily sensations, and these reflections are abnormal in psychiatric conditions. However, emotion-related bodily sensations have not been studied in neurological disorders. OBJECTIVE: The aim of this study was to investigate whether Parkinson's disease (PD) is associated with altered bodily representations of emotions. METHODS: Symptoms and emotion-related sensations were investigated in 380 patients with PD and 79 control subjects, using a topographical self-report method, termed body sensation mapping. The bodily mapping data were analyzed with pixelwise generalized linear models and principal component analyses. RESULTS: Bodily maps of symptoms showed characteristic patterns of PD motor symptom distributions. Compared with control subjects, PD patients showed decreased parasternal sensation of anger, and longer PD symptom duration was associated with increased abdominal sensation of anger (PFWE < 0.05). The PD-related sensation patterns were abnormal across all basic emotions (P < 0.05). CONCLUSIONS: The results demonstrate altered bodily maps of emotions in PD, providing novel insight into the nonmotor effects of PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Subjective Cognitive Complaints in Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Subjective cognitive complaints (SCCs) in Parkinson's disease (PD) are reported frequently, but their prevalence and association with changes on objective testing are not fully known. OBJECTIVE: We aimed to determine the prevalence, clinical correlates, and predictive value of SCCs in PD. METHODS: We conducted a systematic review and meta-analysis. From 204 abstracts, we selected 31 studies (n = 3441 patients), and from these, identified the prevalence, clinical features, associations with neuropsychiatric symptoms, and predictive values of SCCs in PD. RESULTS: The meta-analysis showed an SCC prevalence of 36%. This prevalence, however, was significantly moderated by study heterogeneity regarding female sex, disease severity, levodopa equivalent daily dosage, exclusion from the overall sample of patients with objective cognitive impairment, and measurement instrument. SCC prevalence did not differ between de novo and treated PD patients. SCCs were weakly and negligibly associated with cognitive changes on objective testing in cross-sectional studies. However, in cognitively healthy patients, SCCs had a risk ratio of 2.71 for later cognitive decline over a mean follow-up of 3.16 years. Moreover, SCCs were moderately related to co-occurring symptoms of depression, anxiety, or apathy and were more strongly related to these neuropsychiatric symptoms than objective cognitive functioning. CONCLUSION: Our analyses suggest that SCCs in patients with and without objective cognitive impairment are frequent, occurring in more than one third of PD patients. Establishing uniform measurement instruments for identifying PD-related SCCs is critical to understand their implications. Even in cases lacking evidence of objective cognitive impairment and where SCCs might reflect underlying neuropsychiatric symptoms, the possibility of later cognitive deterioration should not be excluded. Therefore, SCCs in PD patients warrant close monitoring for opportunities for targeted and effective interventions. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association between Subjective Cognitive Complaints and Incident Functional Impairment in Parkinson's Disease.

BACKGROUND: Early identification of subjective cognitive complaints (SCC) in Parkinson's disease (PD) may improve patient care if it predicts cognition-related functional impairment (CFI). OBJECTIVES: The aim was to determine the cross-sectional and longitudinal association between SCC and CFI in PD. METHODS: Data were obtained from Fox Insight, an online longitudinal study that collects PD patient-reported outcomes. Participants completed a PD Patient Report of Problems that asked participants for their five most bothersome disease problems. SCCs were placed into eight categories through human-in-the-loop curation and classification. CFI had a Penn Parkinson's Daily Activities Questionnaire (PDAQ-15) score ≤49. Cox proportional hazards models and Kaplan-Meier survival analyses determined if baseline SCC was associated with incident CFI. RESULTS: The PD-PROP cohort (N = 21,160) was 55.8% male, mean age was 65.9 years, and PD duration was 4.8 years. At baseline, 31.9% (N = 6750) of participants reported one or more SCCs among their five most bothersome problems, including memory (13.2%), language/word finding (12.5%), and concentration/attention (9.6%). CFI occurred in 34.7% (N = 7332) of participants. At baseline, SCC was associated with CFI (P-value <0.001). SCC at baseline was associated with incident CFI (hazard ratio [HR] = 1.58 [95% confidence interval: 1.45, 1.72], P-value <0.001), as did cognitive impairment not otherwise specified (HR = 2.31), executive abilities (HR = 1.97), memory (HR = 1.85), and cognitive slowing (HR = 1.77) (P-values <0.001). Kaplan-Meier curves showed that by year 3 an estimated 45% of participants with any SCC at baseline developed new-onset CFI. CONCLUSIONS: Self-reported bothersome cognitive complaints are associated with new-onset CFI in PD. Remote electronic assessment can facilitate widespread use of patient self-report at population scale. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The effects of rivastigmine on neuropsychiatric symptoms in the early stages of Parkinson's disease: A systematic review.

BACKGROUND AND PURPOSE: Neuropsychiatric symptoms including depression, apathy and psychosis occur frequently in patients with Parkinson's disease. A subgroup of patients develop cognitive impairment, which may increase the risk of falls due to reduced attention. The acetylcholinesterase inhibitor rivastigmine is beneficial in Parkinson's disease dementia, but whether the use of rivastigmine is effective earlier in the disease course is unclear. The aim of this systematic review was to assess the evidence for rivastigmine in the treatment of neuropsychiatric symptoms in Parkinson's disease without dementia. METHODS: Embase, Medline, PsychINFO, Cochrane CENTRAL, NGLC, National Institute for Health and Care Excellence Evidence and medRxiv.org were searched for studies with terms relating to population (Parkinson's disease) and intervention (rivastigmine). Of 1922 references identified, 358 were duplications. Following title and abstract review, 1331 articles were excluded. After full-text review, nine articles remained. RESULTS: Outcomes were heterogenous, therefore, the results are presented in narrative form. The articles included six randomized controlled trials, two open-label trials and one case series. Outcome measures included: time to develop psychosis; frequency of rapid eye movement sleep behaviour disorder (RBD) episodes; apathy; gait variability; falls; cognitive ability; Neuropsychiatric Inventory score; and regional spontaneous brain activity. CONCLUSIONS: There is evidence that rivastigmine is beneficial for RBD and apathy in Parkinson's disease patients without dementia. There is high level evidence that rivastigmine reduces falls, which may be due to improved attention. The impact of rivastigmine on psychotic symptoms is less clear, but is supported by current theoretical models which involve acetylcholine dysfunction in the generation of visual hallucinations in Parkinson's disease.

Compassionate mind training for people with Parkinson's disease: A pilot study and predictors of response.

INTRODUCTION: People with Parkinson's disease (PD) often present with disabling neuropsychiatric symptoms. Compassionate mind training (CMT) is a psychological approach effective in reducing stress and promoting psychological well-being. Heart rate variability (HRV), a measure reflecting sympathovagal balance, has been associated with psychological well-being and a compassionate attitude. AIM: To assess the feasibility and effectiveness of CMT in enhancing the quality of life and psychological well-being in PD patients. Additionally, we evaluated HRV as a physiomarker for assessing the CMT outcomes. METHODS: Twenty-four PD patients participated in the study. A 6-week online CMT intervention was delivered on a weekly basis. At baseline and post-intervention patients completed questionnaires assessing depression, anxiety and quality of life. In a subsample of 11 patients, HRV was measured at baseline and post-intervention in three conditions: at rest, during stress and after 3 min of deep breathing. RESULTS: The attendance rate was 94.3%. Quality of life and perceived stigma improved post-intervention as compared with baseline (p = 0.02 and p = 0.03 for PD Questionnaire-39 total score and Stigma subscore, respectively). After CMT, patients presented better physiological regulation to stress, as measured by higher HRV as compared with baseline (p = 0.005). Notably, patients who were more resilient to stress at baseline (less decrease in HRV during stress) experienced a more substantial reduction in anxiety and depression following CMT. CONCLUSIONS: CMT is feasible and can improve quality of life and stigma in PD patients. HRV emerges as a promising physiomarker for predicting and measuring the outcomes of psychological interventions in PD.

Effects of facial biofeedback on hypomimia, emotion recognition, and affect in Parkinson's disease.

OBJECTIVES: Facial expressions are a core component of emotions and nonverbal social communication. Therefore, hypomimia as secondary symptom of Parkinson's disease (PD) has adverse effects like social impairment, stigmatization, under-diagnosis and under-treatment of depression, and a generally lower quality of life. Beside unspecific dopaminergic treatment, specific treatment options for hypomimia in PD are rarely investigated. This quasi-randomized controlled trial evaluated the short-term effects of facial electromyogram (EMG) based biofeedback to enhance facial expression and emotion recognition as nonverbal social communication skills in PD patients. Furthermore effects on affect are examined. METHOD: A sample of 34 in-patients with PD were allocated either to facial EMG-biofeedback as experimental group or non-facial exercises as control group. Facial expression during posing of emotions (measured via EMG), facial emotion recognition, and positive and negative affect were assessed before and after treatment. Stronger improvements were expected in the EMG-biofeedback in comparison to the control group. RESULTS: The facial EMG-biofeedback group showed significantly greater improvements in overall facial expression, and especially for happiness and disgust. Also, overall facial emotion recognition abilities improved significantly stronger in the experimental group. Positive affect was significantly increased in both groups with no significant differences between them, while negative affect did not change within both groups. CONCLUSIONS: The study provides promising evidence for facial EMG-biofeedback as a tool to improve facial expression and emotion recognition in PD. Embodiment theories are discussed as working mechanism.

Perception of cognitive change by individuals with Parkinson's disease or essential tremor seeking deep brain stimulation: Utility of the cognitive change index.

OBJECTIVE: The Cognitive Change Index (CCI-20) is a validated questionnaire that assesses subjective cognitive complaints (SCCs) across memory, language, and executive domains. We aimed to: (a) examine the internal consistency and construct validity of the CCI-20 in patients with movement disorders and (b) learn how the CCI-20 corresponds to objective neuropsychological and mood performance in individuals with Parkinson's disease (PD) or essential tremor (ET) seeking deep brain stimulation (DBS). METHODS: 216 participants (N = 149 PD; N = 67 ET) underwent neuropsychological evaluation and received the CCI-20. The proposed domains of the CCI-20 were examined via confirmatory (CFA) and exploratory (EFA) factor analyses. Hierarchical regressions were used to assess the relationship among subjective cognitive complaints, neuropsychological performance and mood symptoms. RESULTS: PD and ET groups were similar across neuropsychological, mood, and CCI-20 scores and were combined into one group who was well educated (m = 15.01 ± 2.92), in their mid-60's (m = 67.72 ± 9.33), predominantly male (63%), and non-Hispanic White (93.6%). Previously proposed 3-domain CCI-20 model failed to achieve adequate fit. Subsequent EFA revealed two CCI-20 factors: memory and non-memory (p < 0.001; CFI = 0.924). Regressions indicated apathy and depressive symptoms were associated with greater memory and total cognitive complaints, while poor executive function and anxiety were associated with more non-memory complaints. CONCLUSION: Two distinct dimensions were identified in the CCI-20: memory and non-memory complaints. Non-memory complaints were indicative of worse executive function, consistent with PD and ET cognitive profiles. Mood significantly contributed to all CCI-20 dimensions. Future studies should explore the utility of SCCs in predicting cognitive decline in these populations.

Exploring the lived experiences of individuals with Parkinson's disease and their relatives: insights into care provision experiences, disease management support, self-management strategies, and future needs in Germany (qualitative study).

BACKGROUND: Parkinson's disease (PD) significantly impacts the health-related quality of life of affected individuals and their relatives. In order to support the affected individuals and their families in coping with PD, it is essential to offer comprehensive information about their experiences. A comprehensive understanding of their lived experiences with the disease, the healthcare system, applied self-management strategies and their needs is considered crucial for developing a PD support program. Therefore, we aimed to explore the lived experiences and support needs of individuals with PD and their relatives in Germany. METHODS: This non-interventional, qualitative study conducted an explorative status quo and needs assessment. It generated knowledge through semi-structured focus groups and interviews with individuals with PD at various disease stages and their relatives. The interviews were digitally recorded, transcribed verbatim, and analysed using content analysis. RESULTS: Fifty-two individuals with PD and 29 relatives participated in eight focus groups and 13 paired and 13 individual interviews. Four themes with corresponding subthemes emerged: (1) experiences, revealing individuals' experiences around their diagnosis and with disease-specific care provision; (2) management support offers, clarifying who provides support and the type of support offered; (3) self-management, including comprehensibility, meaningfulness and manageability; and (4) future needs, differentiating between deficits and needs. Most participants expressed a sense of abandonment when obtaining self-management strategies and mastering their lives with PD, often referred to as 'life 2.0'. They identified the lack of structured and adequate provision of information, system orientation and social awareness. CONCLUSIONS: In Germany, there is an urgent need for a comprehensive PD care program that addresses the needs of individuals with PD and their relatives from the start of their care trajectory. It could assist individuals in gaining a comprehensive understanding of the disease, obtaining self-management strategies, building a support network, and becoming experts in self-managing their disease. Moreover, it may positively influence their care trajectory and reduce burdens, such as overburdening, fear of progression, and health anxiety. TRIAL REGISTRATION: German Clinical Studies Register ( https://www.drks.de/DRKS00030090 , No. DRKS00030090, Date of registration: 15.12.2022).

Study protocol for the MIND-PD study: a randomized controlled trial to investigate clinical and biological effects of mindfulness-based cognitive therapy in people with Parkinson's disease.

BACKGROUND: People with Parkinson's disease (PD) are very sensitive to the effects of stress. The prevalence of stress-related neuropsychiatric symptoms is high, and acute stress worsens motor symptoms. Animal studies suggest that chronic stress may accelerate disease progression, but evidence for this in humans is lacking. Mindfulness-based interventions (MBIs) train participants to focus on the present moment, on purpose and without judgement. Previous studies suggest that MBIs may alleviate stress and reduce depression and anxiety in PD. We aim to demonstrate the efficacy of Mindfulness-Based Cognitive Therapy (MBCT) as a non-pharmacologic treatment strategy for neuropsychiatric (and motor) symptoms in PD, and to identify the mechanisms underlying stress and stress reduction in PD. METHODS: In a prospective randomized controlled trial (RCT), we investigate whether 8 weeks of MBCT, as compared to care as usual, can reduce symptoms of anxiety and depression in people with PD. We aim to include 124 PD patients, who experience mild-moderate symptoms of anxiety and depression, are eligible for magnetic resonance imaging (MRI) and naïve to mindfulness, and who have a disease duration ≤ 10 years. Every participant is followed for 12 months. Clinical and biochemical assessments take place at baseline (T0), after 2 months (T1), and after 12 months (T2); MRI assessments take place at T0 and T2. Our primary outcome is the total score on the Hospital Anxiety and Depression Scale (HADS) at T1, while correcting for the HADS score at T0, age, and gender. Beyond testing the effects of MBCT on symptoms of anxiety and depression in PD, we explore whether MBCT: (1) has an effect on motor symptom severity, (2) influences cerebral and biochemical markers of stress, and (3) leads to a change in biomarkers of PD progression. DISCUSSION: MIND-PD is one of the first RCTs with a 1-year follow-up to investigate the effects of MBCT on symptoms of anxiety and depression in PD, and to explore possible mechanisms underlying stress and stress reduction in PD. Insight into these mechanisms can pave the way to new treatment methods in the future. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05779137. Registered on 12 January 2023.

Caregiver Burden in Parkinson Disease: A Scoping Review of the Literature from 2017-2022.

Caregiver burden is a term that refers to the adverse effect of caregiving on the physical, emotional, social, spiritual, and financial well-being of the caregiver. Caregiver burden is associated with providing care to an individual with a chronic illness or disability, and the unique symptoms of Parkinson disease (PD) can amplify a patient's needs and reliance on others, leading to adverse outcomes for patients and their caregivers. In this scoping review of the literature from January 2017 through April 2022 that included 114 studies, we provide an updated, evidence-based summary of patient and caregiver-related factors that contribute to caregiver burden in PD. We also describe the impact of caregiver stress and burden on caregivers based on qualitative research studies and review recent interventions to mitigate burden. By providing clinical updates for practitioners, this review is designed to improve recognition of caregiver burden in the post-pandemic era and foster the development of targeted interventions to reduce caregiver burden in PD.

Reward and Punishment Learning as Predictors of Cognitive Behavioral Therapy Response in Parkinson's Disease Comorbid with Clinical Depression.

Depression is highly comorbid among individuals with Parkinson's Disease (PD), who often experience unique challenges to accessing and benefitting from empirically supported interventions like Cognitive Behavioral Therapy (CBT). Given the role of reward processing in both depression and PD, this study analyzed a subset (N = 25) of participants who participated in a pilot telemedicine intervention of PD-informed CBT, and also completed a Reward- and Punishment-Learning Task (RPLT) at baseline. At the conclusion of CBT, participants were categorized into treatment responders (n = 14) and non-responders (n = 11). Responders learned more optimally from negative rather than positive feedback on the RPLT, while this pattern was reversed in non-responders. Computational modeling suggested group differences in learning rate to negative feedback may drive the observed differences. Overall, the results suggest that a within-subject bias for punishment-based learning might help to predict response to CBT intervention for depression in those with PD.Plain Language Summary Performance on a Computerized Task may predict which Parkinson's Disease Patients benefit from Cognitive Behavioral Treatment of Clinical DepressionWhy was the study done? Clinical depression regularly arises in individuals with Parkinson's Disease (PD) due to the neurobiological changes with the onset and progression of the disease as well as the unique psychosocial difficulties associated with living with a chronic condition. Nonetheless, psychiatric disorders among individuals with PD are often underdiagnosed and likewise undertreated for a variety of reasons. The results of our study have implications about how to improve the accuracy and specificity of mental health treatment recommendations in the future to maximize benefits for individuals with PD, who often face additional barriers to accessing quality mental health treatment.What did the researchers do? We explored whether performance on a computerized task called the Reward- and Punishment-Learning Task (RPLT) helped to predict response to Cognitive Behavioral Therapy (CBT) for depression better than other predictors identified in previous studies. Twenty-five individuals with PD and clinical depression that completed a 10-week telehealth CBT program were assessed for: Demographics (Age, gender, etc.); Clinical information (PD duration, mental health diagnoses, levels of anxiety/depression, etc.); Neurocognitive performance (Memory, processing speed, impulse control, etc.); and RPLT performance.What did the researchers find? A total of 14 participants significantly benefitted from CBT treatment while 11 did not significantly benefit from treatment.There were no differences before treatment in the demographics, clinical information, and neurocognitive performance of those participants who ended up benefitting from the treatment versus those who did not.There were, however, differences before treatment in RPLT performance so that those individuals that benefitted from CBT seemed to learn better from negative feedback.What do the findings mean? Our results suggest that the CBT program benefitted those PD patients with clinical depression that seemed to overall learn best from avoiding punishment rather than obtaining reward which was targeted in CBT by focusing on increasing engagement in rewarding activities. The Reward- and Punishment-Learning Task hence may be a useful tool to help predict treatment response and provide more individualized recommendations on how to best maximize the benefits of psychotherapy for individuals with PD that may struggle to connect to mental health care. Caution is recommended about interpretating these results beyond this study as the overall number of participants was small and the data for this study were collected as part of a previous study so there was no opportunity to include additional measurements of interest.

The lateralized effects of Parkinson's Disease on motor imagery: Evidence from mental chronometry.

Alterations to the content of action representations may contribute to the movement challenges that characterize Parkinson's Disease (PD). One way to investigate action representations is through motor imagery. As PD motor symptoms typically have a unilateral onset, disease-related deficits related to action representations may follow a similarly lateralized pattern. The present study examined if temporal accuracy of motor imagery in individuals with PD differed according to the side of the body involved in the task. Thirty-eight participants with PD completed a mental chronometry task using their more affected and less affected side. Participants had significantly shorter mental versus physical movement times for the more affected. Higher imagery vividness in the kinaesthetic domain predicted shorter mental versus physical movement times for the more affected side, as did lower imagery vividness in the visual domain and poorer cognitive function. These results indicate that people with PD imagine movements differently when the target actions their more affected versus less affected side. It is additionally possible that side-specific deficits in the accurate processing of kinaesthetic information lead to an increased reliance on visual processes and cognitive resources to successfully execute motor imagery involving the more affected side.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.