The Effects of Mindfulness-based Cognitive Therapy in People With Parkinson's Disease

Study Overview
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Brief Summary
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Parkinson's disease (PD) is a debilitating neurodegenerative disorder occurring in 7 million patients worldwide. PD is caused by progressive loss of nigro-striatal dopamine cells, which causes motor symptoms such as slowness of movement and tremor, and non-motor symptoms such as cognitive dysfunction. Converging clinical evidence indicates that PD patients are very sensitive to the effects of psychological stress. There is a high prevalence of stressrelated neuropsychiatric symptoms in PD: 30-40% of patients experience depression and 25-30% have anxiety. Furthermore, stress worsens many motor symptoms, e.g. tremor, freezing of gait, and dyskinesia. In addition to these immediate negative effects, chronic stress may also have detrimental long-term consequences, and specifically by accelerating disease progression, as suggested by animal models. However, this hypothesis remains to be confirmed in humans. Better evidence about the impact of stress on PD would have major treatment consequences: novel stress-reducing interventions may have symptomatic effects, and perhaps also disease-modifying effects. The aim of this study is to test whether a stress-reducing intervention improves clinical symptoms, slows neurodegeneration, and/or enhances neuroplasticity in PD. In a randomized controlled trial, the investigators will compare a stress-reducing mindfulness-based intervention group (MBI; one year) to a treatment as usual (TAU) group on clinical symptoms, cerebral markers of nigro-striatal dysfunction and stressor-reactivity (MRI), and inflammatory markers (serum).

Detailed Description
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Parkinson's disease (PD) is a common and fast-growing neurological disease, clinically characterized by motor slowing (bradykinesia), stiffness (rigidity) and resting tremor. The pathological hallmark of PD is nigro-striatal dopamine depletion, but the noradrenergic (stress) system is also affected. Indeed, the prevalence of stress-related neuropsychiatric symptoms in PD is high and many PD patients suffer from reduced health-related quality of life. Also, (chronic) stress worsens many motor symptoms and may have detrimental long-term consequences by accelerating disease progression, as suggested by animal models. There is no cure for PD, and currently no treatments to slow down disease progression. Therefore, the development of new and effective treatments is crucial. Given the large role of stress on PD symptoms, stress reduction might improve motor as well as non-motor symptoms. Intriguingly, recent evidence suggests that mindfulness training, where mindfulness is the trainable capacity to experience the present moment on purpose and without judgment, is an effective way to achieve such stress reduction. In fact, the effects of mindfulness practice have gained much interest as a topic of scientific research and clinical practise recently, where Mindfulness-Based Cognitive Therapy (MBCT) is one of the most commonly applied interventions, shown to be effective for a variety of somatic and psychiatric disorders. Importantly, previous trials investigating the effect of mindfulness-based interventions (MBIs) on clinical symptoms in PD showed positive effects on depression in 6/8 trials, on anxiety in 4/7 trials and on motor symptoms in 2/3 studies. Also, a large online survey on patients' experiences with stress and mindfulness showed that on one hand, patients experienced considerably more stress than controls, and significant stress-related worsening of PD symptoms; on the other, PD mindfulness users reported positive effects of mindfulness on anxiety and depression. In summary, current evidence suggests a positive effect of MBIs on psychological distress in PD, but clinical evidence is inconclusive. Also, to date, there is no research on the (cerebral) mechanisms underlying the (positive) effects of mindfulness in PD. Insight to the cerebral mechanisms of MBIs can pave the way for developing new, mechanism-based interventions, and can help to uncover the nature of the effects of stress on Parkinson's disease. Specifically, a mechanism based approach allows us to disentangle the symptomatic (stress as an amplifying factor on motor dysfunction) as opposed to neurodegenerative (nigro-striatal cell loss) effects of stress. In this study, the investigators will test the effect of MBCT on the clinical (symptomatic) and neurodegenerative course of PD. If proven to be effective, MBCT can be applied as a new and cost-effective therapy to PD patients. The investigators will perform a randomized controlled trial with MBCT as intervention and a treatment as usual (TAU) control group. The investigators will evaluate whether a MBCT mindfulness course can lead to clinically relevant reductions in psychological distress (measured with the Hamilton Anxiety and Depression Scale) in PD patients with mild to moderate symptoms of psychological distress. Also, the investigators will evaluate the effects of a MBCT mindfulness course on other PD symptoms (e.g. motor dysfunction), cerebral markers of neurodegeneration, and neuroplasticity, and explore whether the intervention lowers systemic inflammatory tone in PD. The total duration of data acquisition per participant will be 12 months, consisting of a baseline measurement (T0), an intervention period of 2 months followed by a post-measurement (T1), and a final measurement (T2) that takes place 12 months after T0.

Official Title
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The Effect of Mindfulness-based Cognitive Therapy on Psychological Distress in People With Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Behavioral: MBCT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of idiopathic PD made by a movement disorders specialist. PD disease duration is ≤10 years, defined as time since diagnosis made by a neurologist. Mild-moderate symptoms of psychological distress (Hospital Anxiety and Depression Scale score >10 points). Subject can read and understand the Dutch language. Exclusion Criteria: Severe neurological or psychiatric co-morbidity (e.g. psychosis or suicidality). Contraindications for MRI (e.g. brain surgery in medical history, claustrophobia, an active implant, epilepsy, pregnancy, and/or metal objects in the upper body that are incompatible with MRI). Moderate to severe head tremor (to avoid artifacts caused by extensive head motion during scanning). Cognitive dysfunction (clinical diagnosis of dementia, or a score of 20 or lower on the MoCA, which will be measured at T0). Previous participation in MBSR or MBCT (>4 sessions).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mindfulness based cognitive therapy (MBCT)<br>62 patients will receive a mindfulness based intervention. | Behavioral: MBCT<br>* Patients will join a mindfulness-based cognitive therapy course at the Radboudumc Center for Mindfulness. The course consists of eight weekly sessions of 2.5-hour and one 6-hour silence day between the 6th and 7th session. The sessions include meditation exercises (body-scan, sitting meditation, gentle movement exercises, three-minute breathing space, daily activities with attention), psychoeducation and group discussion. Psychoeducation includes information on cognitive techniques, like monitoring and scheduling of events and identification of negative automatic thoughts. In addition, all participants will be encouraged to perform daily practice assignments at home for about 30-45 minutes per day, mainly consisting of meditation exercises.<br>|
| No Intervention: Treatment as usual (TAU)<br>62 patients will receive treatment as usual, this will form a (passive) control group to the MBCT group. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psychological distress post-intervention (as assessed by HADS [0-42]) | Our primary outcome will be psychological distress (anxiety and depressive symptoms), measured by the Hospital Anxiety and Depression Scale (HADS) at T1 (post-intervention). The HADS is a validated self-report questionnaire consisting of anxiety and depression subscales, scores can range from 0-42 points. Lower scores mean less stress, i.e. better outcome. It was previously used as primary outcome measure in an MBCT-RCT in cancer, it was used as outcome measure in the largest MBI-RCT to date in PD, and it has been validated in PD. The effect on HADS will all be analyzed with an analysis of covariance (ANCOVA). The dependent variable will be the HADS score at T1; group allocation will serve as fixed factors, and age at T0, sex and the HADS score at T0 will serve as covariates. | Month 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in psychological distress (as assessed by HADS [0-42]) | HADS [0-42] (lower score = better (less stress), see also primary outcome. | Month 12. Change relative to baseline. | 
| Disease severity (as assessed by MDS-UPDRS [0-199]) | MDS-UPDRS [0-199] (higher score = worse (more disability)). We will assess overall symptom severity as a function of time T0/T1/T2 and group (MBCT vs. TAU). | Month 0, month 2, month 12. | 
| Cognitive function (as assessed by MoCA [0-30]) | Montreal Cognitive Assessment; MoCA [0-30] (higher score = better (less disability)) We will test whether clinical scores change significantly between T0, T1 and T2 using mixed models. | Month 0, month 2, month 12. | 
| Tremor severity (indicated by tremor power [log(µV2)]) | We will compare tremor severity as measured with accelerometry during rest, mental arithmetic (coco), posturing and action. We will perform a 2x2x2 ANOVA with between-subjects factor GROUP (MBCT vs. control), and within-subjects factors TIME (T0 vs. T2) and CONDITION (coco vs. rest, posture vs. rest, action vs. rest). | Month 0, month 2, month 12. | 
| Hair cortisol | Hair cortisol levels will be established by means of a hair sample and hair cortisol concentration of the previous 2 months will be assessed and compared between T0/T1/T2 and between groups (MBCT/TAU) | Month 0, month 2, month 12. | 
| Bradykinesia severity (indicated by average keys per second on key tapping test) | We will measure bradykinesia severity by means of a keyboard finger tapping test. Average keys pressed per seconds will be used as dependent variable. More keys per second = less disability. We will test whether clinical scores change significantly between T0, T1 and T2 using mixed models. | Month 0, month 2, month 12. | 
| Inflammatory tone (as assessed by serum C-reactive protein) | We will be assessing inflammatory tone by means of serum C-reactie protein (CRP) levels. Higher CRP = more inflammation. | Month 0, month 2, month 12. | 
| Quality of life questionnaire (as assessed by PDQ-39 [0-100]) | Parkinson Disease Questionnaire 39; PDQ-39 [0 - 100] (higher score = worse (more disability)) We will test whether clinical scores change significantly between T0, T1 and T2 using mixed models. | Month 0, month 2, month 6, month 12. | 
| Perceived stress (as assessed by PSS [0-40]) | Perceived Stress Scale; PSS [0 - 40] (higher score = worse (more perceived stress)) We will test whether clinical scores change significantly between T0, T1 and T2 using mixed models. | Month 0, month 2, month 6, month 12. | 
| Rumination (as assessed by RRS [26-104]) | Ruminative Response Scale; RRS [26-104] (higher score = worse (more ruminative thoughts)) We will test whether clinical scores change significantly between T0, T1 and T2 using mixed models. | Month 0, month 2, month 6, month 12. | 
| Mindfulness skills (as assessed by FFMQ [39-195]) | Five Facet Mindfulness Questionnaire Short Form; FFMQ [39-195] (higher score = better (more mindfulness skills)) We will test whether clinical scores change significantly between T0, T1 and T2 using mixed models. | Month 0, month 2, month 6, month 12. | 
| Self-compassion as assessed by SCS [12-84]) | Self-Compassion Short Form; SCS [12-84] (higher score = better (more self compassion)) We will test whether clinical scores change significantly between T0, T1 and T2 using mixed models. | Month 0, month 2, month 6, month 12. | 
| Self-efficacy (as assessed by GSES [10-40]) | General Self-Efficacy Scale; GSES [10-40] (higher score = better (more self efficacy)) We will test whether clinical scores change significantly between T0, T1 and T2 using mixed models. | Month 0, month 2, month 6, month 12. | 
| Positive appraisal (as assessed by PASS) | Positive Appraisal Style Scale; PASS [for each coping style: 2-10, for humor: 1-8] We will test whether clinical scores change significantly between T0, T1 and T2 using mixed models. | Month 0, month 2, month 6, month 12. | 
| Decision making task | Patients will perform a neuropsychological task designed to track individual decision making and learning processes. Computational modeling will be used to model response patters according to an actor model and a spectator model. Response patterns will be compared as a function of group (MBCT / TAU) and time (T0 / T1/ T2). | Month 0, month 2, month 12. | 
| Salivary cortisol | Acute cortisol levels will be assessed via saliva samples during socially evaluated cold pressure test as a function of group (MBCT/TAU), time (T0/T2), and SECPT time points (pre/post/30mpost/45mpost). | Month 0, month 12. | 
| Resting state network reactivity to a stressor (fMRI) | Resting-state network connectivity will be assessed based on resting state fMRI before and after the socially evaluated cold pressure test (SECPT). In specific, this will be evaluated as a function of group (MBCT / TAU), time (T0 / T2), and SECPT (before / after). Resting state networks of interest include the salience network, central executive network, and default mode network. | Month 0, month 12. | 
| Grey matter volume of stress-related regions (MRI) | By means of a structural T1 scan, we will compare structural changes in stress-related brain regions, e.g. amygdala, hippocampus. Specifically, grey matter volume will be compared as a function of group (MBCT / TAU) and time (T0 / T2). This measure will help us distinguish between structural changes versus network adaptations as a response to the intervention. | Month 0, month 12. | 
| Structural integrity of substantia nigra and locus coeruleus (LC) | To further evaluate structural integrity of the substantia nigra and LC, signal intensity on neuromelanin sensitive MRI scans, as well as diffusion MRI will be determined before and one year after the MBI. Structural integrity will be analysed as a function of group (MBCT / TAU) and time (T0 / T2). | Month 0, month 12. | 
| Functional integrity of nigro-striatal dopamine system | To quantify the functional integrity of the nigro-striatal dopamine system, we will use resting-state fMRI to calculate gradients of cortico-striatal connectivity. This fMRI measure is sensitive to compensatory changes: in PD, cortico-striatal connectivity shifts from more-affected (posterior) to less-affected (anterior) portions of the striatum. To investigate this, functional connectivity profiles of the posterior and anterior putamen specifically will be determined and analysed as a function of group (MBCT / TAU) and time (T0 / T2). | Month 0, month 12. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Mindfulness, Mindfulness-based cognitive therapy, Disease progression