Consolidation of Motor Learning of Writing Skills and Its Related Brain Activity Changes in Parkinson's Disease

The basal ganglia play an important role in motor learning, especially during the consolidation phase of motor learning. This raises the question whether it is possible to sustain learning increments in a neurodegenerative condition such as Parkinson's disease (PD). The aim of this study is to gain knowledge on whether it is possible to relearn skills which are actually affected by PD, such as writing, and determine whether neuroplasticity is possible. In this randomized controlled study, PD patients will either follow intensive writing training or a placebo treatment (stretch and relaxation training) during 6 weeks. The writing training will focus on automatization (withstanding dual task interference), transfer to an untrained task and retention. The placebo program is aimed to reduce stiffness in the upper limbs and has been shown to be ineffective in PD. To date, it is unknown how neural networks change as a result of consolidation after a prolonged period of motor learning in PD. Therefore the second arm of this study will investigate, for the first time, changes in neural connectivity using brain imaging data to elucidate which neuroanatomical regions are involved in consolidation of learning in PD. Finally, DTI and resting state fMRI-analysis will complement insights into the neural changes as a result of learning.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Behavioral: Writing program; Behavioral: Stretch & Relaxation program

Detailed Description

This translational study is a monocentric Randomized Controlled Trial (RCT). The investigators will recruit 40 PD patients from the early Hoehn & Yahr stages. Patients will be randomly allocated to an experimental group (writing training) and a control group (stretch- and relaxation training). All patients will receive the same frequency and duration of intervention. After the training period, patients will be followed up for another 6 weeks. Patients will be tested in the ON-phase of the medication cycle at 3 occasions: before (T1) and after training (T2) and after a 6-week retention period (T3). At T1 & T2 participants will be tested at the behavioral & neural level. At T3 participants will only be tested at the behavioral level.

Motor performance will be measured using MRI-compatible touch sensitive tablets and pencils. This system allows registration and translation of writing movements into online-cursor movements on screen in and outside a scanner environment. Both patient groups will be compared during a behavioral test battery consisting of (i) a trained sequence with and without visual cues; (ii) an untrained sequence with and without visual cues to test transfer; and (iii) a trained dual task to test automatization. Visual cues will consist of differently colored target zones of different band widths, indicating the scale and accuracy of writing.

Functional MRI measurements will take place in a 3T MR Philips Intera scanner. Before scanning, subjects will undergo a training session in a dummy scanner to familiarize them with the scanner environment and task instructions. During the fMRI sessions, participants will perform a trained and untrained sequence, both with and without visual cues. To control for differences in movement speed, all participants will perform the tasks at the same frequency, defined by an auditory pace. In addition to the fMRI measurements, resting state fMRI and DTI will also be performed to reveal alterations of the structural and functional connectivity between critical regions.

Behavioral data will be recorded as xy-coordinates and pressure values at a sampling rate of 200Hz and with a spatial resolution of 32.5µm. Statistical analysis of the behavioral data will have a between-subject factor of group (experimental and placebo group) and a within-subject factor of time (before training, after training and after the retention period).

Image analysis will be performed with Statistical Parametric Mapping (SPM) software. The investigators will contrast for either decreased or increased activation, as different regions may show divergent changes related to learning and transfer, with group as a between-subject factor and time (before and after training) and task condition (trained with cues, trained without cues, untrained with cues and untrained without cues) as within-subject factors.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3001
    • Department of Rehabilitation Sciences KU Leuven

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of PD based on the UK Brain Bank criteria
• Hoehn & Yahr stage I (with impairments on the right side) and II in the on-phase
• Without cognitive impairment (MMSE >24)
• On stable medication
• Right handed

Exclusion Criteria:

• Deep Brain Stimulator
• Other contra-indications for MR scanning
• Colorblind

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Writing program; The program will train participants in maintaining writing amplitude, writing speed, writing fluently and automatization of writing.	Behavioral: Writing program; 6 weeks of at-home training (5days/week, 30minutes/day) using both pen-and-paper exercises and exercises on a writing tablet.
Placebo Comparator: Stretch & Relaxation program; The program will learn participants to alleviate tension in the upper limbs and will consist of exercises performed while lying down or sitting.	Behavioral: Stretch & Relaxation program; 6 weeks of at-home training (5days/week, 30minutes/day) using a DVD with exercises.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in writing amplitude (cm) on tablet after 6 weeks of training	Analysis based on measurement of XYZ coordinates, measured at a spatial resolution of 32.5 μm.	6 weeks
Change from baseline in writing amplitude (cm) on tablet after 12 weeks, including 6 weeks without training	Analysis based on measurement of XYZ coordinates, measured at a spatial resolution of 32.5 μm.	12 weeks
Change from baseline in brain activity during writing (functional MRI) after 6 weeks of training	Analysis of the change in Blood Oxygen Level Dependent (BOLD) response	6 weeks
Change from baseline in brain activity during rest (resting state MRI) after 6 weeks of training	Analysis of the change in Blood Oxygen Level Dependent (BOLD) response	6 weeks
Change from baseline in Diffusion Tensor Imaging after 6 weeks of training	Analysis of the change in Blood Oxygen Level Dependent (BOLD) response	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transfer of change in writing amplitude to an untrained writing sequence after 6 weeks of training	Analysis based on measurement of XYZ coordinates, measured at a spatial resolution of 32.5 μm.	6 weeks
Transfer of change in writing amplitude to an untrained writing sequence after 12 weeks, including 6 weeks without training	Analysis based on measurement of XYZ coordinates, measured at a spatial resolution of 32.5 μm.	12 weeks
Change from baseline in dual task effect (DTE) for writing amplitude after 6 weeks of training	Analysis of the DTE using the following formula: DTE= ((dual task amplitude-single task amplitude)/(single task amplitude))*100	6 weeks
Change from baseline in dual task effect (DTE) for writing amplitude after 12 weeks, including 6 weeks without training	Analysis of the DTE using the following formula: DTE= ((dual task amplitude-single task amplitude)/(single task amplitude))*100	12 weeks
Change from baseline in writing fluency (normalized jerk) on tablet after 6 weeks of training	Analysis based on measurement of XYZ coordinates, measured at a spatial resolution of 32.5 μm.	6 weeks
Change from baseline in writing fluency (normalized jerk) on tablet after 12 weeks, including 6 weeks without training	Analysis based on measurement of XYZ coordinates, measured at a spatial resolution of 32.5 μm.	12 weeks
Systematic Screening of handwriting difficulties (writing on paper) - change from baseline in quality score after 6 weeks of training	Analysis of the quality of handwriting based on different criteria (fluency in letter formation, connections between letters, regularity of letter height, space between words and straightness of the sentence).	6 weeks
Systematic Screening of handwriting difficulties (writing on paper) - change from baseline in quality score after 12 weeks, including 6 weeks without training	Analysis of the quality of handwriting based on different criteria (fluency in letter formation, connections between letters, regularity of letter height, space between words and straightness of the sentence).	12 weeks
Systematic Screening of handwriting difficulties (writing on paper) - change from baseline in writing speed after 6 weeks of training	Analysis of the number of letters written within a period of 5 minutes.	6 weeks
Systematic Screening of handwriting difficulties (writing on paper) - change from baseline in writing speed after 12 weeks, including 6 weeks without training	Analysis of the number of letters written within a period of 5 minutes.	12 weeks
Change from baseline in Purdue Pegboard test after 6 weeks of training	Analysis of the number of pegs placed within 30s.	6 weeks
Change from baseline in Purdue Pegboard test after 12 weeks, including 6 weeks without training	Analysis of the number of pegs placed within 30s.	12 weeks

Collaborators and Investigators

• Sponsor: KU Leuven
• Collaborators: Research Foundation Flanders
• Investigators: Principal Investigator: Alice Nieuwboer, Professor, KU Leuven

Publications and helpful links

General Publications

• Broeder S, Nackaerts E, Nieuwboer A, Smits-Engelsman BC, Swinnen SP, Heremans E. The effects of dual tasking on handwriting in patients with Parkinson's disease. Neuroscience. 2014 Mar 28;263:193-202. doi: 10.1016/j.neuroscience.2014.01.019. Epub 2014 Jan 19.
• Nackaerts E, Vervoort G, Heremans E, Smits-Engelsman BC, Swinnen SP, Nieuwboer A. Relearning of writing skills in Parkinson's disease: a literature review on influential factors and optimal strategies. Neurosci Biobehav Rev. 2013 Mar;37(3):349-57. doi: 10.1016/j.neubiorev.2013.01.015. Epub 2013 Jan 16.

Helpful Links

• Neuromotor Rehabilitation Research Group KU Leuven

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: November 3, 2014
• First Submitted That Met QC Criteria: November 7, 2014
• First Posted (Estimate): November 11, 2014

Study Record Updates

• Last Update Posted (Estimate): January 28, 2016
• Last Update Submitted That Met QC Criteria: January 27, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Handwriting; Motor learning
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: G.0906.11