Effect of Transcranial Magnetic Stimulation on Cognition and Neural Changes in Parkinson's Disease (PD-MCI-TMS)

Effect of Excitatory Theta-Burst Transcranial Magnetic Stimulation on Cognition in Patients With Both Parkinson's Disease and Mild Cognitive Impairment and Analysis of Functional and Structural Brain Changes After Stimulation

Montreal Neurological Institute and Hospital, McGill University, Canadian Institutes of Health Research (CIHR)

Parkinson's disease (PD) affects more than 100,000 Canadians and results in symptoms affecting both motor and cognitive (thinking and memory) functions. Parkinson's disease with Mild Cognitive Impairment (MCI) frequently results in development of dementia for which few treatment options exist. Transcranial Magnetic Stimulation (TMS) is used to alter activity in the outer regions of the brain and has been shown in previous studies to increase cognitive performance in patients with different disorders. This study will investigate the effectiveness of TMS as a clinical treatment for the cognitive deficits associated with Parkinson's disease. 64 male and female participants between the ages of 50 and 90 will attend eight study visits over a period of 63 to 66 days. This study is a double-blind randomized clinical trial meaning the participant will be assigned by chance to either the TMS-treatment group or the Sham-treatment group. Additionally, a combination of memory and thinking tests and Magnetic Resonance Imaging (MRI) will be used to see if there are structural and functional changes within the brain. Genotyping and blood analysis before and after treatment for different biomarkers will also be performed and these data will be compared to the TMS data. Initially, this research will increase knowledge about the effects of TMS on various brain regions. Ultimately, we will be able to determine if TMS can be used as a complementary therapy for PD to improve cognitive performance and to reduce progression into dementia.

Visit 1: Informed Consent Neuropsychological Battery Visit 2: (1-2 days later) Blood Draw Neuropsychiatric Assessment Questionnaires Companion Questionnaire to take home UPDRS Visit 3: (up to a week after visit 2) MRI Scan while performing Executive Task Visit 4: (1-3 days after visit 3) TMS- or Sham-Treatment (two sessions , 20 min each, 1 hour apart) Visit 5: (2-3 days after visit 4) Same as Visit 4 Visit 6: (2-3 days after visit 5) Same as Visit 4 Visit 7: (1 day after visit 6) Neuropsychological Battery UPDRS Visit 8: (1 day after visit 7) MRI Scan while performing Executive Task Blood Draw Visit 9: (1 month after visit 6) Neuropsychological Battery UPDRS

The participant and investigator do not know what treatment is applied (TMS stimulation or Sham-TMS stimulation with a different coil). The outcomes assessor will also be blinded.

Changes in one or more of the five assessed brain domains at baseline and one day after stimulation will be measured by comparing the scores for the different neuropsychological tests. The same neuropsychological assessment one month after TMS stimulation will show, if possible changes from one day after are longer lasting and can still be seen.

Change in structural grey and white matter in the brain at baseline compared to after TMS stimulation

MRI analysis will measure any changes in cortical thickness (mm) or other structural changes in the brain after TMS or Sham-TMS stimulation

The executive task, Wisconsin Card Sorting Task, will be performed in the scanner to measure the level of activation in the basal ganglia and the prefrontal cortex via BOLD functional MRI sequence to see changes after TMS stimulation compared to baseline.

Change in levels of biomarkers of interest (alpha-synuclein and BDNF) in serum after TMS stimulation compared to baseline.

Measure the concentration of alpha-synuclein and BDNF in serum at baseline and after TMS stimulation with the Meso Scale Discovery method. These assays are highly developed ELISA assays using electrochemiluminescence.

Analyze DNA for following genes: COMT, DAT1, MAPT, ApoE, GBA, CHCRA4, SNCA, BDNF These genes of interest will be correlated to changes in the neuropsychological assessments.

Inclusion Criteria: Diagnosis of idiopathic Parkinson's disease any stage Mild Cognitive Behaviour confirmed through neuropsychological assessment MRI Compatibility Exclusion Criteria: Alcohol-dependency Severe psychiatric disorder, neurological disorder, epilepsy or stroke General anaesthesia in the past six months History of cerebrovascular disorders Colour-blindness

Lang S, Gan LS, Yoon EJ, Hanganu A, Kibreab M, Cheetham J, Hammer T, Kathol I, Sarna J, Martino D, Monchi O. Theta-Burst Stimulation for Cognitive Enhancement in Parkinson's Disease With Mild Cognitive Impairment: A Randomized, Double-Blind, Sham-Controlled Trial. Front Neurol. 2020 Dec 21;11:584374. doi: 10.3389/fneur.2020.584374. eCollection 2020.