Cognitive Dysfunction In Parkinson's

NCT ID: NCT02468804

Last Updated: 2021-07-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 107 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-31
• Study Completion Date: 2016-11-30

Brief Summary

We hypothesize that reductions in gamma activity are a key mechanism underlying cognitive dysfunction in PD and that interventions to increase gamma activity will improve cognition.

Detailed Description

Parkinson's disease (PD) is the second most common neurodegenerative illness (after Alzheimer's disease) affecting 1-2% of people over age 65.3 Although PD is traditionally characterized by its motor symptoms (e.g. tremor, stiffness, slowness), research demonstrates that cognitive dysfunction has a greater impact on patient suffering and caregiver burden despite being under-recognized. Cognitive dysfunction is a significant risk factor for psychosis, dementia, nursing home placement and affects 20- 40% of PD patients even at the time of initial diagnosis.4,5 In patients with PD surviving 20 years or longer, cognitive dysfunction is the leading cause of nursing home placement and three fourths of PD patients ultimately develop dementia.6

We know that neurons in the brain communicate with each other by firing at certain frequencies. A growing literature shows that high frequency (30-50 Hz) brain activity called gamma activity is particularly important for communication between distant brain areas and is critical to normal cognition.7 Prior studies also show that gamma activity is reduced in PD.8 However, we do not know why gamma activity is reduced in PD or the relationship between changes in gamma activity and cognitive dysfunction. We hypothesize that reductions in gamma activity are a key mechanism underlying cognitive dysfunction in PD and that interventions to increase gamma activity will improve cognition.

To test this hypothesis we propose to use a novel combination of research methods including magnetoencephalography (MEG) and repetitive transcranial magnetic stimulation (rTMS). MEG measures magnetic activity over the scalp to determine brain activity. We will use MEG to determine whether reductions in gamma activity are related to cognitive dysfunction in PD. TMS uses a magnetic coil placed over the scalp to stimulate brain activity. While there is evidence that repetitive TMS (transcranial magnetic stimulation) increases gamma activity and may improve cognition, it has not been studied for this purpose in PD. We will apply repetitive TMS to PD patients to determine whether gamma activity and/or cognitive function may be improved non-invasively.

Conditions

Parkinson's

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

Parkinson's Disease Subjects, (rTMS)

The PD subjects will be randomized, and on a separate day receive a course of either real (rTMS) or sham TMS. Twenty minutes after this treatment subjects will again perform the same working memory task (at 9am to control for fatigue and diurnal effects) while having MEG data recorded

Group Type: EXPERIMENTAL

rTMS

Intervention Type: DEVICE

TMS: Repetitive TMS will be administered using a 70-mm diameter air-cooled figure-of-8 coil and SuperRapid2 Stimulator (Magstim, Jali Medical US distributors, Woburn, MA). Repetitive pulses will be delivered to the right and left pre-frontal cortex (Brodman area 46) using a frameless stereotactic navigation system and the subject's MRI in Brainsight software. Stimuli will be delivered at 20 Hz at 90% of the subjects resting motor threshold (rMT) for 25 trains of 30 pulses per train, inter-train interval of 30 seconds for a total of 750 pulses per hemisphere. The same TMS parameters as active stimulation but with the coil held at 90° to the scalp to induce similar somatic sensations and noise as in the active group with minimal direct brain effects.

Control Subjects (rTMS)

The control subjects will be randomized, and on a separate day receive a course of either real (rTMS) or sham TMS. Twenty minutes after this treatment subjects will again perform the same working memory task (at 9am to control for fatigue and diurnal effects) while having MEG data recorded

Group Type: EXPERIMENTAL

rTMS

Intervention Type: DEVICE

TMS: Repetitive TMS will be administered using a 70-mm diameter air-cooled figure-of-8 coil and SuperRapid2 Stimulator (Magstim, Jali Medical US distributors, Woburn, MA). Repetitive pulses will be delivered to the right and left pre-frontal cortex (Brodman area 46) using a frameless stereotactic navigation system and the subject's MRI in Brainsight software. Stimuli will be delivered at 20 Hz at 90% of the subjects resting motor threshold (rMT) for 25 trains of 30 pulses per train, inter-train interval of 30 seconds for a total of 750 pulses per hemisphere. The same TMS parameters as active stimulation but with the coil held at 90° to the scalp to induce similar somatic sensations and noise as in the active group with minimal direct brain effects.

Parkinson's Disease Subjects, (sTMS)

The PD subjects will be randomized, and on a separate day receive a course of either real (rTMS) or sham TMS. Twenty minutes after this treatment subjects will again perform the same working memory task (at 9am to control for fatigue and diurnal effects) while having MEG data recorded

Group Type: SHAM_COMPARATOR

Sham TMS

Intervention Type: DEVICE

Sham TMS will be administered with a Magstim sham coil with electrodes attached to mimic the sounds and sensation of real TMS. The site and frequency of stimulation will be identical to the real TMS described above.

Control Subjects (sTMS)

The control subjects will be randomized, and on a separate day receive a course of either real (rTMS) or sham TMS. Twenty minutes after this treatment subjects will again perform the same working memory task (at 9am to control for fatigue and diurnal effects) while having MEG data recorded

Group Type: SHAM_COMPARATOR

Sham TMS

Intervention Type: DEVICE

Sham TMS will be administered with a Magstim sham coil with electrodes attached to mimic the sounds and sensation of real TMS. The site and frequency of stimulation will be identical to the real TMS described above.

Interventions

rTMS

TMS: Repetitive TMS will be administered using a 70-mm diameter air-cooled figure-of-8 coil and SuperRapid2 Stimulator (Magstim, Jali Medical US distributors, Woburn, MA). Repetitive pulses will be delivered to the right and left pre-frontal cortex (Brodman area 46) using a frameless stereotactic navigation system and the subject's MRI in Brainsight software. Stimuli will be delivered at 20 Hz at 90% of the subjects resting motor threshold (rMT) for 25 trains of 30 pulses per train, inter-train interval of 30 seconds for a total of 750 pulses per hemisphere. The same TMS parameters as active stimulation but with the coil held at 90° to the scalp to induce similar somatic sensations and noise as in the active group with minimal direct brain effects.

Intervention Type: DEVICE

Sham TMS

Sham TMS will be administered with a Magstim sham coil with electrodes attached to mimic the sounds and sensation of real TMS. The site and frequency of stimulation will be identical to the real TMS described above.

Intervention Type: DEVICE

Other Intervention Names

Repetitive Transcranial Magnetic Stimulation

Eligibility Criteria

Inclusion Criteria

• We will recruit 60 PD patients through the University Colorado Hospital (UCH) Movement Disorders Clinic diagnosed with probable PD using United Kingdom (UK) Brain Bank Criteria.
• PD patients will be of mild to moderate severity based on the Hohn and Yahr scale (score of 3 or less in on medication state) and be on a stable dose of PD medications.
• Clinical severity will also be assessed using the Unified Parkinson Disease Rating Scale.
• We do not anticipate recruitment to be difficult as UCH Movement clinics see over 800 PD patients annually, the majority of whom are stage 3 or less.
• Controls will be approximately matched for age and gender as a group and recruited through clinic (spouses) and advertisements in the community.

Exclusion Criteria

• Subjects will be excluded if they have significant depression (Beck Depression Inventory33 > 14)
• Dementia (Mini Mental State Examination34 < 26 or Frontal Assessment Battery35 < 14)
• Other neurological or psychiatric illness
• Significant history of head injury, significant systemic medical diseases (e.g. liver failure, kidney failure, poorly controlled diabetes)
• Deep Brain Stimulation (DBS)
• Cognitive enhancing medications (e.g. stimulants or acetylcholinesterase inhibitors) or contraindications to either TMS or MRI (pregnancy, pacemaker, unstable cardiac disease, skull lesion, claustrophobia, history of epilepsy or on medications known to lower seizure threshold).

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Benzi Kluger, MD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

UC Denver Building 534

Aurora, Colorado, United States

Countries

United States

Other Identifiers

10-0771

Identifier Type: -

Identifier Source: org_study_id