Parkinson's Disease
Conditions
Keywords
Parkinson's, TMS, Kluger
Brief summary
This study plans to learn more about the brain function related to thinking problems in individuals with Parkinson's disease.
Detailed description
Dementia is the leading cause of nursing home placement in Parkinson's disease (PD) yet little is known about the cause(s) of cognitive dysfunction in PD and there are no effective treatments. The investigators preliminary data and other published studies suggest that abnormalities in brain activity involving networks important for normal thinking and memory may contribute to cognitive dysfunction in PD and may represent a target for treatment. This proposal will identify abnormalities in cortical activity related to cognitive dysfunction in PD using magnetoencephalography and will perform a randomized control trial of bifrontal repetitive transcranial magnetic stimulation to determine the therapeutic potential of modulating this brain activity.
Interventions
DEVICEReal TMS
real treatment
DEVICESham TMS
placebo treatment
Sponsors
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of probable PD (using United Kingdom Brain Bank criteria) * Diagnosis of mild cognitive impairment * No unstable medical condition
Exclusion criteria
* Features suggestive of other causes of Parkinsonism or other neurological disorders * Prior deep brain stimulation (DBS) or ablation surgery * Evidence for active depression or Hospital Anxiety and Depression Scale (HADS) score greater than or equal to 11 * Motor symptoms expected to interfere with scanning (e.g. sever tremor) * Contraindications to TMS, MEG, or MRI such as pregnancy, pacemaker, unstable cardiac disease, skull lesion, claustrophobia, history of epilepsy, or on medications known to lower seizure threshold * Implanted electronic devices or metal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Magnetoencephalography (MEG) Connectivity Measures | 2 weeks | Our MEG outcome will be a change in small-worldness, global efficiency, nodal efficiency and degree distribution pre-TMS to immediately post-TMS treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-TMS Change From Baseline in Cognitive Scores | 2 weeks | Our behavioral outcome will be a change in the scores of the following tests: Mattis Dementia Rating Scale: Higher raw scores = better cognitive status, ranging from 0 to 144. Normative data in healthy subjects range from 137 to 144. Trail Making Test Trails B: average score is 75 seconds; deficient score is \> 273 seconds. Delis-Kaplan Executive Function System (DKEFS) - Verbal Fluency Test. Higher score = higher ability in language processing. Scales scores vary from 0 min to N/A max (no concrete maximum). DKEFS - Stroop Interference Test measures inhibitory control and cognitive flexibility. Performance is measured by completion time. No min or max value for this test. Test should be discontinued after 90 sec. For those, higher scores = higher abilities: California Verbal Learning Test (declarative memory, scale 0 to 80), Boston Naming Test (language, scale 0 to 60), Brief Test of Attention and Judgment of Line Orientation (scale 0 to 30) |
Countries
United States
Participant flow
Recruitment details
Recruitment was conducted in the United States at one site: University of Colorado Denver - Anschutz Medical Campus. The first participant was enrolled in May 19, 2014.
Pre-assignment details
70 participants were assessed for eligibility (following Inclusion and exclusion criteria), 21 were screen failures, 49 participants were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Real TMS TMS will be administered using a 70-mm diameter air-cooled figure-of-8 coil and SuperRapid2 Magstim Stimulator. Repetitive pulses will be delivered to the right and left dorsolateral pre-frontal cortex (Brodmann area 46) using a frameless stereotactic navigation system and the subject's magnetic resonance imaging (MRI) in Brainsight software. Stimuli will be delivered at 20 Hz at 90% 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. Stimulation will be delivered for 10 consecutive days, excluding the weekends. This dose and duration of repetitive TMS (rTMS) is based on physiological studies of healthy adults and treatment studies of cognition in PD and Alzheimer's disease. Side of first stimulation (left vs right hemisphere) will be counterbalanced across subjects.
Real TMS: real treatment | 22 |
| Sham TMS Sham stimulation will be delivered using a sham coil fitted with electrodes to mimic both the auditory and somatic sensation of real TMS.
Sham TMS: placebo treatment | 24 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Sham TMS | Total | Real TMS |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 31 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 15 Participants | 8 Participants |
| Age, Continuous | 69.5 years STANDARD_DEVIATION 8 | 68.5 years STANDARD_DEVIATION 7.6 | 67.4 years STANDARD_DEVIATION 7.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 44 Participants | 20 Participants |
| Region of Enrollment United States | 24 participants | 46 participants | 22 participants |
| Sex: Female, Male Female | 7 Participants | 13 Participants | 6 Participants |
| Sex: Female, Male Male | 17 Participants | 33 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 24 |
| other Total, other adverse events | 6 / 22 | 1 / 24 |
| serious Total, serious adverse events | 1 / 22 | 0 / 24 |
Outcome results
Primary
Change in Magnetoencephalography (MEG) Connectivity Measures
Our MEG outcome will be a change in small-worldness, global efficiency, nodal efficiency and degree distribution pre-TMS to immediately post-TMS treatment.
Time frame: 2 weeks
Population: No data displayed because Outcome Measure has zero total analyzed. No participants were analyzed for this outcome measure.
Secondary
Post-TMS Change From Baseline in Cognitive Scores
Our behavioral outcome will be a change in the scores of the following tests: Mattis Dementia Rating Scale: Higher raw scores = better cognitive status, ranging from 0 to 144. Normative data in healthy subjects range from 137 to 144. Trail Making Test Trails B: average score is 75 seconds; deficient score is \> 273 seconds. Delis-Kaplan Executive Function System (DKEFS) - Verbal Fluency Test. Higher score = higher ability in language processing. Scales scores vary from 0 min to N/A max (no concrete maximum). DKEFS - Stroop Interference Test measures inhibitory control and cognitive flexibility. Performance is measured by completion time. No min or max value for this test. Test should be discontinued after 90 sec. For those, higher scores = higher abilities: California Verbal Learning Test (declarative memory, scale 0 to 80), Boston Naming Test (language, scale 0 to 60), Brief Test of Attention and Judgment of Line Orientation (scale 0 to 30)
Time frame: 2 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Real TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Mattis Dementia Rating Scale (MDRS) at 2 weeks minus score on the MDRS at baseline | -1.4 Scores on a scale | Standard Deviation 4.55 |
| Real TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Verbal fluency at 2 weeks minus score on the Verbal fluency at baseline | 0.3 Scores on a scale | Standard Deviation 11.35 |
| Real TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Stroop Interference at 2 weeks minus score on the Stroop Interference at baseline | -9.1 Scores on a scale | Standard Deviation 18.55 |
| Real TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Brief Test of Attention (BTA) at 2 weeks minus score on the BTA at baseline | -0.1 Scores on a scale | Standard Deviation 4 |
| Real TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Boston Naming Test (BNT) at 2 weeks minus score on the BNT at baseline | 0.2 Scores on a scale | Standard Deviation 5.95 |
| Real TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Judgment of Line Orientation (JLO) at 2 weeks minus score on the JLO at baseline | 0.9 Scores on a scale | Standard Deviation 4.7 |
| Sham TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Boston Naming Test (BNT) at 2 weeks minus score on the BNT at baseline | 1.4 Scores on a scale | Standard Deviation 2.25 |
| Sham TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Mattis Dementia Rating Scale (MDRS) at 2 weeks minus score on the MDRS at baseline | 0 Scores on a scale | Standard Deviation 5.55 |
| Sham TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Brief Test of Attention (BTA) at 2 weeks minus score on the BTA at baseline | 0.6 Scores on a scale | Standard Deviation 4.15 |
| Sham TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Verbal fluency at 2 weeks minus score on the Verbal fluency at baseline | 1 Scores on a scale | Standard Deviation 15.7 |
| Sham TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Judgment of Line Orientation (JLO) at 2 weeks minus score on the JLO at baseline | 1 Scores on a scale | Standard Deviation 4.2 |
| Sham TMS | Post-TMS Change From Baseline in Cognitive Scores | Score on the Stroop Interference at 2 weeks minus score on the Stroop Interference at baseline | -2.9 Scores on a scale | Standard Deviation 18.85 |
Comparison: We estimated a sample size of 20 per group would provide at least 80% power at a significance level of 0.05 to detect a between-group difference of 10 on the Matthis Dementia Rating Scale-2, an effect size similar to prior studies of rivastigmine.p-value: 0.195% CI: [-4.56, 0.42]Mixed Models Analysis