Autonomic Dysfunction, Depression, Parkinson Disease
Conditions
Brief summary
This is a randomized, single-blinded, triple crossover study focused on determining the feasibility of using transcranial magnetic stimulation (TMS) for treatment of Parkinson's disease related autonomic dysfunction and depression. Participants will undergo TMS to three brain regions: medial prefrontal cortex (mPFC) (experimental site), dorsolateral prefrontal cortex (DLPFC) (alternative experimental site), or primary sensory cortex (S1) (control site) in a triple crossover design. Participants will complete symptom questionnaires, neurologic examination and cognitive assessments, and orthostatic vital signs recording before and after each brain stimulation session.
Interventions
DEVICEtranscranial magnetic stimulation
Transcranial magnetic stimulation (or TMS) is a non-invasive form of brain stimulation in which a magnetic pulse is applied directly to the scalp. This device is FDA approved for treatment of depression and other neuropsychiatric disorders, and is regularly used in neurologic and psychiatric research. iTBS is a particular TMS protocol which delivers the magnetic field in triplet bursts (three stimulations very close together at a frequency of 50 Hz very quickly). The triplet bursts are repeated at a rate of 5 Hz for 2 seconds (30 pulses), followed by 8 seconds rest, repeated 20 times for a total of 600 pulses. Each treatments lasts approximately 3 minutes.
Sponsors
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
Participant will be blinded as to which site is being stimulated, experimental site or control site.
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Men and women between 50 and 90 years of age, without a diagnosis of severe dementia * Carry a diagnosis of idiopathic Parkinson's disease based on the United Kingdom Parkinson's Disease Society Brain Bank clinical diagnostic criteria * Have had symptoms of Parkinson's disease for at least 3 years * Hospital's study-specific informed consent must be obtained * Must have capacity to provide informed consent in English * For female participants, confirmation that a menstrual period has not occurred in over 12 months, or that an effective form of contraception will be used during the study
Exclusion criteria
* Inability to provide informed consent. * Severe dementia * History of epilepsy or brain surgery * Severe tremor or dyskinesia that would interfere with EEG as determined by the PI * Parkinson's patients with clinically significant medical or neurological conditions which may be an alternative cause of orthostatic hypotension, such as neuropathy, renal failure, heart failure, cardiac arrhythmias, severe diabetes, or spinal cord injuries * The investigators will exclude patients who are treated with medications which can significantly lower blood pressure or heart rate, such as antihypertensive medications, diuretics, and alpha-blocking medications * Presence of other known central nervous system disease that may interfere with performance or interpretation of EEG or TMS * Presence of any implanted metal devices including, but not limited to, pacemakers, deep brain stimulators, vagal nerve stimulators, bladder stimulators, or cochlear implants.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Degree of Orthostatic Hypotension and EEG | At least 30 minutes before initial iTBS | Degree of correlation between degree of orthostatic hypotension and frontal midline theta EEG power will be measured extracted from Baseline pre-stimulation visit EEG and blood pressure measures. Orthostatic vital signs will be measured at least 30 minutes before initial iTBS as follows: blood pressure will be measured after at least 3 minutes of rest in the supine position. Blood pressure will again be measured after 3 minutes of standing. Blood pressure reduction is expressed as the magnitude of reduction, thus a positive number reflects a greater reduction. Lack of blood pressure reduction was coded as '0'. A positive correlation coefficient indicates a positive relationship between the assessments; higher FMT power correlates with higher more severe orthostatic hypotension. |
| Change in Frontal Midline Theta EEG Power After Brain Stimulation | At least 30 minutes before initial iTBS, and 30 minutes after each iTBS treatment | Degree of change of frontal midline theta (FMT) power on electroencephalography (EEG) after brain stimulation at each site (medial prefrontal cortex, dorsolateral prefrontal cortex, control site). |
| Correlation Between the Scales for Outcomes in Parkinson's Disease - Autonomic (SCOPA-AUT) Total Score and EEG | At least 30 minutes before initial iTBS | Degree of correlation between the Scales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) total score and frontal midline theta EEG power extracted from Baseline pre-stimulation initial visit EEG and SCOPA-AUT questionnaire. The SCOPA-AUT is a validated autonomic symptom survey for people with Parkinson's disease. It contains 6 domains (gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillary, and sexual). The investigators will use the total composite score including all domains. The score range is 0-69, with a total of 23 questions. 0 means no symptoms, 69 is highest burden of symptoms. The FMT and SCOPA-AUT were assessed at baseline. FMT power and SCOPA-AUT were correlated using the Spearman Correlation Coefficient calculation. A positive correlation coefficient indicates a positive relationship between the assessments; higher FMT power correlates with higher symptom burden. |
| Correlation Between the Orthostatic Hypotension Questionnaire (OHQ) and EEG | At least 30 minutes before initial iTBS | Degree of correlation between the Orthostatic Hypotension Questionnaire (OHQ) composite score and frontal midline theta EEG power extracted from Baseline pre-stimulation initial visit EEG and OHQ questionnaire. The OHQ consists of two sections: 1-orthostatic hypotension symptom assessment, which includes 6 questions with a score range of 0-66 (0 is no symptoms, 66 is most severe symptoms); and 2-the orthostatic hypotension daily activity scale, which rates interference of symptoms on activities of daily living. This part consists of four questions, and score range is 0-44 (0 is no interference, 44 is most severe interference). The composite OHQ score is the average score between these two subsections. FMT power and OHQ were correlated using the Spearman Correlation Coefficient calculation. A positive correlation coefficient indicates a positive relationship between the assessments; higher FMT power correlates with higher symptom burden. |
Other
| Measure | Time frame | Description |
|---|---|---|
| SCOPA-AUT Response to Brain Stimulation | 30 minutes pre-iTBS, and 1 day and 4 days after each iTBS treatment | Change in the SCales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) from 30 minutes before stimulation to 1 day after stimulation and 4 days after stimulation. The SCOPA-AUT is a validated autonomic symptom survey for people with Parkinson's disease. It contains 6 domains (gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillary, and sexual). The investigators will use the total composite score including all domains. The score range is 0-69, with a total of 23 questions. 0 means no symptoms, 69 is highest burden of symptoms |
| OHQ Response to Brain Stimulation | At least 30 minutes pre-iTBS, and day 1 and day 4 after each iTBS treatment | Change in the Orthostatic Hypotension Questionnaire (OHQ) from before to after iTBS. The OHQ will be administered at least 30 minutes before stimulation, and again 1 day and 4 days after stimulation. The OHQ is an orthostatic hypotension symptom survey and consists of two sections. The first is the orthostatic hypotension symptom assessment, which includes 6 questions with a score range of 0-66 (0 is no symptoms, 66 is most severe symptoms). The second part is the orthostatic hypotension daily activity scale, which rates interference of symptoms on activities of daily living. This part consists of four questions, and score range is 0-44 (0 is no interference, 44 is most severe interference). The investigators will calculate the composite OHQ score, which is the average score between these two subsections. |
| Response of Orthostatic Blood Pressure Changes to Brain Stimulation | At least 30 minutes before each iTBS treatment, and 30 minutes after each iTBS treatment | Change in the orthostatic blood pressure change from before to after iTBS. Orthostatic vital signs will be measured as follows: blood pressure will be measured after at least 3 minutes of rest in the supine position. Blood pressure will again be measured after 3 minutes of standing. This will be measured at least 30 minutes before brain stimulation, and again 30 minutes after brain stimulation. |
| Depression Symptom Response to Brain Stimulation | At least 30 minutes before each iTBS treatment, and day 1 and day 4 after each iTBS treatment | Change in the Beck Depression Inventory II (BDI-II) from before to after iTBS. Participants will complete the BDI-II at least 30 minutes before brain stimulation. The questionnaire will be repeated 1 day and 4 days after stimulation. The BDI-II is a validated depression symptom survey. This survey contains 21 questions, with a score range of 0-63, where 0 means no depression symptoms and 63 indicates severe depression symptoms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Medial Prefrontal Cortex - Control Site - Dorsolateral Prefrontal Cortex Participants first undergo transcranial magnetic stimulation to the medial prefrontal cortex. After a 3 week washout period, participants then undergo transcranial magnetic stimulation to the control site. After a 3 week washout period, participants undergo transcranial magnetic stimulation to the dorsolateral prefrontal cortex.
transcranial magnetic stimulation: Transcranial magnetic stimulation (or TMS) is a non-invasive form of brain stimulation in which a magnetic pulse is applied directly to the scalp. This device is FDA approved for treatment of depression and other neuropsychiatric disorders, and is regularly used in neurologic and psychiatric research.
iTBS is a particular TMS protocol which delivers the magnetic field in triplet bursts (three stimulations very close together at a frequency of 50 Hz very quickly). The triplet bursts are repeated at a rate of 5 Hz for 2 seconds (30 pulses), followed by 8 seconds rest, repeated 20 times for a total of 600 pulses. Each treatments lasts approximately 3 minutes. | 5 |
| Medial Prefrontal Cortex - Dorsolateral Prefrontal Cortex - Control Site Participants first undergo transcranial magnetic stimulation to the medial prefrontal cortex. After a 3 week washout period, participants then undergo transcranial magnetic stimulation to the dorsolateral prefrontal cortex. After a 3 week washout period, participants undergo transcranial magnetic stimulation to the control site.
transcranial magnetic stimulation: Transcranial magnetic stimulation (or TMS) is a non-invasive form of brain stimulation in which a magnetic pulse is applied directly to the scalp. This device is FDA approved for treatment of depression and other neuropsychiatric disorders, and is regularly used in neurologic and psychiatric research.
iTBS is a particular TMS protocol which delivers the magnetic field in triplet bursts (three stimulations very close together at a frequency of 50 Hz very quickly). The triplet bursts are repeated at a rate of 5 Hz for 2 seconds (30 pulses), followed by 8 seconds rest, repeated 20 times for a total of 600 pulses. Each treatments lasts approximately 3 minutes. | 2 |
| Dorsolateral Prefrontal Cortex - Medial Prefrontal Cortex - Control Site Participants first undergo transcranial magnetic stimulation to the dorsolateral prefrontal cortex. After a 3 week washout period, participants then undergo transcranial magnetic stimulation to the medial prefrontal cortex. After a 3 week washout period, participants undergo transcranial magnetic stimulation to the control site.
transcranial magnetic stimulation: Transcranial magnetic stimulation (or TMS) is a non-invasive form of brain stimulation in which a magnetic pulse is applied directly to the scalp. This device is FDA approved for treatment of depression and other neuropsychiatric disorders, and is regularly used in neurologic and psychiatric research.
iTBS is a particular TMS protocol which delivers the magnetic field in triplet bursts (three stimulations very close together at a frequency of 50 Hz very quickly). The triplet bursts are repeated at a rate of 5 Hz for 2 seconds (30 pulses), followed by 8 seconds rest, repeated 20 times for a total of 600 pulses. Each treatments lasts approximately 3 minutes. | 4 |
| Dorsolateral Prefrontal Cortex - Control Site - Medial Prefrontal Cortex Participants first undergo transcranial magnetic stimulation to the dorsolateral prefrontal cortex. After a 3 week washout period, participants then undergo transcranial magnetic stimulation to the control site. After a 3 week washout period, participants undergo transcranial magnetic stimulation to the medial prefrontal cortex.
transcranial magnetic stimulation: Transcranial magnetic stimulation (or TMS) is a non-invasive form of brain stimulation in which a magnetic pulse is applied directly to the scalp. This device is FDA approved for treatment of depression and other neuropsychiatric disorders, and is regularly used in neurologic and psychiatric research.
iTBS is a particular TMS protocol which delivers the magnetic field in triplet bursts (three stimulations very close together at a frequency of 50 Hz very quickly). The triplet bursts are repeated at a rate of 5 Hz for 2 seconds (30 pulses), followed by 8 seconds rest, repeated 20 times for a total of 600 pulses. Each treatments lasts approximately 3 minutes. | 2 |
| Control Site - Medial Prefrontal Cortex - Dorsolateral Prefrontal Cortex Participants first undergo transcranial magnetic stimulation to the control site. After a 3 week washout period, participants then undergo transcranial magnetic stimulation to the medial prefrontal cortex. After a 3 week washout period, participants undergo transcranial magnetic stimulation to the dorsolateral prefrontal cortex.
transcranial magnetic stimulation: Transcranial magnetic stimulation (or TMS) is a non-invasive form of brain stimulation in which a magnetic pulse is applied directly to the scalp. This device is FDA approved for treatment of depression and other neuropsychiatric disorders, and is regularly used in neurologic and psychiatric research.
iTBS is a particular TMS protocol which delivers the magnetic field in triplet bursts (three stimulations very close together at a frequency of 50 Hz very quickly). The triplet bursts are repeated at a rate of 5 Hz for 2 seconds (30 pulses), followed by 8 seconds rest, repeated 20 times for a total of 600 pulses. Each treatments lasts approximately 3 minutes. | 6 |
| Control Site - Dorsolateral Prefrontal Cortex - Medial Prefrontal Cortex Participants first undergo transcranial magnetic stimulation to the control site. After a 3 week washout period, participants then undergo transcranial magnetic stimulation to the dorsolateral prefrontal cortex. After a 3 week washout period, participants undergo transcranial magnetic stimulation to the medial prefrontal cortex.
transcranial magnetic stimulation: Transcranial magnetic stimulation (or TMS) is a non-invasive form of brain stimulation in which a magnetic pulse is applied directly to the scalp. This device is FDA approved for treatment of depression and other neuropsychiatric disorders, and is regularly used in neurologic and psychiatric research.
iTBS is a particular TMS protocol which delivers the magnetic field in triplet bursts (three stimulations very close together at a frequency of 50 Hz very quickly). The triplet bursts are repeated at a rate of 5 Hz for 2 seconds (30 pulses), followed by 8 seconds rest, repeated 20 times for a total of 600 pulses. Each treatments lasts approximately 3 minutes. | 5 |
| Total | 24 |
Baseline characteristics
| Characteristic | Medial Prefrontal Cortex - Control Site - Dorsolateral Prefrontal Cortex | Medial Prefrontal Cortex - Dorsolateral Prefrontal Cortex - Control Site | Dorsolateral Prefrontal Cortex - Medial Prefrontal Cortex - Control Site | Dorsolateral Prefrontal Cortex - Control Site - Medial Prefrontal Cortex | Control Site - Medial Prefrontal Cortex - Dorsolateral Prefrontal Cortex | Control Site - Dorsolateral Prefrontal Cortex - Medial Prefrontal Cortex | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.8 years STANDARD_DEVIATION 7.36 | 68.5 years STANDARD_DEVIATION 7.5 | 69.5 years STANDARD_DEVIATION 3.77 | 74.0 years STANDARD_DEVIATION 1 | 67.0 years STANDARD_DEVIATION 9.27 | 67.2 years STANDARD_DEVIATION 8.73 | 67.92 years STANDARD_DEVIATION 7.78 |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | 0 Participants |
| Region of Enrollment United States | 5 participants | 2 participants | 4 participants | 2 participants | 6 participants | 5 participants | 24 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 3 Participants | 0 Participants | 5 Participants | 3 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 26 | 0 / 25 |
| other Total, other adverse events | 1 / 25 | 1 / 26 | 0 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 26 | 0 / 25 |
Outcome results
Primary
Change in Frontal Midline Theta EEG Power After Brain Stimulation
Degree of change of frontal midline theta (FMT) power on electroencephalography (EEG) after brain stimulation at each site (medial prefrontal cortex, dorsolateral prefrontal cortex, control site).
Time frame: At least 30 minutes before initial iTBS, and 30 minutes after each iTBS treatment
Population: Data are reported for participants who completed all 3 treatment interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Medial Prefrontal Cortex Stimulation | Change in Frontal Midline Theta EEG Power After Brain Stimulation | 1.03 microvolts^2/Hz | Standard Deviation 2.41 |
| Dorsolateral Prefrontal Cortex Stimulation | Change in Frontal Midline Theta EEG Power After Brain Stimulation | 0.44 microvolts^2/Hz | Standard Deviation 2.55 |
| Control Site Stimulation | Change in Frontal Midline Theta EEG Power After Brain Stimulation | 1.01 microvolts^2/Hz | Standard Deviation 2.13 |
p-value: 0.08Wilcoxon (Mann-Whitney)
p-value: 0.54Wilcoxon (Mann-Whitney)
p-value: 0.03Wilcoxon (Mann-Whitney)
p-value: 0.98ANOVA
p-value: 0.41ANOVA
p-value: 0.63ANOVA
Primary
Correlation Between Degree of Orthostatic Hypotension and EEG
Degree of correlation between degree of orthostatic hypotension and frontal midline theta EEG power will be measured extracted from Baseline pre-stimulation visit EEG and blood pressure measures. Orthostatic vital signs will be measured at least 30 minutes before initial iTBS as follows: blood pressure will be measured after at least 3 minutes of rest in the supine position. Blood pressure will again be measured after 3 minutes of standing. Blood pressure reduction is expressed as the magnitude of reduction, thus a positive number reflects a greater reduction. Lack of blood pressure reduction was coded as '0'. A positive correlation coefficient indicates a positive relationship between the assessments; higher FMT power correlates with higher more severe orthostatic hypotension.
Time frame: At least 30 minutes before initial iTBS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Medial Prefrontal Cortex Stimulation | Correlation Between Degree of Orthostatic Hypotension and EEG | 0.429 Spearman Correlation coefficient |
p-value: 0.156Regression, Linear
Primary
Correlation Between the Orthostatic Hypotension Questionnaire (OHQ) and EEG
Degree of correlation between the Orthostatic Hypotension Questionnaire (OHQ) composite score and frontal midline theta EEG power extracted from Baseline pre-stimulation initial visit EEG and OHQ questionnaire. The OHQ consists of two sections: 1-orthostatic hypotension symptom assessment, which includes 6 questions with a score range of 0-66 (0 is no symptoms, 66 is most severe symptoms); and 2-the orthostatic hypotension daily activity scale, which rates interference of symptoms on activities of daily living. This part consists of four questions, and score range is 0-44 (0 is no interference, 44 is most severe interference). The composite OHQ score is the average score between these two subsections. FMT power and OHQ were correlated using the Spearman Correlation Coefficient calculation. A positive correlation coefficient indicates a positive relationship between the assessments; higher FMT power correlates with higher symptom burden.
Time frame: At least 30 minutes before initial iTBS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Medial Prefrontal Cortex Stimulation | Correlation Between the Orthostatic Hypotension Questionnaire (OHQ) and EEG | 0.261 Spearman Correlation coefficient |
p-value: 0.67Regression, Linear
Primary
Correlation Between the Scales for Outcomes in Parkinson's Disease - Autonomic (SCOPA-AUT) Total Score and EEG
Degree of correlation between the Scales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) total score and frontal midline theta EEG power extracted from Baseline pre-stimulation initial visit EEG and SCOPA-AUT questionnaire. The SCOPA-AUT is a validated autonomic symptom survey for people with Parkinson's disease. It contains 6 domains (gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillary, and sexual). The investigators will use the total composite score including all domains. The score range is 0-69, with a total of 23 questions. 0 means no symptoms, 69 is highest burden of symptoms. The FMT and SCOPA-AUT were assessed at baseline. FMT power and SCOPA-AUT were correlated using the Spearman Correlation Coefficient calculation. A positive correlation coefficient indicates a positive relationship between the assessments; higher FMT power correlates with higher symptom burden.
Time frame: At least 30 minutes before initial iTBS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Medial Prefrontal Cortex Stimulation | Correlation Between the Scales for Outcomes in Parkinson's Disease - Autonomic (SCOPA-AUT) Total Score and EEG | 0.255 Spearman Correlation coefficient |
p-value: 0.38Regression, Linear
Other Pre-specified
Depression Symptom Response to Brain Stimulation
Change in the Beck Depression Inventory II (BDI-II) from before to after iTBS. Participants will complete the BDI-II at least 30 minutes before brain stimulation. The questionnaire will be repeated 1 day and 4 days after stimulation. The BDI-II is a validated depression symptom survey. This survey contains 21 questions, with a score range of 0-63, where 0 means no depression symptoms and 63 indicates severe depression symptoms.
Time frame: At least 30 minutes before each iTBS treatment, and day 1 and day 4 after each iTBS treatment
Other Pre-specified
OHQ Response to Brain Stimulation
Change in the Orthostatic Hypotension Questionnaire (OHQ) from before to after iTBS. The OHQ will be administered at least 30 minutes before stimulation, and again 1 day and 4 days after stimulation. The OHQ is an orthostatic hypotension symptom survey and consists of two sections. The first is the orthostatic hypotension symptom assessment, which includes 6 questions with a score range of 0-66 (0 is no symptoms, 66 is most severe symptoms). The second part is the orthostatic hypotension daily activity scale, which rates interference of symptoms on activities of daily living. This part consists of four questions, and score range is 0-44 (0 is no interference, 44 is most severe interference). The investigators will calculate the composite OHQ score, which is the average score between these two subsections.
Time frame: At least 30 minutes pre-iTBS, and day 1 and day 4 after each iTBS treatment
Other Pre-specified
Response of Orthostatic Blood Pressure Changes to Brain Stimulation
Change in the orthostatic blood pressure change from before to after iTBS. Orthostatic vital signs will be measured as follows: blood pressure will be measured after at least 3 minutes of rest in the supine position. Blood pressure will again be measured after 3 minutes of standing. This will be measured at least 30 minutes before brain stimulation, and again 30 minutes after brain stimulation.
Time frame: At least 30 minutes before each iTBS treatment, and 30 minutes after each iTBS treatment
Other Pre-specified
SCOPA-AUT Response to Brain Stimulation
Change in the SCales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) from 30 minutes before stimulation to 1 day after stimulation and 4 days after stimulation. The SCOPA-AUT is a validated autonomic symptom survey for people with Parkinson's disease. It contains 6 domains (gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillary, and sexual). The investigators will use the total composite score including all domains. The score range is 0-69, with a total of 23 questions. 0 means no symptoms, 69 is highest burden of symptoms
Time frame: 30 minutes pre-iTBS, and 1 day and 4 days after each iTBS treatment