Parkinson's Disease
Conditions
Keywords
Parkinson's disease, Apathy, rTMS, Repetitive transcranial magnetic stimulation, Depression
Brief summary
The purpose of this research study is to attempt to treat apathy in Parkinson's disease (PD) using high-frequency repetitive transcranial magnetic stimulation (rTMS) of the brain and to investigate the patterns of brain activation that may be involved in apathy. It is hypothesized that high-frequency rTMS of the left mid-dorsolateral frontal cortex will improve apathy in PD.
Detailed description
Apathy is a syndrome characterized by a primary lack of motivation and it manifests in three domains: behavioral (lack of effort and productivity, dependence on others for structuring daily activities), cognitive (loss of interest in new experiences, lack of concern for one's problems) and affective (flattened affect and lack of response to positive or negative events). Apathy has been consistently attributed to functional disturbance of neural systems involving mesial frontal and the anterior cingulate cortex (ACC), an area with reciprocal connections with limbic, frontal cortices and the basal ganglia. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive tool used to manipulate activity in specific brain neural circuits through the skull and, in turn, induce short-term (milliseconds) and long-term (minutes to hours) changes in behavior. The duration of effect depends on the stimulation mode. Several studies have now demonstrated that rTMS may facilitate or modulate behavior beyond the actual stimulation. rTMS of the mid-dorsolateral frontal cortex (MDLFC) has been used to treat depression presumably because of its modulatory effect on the fronto-cingulate system (MDLFC and the ACC circuitry). Studies have shown that rTMS of the left MDLFC modulates the blood flow response in the ACC. We therefore hypothesize that high-frequency rTMS of the left MDLFC will also improve apathy in PD.
Interventions
In patients randomized to receive left prefrontal rTMS, each treatment will consist of 2000 stimuli (50 - 8-second trains of 40 stimuli at 5 Hz). We will administer rTMS trains every 30 seconds for 25 minutes. Stimulus intensity for the first and second trains will be 80 and 90% of MEP threshold, respectively.
DEVICESham Repetitive Transcranial Magnetic Stimulation
Patients randomized to receive sham rTMS will undergo the same procedure for identifying stimulus location used in patients receiving real rTMS. Simulated rTMS will be administered using Magstim Placebo 70 mm figure-of-8 shaped coils which produce discharge noise and vibration similar to a real 70 mm coil without stimulating the cerebral cortex. However, in addition to obvious coil discharge noise, rTMS also causes electrical stimulation of the scalp. We will simulate this experience by attaching surface electrodes underneath the sham coil and in contact with the scalp.
Sponsors
Michael J. Fox Foundation for Parkinson's Research
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. diagnosis of probable PD, defined by the presence of at least 2 out of 3 cardinal motor features of PD (resting tremor, rigidity, and bradykinesia, plus a sustained and significant response to dopaminergic treatment); 2. age 30 or over; and 3. on stable medications for at least 30 days.
Exclusion criteria
1. features suggestive of other causes of parkinsonism/ parkinson-plus syndromes; 2. history of deep brain stimulation or ablation surgery, significant headaches, epilepsy or seizure disorder, mass brain lesions, or major head trauma leading to loss of consciousness of any length; 3. family (1st degree relatives) history of epilepsy; 4. evidence for dementia; 5. presence of contraindications for functional magnetic resonance imaging (fMRI); 6. history of schizophrenia, schizoaffective disorder, other psychosis, rapid-cycling bipolar illness, alcohol/drug abuse within the past year; 7. need for rapid clinical response due to conditions such as initiation, psychosis, or suicidality; 8. unstable medical condition such as diabetes, cardiac disease, hypertension; 9. pregnancy; and 10. colorblindness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apathy Evaluation Scale (AES) | Pre-Tx; 10 days post tx | The apathy evaluation scale is a 14-item self-report questionaire that provides a quantitative estimate of apathy symptoms. Items are given a score of 0-3, and a total score is summated using all items. Scores may range between 0 and 42. Higher scores are indicative of greater symptoms of apathy, and a score of 14 is suggestive of clinically significant symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lille Apathy Rating Scale (LARS) | Pre-Tx; 10 days post-tx | The Lille Apathy Rating Scale (LARS) is a 33-item interviewer administered structured questionaire designed to assess level of apathetic symptoms. The first 3 items are scored from -2 to +2, while the remainder items are scored from -1 to +1. Scores can range between -36 to +36. The more positive the score, the greater level of apathy symptoms. |
| Beck Depression Inventory-Second Edition (BDI-II) | Pre-Tx; 10 days post-tx | The Beck Depression Inventory-Second Edition (BDI-II) is a 21-item self-report questionaire that measures depressive symptoms. Each item is scored on a scale of 0-3, and items are summated to yield a total score. A higher score is indicative of greater symptoms of depression. Total scores may range between 0 and 63. A score greater than or equal of 14 is suggestive of clinically significant symptoms. |
| Hamilton Depression Rating Scale (HAM-D) | Pre-Tx; 10 days post-tx | The Hamilton Depression Rating Scale (HAM-D) is a 24-item interviewer administered structure questionaire designed to assess symptoms of depression. Items are scored with a range of 0-4, though 11 of the items are scored between 0 and 2. A total score is then calculated of all items which can range from 0 to 74. A higher score is indicative of more depressive symptoms, and a lower score post-tx is indicative of better outcome. |
Countries
United States
Participant flow
Recruitment details
Patients seen clinically for routine clinical care were determined by clinicians if they appeared to qualify for the study. Subjects were asked and consented in a non-coercive manner if they wished to be contacted via telephone about future study participation. Recruitment occurred between March 2007-December 2009.
Participants by arm
| Arm | Count |
|---|---|
| rTMS Treatment Participants in this group received rTMS treatment. | 16 |
| Sham Treatment Participants in this group did not receive rTMS treatment. | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | Sham Treatment | rTMS Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 6 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 10 Participants | 10 Participants |
| Age Continuous | 72.8 years STANDARD_DEVIATION 5.7 | 63.8 years STANDARD_DEVIATION 7.2 | 66.8 years STANDARD_DEVIATION 7.9 |
| Region of Enrollment United States | 8 participants | 16 participants | 24 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 14 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 16 | 3 / 8 |
| serious Total, serious adverse events | 0 / 16 | 1 / 8 |
Outcome results
Primary
Apathy Evaluation Scale (AES)
The apathy evaluation scale is a 14-item self-report questionaire that provides a quantitative estimate of apathy symptoms. Items are given a score of 0-3, and a total score is summated using all items. Scores may range between 0 and 42. Higher scores are indicative of greater symptoms of apathy, and a score of 14 is suggestive of clinically significant symptoms.
Time frame: Pre-Tx; 10 days post tx
Population: All participants who completed study procedures were included for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rTMS Pre TX | Apathy Evaluation Scale (AES) | 19.6 units on a scale | Standard Deviation 5.1 |
| Sham Pre TX | Apathy Evaluation Scale (AES) | 18.8 units on a scale | Standard Deviation 3.9 |
| rTMS Post TX (Immediate) | Apathy Evaluation Scale (AES) | 17.9 units on a scale | Standard Deviation 7 |
| Sham Post Tx (Immediate) | Apathy Evaluation Scale (AES) | 16.8 units on a scale | Standard Deviation 4.6 |
Secondary
Beck Depression Inventory-Second Edition (BDI-II)
The Beck Depression Inventory-Second Edition (BDI-II) is a 21-item self-report questionaire that measures depressive symptoms. Each item is scored on a scale of 0-3, and items are summated to yield a total score. A higher score is indicative of greater symptoms of depression. Total scores may range between 0 and 63. A score greater than or equal of 14 is suggestive of clinically significant symptoms.
Time frame: Pre-Tx; 10 days post-tx
Population: All participants who completed study procedures were included for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rTMS Pre TX | Beck Depression Inventory-Second Edition (BDI-II) | 17.1 units on a scale | Standard Deviation 8.4 |
| Sham Pre TX | Beck Depression Inventory-Second Edition (BDI-II) | 17.8 units on a scale | Standard Deviation 9.8 |
| rTMS Post TX (Immediate) | Beck Depression Inventory-Second Edition (BDI-II) | 11.8 units on a scale | Standard Deviation 8.8 |
| Sham Post Tx (Immediate) | Beck Depression Inventory-Second Edition (BDI-II) | 11.8 units on a scale | Standard Deviation 5.4 |
Secondary
Hamilton Depression Rating Scale (HAM-D)
The Hamilton Depression Rating Scale (HAM-D) is a 24-item interviewer administered structure questionaire designed to assess symptoms of depression. Items are scored with a range of 0-4, though 11 of the items are scored between 0 and 2. A total score is then calculated of all items which can range from 0 to 74. A higher score is indicative of more depressive symptoms, and a lower score post-tx is indicative of better outcome.
Time frame: Pre-Tx; 10 days post-tx
Population: All participants who completed study procedures were included for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rTMS Pre TX | Hamilton Depression Rating Scale (HAM-D) | 12.5 units on a scale | Standard Deviation 7.3 |
| Sham Pre TX | Hamilton Depression Rating Scale (HAM-D) | 11.9 units on a scale | Standard Deviation 6.5 |
| rTMS Post TX (Immediate) | Hamilton Depression Rating Scale (HAM-D) | 7.9 units on a scale | Standard Deviation 4.8 |
| Sham Post Tx (Immediate) | Hamilton Depression Rating Scale (HAM-D) | 8.5 units on a scale | Standard Deviation 5.4 |
Secondary
Lille Apathy Rating Scale (LARS)
The Lille Apathy Rating Scale (LARS) is a 33-item interviewer administered structured questionaire designed to assess level of apathetic symptoms. The first 3 items are scored from -2 to +2, while the remainder items are scored from -1 to +1. Scores can range between -36 to +36. The more positive the score, the greater level of apathy symptoms.
Time frame: Pre-Tx; 10 days post-tx
Population: All participants who completed study procedures were included for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rTMS Pre TX | Lille Apathy Rating Scale (LARS) | -15.6 units on a scale | Standard Deviation 9.1 |
| Sham Pre TX | Lille Apathy Rating Scale (LARS) | -18.9 units on a scale | Standard Deviation 4.5 |
| rTMS Post TX (Immediate) | Lille Apathy Rating Scale (LARS) | -20.1 units on a scale | Standard Deviation 7.8 |
| Sham Post Tx (Immediate) | Lille Apathy Rating Scale (LARS) | -22.1 units on a scale | Standard Deviation 5.2 |