Parkinson's Disease
Conditions
Brief summary
This study will investigate cortical stimulation to treat mood and behavioral symptoms in Parkinson's disease patients.
Detailed description
Depression, anxiety and impulse control disorders are among the most prominent neuropsychiatric symptoms in Parkinson's disease (PD) that greatly impact patients' and caregivers' quality of life. However, the neural correlate underlying these symptoms is still largely unknown preventing the development of comprehensive treatment for these symptoms. The aims of this study are to 1) Determine the neural correlates of non-motor symptoms, 2) Determine how cortical stimulation can reduce these symptoms and normalize the abnormal brain signals, and 3) Teach patients how to voluntarily modulate the abnormal brain signals. Ten PD patients undergoing deep brain surgery (DBS) implantation and diagnosed with mild to moderate mood disorder and/or impulsive behavior will be enrolled in this study. In addition to the standard therapeutic DBS electrode used to treat motor symptoms, a flexible electrode will be placed over the prefrontal cortex. Both electrodes will be attached to the Medtronic Activa PC+S pulse generator (and Medtronic Summit RC+S pulse generator as replacements), investigational devices that allows therapeutic stimulation and chronic brain recordings. At multiple time points, up to 2 years post-implantation, in our clinic or patient's home, brain signals will be recorded while patients are resting or performing emotion/cognition tasks. Symptoms will be assessed using validated questionnaires and tasks to allow identification of neurophysiological correlates of non-motor symptoms. There is also an optional sleep study included for better understanding of the brain's physiology. The investigators will then investigate the effect of cortical stimulation on both symptoms severity and brain signals that may be related to symptom expression. These signals will then be used to implement closed-loop controlled cortical stimulation and neuro-feedback controlled strategies.
Interventions
DEVICEMedtronic Activa PC+S System with Chronic Neural Recording
Participants received a Medtronic Activa PC+S system incorporating standard-of-care DBS leads implanted in the basal ganglia (subthalamic nucleus or globus pallidus internus) for management of Parkinson's disease motor symptoms. Additionally, a permanent 4-contact subdural electrocorticography (ECoG) strip was implanted over the prefrontal cortex (e.g., dorsolateral, orbitofrontal, or frontopolar regions) to enable chronic recording of local field potentials. The system allowed for long-term, wireless neural recordings in naturalistic or task-based conditions.
BEHAVIORALEffort-Reward Decision-Making Task
Participants performed a structured task involving repeated choices to accept or reject offers requiring different levels of physical effort in exchange for variable rewards. The task was used to assess motivation and effort-based valuation processes.
OTHERPrefrontal Cortex Stimulation
In one participant, high-frequency stimulation was delivered to the prefrontal cortex via the ECoG strip during a behavioral paradigm. Stimulation was alternated On and Off in a blinded block-wise fashion during the behavioral task to assess causal effects on motivated behavior. In two patients, orbitofrontal cortex (OFC) stimulation was also assessed chronically at home in a within subject, repeated design.
BEHAVIORALTablet-Based Mood Tracking (Immediate Mood Scaler)
Participants used a tablet-based Immediate Mood Scaler (IMS) to self-report symptoms related to depression and anxiety in real-time, naturalistic settings. These repeated, in-the-moment assessments were temporally paired with prefrontal cortical recordings to study physio markers of mood fluctuations over several months. No stimulation was delivered through the prefrontal cortex electrode.
Sponsors
Simon J. Little, MBBS, PhD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Ability to give informed consent for the study * Age 30-75 * Diagnosis of Parkinson's disease by a movement disorders specialist * Movement disorder symptoms that are sufficiently severe, in the setting of best medical therapy, to warrant surgical implantation of deep brain stimulators according to standard clinical criteria * UPDRS-III score off medication between 20 and 80 and an improvement of at least 30% in the baseline UPDRS-III on medication score, compared to the baseline off-medication score. OR Patients with tremor-dominant PD (a tremor score of at least 2 on a UPDRS-III sub-score for tremor), treatment resistant, with significant functional disability despite maximal medical management OR Patients intolerant to medication causing significant functional disability * Have one or several mild to moderate mood or impulsive behavior as defined by: 1. depression (BDI\>=13) 2. anxiety (BAI \>=7) 3. impulsive behavior as indicated by a positive score on the Questionnaire for Impulsive-Compulsive disorders in Parkinson's Disease (QUIP-A) or as determined by clinical interview or informant report 4. Mood or behavior symptom fluctuations corresponding to minimum 30% improvement in non-motor symptoms when comparing visual analogue scales (VAS) scores in the on versus off medication state * Stable doses of anti-Parkinsonian medications for at least 30 days prior to their baseline assessment.
Exclusion criteria
* Pregnancy or breast feeding * MRI showing cortical atrophy out of proportion to age * MRI showing focal brain lesions that could indicate a disorder other than idiopathic PD * Major comorbidity increasing the risk of surgery (prior stroke, severe hypertension, severe diabetes, or need for chronic anticoagulation other than aspirin) * Any prior intracranial surgery except DBS surgery * Significant cognitive impairment (MoCA\<20). * History of seizures * Immunocompromised * Has an active infection * Requires diathermy, electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) to treat a chronic condition * Inability to comply with study follow-up visits * Any personality or mood symptoms that study personnel believe will interfere with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Association Between Basal Ganglia Beta Power and Effort Level (Beta Coefficient) | Single recording session per participant (approximately 90 minutes total; 3 blocks of 25 trials each), with outcome assessed at each trial and data aggregated across all trials for all participants. | Mean beta-band (12-20 Hz) oscillatory power in the basal ganglia (BG) during the decision period, analyzed as a function of the current trial effort level during the reward-effort decision-making task. |
| Prefrontal Cortex Theta Power Relative to Previous Trial Reward (Beta Coefficient) | Single recording session per participant (approximately 90 minutes total; 3 blocks of 25 trials each), with outcome assessed at each trial and data aggregated across all trials for all participants. | Mean theta-band (4-7 Hz) oscillatory power in the prefrontal cortex (PFC) was assessed during the decision period of each trial. Theta power was modeled as a function of the reward received in the previous trial using linear mixed-effects models. The analysis included trials from structured decision-making task sessions. |
| Effect of Reward Magnitude and Effort Cost on Offer Acceptance Probability | Single recording session per participant (approximately 90 minutes total; 3 blocks of 25 trials each), with outcome assessed at each trial and data aggregated across all trials for all participants. | This outcome measures the effect of reward magnitude and effort cost on the probability of participants accepting offers during a decision-making task. Effects were assessed using generalized linear mixed models (LMMs) to estimate the relationship between reward, effort, and choice behavior. |
| Association Between Prefrontal Cortex Beta Band Spectral Power and Mood Symptoms | Daily paired assessments of neural recordings and IMS scores over 3-5 months for each participant. | This outcome measures the association between prefrontal cortex (PFC) beta band spectral power recorded via chronic subdural ECoG and self-reported symptoms of depression and anxiety assessed using standardized scales. Associations were evaluated using Spearman correlation coefficients calculated for each participant. The Beck Depression Inventory (BDI) ranges from 0 to 63, with higher scores indicating more severe depressive symptoms. The Beck Anxiety Inventory (BAI) ranges from 0 to 63, with higher scores indicating more severe anxiety symptoms. |
| Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings | Daily paired assessments of neural recordings and IMS scores over 14 days for each participant. | This outcome measures self-reported symptoms of depression, anxiety, and energy levels in participants undergoing chronic orbitofrontal cortex (OFC) stimulation at home. Participants received blinded OFC stimulation for 14 days, with alternating sham and active stimulation days. Symptoms were assessed daily using visual analogue scales (VAS) for depression, anxiety, and energy, as well as the Hamilton Depression Rating Scale (HAM-D). The VAS ranges from 0 to 100. For the depression and anxiety VAS, higher scores indicate worse symptoms, whereas for the energy VAS, higher scores indicate greater energy. The HAM-D ranges from 0 to 52, with higher scores indicating more severe depressive symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Prefrontal Cortex Stimulation on Acceptance Rate of Work Offers During Effort-Based Decision-Making Task | Six recording blocks (three with stimulation On and three with stimulation Off), each approximately 15 minutes in duration (total ~90 minutes), with outcome assessed on each trial and data aggregated across both conditions for the participant. | Measured the effect of high-frequency prefrontal cortex (PFC) stimulation on the acceptance rate of work offers during an effort-based decision-making task in one participant (PD5). Stimulation was delivered in a single-blinded, randomized, counterbalanced block-wise design at an amplitude below detectability threshold and without motor effects. Acceptance rate was modeled using a linear mixed model with stimulation condition (On vs Off) as a fixed effect. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease Participants with Parkinson's disease underwent implantation of deep brain stimulation (DBS) leads targeting the basal ganglia (subthalamic nucleus or globus pallidus internus) for motor symptom management, along with a permanent 4-contact subdural electrocorticography (ECoG) strip placed over the right prefrontal cortex. The ECoG strip was connected to a Medtronic Activa PC+S neurostimulator to enable chronic recording of local field potentials from the prefrontal cortex during everyday life and experimental tasks. All participants contributed neural and behavioral data, either during structured decision-making tasks or through longitudinal self-tracking of mood and symptoms using a tablet-based tool. One participant also underwent blinded, block-wise prefrontal cortex stimulation via the ECoG strip during a behavioral task to assess causal effects on motivation and decision-making. Two patients tested at home blinded chronic Prefrontal stimulation over 14 days in addition to their subcortical motor stimulation and provided self report ratings of mood and anxiety. Clinical DBS and medication adjustments were made only as part of routine care and not influenced by study participation. | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Participant developed cognitive decline and was unable to provide regular symptom assessments | 1 |
Baseline characteristics
| Characteristic | Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 61 years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 1 / 5 |
| serious Total, serious adverse events | 2 / 5 |
Outcome results
Primary
Association Between Basal Ganglia Beta Power and Effort Level (Beta Coefficient)
Mean beta-band (12-20 Hz) oscillatory power in the basal ganglia (BG) during the decision period, analyzed as a function of the current trial effort level during the reward-effort decision-making task.
Time frame: Single recording session per participant (approximately 90 minutes total; 3 blocks of 25 trials each), with outcome assessed at each trial and data aggregated across all trials for all participants.
Population: Five participants were enrolled in the study. However, one participant developed cognitive decline during the study and was unable to provide regular symptom assessments, so only four participants were included in the final analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Association Between Basal Ganglia Beta Power and Effort Level (Beta Coefficient) | -0.175 beta coefficient |
p-value: 0.007Mixed Models Analysis
Primary
Association Between Prefrontal Cortex Beta Band Spectral Power and Mood Symptoms
This outcome measures the association between prefrontal cortex (PFC) beta band spectral power recorded via chronic subdural ECoG and self-reported symptoms of depression and anxiety assessed using standardized scales. Associations were evaluated using Spearman correlation coefficients calculated for each participant. The Beck Depression Inventory (BDI) ranges from 0 to 63, with higher scores indicating more severe depressive symptoms. The Beck Anxiety Inventory (BAI) ranges from 0 to 63, with higher scores indicating more severe anxiety symptoms.
Time frame: Daily paired assessments of neural recordings and IMS scores over 3-5 months for each participant.
Population: Five participants were enrolled in the study. However, one participant developed cognitive decline during the study and was unable to provide regular symptom assessments, so only four participants were included in the final analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Association Between Prefrontal Cortex Beta Band Spectral Power and Mood Symptoms | 0.415 Spearman correlation coefficient (r) |
Primary
Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings
This outcome measures self-reported symptoms of depression, anxiety, and energy levels in participants undergoing chronic orbitofrontal cortex (OFC) stimulation at home. Participants received blinded OFC stimulation for 14 days, with alternating sham and active stimulation days. Symptoms were assessed daily using visual analogue scales (VAS) for depression, anxiety, and energy, as well as the Hamilton Depression Rating Scale (HAM-D). The VAS ranges from 0 to 100. For the depression and anxiety VAS, higher scores indicate worse symptoms, whereas for the energy VAS, higher scores indicate greater energy. The HAM-D ranges from 0 to 52, with higher scores indicating more severe depressive symptoms.
Time frame: Daily paired assessments of neural recordings and IMS scores over 14 days for each participant.
Population: Five participants were enrolled in the study. 2 participants completed this (1 participant dropped out of research activities, 1 declined and 1 moved away from the study centre and so couldn't be followed).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings | VAS Anxiety Score (Sham Condition) | 23.23 score on a scale | Standard Deviation 23.71 |
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings | VAS Energy Score (Sham Condition) | 67.62 score on a scale | Standard Deviation 23.59 |
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings | VAS Depression Score (Sham Condition) | 19.15 score on a scale | Standard Deviation 22.71 |
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings | VAS Anxiety Score (Active Condition) | 33.00 score on a scale | Standard Deviation 30.35 |
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings | VAS Depression Score (Active Condition) | 28.63 score on a scale | Standard Deviation 28.45 |
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings | HAM-D Score (Sham Condition) | 2.31 score on a scale | Standard Deviation 2.72 |
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings | HAM-D Score (Active Condition) | 2.25 score on a scale | Standard Deviation 2.96 |
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Chronic Orbitofrontal Cortex (OFC) Stimulation on Depression, Anxiety, and Energy Ratings | VAS Energy Score (Active Condition) | 71.06 score on a scale | Standard Deviation 20.24 |
Primary
Effect of Reward Magnitude and Effort Cost on Offer Acceptance Probability
This outcome measures the effect of reward magnitude and effort cost on the probability of participants accepting offers during a decision-making task. Effects were assessed using generalized linear mixed models (LMMs) to estimate the relationship between reward, effort, and choice behavior.
Time frame: Single recording session per participant (approximately 90 minutes total; 3 blocks of 25 trials each), with outcome assessed at each trial and data aggregated across all trials for all participants.
Population: Five participants were enrolled in the study. However, one participant developed cognitive decline during the study and was unable to provide regular symptom assessments, so only four participants were included in the final analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Reward Magnitude and Effort Cost on Offer Acceptance Probability | Reward magnitude effect (higher reward, higher acceptance) | 1.05 beta coefficient |
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Reward Magnitude and Effort Cost on Offer Acceptance Probability | Effort cost effect (higher effort, lower acceptance) | -2.37 beta coefficient |
Comparison: This statistical analysis corresponds to the first outcome row, Reward magnitude effect (higher reward, higher acceptance). The generalized linear mixed model examined the effect of reward magnitude on the probability of accepting offers.p-value: <0.0001Mixed Models Analysis
Comparison: This statistical analysis corresponds to the second outcome row, Effort cost effect (higher effort, lower acceptance). The generalized linear mixed model examined the effect of effort cost on the probability of accepting offers.p-value: <0.0001Mixed Models Analysis
Primary
Prefrontal Cortex Theta Power Relative to Previous Trial Reward (Beta Coefficient)
Mean theta-band (4-7 Hz) oscillatory power in the prefrontal cortex (PFC) was assessed during the decision period of each trial. Theta power was modeled as a function of the reward received in the previous trial using linear mixed-effects models. The analysis included trials from structured decision-making task sessions.
Time frame: Single recording session per participant (approximately 90 minutes total; 3 blocks of 25 trials each), with outcome assessed at each trial and data aggregated across all trials for all participants.
Population: Five participants were enrolled in the study. However, one participant developed cognitive decline during the study and was unable to provide regular symptom assessments, so only four participants were included in the final analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Prefrontal Cortex Theta Power Relative to Previous Trial Reward (Beta Coefficient) | 0.424 beta coefficient |
p-value: 0.018Mixed Models Analysis
Secondary
Effect of Prefrontal Cortex Stimulation on Acceptance Rate of Work Offers During Effort-Based Decision-Making Task
Measured the effect of high-frequency prefrontal cortex (PFC) stimulation on the acceptance rate of work offers during an effort-based decision-making task in one participant (PD5). Stimulation was delivered in a single-blinded, randomized, counterbalanced block-wise design at an amplitude below detectability threshold and without motor effects. Acceptance rate was modeled using a linear mixed model with stimulation condition (On vs Off) as a fixed effect.
Time frame: Six recording blocks (three with stimulation On and three with stimulation Off), each approximately 15 minutes in duration (total ~90 minutes), with outcome assessed on each trial and data aggregated across both conditions for the participant.
Population: One participant performed the decision-making task with PFC stimulation alternated On and Off between blocks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chronic Neural Recording With Prefrontal Cortex ECoG in Parkinson's Disease | Effect of Prefrontal Cortex Stimulation on Acceptance Rate of Work Offers During Effort-Based Decision-Making Task | 9.646 beta coefficient |