Enhancing Frontal Lobes Plasticity and Function in Patients With Mild Cognitive Impairment
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- PAS-Long-term-potentiation (PAS-LTP)
研究概览
简要总结
More than 5 million people live with Alzheimer's dementia (AD) in North America. No effective treatment exists yet probably because by the time AD has developed it is too late to intervene. Mild Cognitive Impairment (MCI) is a clinical state that typically precedes AD. In MCI, the prefrontal cortex supports compensatory mechanisms that depend on robust synaptic plasticity and that delay progression to AD. Using a neurostimulation approach that enhances prefrontal cortical plasticity in vivo, this project aims to enhance prefrontal cortical plasticity and function in patients with MCI. If successful, this project would discover a treatment modality that enhances compensation in MCI and ultimately, prevents progression to AD.
详细描述
Paired Associative Stimulation (PAS) is a neurostimulation approach that induces cortical plasticity by simulating spike-timing-dependent plasticity. Combining PAS with electroencephalography (EEG) (PAS-EEG), we can assess dorsolateral prefrontal cortex (DLPFC) plasticity in vivo. Using PAS-EEG, we have demonstrated that patients with AD are impaired on DLPFC plasticity compared to healthy control (HC) individuals and that DLPFC plasticity is associated with working memory in AD and HC individuals. We have also shown that a 2-week course of daily PAS to the left DLPFC restores DLPFC plasticity in patients with AD and enhances their working memory.
Thus, we propose to study DLPFC plasticity and its relationship to executive function in MCI and then assess the efficacy of a 2-week course of PAS in enhancing DLPFC plasticity and executive function in this population.
If successful, this project will identify a novel neurostimulation intervention (PAS) to enhance prefrontal cortical function in MCI patients. This enhancement could result in modifying the trajectory of Alzheimer's disease by delaying the progression from MCI to clinical AD. This project will also identify a mechanism (neuroplasticity) that underlies enhanced prefrontal cortical function. Other interventions (e.g. behavioral, neurostimulation, pharmacological) could then be tested whether they engage neuroplasticity to enhance prefrontal cortical function.
The objectives and hypotheses of the study are as follows:
Objective 1: To compare baseline DLPFC plasticity and its relationship to executive function in MCI vs. HC participants. Hypothesis 1a: MCI participants will be impaired on PAS-LTP (TMS-induced cortical evoked activity) in the left DLPFC compared to HC participants. Hypothesis 1b: MCI participants will be impaired on 2-back d' compared to HC participants. Hypothesis 1c: MCI participants will be impaired on a composite executive function measure compared to HC participants. Hypothesis 1d: PAS-LTP will be associated with 2-back d' in MCI and HC participants after controlling for age, sex, and education. Hypothesis 1e: PAS-LTP will be associated with composite executive function measure in MCI and HC participants after controlling for age, sex, and education.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
A unique advantage of Paired Associative Stimulation (PAS) over other TMS-based interventions is that its control condition (PAS-C) is almost impossible to distinguish from active PAS. Thus, the RCT phase of the study will be completed under triple-blind conditions. First, participants will be blind to whether they are randomized to PAS or PAS-C. Second, the investigator team (investigators and interventionists delivering the 10-session course) will be blind to group assignment. Third, the outcomes assessors conducting the clinical, cognitive and PAS-EEG assessments at baseline and follow-ups will be blind to group assignment.
入排标准
- 年龄范围
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Inclusion Criteria:
- •Age 60 years or above.
- •Right-handed (to minimize heterogeneity with respect to cognitive reserve and plasticity) and as determined by the Edinburgh Handedness Questionnaire.
- •Diagnosis of MCI due to AD using the core clinical criteria by the National Institute on Aging and Alzheimer's Association for MCI participants (NIA-AA) and ascertained by a study investigator. The following checklist will be used to ascertain the MCI diagnosis:
- •Cognitive concern reflecting a change in cognition reported by patient or informant or clinician (i.e., historical or observed evidence of decline over time).
- •Not demented ascertained using the study investigator opinion.
- •No vascular, traumatic, or medical causes of cognitive decline ascertained using the study investigator opinion.
- •Evidence of longitudinal decline in cognition, when feasible, and ascertained using the study investigator opinion.
- •Objective evidence of single or multi domain MCI, where single domain MCI refers to deficits using NP battery on only one of the cognitive domains (Speed of Processing; Working Memory; Executive Functioning; Verbal Memory; Visual Memory; Language)and multi domain MCI refers to deficits in more than one of these domains. To determine impairment in one or more cognitive domain, after the NP battery is administered and double scored, a consensus meeting will be held with the research study staff, the study Principal Investigator and the study Neuropsychologist during which eligibility will be discussed. The meeting attendees will take into consideration the participant's education, parental education, pre-morbid IQ, physician's assessment and NP scores to determine if the participant has impairment in one or more cognitive domain.
- •Willingness to provide informed consent.
- •Ability to read and communicate in English (with corrected vision and hearing, if needed).
排除标准
- •Current use of an acetylcholine esterase inhibitor or memantine ascertained using a Medication List.
- •Major Depressive Disorder with active symptoms in the last 3 months ascertained using the Structured Clinical Interview for DSM 5 (SCID-5).
- •A lifetime diagnosis of bipolar disorder; intellectual disability; or a psychotic disorder ascertained using the SCID-
- •Substance use disorder active in the last 3 months ascertained using the SCID-
- •Any other DSM-5 diagnosis ascertained using the SCID-5 that may be associated with prefrontal cortical dysfunction as ascertained using a study investigator opinion.
- •Current anticonvulsant use due to its impact on TMS induced activity and ascertained using a Medication List. An exception will be made if they are taking gabapentin or pregabalin AND if the dose had been stable for at least 4 weeks prior to study entry AND if prescribed for chronic pain.
- •Current benzodiazepine use of more than what is equivalent to lorazepam 2 mg/day as ascertained using a Medication List. This is due to their known pro-GABAergic activity and the suppressive effect of GABAergic agents on cortical plasticity.
- •Any contraindication to MRI or contraindication to TMS (e.g., cardiac pacemaker, acoustic device, history of seizures) ascertained using the TMS Adult Safety Screen (TASS).
- •Healthy Controls
- •Inclusion Criteria:
- •Age 60 years or above.
- •Right-handed (to minimize heterogeneity with respect to cognitive reserve and plasticity) and as determined by the Edinburgh Handedness Inventory.
- •MoCA score >
- •Ability to read and communicate in English (with corrected vision and hearing, if needed).
- •Willingness to provide informed consent.
- •Exclusion Criteria:
- •Diagnosis of MCI due to AD using the core clinical criteria by the National Institute on Aging and Alzheimer's Association for MCI participants and ascertained by a study investigator.
- •Any lifetime DSM-5 diagnosis ascertained using the SCID-5 (except for simple/specific phobias) or diagnosis that may be associated with prefrontal cortical dysfunction as ascertained using a study investigator opinion.
- •Any current use of a psychotropic medication for a CNS condition as ascertained using the Medication List.
- •Current anticonvulsant use due to its impact on TMS induced activity and ascertained using a Medication List. An exception will be made if they are taking gabapentin or pregabalin AND if the dose had been stable for at least 4 weeks prior to study entry AND if prescribed for chronic pain.
- •Current benzodiazepine use of more than what is equivalent to lorazepam 2 mg/day as ascertained using a Medication List. This is due to their known pro-GABAergic activity and the suppressive effect of GABAergic agents on cortical plasticity.
- •Any contraindication to MRI or contraindication to TMS (e.g., cardiac pacemaker, acoustic device, history of seizures) ascertained using the TMS Adult Safety Screen (TASS).
研究组 & 干预措施
Healthy Control
Healthy Controls will complete screening and baseline N-Back and PAS-EEG. 10 HC participants will also complete the optional pilot eye tracking VPC assessment following N-Back at the Baseline visit. HC participants will not complete the 10-session course of PAS or follow-up assessments.
Active PAS
MCI participants will complete the baseline N-back and PAS-EEG assessments at Visit 4. Additionally, 10 MCI participants will complete the optional pilot eye tracking VPC assessment following N-back and prior to PAS-EEG. Afterwards, MCI participants randomized to the active condition will receive a 10-session course of PAS (Visits 5-14), followed by the three follow-up assessments at 0 days, 7 days, and 28 days post intervention.
干预措施: Paired Associative Stimulation (PAS) (Device)
PAS-Control (PAS-C)
MCI participants will complete the baseline N-back and PAS-EEG assessments at Visit 4. Additionally, 10 MCI participants will complete the optional pilot eye tracking VPC assessment following N-back and prior to PAS-EEG. Afterwards, MCI participants randomized to the sham condition will receive a 10-session course of PAS-C (Visits 5-14), followed by the three follow-up assessments at 0 days, 7 days, and 28 days post intervention.
干预措施: Paired Associative Stimulation (PAS) (Device)
结局指标
主要结局
PAS-Long-term-potentiation (PAS-LTP)
时间窗: Baseline
PAS-LTP is measured as the ratio of TMS-induced cortical evoked activity (CEA) post-PAS to TMS-induced CEA pre-PAS
Change in PAS-Long-term-potentiation (PAS-LTP)
时间窗: Baseline, immediately and 1 and 4 weeks following the 10-session course
PAS-LTP is measured as the ratio of TMS-induced cortical evoked activity (CEA) post-PAS to TMS-induced CEA pre-PAS
N-Back Performance
时间窗: Baseline
The primary outcome measure will be based on the 2-back condition of the N-Back. N-back accuracy will be assessed using d', which is a sensitivity index based on the z scores of hit rates (H- correctly responding to target trials as target trials) and false alarm rates (F- incorrectly responding to non-target trials as target trials) using the following formula: d' = z(H) - z(F).
Change in N-Back Performance
时间窗: Baseline, immediately and 1 and 4 weeks following the 10-session course
The primary outcome measure will be based on the 2-back condition of the N-Back. N-back accuracy will be assessed using d', which is a sensitivity index based on the z scores of hit rates (H- correctly responding to target trials as target trials) and false alarm rates (F- incorrectly responding to non-target trials as target trials) using the following formula: d' = z(H) - z(F).
次要结局
- Executive Function Composite Measure(Baseline)
- Change in Executive Function Composite Measure(Baseline, immediately and 4 weeks following the 10-session course)