- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03846492
Targeting Brain Physiology to Treat Neuropsychiatric Symptoms of Dementia Using TMS-EEG and tDCS (tTED)
Study Overview
Status
Intervention / Treatment
Detailed Description
Alzheimer's dementia (AD) and related neurodegenerative diseases are inflicting a global healthcare crisis. Neuropsychiatric symptoms including agitation and aggression affect up to 80% of patients with AD. Among these symptoms, agitation and aggression are the most burdensome for patients, families, caregivers, and the health care system. The mechanisms of agitation in AD are poorly understood and the current interventions are only modestly effective while having serious adverse effects.
In this study, the investigators propose to assess the mechanisms and treatment of neuropsychiatric symptoms in AD with the use of non-invasive, brain stimulation approaches. Agitation/aggression is associated with abnormalities in the balance of cortical excitation/inhibition. Transcranial magnetic stimulation (TMS) using single and paired pulse TMS paradigms such as long interval cortical inhibition (LICI) and short interval intracortical inhibition (SICI) can assess this cortical excitation/inhibition balance in vivo. The investigators will use TMS, combined with electroencephalography (EEG), to assess cortical excitation/inhibition balance in the dorsolateral prefrontal cortex (DLPFC) of participants with AD with and without agitation/aggression and age matched healthy comparators.
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that uses a very low intensity electric current to modulate cortical excitability and brain plasticity. tDCS can restore excitation and inhibition balance by altering GABA and glutamate activity in the brain. tDCS can be safely administered to awake persons and is very well tolerated. Studies in healthy individuals and patients with AD have shown that tDCS applied to frontal brain regions can enhance cognitive function. Further, tDCS applied to frontal brain regions can improve depressive symptoms. The effects of tDCS on neuropsychiatric symptoms are not known. In this study, the investigators will use tDCS applied to the frontal brain regions to target deficits in inhibition and symptoms of agitation/aggression in AD.
This study will be done over a period of 3 years at Centre for Addiction and Mental Health Geriatric Psychiatry Division and Temerty Centre for Therapeutic Brain Intervention. The investigators will recruit and enroll 30 individuals with AD + Agitation (mild to moderate agitation), 30 individuals with AD without agitation and 30 older healthy individuals. Medical work up will be done as part of clinical care prior to study enrollment to rule out medical causes of agitation. Clinical and cognitive assessments will be performed to characterize participants at baseline. The investigators will assess cortical inhibition using TMS EEG at baseline in the three groups. Individuals with AD + agitation will then receive a 2 week course of active/sham cathodal tDCS to frontal brain region in a double blind 1:1 randomized control design. Assessment of cortical inhibition using measures identical to baseline will be done at the end of tDCS course. The investigators will also repeat clinical and cognitive assessments after tDCS course and 2 weeks later. Measures of cortical inhibition will first be compared between HC and AD, and between AD and AD + Agitation groups. The treatment effects on clinical symptoms, cortical inhibition and the rate adverse events will be compared between active and sham tDCS groups.
During the Covid-19 pandemic, the study has been modified to be administered in a hybrid manner to accommodate both in-person and virtual assessments. Clinical and cognitive assessments can be done in-person or remotely. The initial tDCS course will be conducted in-person with the research staff. The remaining tDCS intervention will be completed onsite or at the participant's home with virtual supervision from the research team.
Study Type
Enrollment (Estimated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Gifty Asare, MSc
- Phone Number: 32796 416-535-8501
- Email: Gifty.Asare@camh.ca
Study Locations
-
-
Ontario
-
Toronto, Ontario, Canada, M6J 1H4
- Recruiting
- Centre for Addiction and Mental Health
-
Contact:
- Sanjeev Kumar, MD, FRCPC
- Phone Number: 39384 416-535-8501
- Email: sanjeev.kumar@camh.ca
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Participants with AD+Agitation
Inclusion:
- Age 50 years or older.
- Participant or substitute decision maker able and willing to provide informed consent.
- Dementia due to probable or possible AD as defined by NIA-AA criteria.
- Presence of mild to moderate agitation and/or aggression as defined by: Agitation in cognitive disorders. International Psychogeriatric Association Provisional Consensus Clinical and Research Definition.
- Availability of a support person to accompany the participant to study appointments and provide collateral information as needed.
- If taking medication for neuropsychiatric symptoms, the dose should be stable for at least 1 week.
Exclusion:
- Psychiatric diagnosis other than dementia significantly impacting the presentation.
- Presence of delirium or other acute medical condition significantly contributing to agitation/aggression or making the study participation unsafe for a participant.
- Any contraindication to TMS or tDCS.
- Any other condition that in the opinion of principal investigator will make the study participation unsafe or non-feasible for the participant.
- Currently taking anticonvulsants or benzodiazepines at a dose sufficient to cause interference with TMS-EEG.
Participants with AD without aggression
All the above inclusion/exclusion criteria except meeting the inclusion criterion 4 pertaining to agitation/aggression. Participants with significant agitation/aggression will be excluded from this group.
Healthy comparator participants
Inclusion:
- Age 50 years or older.
- Able and willing to provide informed consent.
- Free from any significant neurological disorder.
Exclusion:
- Lifetime DSM-5 diagnosis other than simple phobias or adjustment disorder.
- Any Contraindication to TMS.
- Currently taking anticonvulsants or benzodiazepines at a dose sufficient to cause interference with TMS-EEG.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Active tDCS
The direct current will be delivered at 2 mA intensity via rubber electrodes in saline- soaked sponges for 30 min per day for 2 weeks, 5 days/week.
Inhibitory stimulation will be delivered to the frontal lobes.
|
tDCS is a non-invasive brain stimulation modality that does not require general anesthesia or surgical implantation of a device.
tDCS utilizes low intensity electrical current either to increase cortical excitability with an anodal electrode or to suppress cortical excitability with a cathodal electrode.
It uses 3 AAA batteries to deliver direct current via rubber electrodes enclosed in saline soaked sponges.
|
Sham Comparator: sham tDCS
Sham tDCS will use the same parameters except that the device will automatically turn off after a certain duration.
|
tDCS is a non-invasive brain stimulation modality that does not require general anesthesia or surgical implantation of a device.
tDCS utilizes low intensity electrical current either to increase cortical excitability with an anodal electrode or to suppress cortical excitability with a cathodal electrode.
It uses 3 AAA batteries to deliver direct current via rubber electrodes enclosed in saline soaked sponges.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Long Interval Cortical Inhibition (LICI), a TMS paradigm, will be used to assess the extent of cortical inhibition
Time Frame: Baseline
|
LICI will be measured using single and paired TMS pulses applied to the Dorsolateral Prefrontal Cortex (DLPFC).
LICI will be compared between the 3 groups (AD, AD+agitation and healthy comparators).
|
Baseline
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Short Interval Cortical Inhibition (SICI), another TMS paradigm, will be used to assess the extent of cortical inhibition
Time Frame: Baseline
|
SICI will be measured using single and paired TMS pulses applied to the DLPFC and motor cortex.
SICI will be compared between the 3 groups (AD, AD+agitation and healthy comparators).
|
Baseline
|
The rate of successful completion of the 2 week tDCS treatment course
Time Frame: Approximately 2 weeks after baseline
|
This will be assessed by the successful completion of the intervention in at least 80% of participants without any treatment associated serious adverse effects.
|
Approximately 2 weeks after baseline
|
Effects of a 2 week course of tDCS on cortical/inhibition balance
Time Frame: Approximately 2 weeks after baseline
|
TMS using single and paired pulse paradigms, such as LICI and SICI, will be repeated after completion of the 2 week course of tDCS.
|
Approximately 2 weeks after baseline
|
Change in clinical symptoms of agitation as assessed by the Clinical Global Impression of Change (CGIC)
Time Frame: Approximately 2 and 4 weeks after baseline
|
The clinical symptoms will be assessed at baseline, after completion of the tDCS intervention and at follow up 2 weeks after last tDCS session.
CGIC scores range from 0-7, higher scores indicating worsening compared to baseline.
|
Approximately 2 and 4 weeks after baseline
|
Change in clinical symptoms of agitation as assessed by the Neuropsychiatric Inventory (NPI) agitation/aggression subscale score
Time Frame: Approximately 2 and 4 weeks after baseline
|
The clinical symptoms will be assessed at baseline, after completion of the tDCS intervention and at follow up 2 weeks after last tDCS session.
NPI frequency of symptoms are rated on a scale of 0 - 4 (Higher scores indicate symptoms occur more frequently).
Severity / intensity of symptoms are rated on a scale of 0 to 3 (Higher scores indicate greater severity of symptoms).
Caregiver distress is rated on a scale of 0 to 5 (Higher scores indicate increased caregiver distress).
|
Approximately 2 and 4 weeks after baseline
|
Change in clinical symptoms of agitation as assessed by the Cohen Mansfield Agitation Inventory scores (CMAI)
Time Frame: Approximately 2 and 4 weeks after baseline
|
The clinical symptoms will be assessed at baseline, after completion of the tDCS intervention and at follow up 2 weeks after last tDCS session.
CMAI-frequency score ranges between 29 to 203 and CMAI-disruptiveness ranges from 29 to 145 for each category.
Higher scores indicate worsening of symptoms.
|
Approximately 2 and 4 weeks after baseline
|
Assess brain structure using Magnetic Resonance Imaging (MRI)
Time Frame: Baseline
|
Brain structure (e.g.
cortical atrophy and white matter integrity) will be compared between the 3 groups (AD, AD+agitation and healthy comparators).
|
Baseline
|
Assess resting state connectivity using Functional Magnetic Resonance Imaging (fMRI)
Time Frame: Baseline
|
Resting state connectivity using Brain Oxygen Level Dependent (BOLD) signal will be compared between the 3 groups (AD, AD+agitation and healthy comparators).
|
Baseline
|
Assess GABA and glutamate levels using Magnetic Resonance Spectroscopy (MRS)
Time Frame: Baseline
|
GABA and glutamate concentrations will be measured in the left DLPFC and compared between the 3 groups (AD, AD+agitation and healthy comparators).
|
Baseline
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Sanjeev Kumar, MD, FRCPC, Centre for Addiction and Mental Health
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 093/2018
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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