TACS to Engage Theta-Gamma Coupling and Enhance Working Memory in Patients with MCI (tACS-MCI)

This study is looking at a new non-invasive brain stimulation methods called transcranial alternating current stimulation (tACS) to see if it can improve working memory and thinking processes in people with Mild Cognitive Impairment (MCI). tACS is a low-risk, non-painful, low electrical current that circulates through the brain of awake participants and stimulates their brain cells. Participants must be 60 years of age and have a diagnosis of mild cognitive impairment. Participants will undergo treatment sessions that range from 1 to 1.5 hours at CAMH, 5 days a week, over a total of 2 weeks. In addition, participants will complete clinical and cognitive assessments and bloodwork at baseline and again after treatment.

Current treatments for Alzheimer's disease dementia (AD) have limited efficacy probably because by the time AD is manifest it is too late to intervene. Thus, discovering interventions that will prevent AD is highly needed.

Mild Cognitive Impairment (MCI) is a condition that is considered a pre-stage to AD. In MCI, the frontal part of the brain supports the ability to compensate for memory problems which could delay progression to AD. This compensation is supported by "flexible" thinking which includes the ability to hold and manipulate information in mind for brief periods of time (e.g. doing mental math), also called working memory. Working memory has been shown by us and others to depend on the linking of brain waves across multiple brain waves frequencies.

Transcranial Alternating Current Stimulation (tACS) is a non-invasive electrical stimulation, applied to the scalp, that has been shown to improve this linking of brain waves in healthy older individuals. It has also been shown to enhance working memory in older individuals when this linking is enhanced. The effect of tACS on working memory and linking of brain waves in patients with MCI has not been demonstrated yet.

The study investigators propose to study the feasibility and preliminary effects of tACS on TGC and working memory in MCI participants. This proof-of-concept study will test whether tACS engages TGC as a target and, in turn, enhances working memory. Additionally, the investigators will explore the relationship among tACS effects and stress neuroreactivity and neuroimmune/inflammatory response (i.e., the interaction between the nervous system and the immune system), as well as the potential links with working memory.

If successful, our project will serve as a model for a larger trial to confirm the ability of tACS to prevent AD over multiple years of follow-up.

Objective 1: To determine the feasibility of tACS in older individuals with MCI. The investigators will examine recruitment and retention. Hypothesis 1a: At least 30% of screened participants will agree and be eligible to receive the intervention they are assigned to, i.e., tACS. Hypothesis 1b: At least 70% of participants will attend at least 80% of their treatment sessions.

Objective 2: To determine TGC engagement in response to tACS. The investigators will assess whether TGC increases in response to tACS. Hypothesis 2: Participants randomized to tACS will experience higher increase in TGC than those randomized to sham-tACS.

Objective 3: To determine change in working memory in response to tACS, and whether changes in TGC mediate changes in N-back performance with 2-back d' being the primary N-back outcome measure. Hypothesis 3a: Participants randomized to tACS will experience more improvement on N-back from baseline following the intervention than those randomized to sham-tACS. Hypothesis 3b: Across all participants, change in TGC will mediate change in N-back performance.

Exploratory Objective 4: To explore the relationships among tACS effects and stress neuroreactivity and neuroimmune/inflammatory response, as well as the potential links with working memory. Exploratory Hypothesis 4a: Baseline measure of stress neuroreactivity (i.e., salivary α-amylase and cortisol levels) will moderate response to tACS vs. sham-tACS. Exploratory Hypothesis 4b: Baseline measure of neuroimmune/inflammatory response (i.e., s100B, NSE, and MBP / IL-1β, IL-6, CRP, and TNF-α) will moderate response to tACS vs. sham-tACS. Exploratory Hypothesis 4c: Participants randomized to tACS will experience better stress neuroreactivity (i.e., salivary α-amylase and cortisol levels) from baseline following the intervention than those randomized to sham-tACS. Exploratory Hypothesis 4d: Participants randomized to tACS will experience better neuroimmune/inflammatory response (i.e., s100B, NSE, and MBP / IL-1β, IL-6, CRP, and TNF-α) from baseline following the intervention than those randomized to sham-tACS.

Exploratory Mediation Hypothesis: Across all participants, changes in stress neuroreactivity (i.e., salivary α-amylase and cortisol levels) and neuroimmune/inflammatory response (i.e., s100B, NSE, and MBP /I L-1β, IL-6, CRP, and TNF-α) will mediate change in TGC, N-back performance, and working memory.

Eligibility Criteria:
Inclusion Criteria:

1. Age 60 years or above,
2. 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:

   1. Cognitive concern reflecting a change in cognition reported by patient or informant or clinician (i.e., historical or observed evidence of decline over time)
   2. Not demented ascertained using the study investigator opinion.
   3. No vascular, traumatic, or medical causes of cognitive decline ascertained using the study investigator opinion.
   4. Evidence of longitudinal decline in cognition, when feasible, and ascertained using the study investigator opinion.
3. Objective evidence of single or multi domain MCI, where single domain MCI refers to deficits using neuropsychology (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 Analyst/Fellow, 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.
4. Willingness to provide informed consent,
5. Ability to read and communicate in English (with corrected vision and hearing, if needed)

Exclusion Criteria:

1. Current use of an acetylcholine esterase inhibitor or memantine ascertained using a Medication List.
2. Major Depressive Disorder with active symptoms in the last 3 months ascertained using the MINI International Neuropsychiatric Interview
3. A lifetime diagnosis of bipolar disorder; intellectual disability; or a psychotic disorder ascertained using the MINI
4. Substance use disorder active in the last 3 months ascertained using the MINI
5. Any other DSM-5 diagnosis ascertained using the MINI that may be associated with prefrontal cortical dysfunction as ascertained using a study investigator opinion.
6. Current anticonvulsant use due to its impact on brain stimulation 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.
7. 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
8. Any contraindication to MRI or contraindication to tACS (e.g., cardiac pacemaker, acoustic device, history of seizures) ascertained using the TMS Adult Safety Screen (TASS)