Deep rTMS for Mild Neurocognitive Disorder in Older Adults

Percentage of intervention sessions completed

Percentage of participants who complete study once enrolled

Number of participants (n) screened; n enrolled as a percentage of n screened monthly

Total number of participants recruited and enrolled per month.

Compared to estimated times, the actual mean times (in min) from start to finish for each dTMS intervention session and mean time (in hours) from start to finish for each visit.

Total number of adverse events reported during the treatment sessions assessed by the Side Effects Questionnaire for dTMS (custom-developed for study). At each dTMS stimulation session, participants will complete a questionnaire to evaluate potential adverse effects of dTMS (headache, neck pain, itching and redness at the site of stimulation) according to a 4-point scale.

Percentage of participants withdrawn or terminated following enrollment due to adverse events

The Everyday Memory Questionnaire (EMQ) is a 28-item self-report tool, that will be used to assess the frequency and impact of everyday memory problems. It will be measured at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up.

The CNS Vital Signs is the name of a standardized computerized neurocognitive test battery and not a set of physiological vital signs like heart rate or blood pressure. The assessments within CNS Vital Signs are cognitive domains such as memory, executive function, processing speed, etc., not physiological measurements.

It will be measured at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up.

Symptoms of depression will be assessed with the HDRS- 24 item (a 24-item depression checklist) at multiple visits: at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up.

Symptoms of anxiety will be assessed using this 7-item questionnaire at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up. Scores of 0-4 indicate minimal anxiety; 5-9: mild anxiety; 10-14: moderate anxiety; and 15 or greater: severe anxiety.

Sleep will be monitored and assessed using the Pittsburgh Sleeping Quality Index (PSQI) at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up.

Somatic symptoms will be evaluated using the Patient Health Questionnaire (PHQ) somatic inventory at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up.

The Mulitfactorial Memorial Questionnaire (MMQ) is a self-report tool to evaluate three distinct aspects of memory: satisfaction with memory (MMQ-Satisfaction), the frequency of memory lapses (MMQ-Ability), and the use of memory strategies (MMQ-Strategy). It will be measured at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up.

Using electroencephalography (EEG), we will assess alpha, theta and gamma rhythms in fronto-temporo-parietal region, including assessment of connectivity and coherence. We will additionally measure cross-frequency coupling named theta (4-8Hz)-gamma (>25Hz) phase-amplitude coupling (PAC). We will also investigate phase synchronization in upper theta frequency band between prefrontal and temporal areas. Changes in these EEG parameters will be correlated with changes in mood severity and cognitive status, with a focus on working memory improvements. EEG will be performed before dTMS sessions at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up, by using a wireless dry electrode portable EEG system (CGX Quick 20r). Resting state connectivity, coherence, PAC, and synchronization assessed by EEG will use standardized data processing pipelines in EEG Lab

WHOQOL-BREF will measure quality of life in physical, psychological and social domains. This will be measured at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up.

The PGI-I is a single-item global assessment scale used to measure the patient's perceived improvement following an intervention or treatment. This will be measured at midpoint (V11), end of the treatment (V20) and at one-month follow-up.

Delay discounting task which assess propensity to devalue future rewards by asking participants to choose between an immediate small monetary amount and a delayed larger monetary amount. Rewards are hypothetical. This will be measured at baseline (V1), midpoint (after 10th session - before deep TMS treatment on V11) and end point, as well as follow-up

Quantity specific biomarkers associated with neurodegeneration {Brain-derived neurotrophic factor (BDNF), Beta-amyloid ratio (Aβ1-42/Aβ1-40 ratio), Phosphorylated Tau 217 (pTAU-217), Neurofilmament light chain (NfL), Cytokines (IGF-1, VEGF, TGF-β1, MCP-1, IL-18)}, will be analyzed using immunoassays, including enzyme-linked immunosorbent assays (ELISA) and single molecular array (SIMOA) technology. These will be measured at baseline (V1) and at one-month follow-up.