Cognitive impairment, including mild cognitive impairment (MCI) and mild dementia, is a growing public health challenge with limited effective treatment options. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that has shown promise for improving cognitive function, but most studies have used conventional protocols and relied on global screening tools that may not capture domain-specific changes. The purpose of this study is to evaluate the efficacy and tolerability of repetitive transcranial magnetic stimulation (rTMS) delivered via the EXOMIND™ device (BTL-699-2) for improving cognitive function in adults aged 50 to 90 years with mild to moderate cognitive impairment. The study asks whether a course of 6 rTMS sessions targeting the left dorsolateral prefrontal cortex, administered twice weekly over approximately 3 weeks, can produce meaningful and sustained improvements in global and domain-specific cognitive function over a 3-month follow-up period. This is a single-center, open-label, prospective pilot study enrolling 80 participants with documented cognitive decline (Montreal Cognitive Assessment \[MoCA\] score 10-25). Participants will receive 6 sessions of high frequency rTMS (6,300 pulses per session at alternating frequencies of 12, 15, and 18 Hz) over approximately 3 weeks. The primary outcome is the change from baseline in MoCA score at 1-month follow-up. Secondary outcomes include changes in MoCA score at post-treatment and 3-month follow-up, changes in domain-specific cognitive measures (visual spatial working memory, episodic memory, deductive reasoning, mental rotation, verbal short term memory, and attention) assessed by the Creyos cognitive battery, and changes in depressive symptoms measured by the Patient Health Questionnaire-9 (PHQ-9). Assessments are performed at baseline, post treatment, 1-month follow-up, and 3-month follow-up. Total study duration per participant is up to 139 days.
Background and Rationale Mild cognitive impairment (MCI) affects approximately 22% of adults over age 65 and represents a significant risk state for progression to dementia. Current pharmacological interventions, including cholinesterase inhibitors and memantine, demonstrate only modest efficacy (1-2.5 point improvements on cognitive scales), provide no established benefit specifically for MCI, and carry notable adverse effects including gastrointestinal symptoms, bradycardia, and falls. This has driven interest in non-pharmacological approaches, particularly repetitive transcranial magnetic stimulation (rTMS). Recent meta-analyses demonstrate that rTMS produces medium-to-large effect sizes (standardized mean difference = 0.93) for immediate cognitive improvements in MCI and Alzheimer's disease, with sustained benefits at long-term follow-up (SMD = 0.42). High-frequency rTMS targeting the dorsolateral prefrontal cortex (DLPFC) shows particular efficacy in enhancing memory and executive function, with benefits lasting 4-12 weeks post-treatment. These improvements are thought to be mediated through upregulation of brain-derived neurotrophic factor, enhanced synaptic plasticity, and functional reorganization of large-scale brain networks. Despite this evidence, critical gaps remain. Most existing studies employ conventional protocols with daily sessions over several weeks, which may limit accessibility and adherence. Furthermore, prior studies have relied primarily on global cognitive screening tools such as the Montreal Cognitive Assessment (MoCA), which may lack sensitivity to detect changes in specific cognitive domains. The neurophysiological trajectory of cognitive changes over extended follow-up periods also requires systematic characterization. Study Design and Intervention This is a single-center, open-label, prospective pilot study conducted at the San Francisco Neurology and Sleep Center. The study consists of three phases: a screening phase (up to 14 days), an open-label treatment phase (approximately 21 days), and a follow-up phase (90 days), for a total participation duration of up to 139 days. During the treatment phase, participants receive 6 sessions of rTMS using the EXOMIND™ device (BTL-699-2), administered twice weekly over approximately 3 weeks. Each session delivers 6,300 pulses at alternating frequencies of 12, 15, and 18 Hz, with a total session duration of 24 minutes and 30 seconds. The stimulation target is the left DLPFC, localized using the standard 5-cm rule. Motor threshold is determined individually for each participant as the minimum stimulus intensity required to induce contraction of the right thumb. Cognitive Assessment Strategy A key methodological feature of this study is the dual-assessment approach combining global cognitive screening with domain-specific evaluation. The MoCA provides a validated measure of overall cognitive status, while the Creyos cognitive battery enables granular analysis of treatment effects across six specific domains: visual spatial working memory, episodic memory, deductive reasoning, mental rotation, verbal short-term memory, and attention. To minimize practice effects associated with repeated MoCA administration, alternate validated versions are used at each time point: Version 8.1 (original) at baseline, Version 8.2 at post-treatment, Version 8.3 at 1-month follow-up, and Version 8.1 at 3-month follow-up. A Creyos cognitive battery training session is conducted during screening to familiarize participants with the testing procedures and reduce learning effects during the study. Depressive symptoms are assessed using the Patient Health Questionnaire-9 (PHQ-9) at each time point, given the known relationship between mood and cognitive performance and the established effects of DLPFC stimulation on depressive symptoms. Assessment Schedule Cognitive and clinical assessments are performed at four time points: baseline (screening), post-treatment (Day 21, approximately), 1-month follow-up (Day 51 ± 7 days), and 3-month follow-up (Day 111 ± 7 days). Vital signs (blood pressure and heart rate) are recorded at every treatment session and study visit. Adverse events are monitored at each treatment session and follow-up visit using a standardized checklist derived from existing TMS safety literature. Statistical Approach Repeated measures ANOVA will be used to assess changes in MoCA scores and each Creyos cognitive domain across the four time points. Paired t-tests will evaluate pairwise changes between baseline and each subsequent time point. Cohen's d will be calculated for all primary and secondary endpoints to quantify effect sizes. The proportion of participants achieving a clinically meaningful improvement, defined as a ≥2-point increase in MoCA score, will be reported at each post-baseline time point. Both intention-to-treat (ITT) and per-protocol (PP) analyses will be conducted. The last observation carried forward (LOCF) method will be used for sensitivity analyses in cases of missing data or early withdrawal. Exploratory subgroup analyses may be performed based on baseline cognitive severity (mild vs. moderate impairment), age, and sex. Adverse events will be summarized by frequency, severity, and relationship to treatment. A p-value of less than 0.05 will be considered statistically significant. Significance This pilot study addresses key gaps in the rTMS literature by evaluating a condensed treatment protocol (6 sessions over 3 weeks rather than daily sessions over several weeks), incorporating domain-specific cognitive assessment alongside global screening, and characterizing the trajectory of cognitive changes over an extended 3-month follow-up. Positive findings would support the design of larger, controlled trials and inform the potential integration of rTMS as a non-pharmacological therapeutic option for cognitive impairment.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
80
The EXOMIND™ (BTL-699-2) is a repetitive transcranial magnetic stimulation (rTMS) device that delivers targeted electromagnetic pulses to cortical brain regions. In this study, stimulation is applied to the left dorsolateral prefrontal cortex (DLPFC), a region implicated in executive function, working memory, and attention. The DLPFC target is localized using the standard 5-cm rule, measured anterior to the motor cortex hot spot. Each treatment session uses a multi-frequency protocol alternating between 12, 15, and 18 Hz stimulation frequencies, delivering a total of 6,300 pulses over 24 minutes and 30 seconds. Stimulation intensity is calibrated to each participant's resting motor threshold, defined as the minimum stimulus intensity required to produce a visible contraction of the right abductor pollicis brevis muscle. Six sessions are administered twice weekly over approximately 3 weeks. The procedure is performed on
San Francisco Neurology and Sleep Center
San Francisco, California, United States
RECRUITINGChange from baseline in the Montreal Cognitive Assessment (MoCA) score at 1-month follow-up.
The Montreal Cognitive Assessment (MoCA) is a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Total Score Range: 0 to 30. Interpretation: Higher scores indicate better cognitive function (a score of 26 or above is generally considered normal). Metric: The change is calculated by subtracting the baseline score from the 1-month follow-up score.
Time frame: From baseline to the 1-month follow up
Change from baseline in the Montreal Cognitive Assessment (MoCA) score at the last treatment session
The Montreal Cognitive Assessment (MoCA) is a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Total Score Range: 0 to 30. Interpretation: Higher scores indicate better cognitive function (a score of 26 or above is generally considered normal). Metric: The change is calculated by subtracting the baseline score from the 1-month follow-up score.
Time frame: From baseline to the end of treatment (approximately Day 21)
Change from baseline in the Montreal Cognitive Assessment (MoCA) score at the 3-month follow-up visit
The Montreal Cognitive Assessment (MoCA) is a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Total Score Range: 0 to 30. Interpretation: Higher scores indicate better cognitive function (a score of 26 or above is generally considered normal). Metric: The change is calculated by subtracting the baseline score from the 1-month follow-up score.
Time frame: From baseline to the end of treatment at 3-month follow-up
Change from baseline in the following domain-specific cognitive measures assessed by the Creyos cognitive battery at the last treatment session
Cognitive performance will be assessed using the Creyos online platform. This measure evaluates specific cognitive domains through validated tasks. For this study, the following domains and their corresponding primary metrics are assessed: Memory (Monkey Ladders Task): Measures visuospatial working memory. Reasoning (Odd One Out Task): Measures deductive reasoning and fluid intelligence. Concentration (Feature Match Task): Measures attention and mental processing speed. Planning (Spatial Planning Task): Measures executive function and strategy. Scoring Parameters: Scale Title: Creyos Cognitive Assessment Score (Standardized Score). Minimum and Maximum Values: Scores are standardized with a mean of 100 and a standard deviation of 15. While theoretically open-ended, the effective range for clinical reporting is typically 0 to 150. Interpretation: Higher scores mean a better outcome, indicating superior cognitive performance relative to the normative database. Metric: The change
Time frame: From baseline to the end of treatment (approximately Day 21)
Change from baseline in the following domain-specific cognitive measures assessed by the Creyos cognitive battery at the 1-month follow-up
Cognitive performance will be assessed using the Creyos online platform. This measure evaluates specific cognitive domains through validated tasks. For this study, the following domains and their corresponding primary metrics are assessed: Memory (Monkey Ladders Task): Measures visuospatial working memory. Reasoning (Odd One Out Task): Measures deductive reasoning and fluid intelligence. Concentration (Feature Match Task): Measures attention and mental processing speed. Planning (Spatial Planning Task): Measures executive function and strategy. Scoring Parameters: Scale Title: Creyos Cognitive Assessment Score (Standardized Score). Minimum and Maximum Values: Scores are standardized with a mean of 100 and a standard deviation of 15. While theoretically open-ended, the effective range for clinical reporting is typically 0 to 150. Interpretation: Higher scores mean a better outcome, indicating superior cognitive performance relative to the normative database. Metric: The change
Time frame: From baseline to the end of treatment at 1-month follow-up
Change from baseline in the following domain-specific cognitive measures assessed by the Creyos cognitive battery at the 3-month follow-up
Cognitive performance will be assessed using the Creyos online platform. This measure evaluates specific cognitive domains through validated tasks. For this study, the following domains and their corresponding primary metrics are assessed: Memory (Monkey Ladders Task): Measures visuospatial working memory. Reasoning (Odd One Out Task): Measures deductive reasoning and fluid intelligence. Concentration (Feature Match Task): Measures attention and mental processing speed. Planning (Spatial Planning Task): Measures executive function and strategy. Scoring Parameters: Scale Title: Creyos Cognitive Assessment Score (Standardized Score). Minimum and Maximum Values: Scores are standardized with a mean of 100 and a standard deviation of 15. While theoretically open-ended, the effective range for clinical reporting is typically 0 to 150. Interpretation: Higher scores mean a better outcome, indicating superior cognitive performance relative to the normative database. Metric: The change
Time frame: From baseline to the end of treatment at 3-month follow-up
Change from baseline in depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) at the last treatment session
The PHQ-9 is a 9-item self-report scale used to measure the severity of depression. Each item is scored from 0 (not at all) to 3 (nearly every day). The total score ranges from 0 to 27, with higher scores indicating more severe depressive symptoms. "Change" is defined as the difference between the baseline score and the score at the last treatment session.
Time frame: From baseline to the end of treatment (approximately Day 21)
Change from baseline in depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) at the 1-month follow-up
The PHQ-9 is a 9-item self-report scale used to measure the severity of depression. Each item is scored from 0 (not at all) to 3 (nearly every day). The total score ranges from 0 to 27, with higher scores indicating more severe depressive symptoms. "Change" is defined as the difference between the baseline score and the score at the last treatment session.
Time frame: From baseline to the 1-month follow-up
Change from baseline in depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) at the 3-month follow-up
The PHQ-9 is a 9-item self-report scale used to measure the severity of depression. Each item is scored from 0 (not at all) to 3 (nearly every day). The total score ranges from 0 to 27, with higher scores indicating more severe depressive symptoms. "Change" is defined as the difference between the baseline score and the score at the last treatment session.
Time frame: From baseline to the 3-month follow-up
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