Effects of Accelerated rTMS on Cognitive Function

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.

Inclusion criteria

Each potential subject must satisfy all of the following criteria to be enrolled in the study:

• Subject must be 50 to 90 years of age, inclusive, on the day of signing informed consent.
• Documented cognitive function decline, defined as:

MoCA score of 10 to 25, inclusive (indicating mild to moderate cognitive impairment), OR Clinical diagnosis of mild cognitive impairment (MCI) or mild dementia based on established DSM-5 diagnostic criteria.

• Ability to provide written informed consent, or availability of a legally authorized representative to provide consent.
• Subject must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
• Sufficient visual and auditory acuity to complete cognitive assessments.
• Stable doses of any cognitive-enhancing medications (e.g., cholinesterase inhibitors, memantine) for at least 4 weeks prior to screening, with no anticipated changes during the study period.
• Availability and willingness to complete all scheduled study visits.
• Presence of a reliable study partner or caregiver who can provide information about the participant's cognitive and functional status.
• Ability to determine the motor threshold of the participant. The participant's motor threshold could be established as the minimum stimulus required to induce contraction of the right thumb.
• Subjects willing and able to abstain from partaking in any treatments other than the study procedure for the improvement in cognitive function, including non-invasive brain stimulation treatments other than the study procedure during study participation.
• Subjects willing and able to maintain their regular (pre-procedure) diet and exercise regimen without affecting significant change in either direction during study participation.
• Willingness to comply with study instructions and to return to the clinic for the required visits.
• Women of child-bearing potential are required to use birth control measures during the whole duration of the study.

Exclusion criteria

Any potential subject who meets any of the following criteria will be excluded from participating in the study:

• Electronic implants in or near the head - rTMS devices are contraindicated for use in patients who have active or inactive implants in or near the head including device leads, deep brain stimulators, cochlear implants, ocular implants, and vagus nerve stimulators, implanted devices such as cardiac pacemakers, defibrillators, and neurostimulators.
• Metallic, ferromagnetic, or other magnetic-sensitive implants/objects in or near the head - rTMS devices are contraindicated for use in patients who have conductive, ferromagnetic, or other magnetic-sensitive metals implanted in their head (with some exceptions in the mouth - see Operator's Manual) or within 12 inches (30 cm) of the therapy coil. Examples include implanted electrodes/stimulators, aneurysm clips or coils, stents, bullet fragments, jewelry, hair barrettes, and tattoos with metallic ink.
• Drug pumps within 12 inches (30 cm) of the therapy coil.
• Inability to determine the motor threshold of the participant (i.e., the minimum stimulus required to induce contraction of the right thumb cannot be established).
• History of seizure disorder or epilepsy, except for a single remote seizure more than 5 years ago, which may be permitted at investigator discretion.
• Elevated risk of seizure due to traumatic brain injury with loss of consciousness >30 minutes within the past 12 months.
• Current use of medications known to significantly lower seizure threshold (e.g., clozapine, bupropion at doses >450 mg/day, theophylline, high-dose tricyclic antidepressants) or recent dose reduction of anticonvulsant medications or benzodiazepines within 4 weeks of screening.
• Severe dementia, defined as MoCA score below 10, or inability to follow simple verbal commands or complete basic cognitive assessments.
• Rapidly progressive dementia (e.g., suspected prion disease, autoimmune encephalitis).
• Brain tumor, intracranial hemorrhage within the past 12 months, arteriovenous malformation, or increased intracranial pressure.
• Acute stroke within the past 3 months (stable chronic stroke with cognitive sequelae may be included at investigator discretion).
• Has a current diagnosis of psychotic disorder, bipolar disorder, or other psychiatric condition that, in the investigator's opinion, would interfere with the subject's ability to participate in the trial.
• Has a current or recent history of serious suicidal ideation within the past 6 months, corresponding to a positive response on item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) on the C-SSRS, or a history of suicidal behavior within the past year, as validated by the C-SSRS at screening.
• History of substance or alcohol use disorder of moderate to severe severity according to DSM-5 criteria within 6 months before screening, or positive test result(s) for drugs of abuse (including opiates, cocaine, cannabinoids, methamphetamines, amphetamines) at screening.
• Has history of or current clinically significant and/or unstable medical condition that could interfere with study participation or pose safety concerns, including but not limited to:

Moderate or severe hepatic impairment (Child-Pugh Score ≥7) Severe renal impairment (estimated creatinine clearance below 30 mL/min or serum creatinine >2 mg/dL) Unstable cardiac, vascular, or pulmonary disease Note: Subjects with chronic but stable, well-controlled conditions may be allowed in the study upon agreement with the investigator.

• Has uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg, despite diet, exercise, or a stable dose of antihypertensive therapy) at screening. A subject with hypertension may be included if the subject's hypertension has been controlled for at least 3 months prior to screening, and the dosage of any antihypertensive medication has been stable for the past 3 months.
• Has clinically significant ECG abnormalities at screening, defined as:

QTc interval (Fridericia's formula): ≥450 msec (males); ≥470 msec (females) Evidence of 2nd or 3rd degree atrioventricular block, or 1st degree atrioventricular block with PR interval >210 msec Left bundle branch block Features of new ischemia Other clinically important arrhythmia Note: Subjects with right bundle branch block may be allowed provided confirmation that right bundle branch block is not associated with underlying cardiac/lung diseases.

• Has a known malignancy or history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that, in the opinion of the investigator, is considered cured with minimal risk of recurrence).

Had clinically significant acute illness within 7 days prior to study rTMS treatment.

• Had major surgery (e.g., requiring general anesthesia) within 2 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study.

Note: Subjects with planned surgical procedures to be conducted under local anesthesia may participate.

• Is pregnant or breastfeeding while enrolled in this study or within 1 month after the last session of study rTMS treatment.
• Has received an investigational drug or used an invasive investigational medical device within 3 months before screening, or is currently enrolled in an investigational study.
• Prior treatment with rTMS within 6 months of screening.
• Subjects willing to partake in any treatments other than the study procedure for the improvement in cognitive function, including non-invasive brain stimulation treatments other than the study procedure, during study participation.
• Has psychological and/or emotional problems which would render the informed consent invalid, or limit the ability of the subject to comply with the study requirements.
• Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• Is an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.

NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject's clinical status changes after screening but before the first rTMS treatment session such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study.