Effects of Accelerated rTMS on Cognitive Function

NCT07547319 | Not Yet Recruiting FDA Device

• 1 other identifier: SFNSC-2026-002
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cognitive Decline; Cognitive Impairment

Keywords

rTMS; ExoMind; Cognitive Decline; MCI

Outcome Measures

Primary Outcomes (1)

• Change 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.

  From baseline to the 1-month follow up

Secondary Outcomes (8)

• Change from baseline in the Montreal Cognitive Assessment (MoCA) score at the last treatment session

  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

  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

  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

  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

  From baseline to the end of treatment at 3-month follow-up

Study Arms (1)

rTMS Treatment

ACTIVE COMPARATOR

Participants receive 6 sessions of repetitive transcranial magnetic stimulation (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 to the left dorsolateral prefrontal cortex (DLPFC), localized using the 5-cm rule, with a total session duration of 24 minutes and 30 seconds. Motor threshold is individually determined as the minimum stimulus intensity required to induce contraction of the right thumb. Cognitive function is assessed using the Montreal Cognitive Assessment (MoCA) and the Creyos cognitive battery at baseline, post-treatment (Day 21), 1-month follow-up (Day 51 ± 7), and 3-month follow-up (Day 111 ± 7). Depressive symptoms are assessed using the PHQ-9 at each time point. Adverse events and vital signs are monitored throughout.

Device: TMS

Interventions

TMS DEVICE

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

rTMS Treatment

Eligibility Criteria

• Age: 50 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• San Francisco Neurology and Sleep Center: lead

Study Sites (1)

San Francisco Neurology and Sleep Center

San Francisco, California, 94108, United States

Location

Related Publications (10)

• Chen Y, Hou X, Zhou H, Lv T, Han R, Yang Z, Zheng W, Bai F. Cortical plasticity, therapeutic effects, and neural circuit activity of angular gyrus rTMS in amnestic mild cognitive impairment. Clin Neurophysiol. 2025 Jun;174:198-211. doi: 10.1016/j.clinph.2025.04.012. Epub 2025 Apr 18.

  PMID: 40305881 BACKGROUND

• Wu Q, Xu X, Zhai C, Zhao Z, Dai W, Wang T, Shen Y. High-frequency repetitive transcranial magnetic stimulation improves spatial episodic learning and memory performance by regulating brain plasticity in healthy rats. Front Neurosci. 2022 Aug 5;16:974940. doi: 10.3389/fnins.2022.974940. eCollection 2022.

  PMID: 35992904 BACKGROUND

• Sharbafshaaer M, Gigi I, Lavorgna L, Esposito S, Bonavita S, Tedeschi G, Esposito F, Trojsi F. Repetitive Transcranial Magnetic Stimulation (rTMS) in Mild Cognitive Impairment: Effects on Cognitive Functions-A Systematic Review. J Clin Med. 2023 Sep 25;12(19):6190. doi: 10.3390/jcm12196190.

  PMID: 37834834 BACKGROUND

• Zhang X, Lan X, Chen C, Ren H, Guo Y. Effects of Repetitive Transcranial Magnetic Stimulation in Patients With Mild Cognitive Impairment: A Meta-Analysis of Randomized Controlled Trials. Front Hum Neurosci. 2021 Oct 26;15:723715. doi: 10.3389/fnhum.2021.723715. eCollection 2021.

  PMID: 34764859 BACKGROUND

• Chou YH, Ton That V, Sundman M. A systematic review and meta-analysis of rTMS effects on cognitive enhancement in mild cognitive impairment and Alzheimer's disease. Neurobiol Aging. 2020 Feb;86:1-10. doi: 10.1016/j.neurobiolaging.2019.08.020. Epub 2019 Aug 27.

  PMID: 31783330 BACKGROUND

• Wang B, Wang Y, Yang F, Han F, Li K, Sun K, Liang P. The effect of repetitive transcranial magnetic stimulation on immediate and long-term cognitive functions in Alzheimer's dementia and mild cognitive impairment: a meta-analysis. J Neuroeng Rehabil. 2025 Dec 15;22(1):262. doi: 10.1186/s12984-025-01777-8.

  PMID: 41398677 BACKGROUND

• Jamil Y, Krishnaswami A, Orkaby AR, Stimmel M, Brown Iv CH, Mecca AP, Forman DE, Rich MW, Nanna MG, Damluji AA. The Impact of Cognitive Impairment on Cardiovascular Disease. J Am Coll Cardiol. 2025 Jul 1;85(25):2472-2491. doi: 10.1016/j.jacc.2025.04.057.

  PMID: 40562512 BACKGROUND

• Patnode CD, Perdue LA, Rossom RC, Rushkin MC, Redmond N, Thomas RG, Lin JS. Screening for Cognitive Impairment in Older Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2020 Feb 25;323(8):764-785. doi: 10.1001/jama.2019.22258.

  PMID: 32096857 BACKGROUND

• Manly JJ, Jones RN, Langa KM, Ryan LH, Levine DA, McCammon R, Heeringa SG, Weir D. Estimating the Prevalence of Dementia and Mild Cognitive Impairment in the US: The 2016 Health and Retirement Study Harmonized Cognitive Assessment Protocol Project. JAMA Neurol. 2022 Dec 1;79(12):1242-1249. doi: 10.1001/jamaneurol.2022.3543.

  PMID: 36279130 BACKGROUND

• Lazar RM, Howard VJ, Kernan WN, Aparicio HJ, Levine DA, Viera AJ, Jordan LC, Nyenhuis DL, Possin KL, Sorond FA, White CL; American Heart Association Stroke Council. A Primary Care Agenda for Brain Health: A Scientific Statement From the American Heart Association. Stroke. 2021 Jun;52(6):e295-e308. doi: 10.1161/STR.0000000000000367. Epub 2021 Mar 15.

  PMID: 33719523 BACKGROUND

MeSH Terms

Conditions

Cognitive Dysfunction

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Central Study Contacts

Joy Shihui Meng, MD

CONTACT

415-666-2536; joymengmd@sf-neurology.com

Junyi Sun, MD, PhD

CONTACT

628-249-5656; office@sf-neurology.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: President

Model Details: Prospective, open-label, single-arm clinical study

Study Record Dates

• First Submitted: April 7, 2026
• First Posted: April 23, 2026
• Study Start: May 1, 2026
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: April 23, 2026

Record last verified: 2026-04

Locations

US (1)