fMRI-guided TMS for prevention of cognitive decline

Decreased fronto-temporal connectivity in a patient with risk factors for neurodegenerative diseases prior to treatment

Our brain changes continuously as we grow up and older. The most rapid changes happen in early life when our body has the fastest growth rate and every experience is new. As we grow over forty, we notice increasing forgetfulness that might start causing irritations, disruption of our daily function and even depression. Most people notice it when they see that it takes longer to think of a word or to remember an event or someone’s name.

Some of the early manifestation of cognitive impairment could be forgetting things more often, or important events such as appointments or social engagements at first.

Normalized fronto-temporal connectivity in the same patient with risk factors for neurodegenerative diseases after treatment

But gradually, it could evolve into a loss of train of thoughts during a conversation or losing the storyline while reading books or watching movies. Such experiences, result into a feeling of being overwhelmed, specially for the situations requiring decisions at home, or planning steps for implementing a task at work, or even being able to follow instructions given by a physician or your boss at work. Most people attribute these to the natural aging process until it deteriorates into situations like losing your way while driving home, or trouble finding your way around home or other familiar environments.

This results into becoming more impulsive, that causes having steadily poor judgment.

Normal fronto-temporal connectivity in healthy volunteers at their peak of cognitive development

Most family members and friends notice these changes and slowly conclude that you are exhibiting signs of aging and treat you accordingly.

Using fMRI, we have learned that there’s no single cause of mild cognitive impairment (MCI), and among the many contributors, aging plays an important role in the disorder. If an event or series of events, a disease, or a trauma cause damage to certain brain regions, we could forget a skill or a set of skills. fMRI is a powerful tool that can help us to prevent cognitive impairment and its progress to Alzheimer’s disease or another type of dementia.

Decreased temporo-frontal connectivity in a patient with risk factors for neurodegenerative diseases prior to treatment

Recent evidence indicates that MCI might be due to reduced blood flow through brain blood vessels. Brain-imaging studies show that stimulation of the brain could be beneficial in impeding events that cause cognitive impairment. Transcranial magnetic stimulation (TMS) is a technique that can selectively stimulate specific brain regions non-invasively. This is particularly important since there aren’t that many other options available. In fact, the absence of effective pharmacological options for prevention of cognitive impairment is depicted in 2018 report of the American Academy of Neurology1 in which it is recommended that “Clinicians should discuss diagnosis, prognosis, long-term planning, and the lack of effective medicine options …”.

Normalized temporo-frontal connectivity in the same patient with risk factors for neurodegenerative diseases after treatment

For example, we know that aging can cause cognitive impairment. One of such impairments are caused by vascular degradations2,3. Vascular cognitive impairment (VCI) is caused by blockage of micro vasculatures that their inability to supply oxygen and nutrients to different brain regions cause a decline in cognition. Sometimes, this inability is caused by cerebrovascular injury. Therefore, mild VCI, vascular dementia (VaD), and mixed dementia3-5 are the most common types of cognitive impairment. Mild VCI is a decline in cognition not fully satisfying the diagnostic criteria for dementia6,7. VaD is referred to cognitively impaired patients who have lost their functional independence due to vascular lesions.

Normal temporo-frontal connectivity in healthy volunteers at their peak of cognitive development

VaD includes subtypes, such as post-stroke dementia, multi-infarct dementia, strategic infarct dementia, and the subcortical ischemic VaD. In addition to vascular-based dementia there is also degenerative dementia (which is most common in Alzheimer’s disease)8. Combining these two types, covers the majority of cases of dementia. However, VCI is the most common cognitive disorder that comes with age and because of that has a high impact on patients’ quality of life. Because of the fact that vascular-based impairment is the root cause of all types of cognitive decline, approaches that can prevent such considerable deficits have the potential of making life changing effects for many people in latter parts of their lives9,10. In this regard, many research results have shown that cognitive decline is treatable and preventable and they are not an irreversible consequence of aging.

Decreased connectivity between regions within the dorsal-attention pathway in a patient with risk factors for neurodegenerative diseases prior to treatment

It is known that TMS is capable of brain stimulation to improve memory11-13. This means that TMS can also prevent cognitive decline by strengthening brain activity and connectivity in most vulnerable regions, like specific locations within the frontal and temporal lobes detected by our fMRI-based biomarkers. We have been successful in treating MCI patients using our fMRI guided TMS approach, and have used that experience to develop a new protocol for preventing decline of everyday memory in asymptomatic patients with risk of MCI and Alzheimer’s disease, due to family history or cardiovascular disease. This protocol involves: (1) the analysis of resting state fMRI (rsfMRI) images taken of the patient’s brain to construct brain networks, (2) the use of our biomarkers to detect most vulnerable brain regions in each individual, and (3) the delivery of fMRI guided TMS over a course of 20 sessions.

Normal connectivity between regions within the dorsal-attention pathway in healthy volunteers

Patients will receive a second fMRI after the last session to compare baseline and post-treatment brain maps to calculate the efficacy measure. Patients will also receive another fMRI at one-year follow-up to monitor evolution of brain activity and connectivity, and the need of another cycle of 20 sessions with fMRI guided TMS will be assessed by our biomarkers, and delivered as needed over the course of the lifespan. Our findings with MCI patients suggest that fMRI guided TMS could be an effective therapy for preventing cognitive decline and probably a tool to delay deterioration.


1. Petersen RC, Lopez O, Armstrong MJ, Getchius TSD, Ganguli M, Gloss D, Gronseth GS, Marson D, Pringsheim T, Day GS, Sager M, Stevens J, Rae-Grant A. Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018 Jan 16;90(3):126-135.

2. Cantone M, Lanza G, Fisicaro F, Pennisi M, Bella R, Di Lazzaro V, Di Pino G. Evaluation and Treatment of Vascular Cognitive Impairment by Transcranial Magnetic Stimulation. Neural Plast. 2020 Oct 27;2020:8820881.

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7. Skrobot OA, Black SE, Chen C, DeCarli C, Erkinjuntti T, Ford GA, Kalaria RN, O’Brien J, Pantoni L, Pasquier F, Roman GC, Wallin A, Sachdev P, Skoog I; VICCCS group, Ben-Shlomo Y, Passmore AP, Love S, Kehoe PG. Progress toward standardized diagnosis of vascular cognitive impairment: Guidelines from the Vascular Impairment of Cognition Classification Consensus Study. Alzheimers Dement. 2018 Mar;14(3):280-292.

8. Emrani S, Lamar M, Price CC, Wasserman V, Matusz E, Au R, Swenson R, Nagele R, Heilman KM, Libon DJ. Alzheimer’s/Vascular Spectrum Dementia: Classification in Addition to Diagnosis. J Alzheimers Dis. 2020;73(1):63-71.

9. Gorelick PB, Counts SE, Nyenhuis D. Vascular cognitive impairment and dementia. Biochim Biophys Acta. 2016 May;1862(5):860-8.

10. Azarpazhooh MR, Hachinski V. Vascular cognitive impairment: A preventable component of dementia. Handb Clin Neurol. 2019;167:377-391.

11. Drumond Marra HL, Myczkowski ML, Maia Memória C, Arnaut D, Leite Ribeiro P, Sardinha Mansur CG, Lancelote Alberto R, Boura Bellini B, Alves Fernandes da Silva A, Tortella G, Ciampi de Andrade D, Teixeira MJ, Forlenza OV, Marcolin MA. Transcranial Magnetic Stimulation to Address Mild Cognitive Impairment in the Elderly: A Randomized Controlled Study. Behav Neurol. 2015;2015:287843.

12. 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.

13. Taylor JL, Hambro BC, Strossman ND, Bhatt P, Hernandez B, Ashford JW, Cheng JJ, Iv M, Adamson MM, Lazzeroni LC, McNerney MW. The effects of repetitive transcranial magnetic stimulation in older adults with mild cognitive impairment: a protocol for a randomized, controlled three-arm trial. BMC Neurol. 2019 Dec 16;19(1):326.

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