Alvaro Pascual-Leone, MD, PhD

Professor in Neurology,
Harvard Medical School

Medical Director, Deanna and Sidney Wolk Center for Memory Health
Senior Scientist, Hinda and Arthur Marcus Institute for Aging Research
Hebrew SeniorLife

“Precision Neuromodulation”

In the past decades, neuroimaging techniques such as computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), magneto-encephalography (MEG) and electro- encephalography (EEG) have shaped the way in which we model and understand brain-behavior relations. Anatomical neuroimaging techniques have produced ever more detailed descriptions of the extent of lesions produced by brain injury. Functional neuroimaging methods have revealed associations between various behaviors and patterns of activity in cortical and subcortical structures. Functional MRI and PET can inform us about the location of a brain activity associated with a function, while event related potentials using EEG or MEG can provide information about the timing of a brain activation during a task. Careful design of neuroimaging experiments may allow us to conclude with reasonable certainty that the correlation of brain activity with behavior is likely to be due to a causal connection (i.e. that the brain activity produces the behavior). Nevertheless, imaging alone can never provide proof of that assertion.

The functional units of the brain are ensembles of neurons – brain circuits or networks – which are highly plastic and can be characterized by spatio-temporal signatures of brain activity: patterns of activity across definable brain structures or nodes. Such spatio-temporal signatures represent each thought, behavior, emotion. Alterations of specific spatio-temporal signatures are the substrate of each sign and symptom of disease and thus the neural substrate of disability. Identification and modulation of spatio-temporal signatures of brain activity enables unique causal insights into the neural substrate of brain-behavior relations, and offers the opportunity of highly personalized, precision approaches to neurotherapeutics aimed at addressing symptoms and disabilities.

The use of brain physiology-guided neuromodulation methods to modify brain spatio-temporal signatures of disability can thus offer personalized and targeted therapeutic interventions. A number of noninvasive brain stimulation techniques are being developed to target and modulate brain activity. Particularly transcranial magnetic stimulation (TMS) and transcranial current stimulation (tCS) have become established as valuable neuromodulation tools with diagnostic and therapeutic potential in psychiatry and neurology. TMS and tCS allow us to interfere actively with brain function, and thus investigate the relationship between brain activity and behavior, trace the timing at which a cortical region contributes to a given task, and map the functional connectivity between brain regions. In addition, repetitive TMS and tCS provide means of modifying specific spatio-temporal patterns of brain activity and hence offer precision approaches to modify behavior and treat neuropsychiatric disorders.

However, the knowledge about noninvasive brain stimulation and its diagnostic and therapeutic potential remains limited in the medical community and is distorted by popular press and anecdotal accounts. Optimization of use of noninvasive brain stimulation requires a deeper understanding of neurobiological mechanisms of actions, clear sense of “known-unknowns”, as well as technological developments.

In this talk, I will discuss:
(1) The use of neurotechnologies to capture digital biomarkers of cognitive performance and behavior across the lifespan to enable deep insights into an individual’s state of brain health, and allow for true precision health for the brain
(2) The use of perturbation biomarkers integrating noninvasive brain stimulation approaches with imaging and neurophysiologic methods as toy models of the response of the individual nervous system to stressors, insults or injuries
(3) The use of brain physiology-guided neuromodulation methods to modify brain spatio-temporal signatures of disability and offer personalized and targeted therapeutic interventions
(4) The availability of noninvasive brain stimulation methods capable of selective, and precise targeting of deep brain structures and multi-focal network modulation
(5) The use of AI-driven, closed-loop learning systems to ensure iterative optimization of therapeutic algorithms.

Alvaro Pascual-Leone, MD, PhD, is a Professor of Neurology, Harvard Medical School, a Senior Scientist at the Hinda and Arthur Marcus Institute for Aging Research and Medical Director of the Deanna and Sidney Wolk Center for Memory Health at Hebrew SeniorLife (HSL). Dr. Pascual–Leone is an international leader in the study and modulation of human cortical plasticity and a pioneer in the use of noninvasive brain stimulation and its application for the study of brain behavior relations and the development of diagnostic and therapeutic interventions in neuropsychiatry. An overarching goal has been the development of translational approaches to characterize and modulate brain activity to help patients with debilitating neuropsychiatric disorders while gaining fundamental insights into human brain function. A major focus of Dr. Pascual-Leone’s research is on maintenance of brain health across the lifespan. Dr. Pascual-Leone brought together a group of international investigators and funding partners to establish the Barcelona Brain Health Initiative ( – a multiyear, longitudinal effort supported by La Caixa and Institut Guttmann, that aims at identifying markers of brain health across the lifespan and developing and testing multimodal interventions and lifestyle changes that sustain brain health and prevent age-related cognitive decline. Dr. Pascual-Leone leads this one-of-a-kind study as its scientific director.

Dr. Pascual-Leone established and directs the Sidney Baer Jr. Fellowship in Clinical Neurosciences, training the future leaders of medical brain sciences, working in the interface of neurology and psychiatry. He also established and directs a training program in noninvasive brain stimulation that has trained over 1,000 clinicians from around the world. Dr. Pascual-Leone has authored over 750 scientific papers and several books and is listed as an inventor on several patents. His work is highly regarded for its innovation and quality and is highly cited (h-index 165; i10-index 626). Dr. Pascual-Leone has been recognized by Thomson Reuters as a one of the world’s top 15 neuroscientists, and one of the “World’s Most Influential Scientific Minds”. He has been honored with many international awards, and is an elected member of the Spanish Royal Academy of Science (Pharmacy). His work has also gained wide general public appeal and outreach through dissemination in the lay press, television and radio, and several books (e.g. Norman Doidge’s The Brain That Changes Itself; and John E. Robison’s Switched On). Most recently Dr. Pascual-Leone co-authored, with A. Fernandez and D. Bartres-Faz, El Cerebro que Cura (2019).

Reading List

Benussi, A., Cantoni, V., Grassi, M., Brechet, L., Michel, C. M., Datta, A., Thomas, C., Gazzina, S., Cotelli, M. S., Bianchi, M., Premi, E., Gadola, Y., Cotelli, M., Pengo, M., Perrone, F., Scolaro, M., Archetti, S., Solje, E., Padovani, A., … Borroni, B. (2022). Increasing brain gamma activity improves episodic memory and restores cholinergic dysfunction in alzheimer’s disease. Annals of Neurology, 92(2), 322–334.

Fox, M. D., Buckner, R. L., Liu, H., Chakravarty, M. M., Lozano, A. M., & Pascual-Leone, A. (2014). Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases. Proceedings of the National Academy of Sciences, 111(41).

Ozdemir, R. A., Tadayon, E., Boucher, P., Momi, D., Karakhanyan, K. A., Fox, M. D., Halko, M. A., Pascual-Leone, A., Shafi, M. M., & Santarnecchi, E. (2020). Individualized perturbation of the human connectome reveals reproducible biomarkers of network dynamics relevant to cognition. Proceedings of the National Academy of Sciences, 117(14), 8115–8125.

Pascual-Leone, A., Rubio, B., Pallardó, F., & Catalá, M. D. (1996). Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. The Lancet, 348(9022), 233–237.

Violante, I. R., Alania, K., Cassarà, A. M., Neufeld, E., Acerbo, E., Carron, R., Williamson, A., Kurtin, D. L., Rhodes, E., Hampshire, A., Kuster, N., Boyden, E. S., Pascual-Leone, A., & Grossman, N. (2023b). Non-invasive temporal interference electrical stimulation of the human hippocampus. Nature Neuroscience, 26(11), 1994–2004.