Research

Approach

1. Inventing tools and principles to non-invasively control neural activity with high spatiotemporal precision.
2. Discovering mechanisms of action to boost activity-dependent cellular homeostasis and cognitive functions
3. Translating the tools and mechanistic insights to disease-modifying interventions.

Our experimental methodologies include:

•Electrical engineering instrumentation to develop and characterize custom-made devices
•Electrophysiology (whole-cell patch-clamp, local field potential) and optical imaging in rodents (widescale calcium) to investigate the response of single neural cells and neural networks.
•Electrophysiology (electrooculography, EEG) and neuroimaging (functional magnetic resonance imaging, fMRI; positron emission tomography, PET) to translate the work to treat patients via experimental medicine.

Our computational methodologies include

•Finite element method (FEM) modelling to explore the distribution of electromagnetic fields in anatomical models
•Physiological modelling of single neural cells and neural networks to gain mechanistic insights into the neural response to electromagnetic field stimulation
•Feature-based machine learning to gain mechanistic insights

Specific aims

Development of Non-invasive Deep Brain Stimulation Therapy

The cognitive capability of our brain is mediated by the coordinated electrical activity of neural cells organized in functional circuits. In the early stages of AD this coordinated electrical activity is disrupted in deep brain regions critical for learning and memory functions. Chronic disruption of the coordinated activity in these regions breaks the connectivity of the neural circuits and promotes cells degeneration, ultimately resulting in the impairment of the circuits’ functionality that underpins dementia. We aspire to reverse the progression of AD and dementia by noninvasively boosting the coordinated activity in the affected deep brain regions.
Temporal interference (TI) brain stimulation. We have developed a technology that allows for the first time to noninvasively modify the activity in deep brain structures – a procedure that previously required invasive brain surgery. The so-called temporal interference (TI) brain stimulation technology uses multiple kHz-range electric fields with a difference frequency low enough to drive neural activity to induce a three-dimensional focal neural stimulation deep in the brain (Grossman et al. 2017). We demonstrated that transcranial TI stimulation could selectively mediate activation in deep structures such as the hippocampus without the overlying cortex and steerably target brain regions without physically moving the electrodes. The TI brain stimulation was awarded the Neuromodulation Prize by the American Association for the Advancement of Science (AAAS) and the Science journal (Grossman 2018).
Translation to disease-modifying intervention. We build on this fundamental technological innovation to develop a non-invasive therapeutic DBS for patients with neurodegenerative brain conditions by uncovering mechanisms of action on homeostatic processes and memory functions, synergistically in animal models and patients with dementia. In addition, we iteratively improve our technology via exploration of the biophysical mechanism and exploitation of fundamental engineering and physics principles.

Key publications

•Grossman, Nir, David Bono, Nina Dedic, Suhasa B. Kodandaramaiah, Andrii Rudenko, Ho-Jun Suk, Antonino M. Cassara, et al. 2017. “Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields.” Cell 169 (6): 1029–41.
•Grossman, Nir. 2018. “Modulation without Surgical Intervention.” Science 361 (6401): 461–62.

Development of Phase-Locking Brain Stimulation Therapy 

Synchronous oscillatory firing in large populations of neurons has diverse functional roles in the central nervous system (CNS), including regulation of global homeostasis states and providing spatiotemporal reference frames for cognitive functions. Aberrant synchronous oscillations have been associated with numerous brain disorders. However, such aberrant oscillations require a delicate cascade of coherent activities across the network components. We aspire to mitigate the aberrant oscillations to restore the dependent brain’s homeostasis and functions. 
Endpoint corrected Hilbert transform (ecHT). To enable phase-locking of stimulation to oscillatory activity, we have developed a strategy to compute the instantaneous phase of oscillatory signals in real-time. The so-called endpoint corrected Hilbert transform (ecHT) is based on applying a causal bandpass filter to the discrete Fourier transform (DFT) of the analytic signal to mitigate the distortion, known as the Gibbs phenomenon, from its end. The ecHT is a simple, yet powerful method, allowing implementation in simple and portable hardware. We demonstrated that ecHT-based phase-locked transcranial electrical stimulation of the cerebellum could suppress the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder (Schreglmann et al. 2021).
Translation to disease-modifying intervention. We build on this fundamental technological innovation to develop non-invasive phase-locking brain stimulation interventions to promote homeostatic processes and cognitive functions in patients with early stages of dementia. In addition, we iteratively improve our technology by exploring computational and engineering principles. 

•Schreglmann, Sebastian R., David Wang, Robert L. Peach, Junheng Li, Xu Zhang, Anna Latorre, Edward Rhodes, et al. 2021. “Non-Invasive Suppression of Essential Tremor via Phase-Locked Disruption of Its Temporal Coherence.” Nature Communications 12 (1).