Theory & Data Analysis Tools

Project Summary Electrical stimulation of deep brain structures is an essential tool for the causal investigation of neural systems that regulate learning and decision making. Deep brain electrical stimulation is also a valuable tool for treating neurological disorders such as Parkinson's disease and tremor, and recent data suggests that electrical brain stimulation may effectively treat epilepsy and severe depression.

Non-invasive neuromodulation approaches have been developed to enable the modulation of neural tissue without necessitating invasive surgical procedures. Low-intensity transcranial focused ultrasound (tFUS) neuromodulation has proven its efficacy and precision in modulating the brain, from the neuron to circuit level. However, there is an urgent unmet need to elucidate the in vivo neuronal and inter-neuronal effects of the tFUS neuromodulation, thus advancing the translational application of tFUS neuromodulation on humans.

Measurements of cortical field potentials are widely used throughout basic and clinical neuroscience, including in electroencephalography (EEG), electrocorticography (ECoG) and local field potential (LFP) recordings. However, the neural origins of field potentials remain poorly understood, due to a lack of techniques for dissecting how different classes of cells contribute to field potential signals.

Unveiling mechanisms of neural stimulation technologies is an important goal of the Brain Initiative (RFA-NS-20-006). Transcranial electric stimulation (TES) is a non-invasive neuromodulation technique to provide wide-range effects on seizure control, behaviors, and cognition by generating weak electric fields in the brain. It is still an open question of how these weak electric fields can interact effectively with neural activity, and the mechanism of action of TES is still unknown.

Neurostimulation, including invasive methods like deep brain stimulation (DBS), is an increasingly important approach to treating mental illness. It offers the possibility of directly targeting the circuit dysfunctions that produce mental disorders. The clinical use of brain stimulation, and DBS in particular, has been limited by a lack of mechanistic understanding. We do not know why/how stimulating a specific region or pathway leads to symptom improvement. This limits our ability to correctly “dose” stimulation, or to verify biological target engagement.

This proposal responds to BRAIN Initiative RFA-NS-20-006 and aims to elucidate the neural and biophysical mechanisms of noninvasive focused ultrasound (FUS) neuromodulation.

The cerebellum has been overlooked for its potential for neuromodulation for decades. Traditionally thought of as critical for motor coordination, anatomical, clinical and imaging evidence now indicate that the cerebellum also has central roles in cognition and emotion, and that cerebellar dysfunction impacts these functions. Consistent with these findings of cerebellar involvement in motor and non-motor functions, projections from the cerebellar nuclei (CN) target, via the thalamus, both motor and non-motor areas of the cortex and the basal ganglia.

Project Summary The ability to remember information, whether after short or long delays, is a fundamental human ability. There is enormous research into understanding working memory and long-term memory in isolation, but also a longstanding debate about the interactions between working memory and long-term memory.

PROJECT SUMMARY Gene regulation at multiple levels is critical for nervous system development and function. A number of mutations leading to global dysregulation of gene expression have been found to disproportionately affect the nervous system, leading to neurodevelopmental and neurodegenerative disorders. Transfer RNAs (tRNAs), which recognize codons and add the appropriate amino acid to growing polypeptides, can dynamically regulate translation.

Project Summary Preeclampsia, a hypertensive disorder of pregnancy, can advance to eclampsia, when the mother displays novel seizures. The mechanisms that cause some preeclampsia patients to advance to eclampsia are unknown. The long-term goals are to identify therapeutic targets to prevent seizures in pregnancy and preeclampsia and to pursue a career as an academic scientist.