Theory & Data Analysis Tools

Magnetic resonance imaging (MRI), by offering the sole means of imaging human brain structure and activity with high spatial resolution, has evolved into an indispensable tool for studying brain function in health and disease. It is uniquely suited to examining the neural basis of higher order behaviors and cognition, as well as neurodegenerative and developmental disorders, for which animal models are of limited applicability. Yet, because of current experimental limitations, there is wide range of subjects and human behaviors that are completely inaccessible by MRI techniques.

SUMMARY The overarching objective of our proposal is to bring noninvasive human brain imaging into the microscale (50-500 micron isotropic) resolution in order to create a tool for studies of neuronal circuitry and network organization in the human brain. Our breakthrough technology, MR Corticography (MRCoG), represents substantial advances over existing MRI approaches. MRCoG achieves dramatic gains in spatial and temporal resolutions by focusing several different types of coil arrays on the cerebral cortex of the live human brain.

PROJECT SUMMARY/ABSTRACT Neuropsychiatric disorders represent a leading cause of disability, affecting nearly 19% of the US population. Only 9% of neuropsychiatric drugs entering clinical trials reach the market, which is one of the lowest success rates across all therapeutic areas. Fundamental differences between the neurobiology of rodents and humans have been proposed to account for translational failures in development of effective therapeutic strategies to mitigate neurological or neurodegenerative diseases or disorders.

PROJECT SUMMARY While mice are essential models for many areas of neuroscience, there are also many aspects of higher brain function and dysfunction that cannot be adequately modeled in rodents. Thus, there is a need for new genetic models that have brain structure and function closer to humans. For these reasons, non-human primates (NHP) provide an attractive model to study higher brain function and brain disorders. A promising emerging NHP model is the common marmoset, a small New World primate that has many advantages as a genetic model.

ABSTRACT The common marmoset provides a very relevant primate model for understanding the organization of the human nervous system and the diseases that affect it. Like humans, marmosets also demonstrate cooperative social behavior and have advanced cognitive processes, making them of great interest in the field for modeling developmental and psychiatric diseases and their therapies. They are also ideal for multigenerational genetic experiments as they give birth twice a year and mature faster than most primates.

Tools for Gene Editing in Marmosets SUMMARY The goal of this proposal is to create an efficient new set of tools and techniques for the generation of genetically modified marmosets suitable for use as models of brain physiology and function. Development of efficient methods of genetic manipulation in the species will require refinement of genome editing technologies, breeding technologies, ovarian stimulation and oocyte retrieval, embryo culture, and pre-implantation screening of embryos for the desired genetic alternations.

PROJECT SUMMARY The goal of the proposed research career development program is to allow the applicant to acquire training in a new form of brain stimulation using ultrasonic waves. The career development activities will be carried out in a prominent ultrasound laboratory, where the candidate will receive hands-on training in the application and analysis of ultrasonic stimulation in animal models.

ABSTRACT The basal ganglia are critical for the learning and subsequent selection of motor programs. In health, adaptive plasticity in the basal ganglia enables easy execution of complex motor tasks through formation of habits. Conversely, in disease, repetitive behaviors, addictions and compulsions are thought to derive from maladaptive plasticity involving basal ganglia circuitry.

Transcranial magnetic stimulation (TMS) is a noninvasive technique used for neuroscience research and treatment of psychiatric and neurological disorders. During TMS, a current-carrying coil placed on the scalp induces an electric field that modulates targeted neuronal circuits. Computational simulations of the electric field (E-field) induced by TMS are increasingly used to gain a mechanistic understanding of the effect of TMS on the brain and to inform its administration.

We experience the world as a continuous sequence of events, but we remember the events as segmented episodes (e.g., my sister’s wedding). During encoding, we associate a sequence of relevant events and segment deviant events. At retrieval, episodic memory utilizes the encoded associations to replay the flow of events. The encoded associations lead to remembering the sequence of events that occurred within an episode better than the flow of events across segments.