Ziv Williams - US grants

DESCRIPTION (provided by applicant): The inability to communicate underlies one of the most disabling aspects of injury to the central nervous system, and includes the inability to perform rudimentary tasks such as flexing and extending ones'limb or moving a simple cursor on a screen. While the majority of studies thus far have targeted the intrinsic repair or regeneration of damaged areas of the central nervous system such as brainstem or proximal cervical spinal cord, alternative approaches for redirecting information between areas that remain functionally intact is largely unexplored. Work by our group and others has demonstrated that neuronal activity in cortical and subcortical areas responsible for motor control can accurately predict volitional movement intention, and that delivery of event-related electrical stimuli in areas responsible for motor production can reproducibly alter targeted limb movement. In the current study, we aim to extend these findings by systematically matching and altering motor intent with movement production in primates performing a motor directional task. To this end, we will obtain single-neuronal recording from the same subcortical areas shown to predict motor intention and use a similar system design to deliver electrical stimuli to the ventral spinal cord in order to approximate and alter movement production. Changes in neuronal activity will be examined over multiple trials as observed movements predicted by neuronal activity are made to either correspond or mismatch movements produced by spinal cord stimulation. These findings will provide a unique perspective into the individual roles that motor neuronal plasticity and spinal efferent activity play in adaptive motor control, and may offer valuable new insight into the development of prosthetic designs aimed at restoring volitional movement. PUBLIC HEALTH RELEVANCE: Motor deficit is among the most debilitating aspects of subjects suffering injury to the central nervous system. Despite continued efforts to develop treatments for patients with such injury, there remain few and often no options available for reconstituting volitional motor control. The proposed project aims to explore a novel approach for restoring motor communication that is based on a system design developed by our group for use in awake-behaving primates. The significant social impact of such devices has already been demonstrated with the emergence of cochlear, brainstem and retinal prosthetic implants, and may similarly provide significant benefit for patients with motor disability resulting from brainstem and proximal spinal cord injury.

? DESCRIPTION (provided by applicant): A fundamental question in neuroscience is how memories are represented by the collective pattern of spiking within neural populations. A related question is whether the same collective pattern used to represent memories during learning are reactivated during later recall, or if the nature of the population code is vitally different. While prior theoretical work and more recent work in animal models have provided valuable initial insights into how memories are likely represented, the neural process by which memories are actually retrieved at the network-wide level, what exact aspects of the first-, second- and higher-order network structure are informative of the retrieved memories, and by what rapid sub-second dynamic do such informative patterns evolve within individual trials remain fundamentally unknown. This limited understanding is particularly true of hetero-associative memory processes such as cued recollection in which the items being recalled are both absent and completely unique from the presented items used to cue their retrieval. Here, we aim to systematically define, for the first time, the combined network-level processes that underlie these basic forms of auto-associative (recognition) and hetero-associative (recollection) memory. Towards these ends, we will use the shared expertise of the two principal investigators to perform simultaneous multi-electrode recordings from frontal and temporal cortical populations in Rhesus macaques; devise and test novel analysis methodologies that can both reliably infer the collective first-, second- and higher-order functional network structures from stochastic spiking data; track their rapid sub-second dynamics within individual trials; identify which structures are informative of the memories being recalled; determine when and to what extent spiking network structures observed during learning reactivate during recall within individual-day sessions; and, perhaps most importantly, determine whether pattern reactivation, at the spiking network-level, is causatively related to recall accuracy at the behavioral level. Th present proposal will allow us to directly test, for the first time, a number of central hypotheses on memory processing using a novel set of technical and methodological innovations that will have broad practical implications to the study of memory-related developmental, behavioral and neurodegenerative disorders.

Using game theory in primates to study the distributed neuronal and time- causal underpinnings of interactive social behavior Despite the importance of joint interactive social behavior and its broad involvement in many neurocognitive disorders, its single-neuronal basis, population-level encoding and time-causal underpinnings are still largely unknown. A major part of this limitation has come from our inability to ask such questions in humans. Game theory, and the iterated Prisoner's Dilemma (iPD) game in particular, provides a well-studied platform for investigating and dissociating the multi-dimensional encoding of interactive social decisions. Here, we will build on recent innovations by our group with dual interacting primate-pairs, neural population recording and deep brain stimulation (DBS) in order to systematically investigate the basic neuronal building blocks of interactive social behavior. In preliminary studies performed by our groups, we have already identified some of the key neuronal computations underlying joint social decisions. We have also established important behavioral validation measures, social context controls and cross-pair confirmations for the primate model. In this study, we will investigate, for the first time, the involvement of three principal areas theorized to comprise the ?social brain? in distributively encoding and modulating distinct aspects of interactive social behavior. These areas include the dorsal anterior cingulate cortex, anterior intraparietal area and the basolateral amygdala. We will specifically examine the single-neuronal and population encoding of self vs. other agency, joint interaction, social context and agent identity. We will test how these representations are modulated by social cues and examine the targeted modulation of the different areas by both standard and event-triggered DBS. Overall, this proposal represents a completely new line of investigation that is not possible to conduct in humans, and opens up an important unexplored area in neuroscience. The proposed set of studies will provide the first comprehensive roadmap of the primate ?social brain? at the neuronal and population level, and offer critical guidance for future targeted treatments of social behavioral disorders.

ABSTRACT This is a renewal proposal describing the Research Training Program for Neurology and Neurosurgery Residents at Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) of Harvard Medical School (HMS). The program combines the exciting variety of collaborative research opportunities available at these campuses with a dedicated core group of neuroscience mentors aligned in a two tiered system which includes a `research' mentor directly responsible for the scientific activities of the candidate and a `gateway' mentor responsible for the overall career development of the R25 candidate. Research mentors are selected from the enormous field of researchers at our two institutions and other institutions in the Boston area. The gateway mentors are selected on the basis of research activity, experience guiding clinicians in the early stages of successful research careers, and commitment to this program to develop neurology and neurosurgery residents into effective physician-scientists. In addition, a steering committee closely oversees all aspects of the resident research training experience. This program has already had tremendous success in its first 9 years of funding which has included 50 trainees who have produced numerous high-impact first author publications and earned foundation as well as K12, K23 and K08 funding and been hired into faculty positions. This programmatic structure builds on these successes to ensure that neurology and neurosurgical residents obtain the highest level of training possible to launch careers as outstanding physician-scientists.

An integrated single-neuronal, population-, local network- and stimulation-based prefrontal investigation of human social cognition This proposal aims to undertake a comprehensive single-cellular, population-, local circuit- and stimulation- based evaluation of the role that the dorsal prefrontal cortex plays in human social cognition. Despite ongoing progress in our understanding of basic elements of social behavior through animal models, astonishingly little is known about the single-neuronal and causal mechanisms that underlie human social cognition. A core network of areas comprising the dorsomedial prefrontal, dorsolateral prefrontal and anterior cingulate cortex of the frontal lobe has been suggested to play a critical role in human social behavior; sub-serving processes that include emotional judgment, social reasoning and theory of mind. Unlike more basic sensorimotor processes, these social processes require individuals not only to represent the observed behavior or actions of others but to also infer their hidden internal states and beliefs which are inherently unobservable and unknown. These higher-order social processes play a central role in human ontogeny and are broadly affected in psychosocial conditions such as schizophrenia, depression and autism spectrum disorder. Yet, despite their importance, extraordinarily little is known about how the activities of neurons in the human brain give rise to these diverse social cognitive functions or what precise role specific prefrontal areas play. Building on our groups unique combined experience in acute single-neuronal recordings from the these dorsal prefrontal areas, social neuroscience and theory, population analyses, computational modeling and real-time stimulation techniques and by using a novel structured multi-set social task, this proposal aims to address, for the first time, vital questions about how social information is processed in humans at the cellular level, what specific cognitive processes are engaged across cortical areas, whether these processes are dissociable from more generalized cognitive mechanisms, how these key computations interrelate and, crucially, what causal contribution do neural activities in these prefrontal areas play in human social cognition at the behavioral level. Together, this systematic cross-modal, inter-disciplinary, multi-institutional collaborative effort promises to provide unprecedented new insights into human social cognition at the cellular level and offer an innovative new framework by which to investigate the prospective contribution of the dorsal prefrontal cortex to psychosocial conditions such as autism spectrum disorder.