Zhe Chen - US grants

DESCRIPTION (Adapted from applicant's description): Studies of early cognitive functioning indicate that infants are capable of inventing strategies for solving novel problems and of generalizing the strategies to unfamiliar problems. However, virtually nothing is known about how they accomplish these feats. To address these issues, the investigators plan to obtain trial-by-trial assessments of infants' problem solving, and 2-year-olds will be presented problems requiring the choice of an appropriate tool for bringing a toy within reach. In each experiment, the infants will encounter a series of isomorphic problems, varying in their features but sharing goal structures and solution strategies. Microgenetic methods, involving intensive observation of problem-solving activities from the initial use of a strategy to its consistent use, will be used to identify when the first use of a new strategy occurs. This identification, in turn, will allow determination of the circumstances that led up to the discovery and of their generalization of the strategy beyond this initial context. Obtaining trial-by-trial data will allow accurate assessments of infants' strategies and of developmental differences in the rate and breadth of their learning. It will also allow examination of factors influencing infants' discovery and generalization of strategies.

DESCRIPTION (provided by applicant): Permanent interstitial brachytherapy (PIB) for early stage organ-confined prostate cancer involves permanent surgical implantation of about 100 radioactive sources into the prostate so that a therapeutic radiation dose can be delivered to the cancer cells while minimizing the doses to the surrounding normal tissues. Potential advantages of this approach include continuous irradiation of cancer cells which reduces the impact of cell- cycle dependent variations in cellular radiosensitivity;reduced dose to normal tissues, which allows escalation of tumor dose for increased tumor control;use of a one-time implant procedure, which is more convenient for patients than the fractionated daily treatments of external beam radiotherapy (EBRT) that often last more than six weeks;and the avoidance of potentially detrimental geometric misses caused by the uncertainties in daily patient setup and by inter- and intra-fractional organ motions in EBRT. To fully achieve the potential of PIB, one must be able to accurately place these sources in a pre-designed spatial pattern for producing adequate tumor coverage and must maintain the initial source positions during the protracted PIB dose delivery, in addition to having an accurate characterization of the dosimetric properties of each source. In prostate PIB, however, variation in post-implant source position is inevitable because edema induced by the surgical procedure causes the prostate gland to swell rapidly (to as large as twice of its pre-surgery volume) followed by a gradual resolution that can require more than a month. A number of recent studies have shown that edema-induced variations in prostate volume and source positions can lead to large variations in the dose delivered to the tumor, which, if ignored, can have detrimental consequences for patients developing moderate or severe edema. This has become an especially urgent issue with the recent introduction and clinical application of a new 131Cs source, which has a shorter radioactivity decay half-life (9.7 day) than radionuclides used previously and therefore is more sensitive to the edema-induced source position variations. The specific aims of this project are: 1) to develop a new and integrated approach for accurate determination of the dosimetric effects of edema so that effective therapeutic intervention strategies can be designed and integrated into the planning and treatment of PIB with or without radiobiology guidance;2) to conduct a systematic validation of the proposed approach and the existing edema models using the histories of edema evolution measured for 15 PIB patients;and 3) to perform a comprehensive evaluation of the clinical significance of edema-induced dosimetric variations and the effectiveness of therapeutic intervention strategies so that the efficacy of PIB can be optimized for each individual patient. We hypothesize that the successful completion of this project will enable effective clinical management of the effects of prostate edema for each patient and thereby help to achieve the full potential of PIB in the treatment of early-stage prostate cancer. Public Health Relevance: Permanent implantation of radioactive seeds containing iodine-125, palladium-103, or cesium-131 in the prostate, also called brachytherapy, has become a popular form of radiation therapy for carefully selected prostate cancer patients. The clinical success of brachytherapy is highly dependent on the ability to properly plan the procedure, implant the radioactive source, and perform dosimetry in a way that ensures that the radiation dose distributions are well defined and appropriate for optimal treatment of the tumor. This ability, however, has been hampered by the inevitable development and resolution of surgery-induced prostate edema, which can last over a month. The primary objective of this project is to develop a new method to consider the effects of edema in radiation dosimetry and treatment planning so that the efficacy of this therapy can be optimized for each patient.

Spatial navigation and episodic memory are important for daily activity and survival in rodents and primates. Episodic memory consists of collections of past experiences that occurred at a particular time and space, expressed in the form of sequences of temporal or spatial events. Spatial (topographical or topological) representation of the environment is pivotal for navigation. The hippocampus plays a significant role in both spatial representations and episodic memory. However, it remains unclear how the spikes of hippocampal neurons might be used by downstream structures in order to reconstruct the spatial environment without the a priori information of the place receptive fields. Little is known how the hippocampal neuronal representation might be affected by experimental manipulation. Furthermore, cortico-hippocampal interplay and communications are critical for memory consolidation, but many questions about their temporal coordination during sleep remains unresolved. This project proposes a collaborative proposal for studying the neural representation of population codes in rodent hippocampal-cortical circuits. The investigators and collaborators at MGH, MIT and Boston University will integrate innovative computational and experimental approaches to explore the neural codes during various spatial navigation and spatial/temporal memory tasks as well as during post-behavior sleep---as sleep is critical to hippocampal-dependent memory consolidation. Notably, due to the lack of measured behavior, it remains a great challenge to analyze or interpret sleep-associated hippocampal or cortical spike data.

The important questions central to this project are: how do hippocampal (or hippocampal-cortical) neuronal representations vary with respect to species (rat vs. mouse), animal (healthy vs. diseased), experience (novel vs. familiar), environment (one vs. two-dimensional), behavioral state (awake vs. sleep), and task (active vs. passive navigation; spatial working memory vs. temporal sequence memory). The investigators will simultaneously record ensemble spike activity from two or multiple areas of the rodent brain (hippocampus, primary visual cortex, prefrontal cortex, and retrosplenial cortex) under different experimental conditions, and will decipher the population codes using a coherent statistical framework. In light of Bayesian inference (variational Bayes or nonparametric Bayes), innovative unsupervised or semi-supervised learning approaches are developed for mining and visualizing sparse (in terms of both sample size and low firing rate) neuronal ensemble spike data.

The outcome of this investigation will improve the understanding of neural mechanisms of hippocampal (or hippocampal-cortical) population coding and its implications in learning, sleep and memory. The derived findings will shed light on the links between the variability of neural responses and the animal behavior (or other external factors), and will provide further insight into memory dysfunction (such as in Alzheimer's disease). Furthermore, this project has broader impacts in developing efficient algorithms to decipher neuronal population spike activity during behavior or sleep, as well as in discovering invariant topological representation of population codes in other cortical areas. In addition to the scientific significance, this proposal bears an educational component for training researchers on advanced quantitative skills in ensemble spike data analysis as well as for disseminating scientific resources (by sharing data and software) to a broad neuroscience community.

Proposal Title: NSF-FO: Closed-loop neuromodulation for chronic pain

Pain is a complex and multi-dimensional experience that nevertheless occurs commonly in people's daily lives. Chronic pain affects 1.5 billion people worldwide and has contributed to major healthcare costs. The treatment of chronic pain remains insufficient, highlighted by the current opioid epidemic. In the past few decades, neuroscience research has provided accumulating knowledge of pain processing in the central nervous system. However, effective analgesic options with limited side effects remain elusive, in large part because the neural mechanism for how chronic pain is perceived and modulated in the brain is poorly understood. This proposal tries to challenge the status quo using chronic pain-treated rodent models. The use of rodent models would allow researchers to examine the brain activity at specific localized neural circuits at a cellular resolution, and to further provide a guideline for neuromodulation-based pain treatment. The project has great translational potential to advance personalized pain medicine and provide therapy for the chronic pain associated with a wide range of neuropsychiatric disorders. This project will also promote education and diversity in training undergraduate/graduate students or postdoctoral fellows, and will be committed to data sharing and outreach activity in order to maximize the benefit to society.


This research project will integrate behavior and electrophysiology studies to investigate the causal impact of neuromodulation on neocortical circuits in chronic pain conditions. The ultimate objective of this proposal is to develop a noninvasive brain machine interface system for detecting and relieving chronic pain in a rodent model. On the one hand, this project will investigate examine basic neuroscience questions regarding the neural variability underlying complex sensory and affective processes. On the other hand, this project will investigate a minimally invasive neuromodulation strategy for treating chronic pain. In Aim 1, in vivo extracellular neural activity (including the ensemble spike activity and local field potentials) will be recorded from the primary somatosensory cortex and anterior cingulate cortex of freely behaving chronic pain-treated rats. This will allow researchers to characterize nociceptive response variability under different chronic pain conditions. In Aim 2, a closed-loop rodent neuromodulation interface will be developed for chronic pain control, which combines the detection of pain signals (?detection arm?) and neuromodualtion (?treatment arm?). This aim will optimize neural signal processing using multi-region local field potentials and further leverage advances in neuromodulation techniques to employ epicranial current stimulation on the targeted brain region (such as the primary motor cortex). In Aim 3, the current stimulation parameters (e.g., intensity and duration) will be optimized using online neurofeedback to improve the efficacy of neuromodulation in light of reinforcement learning. In summary, the brain-machine interface system will tease apart the mechanism of cortical pain circuits, and characterize the nociceptive response variability under different (inflammatory vs. neuropathic) chronic pain conditions. Together, these results will reveal novel insights into circuit mechanisms of chronic pain.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.