Nicholas D. Schiff - US grants

The principal aim of the proposed studies is to examine the role of the nonspecific thalamus in brain information processing. It is well-known that cognitive disturbances may arise from either structural or functional disturbances of the nonspecific thalamus as seen in several neurological disorders. To examine the cellular basis of these disturbances two primate models are proposed. In the propose studies visual processing is chosen as an assay to examine the role of the nonspecific thalamus in cortical information processing and visually guided behavior. In the first study, receptive fields of primary visual cortical neurons (Vl cells) will be studied before, during and after 3/s spike and wave complexes generated by stimulation of nonspecific thalamic structures (either intralaminar nuclei or median dorsalis). This experiment will exploit the advanced knowledge of V1 receptive field properties and the growing understanding the thalamocortical relationships. The second study proposes a primate model of thalamic neglect induced by reversible deactivation of the intraliminar nuclei. In this model behavior will be carefully studied with characterization of general behavior, oculomotor function and perceptual processing. The two projects form a comprehensive training in methods necessary for future independent investigation of the role of the nonspecific thalamus in cognitive disorders. The long-range goals of these studies to lay the foundation for eventual therapeutic intervention for cognitive dysfunction following stroke or head trauma.

DESCRIPTION: (Adapted From The Applicant's Abstract):The immediate aim of the proposed research is to develop an awake behaving primate model to investigate the role of the intralaminar and associated paralaminar thalamic nuclei in visual awareness. The long-range goal is to develop a neurophysiological basis for remediation of acquired cognitive disabilities, including deep brain stimulation in the intralaminar thalamus. Direct injury or functional impairment of the intralaminar thalamic nuclei (ILN) leads to disturbances of attention, working memory, and other cognitive processes. It is proposed that the ELN play a critical role in facilitating specific longrange cortico-cortical communications that link attention, working memory, and gaze control in support of visual awareness. The precise cellular mechanisms of interaction between the ILN and the cortical regions that support these functions are only beginning to be understood. This is the focus of the present proposal. Two research paradigms will be developed: pharmacological inactivation and electrical stimulation of the intralaminar nuclei during a visuospatial attention task. Impaired cognition resulting from head trauma or stroke remains a growing problem for which little intervention is currently available. Several experimental and clinical studies suggest that deep brain stimulation and other approaches aimed at improving cognitive function may be possible. While these are long-range goals, and the studies proposed here do not represent direct investigations of these possibilities, completion of these experiments is necessary and logical step toward these goals.

A recent NIH Consensus Statement (JAMA 1999 282:974) noted that 70-90,000 Americans each year incur long-term substantial loss of function from traumatic brain injury (TBI). The panel further noted that "the more problematic consequences involve the individual's cognition, emotional function, and behavior." The present studies are aimed at developing pilot data to guide a controlled trial for the use of deep brain stimulation technologies in selected TBI patients: those with recovery limited to regained consciousness, minimal self-awareness, and minimal interpersonal communication. Study patients will either be in a minimally conscious state (MCS) or have emerged from a MCS but remain incapable of independent activities of daily living as measured by the Disability Rating Scale. Emergence from MCS is suggested by reliable and consistent demonstration of functional interaction. Many of these patients demonstrate preserved, but fluctuating, capacities for basic communication, memory, attention, intention, and awareness of self and environment. These observations provide clinical evidence that their limited functional capacities do not represent entirely irreversible damage. The immediate goals of the proposed studies are to define appropriate clinical and imaging criteria and outcome measures to evaluate patients for selection into deep brain stimulation studies, and to evaluate physiological measures that can aid the design of stimulation parameters. We present preliminary neuroimaging data both from patients in chronic vegetative states, and from patients with other neurological conditions with implanted deep brain stimulators that demonstrate selective functional brain activations during neurostimulation. We detail potential strategies for selection of patients and for choosing targets within the thalamic intralaminar nuclei of these patients for electrical stimulation. The strategy of selection of patients for neuromodulation of impaired cognitive function will be evaluated via neuroimaging tools and neuropsychologic evaluation. The proposal combines the unique clinical expertise and experience of neurological, functional stereotactic neurosurgical, and neurorehabilitation investigators. To achieve these goals we will develop a strong multi- disciplinary team with recognized expertise in both investigational and therapeutic studies of brain injured patient populations. The long-range goal of the studies proposed here is to provide a foundation for rational therapies for chronic cognitive disabilities following complex brain injuries.

[unreadable] DESCRIPTION (provided by applicant): The minimally conscious state (MCS) describes a low level of functional recovery of cognition following a severe brain injury. Unlike patients in the vegetative state, MCS patients respond to their environment, may show relatively complex responses to verbal commands, and produce limited verbal expressions. Significant functional recoveries at long intervals can be observed in MCS patients (e.g., recovery of speech after years). The present proposal seeks to improve understanding of the neurophysiological mechanisms underlying MCS and to develop diagnostic evaluations to identify potential cognitive reserve in patients with severe brain injuries. Preliminary data obtained from multimodal neuroimaging studies of MCS patients supports a working hypothesis that the MCS brain is chronically underactive, yet may retain dormant large-scale integrative cerebral networks. We plan to carefully and longitudinally characterize brain function in patients who have stabilized at a functional level meeting the accepted criteria for MCS using quantitative electroencephalography (EEG), fluorodeoxyglucose-positron emission tomography (FDG-PET), diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI). Preliminary studies support combining these measures to test the hypothesis that MCS patients recover integrative brain function but, due to low resting neuronal activity resulting from dynamic abnormalities in the thalamocortical system, remain unable to consistently form and maintain dynamical brain activity underlying communication and goal-directed behavior. We will test the additional hypothesis that slow structural remodification of the brain generally arise after severe traumatic brain injury. Approximately 100,000 Americans each year incur long-term substantial loss of function from severe traumatic brain injuries. The immediate goal of the proposed studies is to provide a foundation for developing methods to study the natural history of evolution of recovery of cognitive function following severe brain injury. The long-range goal of the studies proposed here is to build a set of quantitative indices to help identify MCS patients with recruitable neuronal populations who may be candidates for emerging trials of palliative interventions aimed at improving communication. The patient population under study is large, poorly characterized, and vastly underserved; moreover, they are uniquely vulnerable to misdiagnosis and neglect. These neuroimaging studies will help identify patients who have been mistaken as permanently unconscious but may have the capacity to recover communication. Without such studies, these patients will continue to remain categorically excluded from advances in medical diagnostics and therapeutics. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The goal of the proposed studies is to develop two complementary animal models to advance deep brain stimulation (DBS) of the central thalamus (CT) as a therapeutic strategy for the treatment of acquired cognitive disabilities resulting from traumatic brain injury (TBI). Each day of the year approximately 4,000 Americans suffer a traumatic brain injury (TBI), leaving as many as 100,000 persons/year with long-term cognitive disabilities. We will form a multidisciplinary research program utilizing systems neuroscience and bioengineering methods to improve the efficacy of central thalamic brain stimulation (CT/DBS). The research team will be lead by investigators at Weill- Cornell Medical in partnership with researchers at The Rockefeller University and Medical College of Wisconsin. Dr. Nicholas Schiff (Weill-Cornell), a leading neurologist/neuroscientist in the fields of CT/DBS and human brain injury studies, will act as P.I. of the R01 along with Dr. Keith Purpura (Weill-Cornell), an expert systems neurophysiologist, to carry out a series of experimental studies in intact alert, behaving monkeys. The work with monkeys will examine the influence of different patterns of electrical stimulation on rostral central thalamic neurons. These neurons link the brain stem centers that control arousal with the cerebral cortex, and play a crucial role in integrating cortex, striatum and thalamus. Behavioral effects of continuous stimulation and of brief pulses applied at specific times will be evaluated during the performance of two elementary cognitive tasks. Neural activity in the monkey's frontal lobe during and following stimulation will also be examined. Dr. Donald Pfaff (Rockefeller), a world- renowned expert on the cellular basis of behavior, will adapt a vetted set of arousal assays he developed for the mouse to studies of CT/DBS. Preliminary results in his laboratory have shown that CT/DBS in the mouse can facilitate behavioral performance following induced traumatic brain injury. Dr. Christopher Butson (Medical College of Wisconsin), a bioengineer and expert in computational modeling of brain electrical stimulation will develop detailed models of the volume of tissue activated in the animal experiments at Weill-Cornell and Rockefeller. He will also supervise the development and analysis of a probabilistic atlas to identify the sites of optimal application of CT/DBS. This atlas will assist in the construction of a human atlas that could be used in the treatment of non-progressive brain injuries. Thus, the long-range goal of this work is to optimize neuromodulation strategies employing electrical stimulation of the central thalamus to treat cognitive impairment following TBI. PUBLIC HEALTH RELEVANCE: Acquired cognitive impairment following severe brain injury leave as many as 100,000 Americans each year with devastating disabilities. The studies proposed here will help to advance the necessary knowledge to advance and further develop a novel application of electrical brain stimulation aimed at improving the lives of patients suffering with these lifelong challenges.

? DESCRIPTION (provided by applicant): Severe to moderate traumatic brain injury (smTBI) annually afflicts many hundreds of thousands of Americans producing chronic cognitive disabilities that lack effective treatments. The present proposal will develop a critical first-in-an early clinical feasibility study to support a next generation device to provide central thalamic deep brain stimulation (CT-DBS). CT-DBS is proposed as a therapy for the survivors of smTBI who recover to independent functional levels but remain significantly limited in their activities b chronic cognitive impairment (difficulties with sustained attentional effort, working memory, processing speed and fatigue). Stakeholders, including patients identifying their cognitive difficulties as matched to the functions proposed to be supported by CT-DBS, have shown support for this approach and willingness to consider participation after having the concepts and risks of this approach presented to them. The working hypothesis for the present study is that the pattern of cognitive deficits seen after smTBI takes origin in a broad reduction of neuronal connections and cell loss produced by smTBI that will on average produce disproportionate down-regulation of frontostriatal systems and deafferentation of the central thalamus (which collectively support the range of executive cognitive functions typically impaired in smTBI), and that CT-DBS can activate these systems sufficiently to provide effective functional improvements. Preliminary studies including evidence of CT-DBS facilitation of cognitive function in a different, more severely brain-injured population of patients with traumatic brain injuries as well as pre-clinical behavioral, electrophysiological, and computational modeling studies in intact non-human primates (NHP) support the hypothesis and the approach. The present study will use bilateral placement of a research single- electrode system with sensing and recording capabilities to aid the electrophysiological mapping of the central thalamus. Our supporting data demonstrate that behavioral facilitation can be achieved with a single electrode system in both the human and NHP. In NHP studies we have found that a more reliable and robust therapeutic response can be achieved through the use of a multiple electrode system capable of targeted delivery of electric fields across a specific fiber tract in the central thalams. Here we will obtain and analyze neuroimaging, computational modeling, behavioral, and electrophysiological data from human subjects to advance the development of a next-generation system that may allow more flexibility and reliability of for the application of CT-DBS in patients with traumatic brain injuries. These studies will be carried out by an investigative team with multiple, long-standing collaborations aimed at the development of CT-DBS technologies and treatment of cognitive impairment following TBI; the team spans expertise in clinical trials, neurology, neurosurgery, neurophysiology, neurorehabilitation, neuropsychology, radiology, and computational modeling. The early feasibility study proposed has been through a presubmission review for an Investigational Device Exemption with the Food and Drug Administration.