Barry Whitsel - US grants

The functional properties of neurons in the superficial layers of the somatosensory cortex have received considerably less attention than those occupying the middle or deeper layers. A recent investigation focusing on the upper layers of the first somatosensory area (S-I) in cat described a class of neurons that had previously been ignored or overlooked. The proposed project will 1) examine in greater detail than has been accomplished to date, the response properties of superficial S-I neurons of the cat, and 2) determine which spinal tracts provide the various types of input to these neurons. In the first phase of the project, I will test the responsiveness of superficial S-I neurons to a wide battery of cutaneous stimuli -- mechanical and thermal, innocuous and noxious -- using both extracellular and intracellular recording techniques. Ethical considerations require that noxious stimuli only be used in the presence of a general anesthetic. For scientific validity, the agent used to produce anesthesia must not greatly alter the responsivity of the neurons under study. Thus, an initial step in the first phase of this project will be to identify anesthetic agents which would allow the study of a qualitatively unaltered neuronal population in the superficial S-I cortex. The second phase of this project involves determining the relative contributions of the various spinal tracts to the behavior of superficial S-I neurons. If an anesthetic is found that will allow investigation of the functional properties of the upper layer S-I neurons, the influences of the different input pathways will be assessed by electrically stimulating the spinal tracts while recording the responses of superficial S-I neurons. If such an anesthetic is not found, electrophysiological recordings will be made in the S-I cortex after the cat has recovered from a spinal tract lesion. Either method can indicate the spinal pathways providing input to the various types of superficial S-I neurons, and reveal the relative contributions of each pathway. The data gathered in this project could complement neuroanatomical data which indicate that the superficial layers of the somatosensory cortex have different afferent and efferent connectivity than the middle or deeper layers, as well as the more recent histochemical data showing a preferential distribution of certain neuropeptides in the superficial layers of the cerebral cortex. Elucidation of the functional properties of these neurons will extend current views of the S-I somatosensory cerebral cortex as an initial stage in the processing of inputs leading to somatic sensations.

The aims of the project are (i) to identify and characterize the dynamic central nervous system adaptative mechanisms which govern the cerebral cortical response to somatic stimulation in normal subjects, and (ii) to determine their susceptability to manipulations and conditions known to be associated with orofacial sensory disorders in man. A team of investigators having extensive experience in somatosensory neurophysiology, pharmacology, human and animal psychophysics, and computer- aided neurobiological research have joined forces to study (i) the changes in somatosensory nervous system information processing associated with experimental modifications (long- and short-term) of sensory input consistent with those experienced by human subjects either in the course of everyday life or subsequent to traumatic injury or disease; (ii) the changes on somatosensory information processing accompanying clinical pain in man; and (iii) the capacity of normal human subjects and patients with orofacial sensory disorders to evaluate cutaneous motion on the skin. It is anticipated that this program of basic and clinical research will: (i) promote interactions and collaborations between investigators with different backgrounds; (ii) support core facilities designed to facilitate multidisciplinary research on somesthesia; and (iii) stimulate the exchange of ideas, instrumentation, know-how, and experimental materials.

DESCRIPTION (Adapted from Applicant's Abstract): This proposal contains two parts, one experimental and one theoretical, in an integrated attack on the function of somatosensory cortex. The animal experimentation will utilize several methods, including extracellular multiunit recording methods for monitoring response of single neurons or small cortical populations to precisely controlled vibrotactile and moving tactile stimuli; the 14-C-2-DG metabolic mapping technique for demonstrating the spatially patterned global response of the somatosensory cortex to repetitive natural stimuli. Drugs having selective actions on various neocortical systems will be administered. The information obtained at all stages of the project will serve as the experimental basis for studies of a model of somatosensory cortical information representation and processing. These findings are expected to bear directly on a recently proposed view of cortical dynamic peri- and intra-columnar lateral inhibitory interactions which suggest highly specific roles for cortical neurotransmission. This combination of animal and computer modelling studies is intended to provide in-depth information about the dynamical cortical mechanisms involved in the representation of naturally occurring perceptually relevant stimuli.

This application seeks funding for a coordinated research program consisting of experiments on anesthetized squirrel monkeys and simulation studies of a neurobiologically-faithful neural network. The animal experiments will focus on the anterior parietal (SI) cortical response to constant-velocity brushing stimuli applied to the monkey hand, and will employ a newly-developed functional imaging technology (near-infrared - IR - optical imaging). The IR imaging method will be used (l) to observe and characterize development of the large-scale spatiotemporal patterns of SI activity produced by such stimuli and, in the same experiments, (2) to direct the placement of microelectrode penetrations so that the discharge activity of single neurons and small neural aggregates is sampled from different functionally characterized regions of the stimulus-evoked global activity pattern. The stimulus conditions to be employed were selected because of their previously demonstrated capacity to produce (1)- modifications of human subjects' judgements of moving stimulus attributes such as the on/off locus, traverse length, and direction of movement; (2) short-term changes in SI neuron response to tactile motion within the receptive field; and/or (3) large-scale reorganization, with repetitive stimulus application, of the stimulus-evoked global SI activity pattern. Mechanistic explanations for the neurophysiological and IR imaging observations obtained in the animal experiments will be sought through coordinated simulation studies of a model neural network which includes explicit formulations of (l) a recently described manner of SI topographical organization (the "segregate" plan of organization), (2) the radial and lateral intrinsic connectivity of SI, (3) the "classical" fast- acting GABAergic and glutaminergic neurotransmitter systems, as well as the cholinergic neuromodulatory system whose actions are of longer time course, (4) a subset of the repertoire of cellular/molecular mechanisms (including voltage- and/or agonist-gated membrane ionophores) characteristic of neocortical neurons, and -(5) the non-linear interactions between the different dendritic compartments of individual SI neurons.

The effects on the contralateral SI cortex of two different (non-noxious mechanical versus thermal) modes of natural skin stimulation will be studied in intact subjects, and also in subjects lacking either the spinal dorsal column or spinothalamic project pathways. Anesthetized squirrel monkeys will serve as subjects. In each subject a combination of the methods of near-infrared optical intrinsic signal (OIS) imaging and extracellular microelectrode recording will be used to obtain information about the SI neuron population and single neuron responses to the two modes of skin stimulation. In each subject recordings of the spike discharge activity evoke from single SI neurons by each model of skin stimulation. In each subject recordings of the spike discharge activity of the spike discharge activity evoked from single SI neurons by each mode of skin stimulation will be obtained from neurons located in functionally contrasting SI regions (e.g. regions in which the skin stimulus evokes increased vs. regions which undergo a decrease in activity. The microelectrode penetrations will be guided by high-resolution OIS images of the SI optical response to the same stimuli used to evoke single neuron discharge activity. In some experiments direct application of drugs to cerebral cortex or to spinal cord will be used to distinguish the contributions to the SI responses of activity in the NMDA receptor systems of cerebral cortex versus dorsal horn. The project is expected to generate novel information about the contributions of stimulus-directed cortico-cortical interactions to SI information processing and somesthesis. The findings also should bear on current theories of the CNS mechanisms of nonciception and pain

DESCRIPTION (provided by applicant): Treatment of pathological chronic pain remains one of the top clinical problems yet to be solved. Clinical literature, published soon after the First nd Second World Wars, describes numerous cases of soldiers shot through the head, with damage restricted to the postcentral gyrus, who lost the ability to experience pain in some part of the body. These cases, as well as reports of surgical ablations in human chronic pain patients, suggest that some part of the primary somatosensory cortex (SI) is critically involved in pain generation. A cortical region with such power over pain perception would make an attractive target for clinical suppression of pathological pain. Recently, an SI region was found within cytoarchitectonic area 3a that does preferentially respond to noxious stimulation in a manner closely resembling human experience of second or slow pain. The goal of this project is to test the hypothesis that pain loss experienced by humans with parietal cortical damage can be reproduced experimentally by selective inactivation of this nociresponsive region of area 3a. In the present study, which will be conducted in trained squirrel monkeys, the area 3a region revealed by optical imaging to respond selectively to thermonoxious stimulation of the contralateral hand will be reversibly inactivated in test sessions by topical application of GABA agonist muscimol or by local cortical cooling. In a subset of monkeys this nociresponsive area 3a region will be inactivated irreversibly - by ibotenic acid injection - in order to observe long-term effects of the loss of this cortical region. The subject's pain sensibility will be measured o a behavioral operant pain escape task before and after the area 3a inactivation. The prediction is that area 3a inactivation will prominently reduce, if not completely abolish, aversive pain that would normally accompany noxious stimuli applied to the contralateral hand. Unambiguous experimental confirmation or rejection of this hypothesis is of extremely high clinical relevance - the easy accessibility of the nociresponsive neurons of area 3a makes them a most attractive target for minimally invasive and highly selective therapeutic strategies for the amelioration/elimination of pathological pain in human patients.