1985 — 1987 |
Dostrovsky, Jonathan O |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dental Pain: Studies On Trigeminal Nucleus Caudalis
This project aims to determine, for the first time, the functional characteristics of a recently discovered pathway which has been proposed to be a specific pain pathway. Subnucleus caudalis (SNC) is the major site in the trigeminal sensory complex involved in processing pain information arising in the orofacial region and in relaying it to thalamus. The main thalamic projection sites of SNC are the ventroposteromedial nucleus (VPM) and the more medially located intralaminar nuclei. It is believed that the sensory-discriminative aspects of pain are processed in VPM and the motivational-affective components in medial regions of thalamus. However, few studies have investigated the role of the medial thalamus in pain processing in spite of its potential relevance to clinical pain states. Recent anatomical studies have described a hitherto unknown pathway originating in the marginal layer of SNC, relaying in nucleus submedius (Sm) in medial thalamus and terminating in the ventrolateral orbital (VLO) cortex. Indirect evidence strongly suggests that this pathway is involved specifically in processing and relay of pain signals. No physiological studies have addressed this potentially very important pathway. The proposed electrophysiological experiments will study the functional properties of this pathway. Microelectrodes will be placed in VLO cortex, Sm and SNC of anesthetized cats and used to antidromically stimulate SNC neurons which project to Sm and Sm neurons which project to VLO cortex. The functional characteristics of these SNC and Sm projection neurons will be determined by applying various nociceptive and nonnociceptive mechanical, thermal and electrical stimuli to the orofacial region including the tooth pulp. The morphology of the SNC neurons and their location within SNC will be determined by intracellular injection of horseradish peroxidase. The effect of stimulating descending pathways originating in the cortex, periaqueductal gray and raphe magnus on the responses of SNC neurons will be investigated. The results of these studies will contribute to our understanding of the mechanisms involved in dental pain and other painful conditions of the orofacial region and may possibly lead to improved clinical methods for the control of pain.
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1989 — 1991 |
Dostrovsky, Jonathan O |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neural Mechanisms of Nociception in the Face and Mouth
The overall aim of these studies is to increase our understanding of the neural mechanisms involved in mediating the perception of pain. The specific aim of the proposed studies over the next 3 years is to extend our successful studies initiated during the current granting period on (1) the function of the pathway ascending from subnucleus caudalis (SNC) of the brainstem trigeminal (V) nucleus to ventrolateral orbital cortex (VLO) via a relay in nucleus submedius (Sm) in medial thalamus and (2) the characteristics of neurons in the V system activated by sensory stimulation of cerebral blood vessels. Recent anatomical studies have described a pathway originating in the marginal layer of SNC. relaying in Sm and terminating in VLO. Indirect evidence strongly suggests that this pathway is involved specifically in the processing and relay of pain signals. No physiological studies apart from our own have addressed this potentially very important pathway. In addition, virtually nothing is known concerning the sensory receptors associated with the cranial blood vessels. These V afferents are believed to mediate vascular head pains such as migraine and thus it is of scientific and clinical importance to determine their physiological properties. The studies will be carried out in anesthetized rats and cats and employ primarily single cell electrophysiological recording techniques. The studies will characterize the functional properties of neurons in SNC that project to Sm, as well as neurons in Sm and VLO. Other experiments will be devoted to investigating in greater detail the types of peripheral stimuli and chemical agents which activate and influence the sensitivity of the sensory afferents innervating the cerebral vasculature. Some of these latter studies will be conducted in the rat where in addition to recordings from SNC neurons, recordings will be obtained from V ganglion neurons in order to determine the functional characteristics of the sensory fibers innervating the intracerebral vessels. The findings of these various experiments will help provide a clearer explanation of the processes underlying the perception of acute and chronic pain and will help explain the etiology of vascular headaches. In addition, the results may lead to the development of improved clinical methods for the control of pain.
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1994 — 1996 |
Dostrovsky, Jonathan O |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Orofacial Nociception and Thermoreception
DESCRIPTION: The general goals of this project are to elucidate the central mechanisms underlying thermoreception and nociception. The specific aims of the proposed project are to determine the response properties of thermoreceptive neurons in the trigeminal brainstem complex and thalamus and their projection targets as well as to examine the interaction of thermoreceptive afferent inputs on the responses of nociceptive neurons. Electrophysiological extracellular single unitrecording techniques will be employed in anesthetized rats and cats. Recordings will concentrate on neurons located in the marginal layer of the medullary dorsal horn (MDH) although the possible existence of thermoreceptive neurons in deeper layers of the MDH and in trigeminal subnucleus interpolaris will also be examined. The responses of thermoreceptive neurons to innocuous and noxious cold and hot stimuli will be characterized. The projection targets of these neurons in thalamus will be determined by means of antidromic mapping techniques. The influence of descending influences from cortex and brainstem will be ascertained. Other experiments will examined the effects of skin cooling on the responses of nociceptive neurons in the MDH. In the second part of the project recordings will be made in thalamus of cats and rats and the responses and locations of thalamic thermoreceptive neurons characterized. These experiments will provide new data on the processing of temperature information in the trigeminal spinal tract nucleus and thalamus and clarify the mechanisms underlying cold pain. They will also examine the interactions of thermal cutaneous inputs with nociceptive inputs and may provide new insights on the central processing of nociceptive information.
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1997 — 1999 |
Dostrovsky, Jonathan O |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Thalamic Mechanisms of Pain
DESCRIPTION: The overall goal of these studies is to elucidate the thalamic mechanisms underlying the perception of painful stimuli and chronic pain. These novel studies are made feasible by the unique opportunity afforded to us during functional stereotactic neurosurgery when we are able to record the activity of neurons and determine the effects of microstimulation in awake patients with movement disorders or chronic pain. The major aims of the project are to I: Demonstrate the existence of nociceptive neurons within human Vc (the ventrobasal complex; VB), characterize their responses, determine whether microstimulation at such sites gives rise to painful sensations and examine whether blocking the activity of the neurons in this region will result in alteration of pain perception II: Perform similar studies but for neurons located ventroposterior to Vc in a region termed Vcpc/VMpo. III. Perform similar studies as in I and II above but for neurons located in medial thalamus. IV: To analyze the incidence, locations and firing patterns of bursting cells (proposed to contribute to chronic pain) in medial and lateral thalamus and determine the effects of blocking their activity on chronic pain. These goals will be achieved by a combination of extracellular neurons recordings, microstimulation-evoked sensations and effects of temporary block of neuronal activity in awake patients. The proposed studies will test the hypotheses that Vc, Vcpc/VMpo, and medial thalamus are involved in mediating various aspects of the pain experience and that cells firing spontaneously in a bursting pattern may be related to chronic pain. The results of these novel and unique studies should considerably advance our understanding of the role of thalamus in both chronic and acute pain and could provide a radical new conceptual framework of thalamic pain mechanisms. Improved understanding of thalamic mechanisms of acute and chronic pain may lead to the development of new therapeutic approaches.
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2001 — 2003 |
Dostrovsky, Jonathan O |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Deep Brain Stimulation.
Electrical stimulation within the human brain is now an accepted method for the treatment of some types of movement disorders. However the mechanism of action of deep brain stimulation (DBS) is still not well understood. Two current hypotheses are that DBS produces inhibition of the neurons in the vicinity of the electrode by releasing GABA from inhibitory neurons or terminals pr terminals in the region or by causing a depolarization block of the surrounding neurons. Our proposal aims to obtain new information on the possible mechanisms of DBS. A newly developed dual microelectrode recording system will be employed during functional stereotactic surgery for implantation of DBS electrodes in the subthalamic nucleus (STN) and globus pallidus (GP) of Parkinson's disease patients. One of the two electrodes will be used for micro- or in some cases macro-stimulation and the effects of such stimulation assessed on the firing of neurons recorded at distances of 250 mum or more. Additionally, effects of high frequency and of lidocaine and muscimol microinjections into STN will be assessed on tremor, rigidity and bradykinesia. Preliminary studies using these methods have shown that stimulation in the GP very effectively inhibits the firing of most neurons in a manner that strongly suggests release of GABA. However, pilot studies in STN and motor thalamus, suggest that other or additional mechanism(s) might be involved. The findings of these studies focused on STN should provide new insights into the mechanisms underlying DBS and may lead to improvements in electrode design, electrode placement and optimal stimulation parameters thus leading to improvements in the therapeutic efficacy on this technique.
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