Thalamo-Cortical Pain Mechanisms Prof. Fred A. Lenz

Transcription

1 Thalamo-Cortical Pain Mechanisms Hopkins Hospital, Baltimore, USA F.H. Baker, D.S. Borett, T. Chase, D. Chau, H. Chen, R. Coghill, N.E. Crone, R.G Cutler, M.R. DeLong, P.M. Dougherty, J. Dostrovsky, I.M. Garonz ik, S. Goldstein, R.H. Gracely, J.D. Greenspan, S. Grill, M. Hallett, G. Hovey, S. Hua, A.E. Hillis, C.J. Jaeger, J.H. Kim, K. Kobayashi, B.I. Karp, R. Kwong, H.C. Kwan A. Lasker, H.C. Lawson, J.I. Lee, Y.C. Lin, R. Martin, R. Minahan, J.T. Murphy, M. Nicholson, S. Ohara, J. Port, D.D. Price, G. Rasouli, M. Rasouli, S.G. Reich, R. Richardson, L.H. Rowland, S.Schnider, M. Seike, R. Shadmehr, J.I. Suarez, R.R. Tasker, R-D. Treede, D. Veldhuijsen, L. Verhagen, J.L. Vitek, N. Weiss, J. Winberry, K. Yamashiro, T.A. Zirh D. Zee 1 2 A- location of fibers in Spinal Thalamic Tract B- somatotopic organization of the fibers in A C- locations and receptive fields of fibers in the STT Willis WD, The Pain System,

2 4 I. WDR cell responding to brush, progressive pinch, heat and cold II. High threshold cell responding to high but not low intensity pinch onse respo sec 5 6 2

3 Superficial Dorsal Horn potentials corresponding to slow myelinated and C fiber intensity stimulus Response to noxious pinch Response to slow myelinated and C fiber inputs C fiber response 7 Response of lamina 1 units to: A. innocuous cooling B. innocuous heating (middle) C. innocuous cooling then heating 8 Cold-receptive cluster Nociceptive single unit SPIKES per second Time (s) Temprature (ºC) 9 3

4 Lamina I vs. deep laminar neurons of origin Wide dynamic range vs. high threshold STT neurons Mechanical/thermal vs. mechanical/ thermal and innocuous cold Ventral vs. dorsal STT pathway Termination in principle somatic sensory nucleus VP vs. VMPo Lamina I pathway calbinden staining 10 Afferent fibers Sharp pain Burning pain Cool Itch? Figure 1: Summary diagram representing the anatomical basis for afferent inputs to specific cells in lamina I and integrative cells in lamina V 11 Figure 2: Summary diagram of the ascending projections of the lamina I spino-thalamo-cortical system Lamina I Lateral spinothalamic tract 12 4

5 Evidence against a separate thalamic nucleus specific to pain and thermal sensation (VMPo) Injections into VP lead to extensive labeling of both Lamina I and deep lamina (Willis et al. 2002) Injections into superficial spinal nucleus of cranial nerve 5 label VPM area which is separate from the area of calbinden labeling (Graziano and Jones 2004) 13 Frontal section showing calbinden staining (red) separate from STT staining (green) at the medial tip of VP thalamus 14 VPL4 Photomicrograph of the injection site at one level of the thalamus The dark region- injection of tracer Distribution of spinothalamic tract neurons that were retrogradely labeled Stippled area- position of nucleus Willis W. D., Zhang X., Honda C. N., Giesler G. J., Pain, 92, ,

6 Activity in the thalamic relay to cortex Single unit and microstimulation analysis of somatic sensory thalamus 18 6

7 Activity of a cell (061093) in Vc responding to painful mechanical and thermal stimuli A: Location of the cell (arrow) B: Response to the brush, LC, MC and SC C: Response of the neuron to progressive increase in pressure D: Responses to heat stimuli at 42, 45 and 48 C E: Responses to cold stimuli at 12, 18 and 24 C Single unit analysis of somatic sensory thalamus (Lenz et al JCN, 1999) Firing rate (s -1 ) Spont BR LC MC SC Mechanical stimuli Firing rate (s -1 ) Mean ± SEM Spont BR LC MC SC Firing rate (s -1 ) Temprature (ºC) 20 Stimulus evoked spike trains composed of single spikes and bursts related to inhibitory 21 7

8 Thalamocortical non-linearities ^ on Stimulus off ^ Stimulus evoked bursts (50-500Hz) of action potentials in regular firing pattern (approx 10Hz) Inhibition (threshold event) strong enough to evoke maximal calcium spikes with associated bursting; the inhibition is not different between cell types Burst rates are dependent on cell type but not on the stimulus evoking neuronal activity; thus, bursting is a function of inhibitory circuitry but not afferents to that cell (Patel et al. JNP 2005) Thalamocortical circuitry 24 8

9 25 26 Anterior Dorsal Cool Warm Painful Paresthesia No response 27 9

10 Microstimulation analysis of somatic sensory thalamus: - Labelled - Non-labelled (Lenz et al. JNS 2004) 28 Binary, labelled, (non-linear) and analog pathways traversing the thalamus (Lenz et al. JNS, 2004) What are the cortical targets? 29 Transmission of visceral signals in the spinal cord 30 10

11 Figure 3: Peristimulus time histogram of response of a VPL neuron of distension of the urinary bladder, the distal colon, and the lower esophagus. The responses to somatic mechanical stimulation were purely low threshold, while the responses to visceral stimulation were presumably nociceptive. Intraluminal pressures are shown below each graph 31 Figure 13: Somatovisceral convergence in the lateral thalamus. Only neurons with excitatory somatic inputs are considered in this table. According to the location of the somatic receptive fields, these were divided into six categories: hip region (includes lower back, perianal, and suprapubic regions), tail, leg, foot, arm, and face (+, excitatory; -, inhibitory; 0, no response to visceral stimulation) 32 Map of receptive and projected fields for the trajectory 16 mm lateral to the midline Lenz et al., Pain 59, ,

12 Which words describe the sensation that you feel? Questionnaire used for describing sensations associated with the patient s angina (left column, usual angina) and by intraoperative microstimulation (right column, stimulation associated angina) Lenz et al., Pain 59, , Effects of thalamic lesions

13 37 38 Distribution of LEPs N2 P2 Ohara et al., JNP,

14 B A E 42 14

15 Is there nociceptive input to the cortical projection zones of these nuclei? Approach: EP, LFP, synchrony analysis of laser evoked potentials from grids (Lenz et al., JNP, 1999) 43 BESA estimate of dipole location patient H patient P patient C Vogel et al., JNP, M.C KH K.H B.B 45 15

16 K.B CM C.M J.E 46 Insular lesions may be associated with increased pain tolerance, i.e. decreased motivation to escape from pain or inattention to pain or decreased unpleasantness of pain (Greenspan et al., 1999)

17 ACC lesions are associated with increased gain of pain intensity and unpleasantness ratings 49 Functional connectivity and networks Parietal operculum and insula lesions have selective and separate deficits of pain discrimination and tolerance ACC lesions show deficits of control of gain related to pain intensity and unpleasantness Therefore these three cortical areas have double dissociation of pain related function, suggesting hierarchical or modular network architecture 50 Synchrony assessed by phase locked value a measure of functional connectivity SI vs. parasylvian attention condition pre-stimulus period g value Phase-locking 16-24Hz confidence limit laser onset laser onset 51 17

18 52 53 Task-specific functional connectivity Cortical synchrony signaling functional connectivity changes rapidly with the task such as anticipation of the painful stimulus (SI-PS synchrony) followed attention to the stimulus (MF-SI & -PS synchrony) The presence of functional connectivity (SI-PS PS, SI-MF, PS-MF) prior to the painful stimulus predicts the detection of the painful stimulus and increased pain ratings Cortical functional connectivity may mediate pain perception during random fluctuations in connectivity or during attention to pain, consistent with Networks suggested by lesion studies 54 18

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