Biomechanics of Pain: Dynamics of the Neuromatrix Partap S. Khalsa, D.C., Ph.D. Department of Biomedical Engineering
The Neuromatrix From: Melzack R (1999) Pain Suppl 6:S121-6. NIOSH STAR Symposium May 2003 2
Pain Models NIOSH STAR Symposium May 2003 3
Gate Control Theory - I Melzack & Wall Large diameter, myelinated afferents gate transmission of noxious signals by small diameter, unmyelinated afferents (C-fibers) Contribution of brain (not just thalamus) From: Melzack R (1999) Pain Suppl 6:S121-6. NIOSH STAR Symposium May 2003 4
2003 STAR Symposium: Do not copy or reproduce in any form Ant. Cingulate Cortex From: Melzack & Casey, The Skin Senses Ed. Kenshalo, Springfield, Thomas Publ. 1968 Primary Somato-Sensory Cortex NIOSH STAR Symposium May 2003 5
Pain Models post-gct NIOSH STAR Symposium May 2003 6
Antinociceptive Systems Higher CNS Descending neural pathways Modulate or inhibit transmission of nociceptive inputs Local Spinal Cord GABAergic interneurons PAG periaqueductal gray DR dorsal raphe nucleus RVM rostral ventromedial medulla From Harris JA (1996) J Physiology (Paris) 90:15-25. Midbrain NIOSH STAR Symposium May 2003 7 Medulla
Congenital Insensitivity to Pain: Hereditary Sensory & Autonomic Neuropathy HSAN Type I II III IV Sensory Deficits Distal loss of all pain Same as I Diffuse pain insensitivity Same as III Reflexes Absent/ Weak Same as I Same as I Weak/ Normal Tissue Damage Extremities ulcerations Painless Injury Same as I Corneal ulcer Painless injury Ulceration, pain, selfmutilation Neurons Affected All (c-fibers more than others) Myelinated fibers All but Aδ C & Aδ V Distal pain insensitivity Normal Save as IV C NIOSH STAR Symposium May 2003 8
Congenital Insensitivity to Pain: Hereditary Sensory & Autonomic Neuropathy Example Neuropathic (Charcot) Arthropathy Marked sclerosis, fragmentation and joint destruction NIOSH STAR Symposium May 2003 9
Congenital Indifference to Pain Lesion in the limbic system of 17 yr. old boy leads to: Dislocated & deformed left knee Severe atrophic neuropathic changes in right ankle NIOSH STAR Symposium May 2003 10
Modulatory transmitters in nociceptive pathway From: Furst (1999) Brain Res Bul, 48(2):129-41. NIOSH STAR Symposium May 2003 1
Activation of the terminal ending of a nociceptor Noxious mechanical stimulus Suprathreshold => action potential train Secrete SP CGRP Axon Reflex SP inc. permeability of blood vessels extravasation of plasma protein BK Platelets => 5-HT Endothelial cells => PG Ruptured cells => ATP Neurogenic Inflammation Lowers ph => H+ Net effect is Peripheral Sensitization NIOSH STAR Symposium May 2003 2
Ion Channels & Receptor Noxious Mechanical Stimulus Peripheral Sensitization Ligand Interactions From: Graven-Nielsen & Mense (2001) Clin. J. Pain 17(1):1-10. NIOSH STAR Symposium May 2003 3
Change in Gene Expression Due to Sciatic Nerve Ligation Model of Pain Wang et al. (2002) Rat SNL neuropathic pain model Affymetrix chip RG-U34A Scans for over 500 genes 148 genes were found to have more than two-fold regulation 88 genes of neural cells from DRG were upregulated 40 genes were downregulated NIOSH STAR Symposium May 2003 4
Question What local mechanical state is being encoded by muscle mechano-nociceptors during noxious indentation? NIOSH STAR Symposium May 2003 5
What is a Mechanical State? We can easily measure the applied force and displacement, but these are external quantities. The neural receptive endings are embedded in the extracellular matrix of the tissue (e.g., muscle) Experience the internal resultant state due to externally applied loads The mechanical state neurons experience is defined by stress and strain NIOSH STAR Symposium May 2003 6
Experimental Apparatus for testing isolated muscle - nerve Neuron recording compartment saline Gracilis m. Obturator n. saline Hard Platform NIOSH STAR Symposium May 2003 7
Neural Response to Controlled Stress or Strain [From: Ge & Khalsa (2003) J. Neurophys] NIOSH STAR Symposium May 2003 8
Threshold (kpa) 3.0 2.5 2.0 1.5 1.0 0.5 Group III & IV Mechano-nociceptors had the same thresholds and sensitivities n=13 n=7 n=6 Sensitivity (Hz/kPa) 1.0 0.8 0.6 0.4 0.2 n=13 n=7 n=6 0.0 All Group III Group IV 0.0 All Group III Group IV Neurons Neurons [From: Ge & Khalsa (2003) J. Neurophys] NIOSH STAR Symposium May 2003 9
Neural Response (Hz) 10 8 6 4 2 0 Neural Response is better σ (kpa) correlated to stress R 2 =0.91 R 2 =0.47 5 10 15 20 25 30 35 0 200 400 600 800 1000 Force (mn) R 2 =0.72 R 2 =0.72 0 5 10 15 20 25 30 0 50 100 150 200 250 ε (%) Displacement (µm) Indenter raduis (mm) 1.58 2.24 3.16 Single Neuron Under Stress Control. [From: Ge & Khalsa (2003) J. Neurophys] NIOSH STAR Symposium May 2003 10
Neural Response is better correlated to stress for all mechano-nociceptors Pearson Correlation (R 2 ) 1.0 0.8 0.6 0.4 0.2 * * * all group III group IV Under stress control 0.0 Stress Force Strain Displacement Neurons [From: Ge & Khalsa (2003) J. Neurophys] NIOSH STAR Symposium May 2003 1
Neural Response (Hz) Under Strain Control, Neural Response is still better correlated to 8 6 4 2 0 R 2 =0.89 σ (kpa) R 2 =0.33 force (mn) stress R 2 =0.5 0 1 2 3 4 5 0 10 20 30 40 5030 40 50 60 70 80 90 300 400 500 600 700 800 ε(%) R 2 =0.5 Displacement (µm) Indentor radius (mm) 1.58 2.24 3.16 Single Neuron Under Strain Control. [From: Ge & Khalsa (2003) J. Neurophys] NIOSH STAR Symposium May 2003 2
Under Strain Control, Neural Response is still better correlated to stress for all neurons Pearson Correlation (R 2 ) 1.0 0.8 0.6 0.4 0.2 * * all group III group IV 0.0 Stress Force StrainDisplacement Neurons [From: Ge & Khalsa (2003) J. Neurophys] NIOSH STAR Symposium May 2003 3
Humans are pretty good at discriminating painful mechanical stimuli, independent of: force velocity size of object etc. Sensing Pain Response of single nociceptors can be confounded by: force velocity size of object etc. This implies a population is necessary NIOSH STAR Symposium May 2003 4
Cutaneous Innervation NIOSH STAR Symposium May 2003 5
How to study a cutaneous neuronal In-vivo complicated by: In-vitro population? non-linear geometry of skin variable compliance of skin substrate geometry can be linear (i.e. flat) make substrate that emulates in-vivo bulk, non-linear compliance NIOSH STAR Symposium May 2003 6
Stretching & Compression Apparatus A3 A2 A1 Neuron Recording Chamber Skin L3 L2 L1 N A4 A5 A6 L4 L5 L6 L12 L11 L10 A 12 Actuators A A 11 10 C L7 L8 L9 Indenter Motor A7 A8 A9 Force Transducers Side View Compliant Substrate From: Khalsa et al. (2000) J. Neurophys. NIOSH STAR Symposium May 2003 7
Compressive Force (gms) 80 60 40 20 0 Single Trial Compressive Load (gms) Displacement (mm) 0 2 4 6 8 10 12 Time (s) 8 6 4 2 0 Displacement (mm) AM Nociceptor Spike Train From: Khalsa et al. (2000) J. Neurophys. NIOSH STAR Symposium May 2003 8
Predicted Spatial Population Response Y Position (mm) A B C 100 90 80 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 D X Position (mm) From: Khalsa et al. (2000) J. Neurophys. NIOSH STAR Symposium May 2003 9
NIOSH STAR Symposium May 2003 10 Quantitative Comparison of Population Responses + = = 2 0 2 0 0.5 exp ), ( c y y b x x a y x f z From: Khalsa et al. (2000) J. Neurophys.
Edge effects of Indenter Y Position (mm) 6 70 4 60 2 50 40 0 30-2 20 Spikes/10 s -4 10-6 0-6 -4-2 0 2 4 6 From: Khalsa et al. (2000) J. Neurophys. X Position (mm) NIOSH STAR Symposium May 2003 1
Spikes/10 s Stimulus Intensity Encoded by Peak Population Response 120 Aδ C 80 40 0 40 60 80 100 Compressive Force (gms) From: Khalsa et al. (2000) J. Neurophys. NIOSH STAR Symposium May 2003 4
Position (mm) Stimulus Location Encoded by Planar Position of Peak Population Response 2 1 0-1 Aδ x 0 Aδ y 0 C x 0 C y 0-2 40 60 80 100 Compressive Force (gm) From: Khalsa et al. (2000) J. Neurophys. NIOSH STAR Symposium May 2003 5
Width (mm) Spatial Form of Noxious Stimulus Encoded by Constant Proportional Widths of Population Response 4 3 2 Aδ b Aδ c C b C c 1 40 60 80 100 Compressive Force (gm) From: Khalsa et al. (2000) J. Neurophys. NIOSH STAR Symposium May 2003 6
Nociceptor Population Conclusions Nociceptor Spatial Population Response Encodes Stimulus features of: Intensity Location Form (?) Both Aδ & C fiber populations similarly encode these features From: Khalsa et al. (2000) J. Neurophys. NIOSH STAR Symposium May 2003 7
Biomechanics of Pain Conclusions Musculoskeletal Pain perception is driven by primary nociceptors innervating muscle, ligament, skin Nociceptors, like other mechanically sensitive afferents, encode local stress Pain is maintained & augmented by sensitization that occurs in Periphery (primary nociceptors terminal endings) Dorsal Horn of spinal cord Pain is perceived and its character is determined by the neuromatrix (i.e., parallel neural networks in the brain) Modulate transmission of nociceptive inputs from the spinal cord to the brain NIOSH STAR Symposium May 2003 8