23-‐10-‐14 Pain Welke neurofysiologische veranderingen treden op bij patiënten met centrale en perifere sensitisatie Pain receptors Nociceptive neurons & Wide-Dynamic Range (WDR) neurons in dorsal horn Mira Meeus Thalamus Cortical regions 1 Acute pain   Mostly Cortical output 2 Acute pain NOCICEPTION:   Transduction   Transmission   Modulation   Perception: → thalamus → cortex → cortical output nociception: ◦  A-delta fibres: fast ◦  C-fibres: slow, high threshold (sweating, tachycardia, BP ⁭ , motor response …) Pain demands ATTENTION!!! Cortical output of highest priority 3 4 5 6 Nociception ≠ Pain, Pain ≠ Nociception Brain = NO instant processor ⇒ no direct experience based on incoming information ⇒ common output 1 23-‐10-‐14 Nociceptive pain à  Inflammation Nociceptive pain Neuropathic pain à  Tissue injury à  Growing mass à  … à distension à rupture à stimulation mech. receptors Central sensitization à activation nociceptors 7 COX 2   After 8 injury → tissue sensitization   Inflammatory mediators or strong noxious stimulation sensitise primary nociceptors (c-fibres) ⇒ Peripheral sensitization ↓ threshold ↑ firing rate Nerve impulses ↑↑ Primary HYPERALGESIA ALLODYNIA 10 9 Nociceptive pain 11 Neuropathic pain Central sensitization 12 2 23-‐10-‐14 If pain still persists Sensitization In chronic musculoskeletal disorders???? → lack of distinct localisation → lack of tissue damage   No = NEUROPLASTIC PAIN: ◦  Synaptic and non-synaptic changes ◦  Peripheral ◦  Central: spinal cord and brain longer adaptive function ≠ prolonged acute pain ◦  Fibromyalgia, Chronic Fatigue Syndrome ◦  Whiplash Associated Disorders ◦  Aspecific chronic low back pain Neuroplasticity = Planning a better response 14 13 Central Sensitization   Neuroplasticity: Habituation & sensitization normal situation prolonged or strong stimulation central sensitization = Functional & chemical changes: - More receptors - Ion channels longer open - Expansion involved regions - Brain changes … Efficacy signal trandsduction ↗↗ 15 16 Central sensitization     = Hyperexcitability CNS = Hypersensitivity for all mechanic stimuli Allodynia Generalized hyperalgesia Referred pain Chronic pain Symptoms of central sensitization Nijs et al. Manual Therapy 2010;15:135-141. 17 18 3 23-‐10-‐14 C-fibres: -  prolonged discharge -  ubiquitous distribution -  Wind-up: 1/3” >0,5 HZ -  LTP: 0,5-5HZ (tetanic) Wind-up & LTP 1. Overactivation bottom-up system: ↗ nocicep/ve transmission Central Sensitization: mechanisms Meeus & Nijs, 2007; Nijs & Van Houdenhove 2008; Yarnitsky et al. 2010 19 20 normal situation central sensitization: Wind-up ↗ 21 22 Injury Sub P Healing Healing with neuroplastic changes Peripheral sensitization Wind-up LTP CS 23 24 4 23-‐10-‐14 Injury Healing with neuroplastic changes Healing Wind-up LTP Low frequency (0,33 HZ- 0,50HZ) High frequency (0,5-5HZ) Up to few minutes Up to months Can lead to LTP: NMDAr activation + retrograde Sub P Early phase: NMDAr activation + post-synaptic changes Late phase with protein synthesis Rather a paradigm to test excitability Source for CS Activity-dependent After installation no longer activity dependent Homosynaptic Heterosynaptic Dorsal horn Dorsal horn & brain Peripheral sensitization Wind-up LTP CS 25 Wind-up   Paradigm   Enhanced 26 Glia overactive in pathological pain!! glia to evaluate bottom-up excitability wind-up in CS: ◦ Faster ◦ More intense ◦ Longer after-sensations Astrocytes: -  Release of glutamate -  Presynaptic: h Glu release -  Postsynaptic: h excitability -  Reuptake of glutamate -  Release BDNF, NO, IL: neuroplasticity! (Lemming et al. 2102; Staud, etc.;) 27 No injury??? Eg. FM 28 Injury Healing Changes in topdown pathways: Healing with neuroplastic changes Peripheral sensitization Wind-up Central Sensitization: mechanisms LTP CS 29 Meeus & Nijs, 2007; Nijs & Van Houdenhove 2008; Yarnitsky et al. 2010 30 5 23-‐10-‐14 Impaired pain inhibition CS: Impaired pain inhibition   Descending inhibitory pathways in dorsolateral funiculus: ◦  Inhibitory substances (serotonin, opioids, etc.) in synapses in dorsal horn Spinal block ⇒ inhibition ⇒ expansion receptive fields ⇒ hypersensitivity ⇒ faster Wind-up ⇒  Presynaptic activity not essential for CS ⇒  CS by failing endogenous pain inhibition Experimental block or lesions of pathways → equivalent of CS 31 32 normal situation Impaired pain inhibition central sensitization 33 34 35 36 Conditioned pain modulation   9 8 7 6 5 4 3 2 1 0   Defficient in different chronic pain populations Even spatial summation occurs CON FM PPT voor PPT na 6 23-‐10-‐14 Exercise induced analgesia vs hyperalgesia Changes in topdown pathways: Central Sensitization: mechanisms Meeus et al 2010, Van Oosterwijck et al. 2012, etc. Meeus & Nijs, 2007; Nijs & Van Houdenhove 2008; Yarnitsky et al. 2010 37 catastrophizing 38 Chronic stress kinesiophobia somatization   GABA neurotransmission↓ stress   depression   Serotonergic activity↓   Disinhibition Cognitive emotional sensitization   Hyperalgesia Zusman, 2002 Suarez-Roca et al. 2008 39 Gaba, main inhibitory NT 40 Catastrophizing Catastrophizing ≈ increased activity in brain areas related to: ◦  anticipation of pain, ◦  attention to pain (ACC), ◦  emotional aspects of pain ◦  and motor control. (Gracely, 2003) 41 42 7 23-‐10-‐14 Overactive pain neuromatrix Catastropizing -  -  -  Prediction pain intensity in CFS: ± 20% Related to CPM (Weissman-fogel et al. 2008) Related to TS (Goodin et al. 2013) pain (Meeus et al. 2012) CATASTROPHIZING PREDICTS ENDOGENOUS PAIN MODULATION 43 44 Moseley, 2003 Brain changes in FM Structural   Complete gray matter = ?,   Gray matter in specific regions i ◦  ACC, insula: key regions processing of affective pain components ◦  Prefrontal cortex: affective motivational and anticipational components of pain Functional   h pattern of brain activation by equal pain stimuli Cagnie et al. 2014 45 46 Brain changes in CLBP Structural   Complete gray & white matter = ?,   Gray matter in specific regions i ◦  DLPFC, temporal lobes, insula, and S1 Functional     h activity in pain related regions (S1, S2, PCC, and insula), and i activity in the PAG following mechanical stimulation patients coping well, activate different cortical regions than patients showing exaggerated pain-related illness behavior Kregel et al. submitted 47 ? 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