IIS 2021 Tuckey et al article - IIS Hypothesis Flashcards
Name the neurological link between peripheral nociceptors and the SNS:
Somato-sympathetic &/or visceral-sympathetic reflexes
1) What are the pre- & post-ganglionic sympathetic responses to stimulation of unmyelinated A delta & C small fiber nociceptors called and 2) where are they produced?
1) Somato-/visceral-sympathetic reflexes; 2) the Dorsal Horn
Activation of the Somato-sympathetic &/or visceral-sympathetic reflexes results in the release of ______________________ from postganglionic neurons eliciting vaso-_________________ responses. (Choose one):
A. NE (Norepinephrine); -constriction
B. Epinephrine; -dilation
C. NE; -dilation
D. Cortisol; -constriction
A. NE; -constriction
Peripheral vasoconstriction responses have been shown to reduce local blood flow (perfusion) by up to __________:
A. 48%
B. 35%
C. 30%
D. 25%
D. 25%
Identify the best order of events that leads to Sympathetic nerve activation (SNA) [choose one]:
A. Peripheral vasoconstriction leading to NE (Norepinephrine) exposure & nociceptor firing
B. Neurogenic vasodilation overriding local vasoconstriction
C. Nociceptor stimulation & NE exposure (from Somato-Viscero-sympathetic reflexes) with peripheral vasoconstriction
D. Micro circulation disturbance leading to nociceptor stimulation
C. Nociceptor stimulation & NE exposure (from Somato-Viscero-sympathetic reflexes) with peripheral vasoconstriction
True or False: SNA may lead to arterial & venous micro circulation disturbances, which have been documented in myalgia patients and Myofascial pain syndrome patients within the MTrPs
True - & characterized by hypoxia & reduced washout of inflammatory substances
Of significance to the IIS Hypothesis, a 2010 study using ultrasound indicated that ___________________ exists in the constricted vascular bed associated with active MTrPs:
A. NE (Norepinephrine)
B. Tender points
C. Myofilaments
D. Venous stasis
D. Venous stasis
The sequence of reflexive, segmental phenomenon that does not require supraspinal sympathetic activation & can be a primary factor for IIS development is (label 1-4 in proper order of sequence):
___ MTrP formation via nociceptor/DRG sensitization
___ impaired venous return (ie-stasis)
___ ongoing activation of somato-sympathetic reflexes
___ cytokine concentration exceeding threshold to stimulate local nociceptors
(3) MTrP formation via nociceptor/DRG sensitization
(1) impaired venous return (ie-stasis)
(4) ongoing activation of somato-sympathetic reflexes
(2) cytokine concentration exceeding threshold to stimulate local nociceptors
True or False: A dysregulated HPA (hypothalamus-pituitary-adrenal axis) is a sure sign of IIS.
False - it has been associated with PTSD and fibromyalgia concurrently with elevated levels of IL-6 also in common
Psychological considerations are also included in Fig. 2 of the IIS article as chronic stress may lead to increased _________________ inflammation and ___________________ production:
A. Peripheral; NE (Norepinephrine)
B. Centralized; cytokine
C. Neurological; MTrP
D. Sympathetic; nociceptor
A. Peripheral; NE
Activation of ______________________ is the body’s normal response to an acutely stressful/traumatic event:
A. Cortisol
B. MTrPs
C. HPA (hypothalamus-pituitary-adrenal axis)
D. Lymphangions
C. HPA (hypothalamus-pituitary-adrenal axis)
Elevated ___________________ levels are direct evidence of SNA & local vasoconstriction in active MTrPs:
A. Neuropeptides
B. Inflammation
C. TGF-b1
D. NE (Norepinephrine)
D. NE (Norepinephrine)
The IIS authors state that the known correlation between chronic pain and PTSD may be of significance because elevated levels of __________________ and __________________ would create an ideal environment for IIS development.
IL-6 (inflammation); NE [Norepinephrine] (vasoconstriction)
Prelymphatic interstitial sinuses/pathways in Fascial tissues were identified by researchers in which year?
2018
The primary mechanism of lymphatic propulsion is via _______________(which structure?)
Lymphangions - defined as the muscle segment between successive valves
Which specific cytokines can actually disable normal lymphatic pump mechanisms during acute inflammatory events?
IL-1B, IL-6, TNF-a
According to IIS theory, the fascia-myofibroblast contractile responses following expression of ____________ may be able to partially or fully block pre-lymphatic flow or compressible interstitial paths.
TGF-b1
What is thickening of the ECM that is preceded by inflammation or tissue injury called?
Fibrosis or scar tissue formation
What is considered the key component in all types of organ fibrosis?:
A. Overproduction of Collagen 1 by myofibroblasts
B. TNF-a
C. Blocked pre-lymphatic channels
D. Slowed metabolic rate
A. Overproduction of Collagen 1 by myofibroblasts
True or False: since chronic inflammation is the driving force behind myofibroblast proliferation, there is unfortunately no way to resolve the fibrotic process.
False - disruption of the inflammatory process can resolve the fibrotic process.
Pro-inflammatory cytokines released in response to tissue injury &/or immune response have the following impact on NGF (nerve growth factor) synthesis?:
A. Rapidly inhibit it
B. Strongly induce it
C. No known direct impact
D. Initially induces but then slows it down depending on saturation of cytokines
B. Strongly induce it
NGF (nerve growth factor) activity collectively could most likely increase or decrease nociceptive signaling from the periphery to the CNS?
Increase
T or F: In the IIS hypothesis elevated pro-inflammatory cytokine concentrations, NGF production in dorsal horn glial cells, & SAPs (subthreshold action potentials) could all be related to formation of latent TrPs.
True - & thus nociceptor exposure to & signaling from low thresholds of pro-inflammatory cytokines could initiate &/or maintain Centralized Sensitization, injury prone tissues, etc.
In summary the IIS hypothesis describes a pathophysiological hemodynamic process due to a combo. of (choose 2):
A. Impaired vascular perfusion
B. Saturation of myofibroblasts
C. Retrograde neuroinflammation
D. Chronically disrupted local lymphatic pump mechanisms
A. & D.
In IIS hypothesis, IL-1b, IL-6, &TNF-a are the same pro-inflammatory cytokines as found:
A. To be primarily involved in pain perception
B. In Fascial contractions following TGF-b1 production
C. To be elevated in active MTrP sampling studies
D. In ALL of the above
D. In ALL of the above
T or F: Recent support for the IIS hypothesis has come from literature on lymphedema.
True - eg-2020 article describing occluded lumen’s in secondary lymphedema impairing normal lymph. pump mechanism, w/ many of the contractile cells responsible i.d.’d as myofibroblasts
Elevated sympathetic drive from stress is associated with elevated IL-6 & NE levels which may (choose one):
A. Induce vasoconstriction
B. Reduce lymphatic propulsion
C. Increase fibroblast to myofibroblast differentiation
D. Create nociception
E. Affect ALL of the above
E. Affect ALL of the above
(from Discussion) Peripherally, IIS in _________________ pre-lymphatic pathways may be entrapped, lead to ongoing local nociceptor stimulation —>contribute to Centralized Sensitization, chronic pain, & sympathetic activation:
A. Fascial
B. Visceral
C. Vascular
D. Neural
E. ANY/ALL of the above
E. ANY/ALL of the above
(from Discussion) Treatment of all potential pain-producing tissues improves the likelihood of achieving _____________________:
A. Homeostasis
B. Elimination of all MTrPs
C. Pain free function
D. Vasoconstriction
C. Pain free function
(from Discussion) Tuckey et al also theorize that treatment of latent MTrPs could also contribute to pain free function via reducing _________________ related to SAPs:
A. TGF-b1 expression
B. The HPA axis
C. ECF production
D. Centralized sensitization
D. Centralized sensitization (SAPs = subthreshold action potentials)
(from Discussion) Since over 73% of asymptomatic test subjects show evidence of degenerative spinal changes, it is reasonable to infer that ________________ (produced by NGF) may yield vasoconstriction of spinal arteries/veins subsequent to _________________ (choose one):
A. SAPs (subthreshold action potentials); SNA (Symp. nerve activation)
B. SNA; SAPs
C. Pro-inflammatory cytokines; centralized sensitization
D. Pro-inflammatory cytokines; elevated HPA axis
A. SAPs (subthreshold action potentials); SNA (Symp. nerve activation)
(from Discussion) True or False: Subthreshold nociceptive signaling via IIS could lead to silent/asymptomatic spinal DJD/DDD.
True - via creation of vasoconstriction of segmental spinal arteries
(from Discussion) Nociceptive inputs to the Trigeminal Nucleus (including from MTrPs) with SNA may be implicated in the following conditions (choose one or more answer):
A. Tension-type headache
B. Rotator Cuff pathology
C. Idiopathic cranial disorders
D. Post-concussion syndrome
E. ALL of the above
A, C, & D
(from Discussion) IIS affecting 2nd order nociceptive neurons communicating with higher centers via dorsal columns & activating “brain-gut axis” could interfere with normal efferents to the viscera & therefore disrupt ________________ secretion &/or ________________ motility.
Hormonal; GI
(from Discussion) The “brain-gut axis” links the ANS to what important systems?
Neuroendocrine, immune, & enteric nervous systems
(from Discussion) Underlying pathophysiological mechanisms responsible for idiopathic spinal, digestive, endocrine, & cranial disorders may all be able to resolve if ongoing nociceptive sources related to IIS are ________________ (choose one):
A. Ever identified
B. Facilitated
C. Alleviated
D. None of the above
C. Alleviated
(from Discussion) FCS is purported to ________________
nociceptors and alleviate ________________ (choose one):
A: Facilitate; headaches
B. Deactivate; tissue inflammation
C. Facilitate; tissue inflammation
D. Deactivate; tissue decompression
B. Deactivate; tissue inflammation
(from Discussion) IIS hypothesis theorizes that trapped ____________ substances in the ____________ may explain chronic, non-healing pain resistant to pharmacological intervention (choose one):
A. Analgesic; interstitium
B. Algesic; interstitium
C. Algesic; blood cells
D. Analgesic; lymphangions
B. Algesic; interstitium
(from Discussion) True or False: FCS is used to diagnose and directly treat TPs/MTrPs in MPS & idiopathic conditions.
False - FCS is an INDIRECT (manipulative) methodology for diagnosing & treating these conditions, not the TP/MTrPs directly
(from Discussion) Tissue decompression use in FCS is believed to _______________ activated nociceptors & thus _______________ the afferent inputs to the Dorsal Horn (choose one):
A. Silence; reduce
B. Silence; enhance
C. Cause summation of; enhance
D. Cause summation of; reduce
Silence; reduce
(from Discussion) Reduced nociception results in all EXCEPT the following:
A. Deactivation of segmental muscle guarding reflexes
B. Reduced Myofascial tension
C. FIbroblast to Myofibroblast differentiation
D. Diminished Capillary pressure
E. ALL are correct
C. Fibroblast to Myofibroblast differentiation
(from Discussion) In FCS treatment positions are maintained up to 90 s to allow for what to occur?
Regional inflammation (ie - interstitial pro-inflamm. cytokines) to dissipate
(from Discussion) In IIS hypothesis, reduced interstitial NE concentrations from tissue decompression would ______________ somato-/visceral-sympathetic reflexes & help restore venous/arterial _______________ (choose one):
A: Heighten; vasoconstriction
B. Heighten; vasodilation
C. Deactivate; vasoconstriction
D. Deactivate; perfusion
E. NONE of the above
D. Deactivate; perfusion
(from Discussion) In IIS hypothesis, FCS would also accomplish all EXCEPT the following (choose one):
A. Reduce IL-1b, IL-6, & TGF-b1 concentrations
B. Block pre-lymphatic pathways
C. Reduce myofibroblast contraction
D. Normalized lymphatic propulsion
E. ALL are correct
Block pre-lymphatic pathways
(from Discussion) Research into FCS has shown positive tissue morphology effects on experimentally, repetitively strained human fibroblasts & their cytokine production, where inflammatory effects (as measured by decreased fibroblast IL-6 production) were reduced by _____% after 24 h compared to control (choose one):
A. 25%
B. 38%
C. 46%
D. 52%
C. 46%
(from Discussion) FCS may have the capacity to… (choose one or more):
A. Alleviate microvascular stasis in all tissues
B. Break the feedforward cycle that creates Myofascial pain
C. Concentrate cytokine activity within the target organ necessary for healing tissues
D. Possibly break cycles responsible for idiopathic visceral/vascular syndromes
E. ALL of the above
A., B., & D.
(from Discussion) FCS and Acupuncture differ in the following way (choose one):
A. Acupuncture does not directly target peripheral inflammation
B. FCS does not directly target peripheral inflammation
C. FCS is known to stimulate A-delta fibers which leads to inhibition of central pain transmission via enkephalins
D. None -they have essentially the same effect
A. Acupuncture does not directly target peripheral inflammation
(from Discussion) True or False: IIS generated nociception may also be reduced by Dry Needling.
True
(from Discussion) Future studies to help validate IIS hypothesis would expect to find decreased _________________ within the region of hyperirritable MTrPs in contrast to normal tissue (choose one):
A. CO2
B. Nociceptor activity
C. Lymphatic flow
D. Fibrogenesis
C. Lymphatic flow
(from Discussion) To help validate IIS Hypothesis & the role of Fascial contractures, future studies ought consider evidence of fibroblast activation in tissues with lowered pain-pressure thresholds in those with fibromyalgia; if that was found to be so, one might expect to find (choose one or more):
A. Excess TGF-B1 expression
B. Elevated levels of inflammatory mediators
C. Increased Myofibroblast concentrations
D. Excess ECM secretion
E. ANY &/or ALL of above
E. ANY &/or ALL of above
(from Discussion) Animal studies could also be helpful support of IIS hypothesis to further investigate causal relationships between ______________ and altered lymphatic flow (choose one):
A. Cytokine accumulation
B. Cytokine fibrosis
C. Neurofibroblasts
D. Lymphangions
A. Cytokine accumulation
Neuropeptides (eg- Substance P, Glutamate, NGF) have been found ______________ in response to noxious stimuli &/or in fibromyalgia patients (choose one or more):
A. Lacking
B. In CSF (cerebrospinal fluid)
C. Elevated
D. Interstially
B. & C.
[eg- in fibromyalgia CSF Substance P found at levels 3x > healthy controls]
Arrange the letters into the proper sequence of central events that follows IIS, ultimately mediating the transition from acute local to chronic global pain:
A. Release of pro-inflammatory mediators in the CSF
B. Sensitization of dorsal horn
C. Glial cell activation
B., C., A.
True or False: Experimental studies give evidence to support SNS involvement in chronic pain states, including (choose one or more):
A. Decreased NE (Norepinephrine) in migraine patients
B. Reduced muscle perfusion in chronic myalgia patients
C. Decreased electromyographic activity of MTrPs after local injection of sympathetic antagonist
D. Increased electromyographic activity at MTrPs after emotional stress
E. ALL of above
B., C., D.
