Highlights
- •Brainstem pain-modulation circuitry is critical for chronic pain maintenance.
- •Chronic orofacial pain has greater rostral ventromedial medulla-subnucleus reticularis dorsalis-spinal trigeminal nucleus static and dynamic connectivity.
- •Differences may underlie enhanced descending pain-facilitating actions on spinal trigeminal nucleus.
Abstract
There is evidence from preclinical models of chronic pain and human psychophysical
investigations to suggest that alterations in endogenous brainstem pain-modulation
circuit functioning are critical for the initiation and/or maintenance of pain. Whilst
preclinical models have begun to explore the functioning of this circuitry in chronic
pain, little is known about such functioning in humans with chronic pain. The aim
of this investigation was to determine whether individuals with chronic non-neuropathic
pain, painful temporomandibular disorders (TMD), display alterations in brainstem
pain-modulating circuits. Using resting-state functional magnetic resonance imaging,
we performed static and dynamic functional connectivity (FC) analyses to assess ongoing
circuit function in 16 TMD and 45 control subjects. We calculated static FC as the
correlation of functional magnetic resonance imaging signals between regions over
the entire scan and dynamic FC as the correlation of signals in short (50s) windows.
Compared with controls, TMD subjects showed significantly greater (static) FC between
the rostral ventromedial medulla and both the subnucleus reticularis dorsalis and
the region that receives orofacial nociceptive afferents, the spinal trigeminal nucleus.
No differences were found in other brainstem pain-modulating regions such as the midbrain
periaqueductal gray matter and locus coeruleus. We also identified that TMD subjects
experience greater variability in the dynamic functional connections between the rostral
ventromedial medulla and both the subnucleus reticularis dorsalis and spinal trigeminal
nucleus. These changes may underlie enhanced descending pain-facilitating actions
over the region that receives nociceptive afferents, ultimately leading to enhanced
nociceptive transmission to higher brain regions and thus contributing to the ongoing
perception of pain.
Perspective
Psychophysical studies suggest that brainstem pain-modulation circuits contribute
to the maintenance of chronic pain. We report that individuals with painful TMD display
altered static and dynamic FC within the brainstem pain-modulation network. Modifying
this circuitry may alter an individual's ongoing pain.
Key words
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References
- Descending projections from the rostral ventromedial medulla (RVM) to trigeminal and spinal dorsal horns are morphologically and neurochemically distinct.J Chem Neuroanat. 2012; 43: 103-111
- Brain afferents to the medullary dorsal reticular nucleus: A retrograde and anterograde tracing study in the rat.Eur J Neurosci. 2002; 16: 81-95
- The cortical rhythms of chronic back pain.J Neurosci. 2011; 31: 13981-13990
- Putative nociceptive modulatory neurons in the rostral ventromedial medulla of the rat display highly correlated firing patterns.Somatosens Mot Res. 1989; 6: 413-425
- Endogenous pain control systems: Brainstem spinal pathways and endorphin circuitry.Annu Rev Neurosci. 1984; 7: 309-338
- Brain dynamics and temporal summation of pain predicts neuropathic pain relief from ketamine infusion.Anesthesiology. 2018; 129: 1015-1024
- Involvement of the subnucleus reticularis dorsalis in diffuse noxious inhibitory controls in the rat.Brain Res. 1992; 595: 353-357
- Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain.Neuroscience. 2009; 160: 174-185
- Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain.J Neurosci. 2002; 22: 5129-5136
- Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex.Eur J Pain. 2000; 4: 83-96
- Localization and central projections of primary afferent neurons that innervate the temporomandibular joint in cats.Somatosens Res. 1987; 4: 201-213
- Age-related decline in the variation of dynamic functional connectivity: A resting state analysis.Front Aging Neurosci. 2017; 9: 203
- The medullary dorsal reticular nucleus as a relay for descending pronociception induced by the mGluR5 in the rat infralimbic cortex.Neuroscience. 2017; 349: 341-354
- A spatially unbiased atlas template of the human cerebellum.Neuroimage. 2006; 33: 127-138
- The medullary dorsal reticular nucleus enhances the responsiveness of spinal nociceptive neurons to peripheral stimulation in the rat.Eur J Neurosci. 2003; 18: 580-588
- Research diagnostic criteria for temporomandibular disorders: Review, criteria, examinations and specifications, critique.J Craniomandib Disord. 1992; 6: 301-355
- Anatomy and physiology of a nociceptive modulatory system.Philos Trans R Soc Lond B Biol Sci. 1985; 308: 361-374
- Dynamics of pain: fractal dimension of temporal variability of spontaneous pain differentiates between pain States.J Neurophysiol. 2006; 95: 730-736
- Statistical parametric maps in functional imaging: A general imaging approach.J Human Brain Mapp. 1995; 2: 189-210
- Inputs to trigeminal brain stem neurones from facial, oral, tooth pulp and pharyngolaryngeal tissues: II. Role of trigeminal nucleus caudalis in modulating responses to innocuous and noxious stimuli.Brain Res. 1976; 117: 227-238
- Putative nociceptive modulating neurons in the rostral ventromedial medulla of the rat: Firing of on- and off-cells is related to nociceptive responsiveness.Somatosens Mot Res. 1989; 6: 427-439
- Descending control of nociception: Specificity, recruitment and plasticity.Brain Res Rev. 2009; 60: 214-225
- Dynamic functional connectivity: Promise, issues, and interpretations.Neuroimage. 2013; 80: 360-378
- Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: A pilot study.Headache. 2012; 52: 441-454
- Quantitative characterization of ceruleospinal inhibition of nociceptive transmission in the rat.J Neurophysiol. 1986; 56: 1397
- Dynamic resting-state functional connectivity in major depression.Neuropsychopharmacology. 2016; 41: 1822-1830
- GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex.Neuroscience. 2016; 334: 148-159
- Deficiency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder.Pain. 2009; 143: 172-178
- Dynamic functional connectivity of the default mode network tracks daydreaming.Neuroimage. 2014; 100: 471-480
- Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks.Proc Natl Acad Sci U S A. 2013; 110: 18692-18697
- Diffuse noxious inhibitory controls (DNIC) in animals and in man.Patol Fiziol Eksp Ter. 1992; 4: 55-65
- Brain projections from the medullary dorsal reticular nucleus: An anterograde and retrograde tracing study in the rat.Neuroscience. 2006; 140: 577-595
- On spurious and real fluctuations of dynamic functional connectivity during rest.Neuroimage. 2015; 104: 430-436
- DynamicBC: A MATLAB toolbox for dynamic brain connectome analysis.Brain Connect. 2014; 4: 780-790
- The medullary dorsal reticular nucleus as a pronociceptive centre of the pain control system.Prog Neurobiol. 2002; 66: 81-108
- Reversal of neuropathic pain by HSV-1-mediated decrease of noradrenaline in a pain facilitatory area of the brain.Pain. 2010; 151: 137-145
- Noradrenaline increases pain facilitation from the brain during inflammatory pain.Neuropharmacology. 2013; 71: 299-307
- Reticular formation and pain: The past and the future.Front Neuroanat. 2017; 11 (51-51)
- Prefrontal gamma oscillations reflect ongoing pain intensity in chronic back pain patients.Hum Brain Mapp. 2019; 40: 293-305
- Brainstem pain-control circuitry connectivity in chronic neuropathic pain.J Neurosci. 2018; 38: 465-473
- Conditioned pain modulation in patients with acute and chronic low back pain.Clin J Pain. 2016; 32: 116-121
- White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.PAIN. 2012; 153: 1467-1477
- Duvernoy's Atlas of the Human Brain Stem and Cerebellum.Springer-Verlag, Wien, Vienna2009
- Delta opioid receptor mRNA expression is changed in the thalamus and brainstem of monoarthritic rats.J Chem Neuroanat. 2008; 36: 122-127
- Defective endogenous pain modulation in fibromyalgia: a meta-analysis of temporal summation and conditioned pain modulation paradigms.J Pain. 2018; 19: 819-836
- Conditioned pain modulation in temporomandibular disorders (TMD) pain patients.Exp Brain Res. 2014; 232: 3111-3119
- Central modulation of pain.J Clin Invest. 2010; 120: 3779-3787
- Noradrenergic pain modulation.Prog Neurobiol. 2006; 80: 53-83
- Lidocaine in the rostroventromedial medulla and the periaqueductal gray attenuates allodynia in neuropathic rats.Neurosci Lett. 1996; 218: 127-130
- Prestimulus functional connectivity determines pain perception in humans.Proc Natl Acad Sci U S A. 2010; 107: 355-360
- The dynamic functional connectome: State-of-the-art and perspectives.Neuroimage. 2017; 160: 41-54
- The role of trigeminal interpolaris-caudalis transition zone in persistent orofacial pain.Int Rev Neurobiol. 2011; 97: 207-225
- Glial activation in the rostroventromedial medulla promotes descending facilitation to mediate inflammatory hypersensitivity.Eur J Neurosci. 2009; 30: 229-241
- Dynamic retrospective filtering of physiological noise in BOLD fMRI: DRIFTER.Neuroimage. 2012; 60: 1517-1527
- Acute and chronic craniofacial pain: Brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates.Crit Rev Oral Biol Med. 2000; 11: 57-91
- Inputs to trigeminal brain stem neurones from facial, oral, tooth pulp and pharyngolaryngeal tissues: I. Responses to innocuous and noxious stimuli.Brain Res. 1976; 117: 211-226
- REST: A toolkit for resting-state functional magnetic resonance imaging data processing.Plos One. 2011; 6: e25031
- Trigeminal transition zone/rostral ventromedial medulla connections and facilitation of orofacial hyperalgesia after masseter inflammation in rats.J Comp Neurol. 2005; 493: 510-523
- Activity-induced plasticity in brain stem pain modulatory circuitry after inflammation.Neuroreport. 2000; 11: 1915-1919
- Imaging attentional modulation of pain in the periaqueductal gray in humans.J Neurosci. 2002; 22: 2748-2752
- Abnormal resting state functional connectivity of the periaqueductal grey in patients with fibromyalgia.Clin Exp Rheumatol. 2016; 34: S129-S133
- Descending facilitation from the rostral ventromedial medulla maintains visceral pain in rats with experimental pancreatitis.Gastroenterology. 2006; 130: 2155-2164
- Descending facilitation maintains long-term spontaneous neuropathic pain.J Pain. 2013; 14: 845-853
- Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation.Pain. 1999; 80: 127-141
- Anatomical changes at the level of the primary synapse in neuropathic pain: Evidence from the spinal trigeminal nucleus.J Neurosci. 2015; 35: 2508-2515
- Anatomical changes within the medullary dorsal horn in chronic temporomandibular disorder pain.Neuroimage. 2015; 117: 258-266
- DPARSF: A MATLAB toolbox for "pipeline" data analysis of resting-state fMRI.Front Syst Neurosci. 2010; 4
- Differential brain activity in subjects with painful trigeminal neuropathy and painful temporomandibular disorder.Pain. 2014; 155: 467-475
- Pain inhibits pain; human brainstem mechanisms.Neuroimage. 2016; 124: 54-62
- Anterior cingulate cortex contributes to the descending facilitatory modulation of pain via dorsal reticular nucleus.Eur J Neurosci. 2005; 22: 1141-1148
Article info
Publication history
Published online: September 03, 2020
Accepted:
August 22,
2020
Received in revised form:
August 12,
2020
Received:
October 13,
2019
Footnotes
This research was supported by the National Health and Medical Research Council of Australia grant 1130280.
The authors declare there are no conflicts of interest.
Identification
Copyright
© 2020 by United States Association for the Study of Pain, Inc.
