title: Chronic Neuropathic Pain: It's about the Rhythm.
abstract: The neural mechanisms underlying the development and maintenance of chronic neuropathic pain remain unclear. Evidence from human investigations suggests that neuropathic pain is associated with altered thalamic burst firing and thalamocortical dysrhythmia. Additionally, experimental animal investigations show that neuropathic pain is associated with altered infra-slow (<0.1 Hz) frequency oscillations within the dorsal horn and somatosensory thalamus. The aim of this investigation was to determine whether, in humans, neuropathic pain was also associated with altered infra-slow oscillations within the ascending "pain" pathway. Using resting-state functional magnetic resonance imaging, we found that individuals with orofacial neuropathic pain have increased infra-slow oscillatory activity throughout the ascending pain pathway, including within the spinal trigeminal nucleus, somatosensory thalamus, thalamic reticular nucleus, and primary somatosensory cortex. Furthermore, these infra-slow oscillations were temporally coupled across these multiple sites and occurred at frequencies similar to calcium waves in activated astrocytes. The region encompassing the spinal trigeminal nucleus also displayed increased regional homogeneity, consistent with a local spread of neural activity by astrocyte activation. In contrast, no increase in oscillatory behavior within the ascending pain pathway occurred during acute noxious stimuli in healthy individuals. These data reveal increased oscillatory activity within the ascending pain pathway that likely underpins increased thalamocortical oscillatory activity, a self-sustaining thalamocortical dysrhythmia, and the constant perception of pain. Significance statement: Chronic neuropathic pain is associated with altered thalamic firing and thalamocortical dysrhythmia. The mechanisms responsible for these changes remain unknown. In this study, we report in individuals with neuropathic pain increased oscillatory neural activity within the ascending pain pathway with evidence that these changes result from altered neural-astrocyte coupling. We propose a series of neural and glial events after nerve injury that result in the generation of altered thalamocortical activity and a persistent neuropathic pain state. Defining the underlying mechanisms responsible for neuropathic pain is critical if we are to develop more effective treatment regimens.
authors.affiliation: Department of Anatomy and Histology and.
authors.forename: Zeynab
authors.initials: Z
authors.lastname: Alshelh
authors.affiliation: Department of Anatomy and Histology and.
authors.forename: Flavia
authors.initials: F
authors.lastname: Di Pietro
authors.affiliation: Department of Anatomy and Histology and.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Youssef
authors.affiliation: Department of Anatomy and Histology and.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Reeves
authors.affiliation: School of Nursing and Brain Research Institute, University of California, Los Angeles, Los Angeles, California 90095.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Macey
authors.affiliation: Department of Anatomy and Histology and.
authors.forename: E Russell
authors.initials: ER
authors.lastname: Vickers
authors.affiliation: Faculty of Dentistry, University of Sydney, Sydney, New South Wales 2006, Australia, and.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Peck
authors.affiliation: Faculty of Dentistry, University of Sydney, Sydney, New South Wales 2006, Australia, and.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Murray
authors.affiliation: Department of Anatomy and Histology and lukeh@anatomy.usyd.edu.au.
authors.forename: Luke A
authors.identifier: http://orcid.org/0000-0002-1026-0151
authors.initials: LA
authors.lastname: Henderson
mesh_terms: D000328:Adult; D059350:Chronic Pain / Q000175:diagnosis / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000503:physiopathology; D009437:Neuralgia / Q000175:diagnosis / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods*; D010507:Periodicity
keywords: astrocytes; infra-slow oscillations; orofacial pain; regional homogeneity; spinal trigeminal nucleus; thalamocortical rhythm