By Norman Latov, MD, PhD
Professor of Neurology and Neuroscience, Weill Cornell Medical College; Director of the Neuropathy Center, Weill Cornell Medicine
SYNOPSIS: Pain in peripheral neuropathy, referred to as neuropathic pain, is thought to result from overexpression of pain receptors, regeneration of hypersensitive nerve sprouts, and denervation hypersensitivity of neurons in the sensory ganglia. Additionally, activation of the pain pathways appears to induce secondary structural and functional changes in the brain that contribute to pain perception, persistence, and response.
SOURCE: Chao CC, Hsieh PC, Lin CHJ, et al. Limbic connectivity underlies pain treatment response in small-fiber neuropathy. Ann Neurol 2023;93:655-667.
The authors investigated patients with painful small-fiber neuropathy to determine whether there are changes in the brain that can be attributed to the painful neuropathy. They used blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) and diffusion weighted imaging (DWI) to evaluate for functional and structural changes in the connectivity (patterns of links) between brain regions known to be involved in pain processing.
Findings in patients with painful small-fiber neuropathy were compared to those in normal healthy subjects. Brain regions that are involved in pain processing were compared to control regions that are uninvolved. The “network-based statistic (NBS) method” was used to analyze for dysconnectivity or alterations in brain circuits that encode and process spontaneous pain. Changes in connectivity were correlated with the response to anti-neuropathic pain medications and with the degree of small-fiber loss as determined by the reduction in the intraepidermal nerve fiber density.
The authors found that patients with small-fiber neuropathy had reduced functional connectivity in the limbic, somatosensory, cognition-integration, and striatal systems compared to healthy controls; responders to neuralgia medications had a lower pre-treatment functional connectivity compared to non-responders; and there was a correlation between reduction in nerve fiber density and degree of functional dysconnectivity. Small-fiber neuropathy patients also had reduced structural white matter connectivity in the same pattern as the reduction in functional connectivity. Shared functional and structural connectivity reductions were most significant at the right thalamus and putamen, right middle cingulate cortex, and right inferior parietal lobule. There was a correlation between response to anti-neuralgic medications and lower pre-treatment functional connectivity of the insula with the limbic and somatosensory regions.
The authors proposed that the structural changes identified in the study underlie the functional brain changes in patients with neuropathic pain and that further studies are needed to determine whether these could serve as imaging biomarkers in future studies of neuropathic pain or the effect of neuralgia medications.
COMMENTARY
The current study confirms and expands our understanding of the involvement of the limbic system in patients with painful neuropathies, demonstrating the presence of changes at rest in addition to those noted previously in response to painful stimuli. It also provides a structural basis for the functional changes observed. A drawback of the study, however, is the lack of inclusion of patients with non-painful small-fiber neuropathy as controls. As such, it is not possible to know whether the alterations that were found were caused by activation of pain pathways per se rather than to changes in the peripheral nerves that are unrelated to pain.
Not all small-fiber neuropathies are painful; some patients only have numbness or are asymptomatic, and only realize there is something wrong after experiencing a cut or burn or stepping on a sharp object without feeling pain. Multiple studies have shown there is no correlation between the severity of the pain and the reduction in the intraepidermal nerve fiber density.1-3 As such, the correlation between the dysconnectivity and intraepidermal nerve fiber density found in the current study is not necessarily supportive of a pain-mediated mechanism. The reason why some patients with neuropathy experience pain while others do not remains a mystery.
Regardless of the cause, the mechanisms underlying the structural and functional brain changes are of great interest. They could be because of trans-synaptic degeneration triggered by the peripheral neuropathy, possibly via axonal mechanisms, although the reduction in white matter connectivity that was observed in the current study suggests involvement of activated microglial or astrocytes-mediated mechanisms that can spread along the affected nerve fibers.4-6 The authors postulate that the dysconnectivity could result in impaired inhibitory control of nociceptive input by frontoparietal networks, contributing to the symptoms. Given that the limbic system also is involved in emotions, motivation, and autonomic functions, its involvement also may play a role in the anxiety, depression, or poor sense of well-being that often are part of the symptom complex.
REFERENCES
- Karlsson P, Hincker AM, Staehelin Jensen T, et al. Structural, functional, and symptom relations in painful distal symmetric polyneuropathies: A systematic review. Pain 2019;160:286-297.
- Pál E, Fülöp K, Tóth P, et al. Small fiber neuropathy: Clinicopathological correlations. Behav Neurol 2020;2020:8796519.
- Truini A, Biasiotta A, Di Stefano G, et al. Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain? Pain 2014;155:828-832.
- Ferreira N, Goncalves NP, Jan A, et al. Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain. Acta Neuropathol Commun 2021;9:31.
- Tsuda M. Microglia-mediated regulation of neuropathic pain: Molecular and cellular mechanisms. Biol Pharm Bull 2019;42:1959-1968.
- You Y, Joseph C, Wang C, et al. Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease. Brain 2019;142:426-442.
