Pharmacologic treatments, including opioids, certain antidepressant and antiepileptic medications, and topical capsaicin, are often ineffective in treating neuropathic pain.^1,2 While deep brain stimulation (DBS) is commonly used to alleviate Parkinson’s disease symptoms, this therapy has also proven effective in providing long-term benefits for the treatment of neuropathic pain.^3,4 Benefits derived from DBS show great variability, and it is hard to predict procedure success. In addition, procedure parameters (e.g. stimulation frequency) have not been standardized and mechanisms of the response to stimulation are poorly understood. This prompted researchers at the Chinese Academy of Sciences in Suzhou to investigate the role of brain nuclei targeted by DBS for the treatment of neuropathic pain.⁵

Thalamocortical dysrhythmia and alterations of burst firing within the thalamus have been associated with neuropathic pain.^6,7 During thalamocortical dysrhythmia, self-sustained low-frequency theta-range oscillations in the thalamus trigger cortical dysfunction, leading to long-term thalamocortical circuit dysfunction which causes neuropathic pain.⁷ The periaqueductal gray (PAG) and thalamus are directly connected. Recordings of local field potentials (LFPs) in both the PAG and sensory thalamus of chronic pain patients whose PAG was stimulated by DBS showed reduced power of thalamic alpha, beta and theta oscillations, indicating inhibition of the sensory thalamus.⁸

In an endeavor to examine how neuronal activity in the sensory thalamus and periventricular gray/periaqueductal gray (PVAG) correlates with pain relief obtained with DBS, researchers recorded local field potentials with electrodes implanted in the sensory thalamus or PVAG, in 10 neuropathic pain patients who had undergone DBS surgery.⁵ In these patients, pain intensity was reduced from 6% to 64% (23 ± 18%, mean ± SD) following DBS.

LFPs were recorded simultaneously in the sensory thalamus and PVAG post-operatively, and showed oscillatory activity at both low and high frequencies, with prominent peaks visible in the alpha range at ~10 Hz, but also in the theta range (~8 Hz).⁵ Pain was assessed pre-DBS surgery, and between 6-12 months following surgery twice daily over a period of 7 days, using a visual analog scale (VAS), with which patients were asked to rate their pain levels (0=no pain, 10=worst pain ever experienced). The 14 pre- and post-surgery VAS scores were averaged; DBS-mediated pain relief was measured as the VAS percentage change.

A non-linear regression model allowed to evaluate the correlation between pain relief and LFP frequency, and revealed a significant negative correlation with the 6-9 Hz theta range (R=-0.61, P=.005). Conversely, a significant positive correlation was observed in the 10-12 Hz alpha range (R=0.51, P=.009) as well as in the 22-33 Hz beta range (R=0.56;P=.007).

Based on the present findings and previous studies showing that overactive thalamic activity in the theta range may act as a trigger for cortical dysfunction and ensuing thalamocortical dysrhytmia⁹, authors hypothesized that suppressing theta oscillations in the thalamus and PVAG might result in pain relief. This could be achieved through PVAG stimulation at adequate frequencies, which would have to be optimized based on oscillatory characteristics.

References

1.Labuz D, Spahn V, Celik MÖ, Machelska H. Opioids and TRPV1 in the peripheral control of neuropathic pain–Defining a target site in the injured nerve. Neuropharmacology. 2016;101:330-40.

2.Dworkin RH, O’connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237-51.

3.Levy R, Deer TR, Henderson J. Intracranial neurostimulation for pain control: a review. Pain Physician. 2010;13(2):157-65.

4.Boccard SG, Pereira EA, Moir L, Aziz TZ, Green AL. Long-term outcomes of deep brain stimulation for neuropathic pain. Neurosurgery. 2013;72(2):221-30.

5.Huang Y, Luo H, Green AL, Aziz TZ, Wang S. Characteristics of local field potentials correlate with pain relief by deep brain stimulation. Clin Neurophysiol. 2016;127(7):2573-80.

6.Alshelh Z, Di pietro F, Youssef AM, et al. Chronic Neuropathic Pain: It’s about the Rhythm. J Neurosci. 2016;36(3):1008-18.

7.Walton KD, Llinás RR. Central Pain as a Thalamocortical Dysrhythmia: A Thalamic Efference Disconnection? In: Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis; 2010. Chapter 13. Available from: http://www.ncbi.nlm.nih.gov/books/NBK57255/

8.Wu D, Wang S, Stein JF, Aziz TZ, Green AL. Reciprocal interactions between the human thalamus and periaqueductal gray may be important for pain perception. Exp Brain Res. 2014;232(2):527-34.

9.Llinás RR, Ribary U, Jeanmonod D, Kronberg E, Mitra PP. Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci USA. 1999;96(26):15222-7.

 

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