Chronic pain is a significant clinical and societal issue, with current management strategies remaining inadequate. One treatment option that has been shown to be effective in some individuals is spinal cord stimulation (SCS). Whilst SCS is effective at reducing pain in over 50 per cent of individuals with chronic pain, the mechanism via which SCS relieves pain and why some individuals respond and others do not remains unknown.
This study aims to establish the underlying cortical, subcortical and brainstem changes associated with the analgesic effects of spinal cord stimulation (SCS). Functional magnetic resonance imaging (fMRI), arterial spinal labelling and anatomical MRI will be used to determine brain activity patterns associated with pain relief during SCS, with particular focus on the brainstem. In addition, the investigators will use fMRI and arterial spin labelling (ASL) to determine if the state of the brain can predict treatment efficacy.
The goal is to understand how SCS reduces pain and also to establish a biomarker that can predict who will respond to SCS. If we can determine a treatment efficacy biomarker, we may be able to determine whether implanting a SCS is going to be of benefit in an individual subject.
Dr Alister Ramachandran, Westmead Pain Management Centre NSW, Professor Luke Henderson, University of Sydney, Professor Chris Peck, Westmead Hospital, University of Sydney.
The project was awarded $A66,000 through the ANZCA research grants program for 2022.
The overall aim of the proposal was to establish the brain changes responsible for the pain-relieving effects of spinal cord stimulation in individuals with chronic back pain. We also aim to determine if an individual’s resting brain activity patterns as well as individual responses to painful stimuli can predict whether they will gain pain relief during spinal cord stimulation. This information could be used to assess whether an individual will response to spinal cord stimulation before the implant is permanently implanted. Ultimately, if we can understand how the brain reduces pain, particularly in individual with chronic pain, we will be able to develop effective treatments without the need for invasive implants.
Our overall aim is to determine the brain mechanisms responsible for spinal cord stimulation pain relief in chronic pain patients. More specifically we used fMRI to determine the brain mechanisms responsible for spinal cord stimulation pain relief in individuals with chronic pain associated with persistent spinal pain syndrome (PSPS) by determining:
- the effects of spinal cord stimulation (SCS) on on-going brain activity and functional connectivity measured prior to and following a 10 day treatment using SCS in individual with PSPS
- the effects of SCS on analgesic circuitry function measured using conditioned pain modulation measured prior to and following a 10 day treatment using SCS in individual with PSPS
- whether resting brain activity patterns could predict whether an individual with PSPS was going to respond to SCS.
We hypothesised that SCS analgesia will be associated with different connectivity patterns in the regions of the midbrain periaqueductal grey matter, dorsolateral pons and rostral ventromedial medulla. We also hypothesise that these brainstem regions will be driven by higher brain centres such as the dorsolateral prefrontal and cingulate cortices and that these regions will display increased connectivity strengths during pain reductions. Finally, we hypothesised that altered recruitment patterns and connectivity strengths in pain modulatory pathways will predict SCS analgesic responsivity.
Whilst we have not finished data analysis we have found some very interesting and potentially important findings including:
- tracking pain intensity 3 times a day over the course of the SCS period we found that approximately 50% of individuals with FBSS responded with significant pain relief that often increased during the course of SCS treatment.
- Pain relief during SCS was associated with normalization of on-going activity in numerous emotional and analgesic brain regions such as the dorsolateral prefrontal cortex, anterior cingulate cortex, nucleus accumbens.
- Endogenous analgesic ability, measured using conditioned pain modulation (CPM) was significant reduced in PSPS patients compared with controls prior to SCS. That is PSPS was associated with reduced endogenous analgesic ability. This CPM analgesic ability was significantly altered after SCS, that is it began to display good analgesic ability, in those individuals which displayed pain relief with SCS.
- We are currently analysing data to determine if the restoration of CPM analgesic ability following SCS is associated with normalization of activity changes in brain regions such as the orbitofrontal cortex and the brainstem subnucleus reticularis dorsalis and dorsolateral pons – areas we have previously shown to be critical for CPM expression.
- We have also found that PSPS is associated with an altered peripheral immune environment. This environment is largely normalized following SCS and associated pain relief.
We have begun to unravel the brain mechanisms that underpin pain relief in PSPS patients during SCS. Detailing these neural mechanisms will increase our knowledge of how the brain regulates ascending noxious information in individuals with chronic pain. Furthermore, the results from these studies will increase our understanding of how an analgesic treatment can affect these brain circuits to produce pain relief. Importantly, we are beginning to understand why some analgesic treatments work in some individuals with chronic pain and not in others with the same condition.
Whilst we have not finalised our data analysis, we aim to also determine if we can predict whether an individual will respond to SCS using baseline brain activity, connectivity and structural measures. If we can begin to predict subsequent treatment responsivity, we will be in a position to potentially prevent individuals from the current trial and error approach to chronic pain treatment, and potentially begin to relieve pain and the associated alterations in brain function that underpin the carbonification of pain. Any increase in our ability to more effectively treat chronic pain will have a significant positive impact on the lives of individuals with chronic pain and reduce the burden on the health care system.
Manuscripts
Published and submitted
Stefanie Kogias, Jayden A. O’Brien, Rebecca V. Robertson, Allan Peng, Fernando A. T. Mendoza, Alister Ramachandran, Luke A. Henderson, Paul J. Austin: 10kHz high-frequency spinal cord stimulation significantly reduces pro-inflammatory cytokines and distinct populations of monocytes and T lymphocytes in patients with Persistent Spinal Pain Syndrome Type 2. Neuromodulation: Technology at the Neural Interface; Volume 28, Issue 6, August 2025, Pages 937-951; doi.org/10.1016/j.neurom.2025.02.010
Allan Peng, Lewis S. Crawford, Rebecca V. Robertson, James W.M Kang, Alister Ramachandran, Kevin A. Keay and Luke A. Henderson. Regional on-going brain activity associated with chronic pain: a review and activation-likelihood estimate approach. European Journal of Pain; submitted.
In preparation
A. Peng R. Robertson, R. Heidary, L.S. Crawford, N. Meylakh, K.A. Keay, C. Peck, A. Ramachandran, L.A. Henderson. Changes in ongoing regional brain activity and connectivity in Persistent Spinal Pain Syndrome
A. Peng R. Robertson, R. Heidary, L.S. Crawford, N. Meylakh, K.A. Keay, C. Peck, A. Ramachandran, L.A. Henderson. The effects of spinal cord stimulation on ongoing regional brain activity and connectivity in Persistent Spinal Pain Syndrome.
Honours Thesis
1. Ramesh Heidary: Brain mechanisms underlying failed back surgery syndrome and spinal cord stimulation induced pain relief. Awarded end 2022 – 1st class honours
2. Allen Peng: Brain imaging and spinal cord stimulation. Awarded end 2023 – 1st class honours
Note that Allan Peng has started a PhD analysing the data acquired during this project. His thesis is due end 2027.
Conference Presentations
Ramesh Heindry presented her finding at Westmead hospital to pain clinicians
Allen Peng presented SCS results at the Australian Pain Society Meeting in Darwin, April, 2024.