When Pain Persists: Advances in Brain Imaging & Neurostimulation Therapies

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Pain is a universal experience; from our first scream as we are pushed into this world to the labored breath of passing – nearly everyone, regardless of gender, race, or religion – feels pain. It is one of the most profound experiences of living and yet it has been one of the most poorly understood.

Although pain research has seen incredible advances in recent years, understanding why some patients transition from acute pain to chronic pain continues to challenge scientists.1,2 This is due, in part, to the fact that the experience of pain is difficult to characterize; it is tied to the somatosensory cortex but also to the cognitive and emotional processing sectors of the brain. And while the experience of pain may be universal, it’s also subjective.3

Brain imaging studies have begun to revolutionize the way chronic pain is studied in humans, providing clues into the underlying mechanisms.1,3 What does current medical literature tell us about the profound connection between the brain and chronic pain? How does this evidence inform new treatment strategies for patients?

Prevalence of Chronic Pain

Chronic pain, defined as pain persisting longer than three months, is an increasingly common, complex, and at times emotionally troubling condition that has a profound impact on a patient’s quality of life.4,5 The origins of chronic pain are multifold, as it may arise from trauma, from surgery, or as a component of other medical conditions like diabetes and post-herpetic neuralgia.6 However, chronic pain may also manifest without prior illness or injury in conditions such as trigeminal neuralgia or fibromyalgia.6

It is a major cause of suffering worldwide.

A recent study, published in JAMA, found that new cases of chronic pain occur more often among US adults than new cases of several common conditions, including diabetes, depression, and high blood pressure.7 Overall, the study found that the rate of chronic pain and high-impact chronic pain (HICP) among adults is approximately 21% and 8%, respectively. Among those who experience chronic pain, almost two-thirds (61.4%) still suffer from it a year later.7

Globally, chronic pain is in the top 10 leading causes of disability and disease burden, affecting more than 30% of people.8 Of this population, 1.9 billion are people affected by recurrent tension-type headaches – the most common symptomatic chronic condition.4 In the UK, research suggests that chronic pain affects 13-50% of adults; of those living with this condition, approximately 10.4-14.3% have moderate-to-severe disabling chronic pain.4 In China, the prevalence rate is 30%, which is similar to the rate in other low-income and middle-income countries.5

Chronic Pain & the Brain

Multiple cortical and subcortical brain areas are involved in pain processing, including the posterior insula, cingulate and prefrontal cortices, periaqueductal grey, rostroventromedial medulla, and reticular formation.6 The transition of pain from acute to chronic involves peripheral, spinal, and brain changes, and while the peripheral and spinal modifications have been well documented in the literature, the exact mechanisms involving the brain in chronic pain remain unclear.6

One theory is that central sensitization, a process whereby the central nervous system undergoes changes that alter its processing of pain and other sensory stimuli, may be the mechanism underlying chronic pain.1,2 Increases in primary afferent fiber responses, as well as increased spontaneous activity and excitability of dorsal horn neurons and receptive field areas, are associated with central sensitization.2 In this state, sensory messages are amplified, and the central nervous system remains hyperresponsive even in the absence of stimuli. In chronic pain, neuroplasticity primes the nerves to be more sensitive to stimulation, and pain signaling is not just a protective response to noxious stimuli. Chronic pain signals are a consequence of maladaptive changes within the nervous system.1

Over the last 15 years, advances in human neuroimaging have begun to identify the elements of the brain involved in the chronification of pain, including regions involved in processing emotions such as the mPFC and amygdala.2,5 These studies add to the mounting evidence suggesting that chronic pain results from alterations in neural networks.2,5 For example, patients with persistent subacute back pain show a reduction in gray matter density in the insular cortex, primary somatosensory cortex, motor cortex, and NAc.2 Patients with chronic pain conditions also show reductions in gray matter volume in the hippocampus and amygdala.2

In May 2023, researchers for the first time detected chronic pain–related data in human brains using intracranial neural biomarkers within the anterior cingulate cortex (ACC), which is implicated in affective/emotional processing, and the orbitofrontal cortex (OFC), which is connected with the ACC and may influence pain perception.3 In this small study, four participants age 50+ with refractory neuropathic pain, three with post-stroke pain and one with phantom limb pain, were surgically implanted with electrodes targeting their ACC and OFC. Several times a day, for three months, each participant was asked to answer questions related to how they would rate the pain they were experiencing, including strength, type of pain, and how their level of pain was making them feel emotionally. They would then initiate a brain recording by clicking a remote-control device, which provided a snapshot of the activity in the ACC and OFC at that exact moment. Using machine learning analyses, the research team was able to use activity in the OFC to predict the participants’ chronic pain state.3

The researchers also looked at how the ACC and OFC responded to thermal (acute) pain, which was caused by applying heat to areas of the participants’ bodies.3 In two of the four patients, brain activity could again predict pain responses, but in this case, the ACC appeared to be the region most involved. This suggests that the brain may process acute versus chronic pain differently. More studies are needed due to the small study size and other factors. That said, the study represents a significant step toward uncovering the patterns of brain activity that underly a patient’s perception of pain. Identifying personalized pain biomarkers is central to the accurate diagnosis of chronic pain, tracking prognosis, and for future therapeutic strategies.3

Another recent study, published in the European Journal of Pain, found that people with chronic pain have significantly lower levels of certain chemical messengers in the medial prefrontal cortex (mPFC), which helps regulate emotions.9 The researchers compared medial prefrontal neurochemistry in 24 people with chronic pain conditions age 52-60 years to 24 age and sex-matched healthy controls with no history of chronic pain age 49-60 years. Gamma-aminobutyric acid (GABA) and glutamate levels were measured in the mPFC, and psychometric measures regarding pain were recorded and compared.9

The results found a significant reduction in both GABA and glutamate within the mPFC in chronic pain sufferers compared to the control group.9 In a previous study, the authors recently reported that a decrease in medial prefrontal N-acetylaspartate and glutamate is associated with increased emotional dysregulation, indicating there are neurotransmitter imbalances in chronic pain. They suggest that this neurotransmitter dysregulation may be a result of neuroinflammatory and glial processes in persistent pain, independent of chronic pain type, and the disruption to normal mPFC function may result in affective disturbances and mood disorders.9 More studies are needed due to the small study size and other factors.

Several studies demonstrate the high comorbidity of chronic pain with post-traumatic stress disorder (PTSD),10 anxiety,11 and major depressive disorder.12 While there remains some uncertainty about the extent to which psychological trauma and PTSD may promote the development of chronic pain, studies suggests that early trauma is associated with an increased risk of developing chronic pain in adulthood.13 These stressors influence genetic factors and may lead to the epigenetic dysregulation of central glucocorticoid receptors, leading to a disruption of stress processing. As well, both overactivation and under activation of the hypothalamic-pituitary-adrenal axis can lead to an imbalance of the endocannabinoid and the corticomesolimbic systems, which is a central neurobiological correlate of chronic pain. Chronic pain and PTSD alter similar nuclei in the brainstem, hypothalamus, and amygdala.13

Anxiety and depression share similar alterations in neuroplasticity with chronic pain and involve overlapping neurobiological mechanisms; for example, injuries to sensory pathways have been shown to share the same brain regions that are involved in mood management, including the anterior cingulate cortex and prefrontal cortex.11 According to some studies, the mean prevalence of depression in patients with chronic pain is about 50%.14

Non-Pharmacological, Brain-Based Interventions

Due to the medical complexity of chronic pain in individual patients, a comprehensive interdisciplinary treatment strategy that includes effective nonpharmacological approaches is important to consider. The functional medicine model, which underscores the profound power of the therapeutic partnership through the IFM Timeline and other tools, introduces clinicians to a variety of evidence-based modalities to address chronic pain. Research on non-pharmacological therapies is growing; some highlights in the literature connecting chronic pain to the brain include:

High Frequency Repetitive Transcranial Magnetic Stimulation (HF rTMS): High frequency repetitive transcranial magnetic stimulation (HF rTMS) is a noninvasive neuromodulation technique that delivers focal stimulation to an individual’s brain using locally pulsed magnetic fields, which produces analgesic effects.14-16 A 2022 systematic review and meta-analysis suggests that HF rTMS effectively relieves pain and depressive symptoms when used over the dorsolateral prefrontal cortex (DLPFC) in patients.14 Specifically, in neuropathic pain, HF rTMS on the left DLPFC had significant short-term, mid-term, and long-term analgesic effects. For fibromyalgia, the mid-term analgesic effect of HF rTMS on the left DLPFC was significant. WMD = -0.50, 95% CI: [-0.99, -0.01]; WMD = -1.10, 95% CI: [-2.00, -0.19], respectively. The treatment also relieved depressive symptoms effectively for these patients, whose chronic pain was comorbid with depression.14

Another 2022 systematic review of six randomized controlled trials (n=214) indicates that there is moderate-to-high evidence to suggest that HF rTMS is effective in reducing pain in individuals with neuropathic orofacial pain.15 The treatment, however, showed no significant positive effect on psychological conditions and quality of life.15

Transcutaneous Electrical Nerve Stimulation (TENS): Transcutaneous electrical nerve stimulation (TENS) is a noninvasive, inexpensive, and safe analgesic technique used for relieving chronic pain by stimulating peripheral nerves.17 TENS has been shown to inhibit the activity and excitability of central nociceptive transmission neurons, irrespective of acute or chronic pain diagnosis.18

A 2018 interventional study was the first of its kind to investigate the effect of high-frequency TENS on gamma band activity—a kind of brain wave that consists of very rapid oscillations and plays an important role in pain perception as well as pain processing.17 In this study, EEG analysis revealed significant enhancement of gamma total power after inducing pain as compared to baseline. Gamma, like other brain rhythms, can provide a signature of cognitive state as well as network dysfunction. The results demonstrated that the high-frequency TENS could reduce the enhanced gamma band activity after inducing tonic pain in healthy volunteers, a finding that might help as a functional brain biomarker that could be used for pain treatment.17

More recently, a 2022 systematic review and meta-analysis of 381 randomized controlled trials with 24,532 participants suggests there is moderate-certainty evidence that pain intensity is lower during or immediately after TENS compared to placebo.18 Specifically, the mean pain intensity during or immediately after TENS was 0·96 standard deviations lower than placebo (95% CI 1·14 lower to 0·78 lower).18

Neurofeedback or Electroencephalograph (EEG) Biofeedback: Neurofeedback is a form of biofeedback in which patients respond to a display of their own brainwaves or other electrical activity of the nervous system.19 The goal is to enable a behavioral modification by modulating brain activity.20 Volitional neural modulation using neurofeedback has been indicated as a potential treatment for chronic conditions that involve peripheral and central neural dysregulation like fibromyalgia, and research is growing.19 

A 2019 systematic review on the effect of neurofeedback in cancer patients suggests that neurofeedback has the potential to ameliorate symptoms of pain, fatigue, depression, and sleep.20 A 2022 systematic review and meta-analysis suggests that although there is low confidence, EEG neurofeedback may have a clinically meaningful effect on pain intensity in the short-term. Further studies with larger sample sizes and higher quality of evidence are required.21

Functional Medicine Considerations

In functional medicine, developing a diagnosis for a patient’s chronic pain is based on assessing the possible underlying etiologies. As pain is a consequence of biological, psychological, and social factors, guidelines recommend an interdisciplinary, personalized treatment.8 Functional medicine offers such an approach through a set of tools that formalizes both history-taking and mapping symptoms to the categories of root processes that underlie illness.

For chronic pain patients, understanding the neural mechanisms of pain and the brain changes affecting pain factors is important for finding pain treatment methods. In the future, with standardization and additional validation, brain imaging could provide objective biomarkers of chronic pain and further guide treatment for personalized pain management. When combined with a therapeutic, empathetic partnership between patient and clinician, healing can begin.

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