Brain systems at the intersection of chronic pain and self-regulation

Abstract

Chronic pain is a multidimensional experience with cognitive, affective, and somatosensory components that can be modified by expectations and learning. Individual differences in cognitive and affective processing, as well as contextual aspects of the pain experience, render chronic pain an inherently personal experience. Such individual differences are supported by the heterogeneity of brain representations within and across chronic pain pathologies. In this review, we discuss the complexity of brain representations of pain, and, with respect to this complexity, identify common elements of network-level disruptions in chronic pain. Specifically, we identify prefrontal-limbic circuitry and the default mode network as key elements of functional disruption. We then discuss how these disrupted circuits can be targeted through self-regulation and related cognitive strategies to alleviate chronic pain. We conclude with a proposal for how to develop personalized multivariate models of pain representation in the brain and target them with real-time neurofeedback, so that patients can explore and practice self-regulatory techniques with maximal efficiency.

Introduction

Pain is a multidimensional experience, often described in terms of sensory-discriminative, cognitive-evaluative, and affective-motivational components [1,2]. These three categories encompass a variety of processes, including nociception [3], attention [4,5], learning [6], memory [7,8], expectation [9,10], personality [11], culture [[12], [13], [14]], socioeconomic conditions [[15], [16], [17]], and more. When peripheral nociceptive information enters the cortex, the signal becomes integrated with complex multidimensional information and is modified via descending projections [[18], [19], [20], [21]]. Through this mechanism, the pain experience is not only heterogeneous, but personalized. Therefore, to understand pain, we must seek to understand the person in pain [22,23].

Broadening our conceptualization of pain to include dimensions outside of primary nociception and sensation complicates the task of neurobiological research, but it also expands the landscape of treatment possibilities. That is, when we reconceptualize pain as something constructed in the brain, rather than something that happens to the brain, we allow for the development and testing of noninvasive and nonpharmacological interventions, such as self-regulation—a family of cognitive strategies for managing thoughts, emotions, and actions that affects the brain’s activity and neurochemistry and alters neuroplasticity over the course of time ([[24], [25], [26]]; Mischel, Cantor, & Feldman, 1996).

The exploration of nonpharmacological treatments for chronic pain is important. Opioids, though effective in the short term, may not provide long-term pain relief [[27], [28], [29]]. Furthermore, opioids are prone to abuse [30,31]. Aberrant addiction-like behaviors develop in approximately 24% of cases of chronic back pain patients prescribed opioids [32,33]. There is also a growing epidemic of opioid abuse and opioid-related death in Western countries [34,35], which can sometimes be localized to neighborhoods surrounding opioid-prescribing physicians [36]. Therefore, it is critical for scientists to prioritize investigations of non-opioid, as they are not only limited in their effectiveness, but potentially deadly.

Compared to other treatments, opioids are not significantly advantageous. Their efficacy for short-term pain management [37] is comparable to both cyclobenzaprine (a 5-HT2A antagonist, pro-adrenargic muscle relaxant [38];) and antidepressants [39]. Furthermore, nonpharmacological treatments of chronic pain, such as mindfulness [40], hypnosis [41,42], yoga [43], and combinations of psychological and physical treatment programs (biopsychosocial multidisciplinary rehabilitation [44];) produce pain-reducing effects comparable to that of opioids (Fig. 1). Self-regulatory treatments for chronic pain are therefore, a promising, albeit desirable, alternative to pharmacologic agents and are worthy of further research.

In this paper, we briefly discuss the heterogeneity of pain representations in the brain and identify several loci whose activity can be disrupted to alleviate chronic pain conditions through self-regulatory techniques. Specifically, we discuss (1) prefrontal-limbic circuitry and (2) resting state networks, which are altered during the chronification of pain. We propose that prefrontal-limbic circuitry alters the way pain is valued in individuals, while changes to default mode network (DMN) morphometry and connectivity may alter self-referential processes related to the pain experience. These systems can be targeted by self-regulatory strategies that alter evaluative (i.e., reappraisal-based strategies) and self-referential processes (i.e., acceptance-based strategies), respectfully.

The experience of chronic pain is different from that of acute pain. Critically, it is appraised differently; its perceived causes are understood differently, and it connotes different implications for future wellbeing. Acute pain is often appraised as self-limiting, with an identifiable cause and expected resolution. Conversely, chronic pain is appraised as something without a known end that is dissociated from its initial driver and a part of daily life [45].

Likewise, different types of chronic pain are experienced and represented in unique ways. For example, chronic back pain disrupts activity in the mPFC more than post-herpetic neuralgia or knee osteoarthritis [46]. In post-herpetic neuralgia, the most prominent correlates of spontaneous pain are in the amygdala and accumbens, while knee osteoarthritis has greater correlations in the orbitofrontal cortex. Insula activity is central to brain changes associated with fibromylgia [[47], [48], [49], [50]]. Migraine episodes evoke a distributed network of activity with a significant emphasis on subcortical circuitry— signal intensity in the red nucleus and substantia nigra as related to visually-triggered onset [51], and the pons as related to spontaneous migraine experiencing [52], migraine severity [53], and migraine-related changes in morphology [54]. In phantom pain, pain may be best explained by persistent local cortical representations in S1 [55] or maladaptive cortical reorganization [56]. To summarize, brain representations across chronic pain pathologies are unique, though they may implicate common circuitry that overlaps with acute pain at a broad level (Fig. 2).

For at least some types of pain—and chronic low back pain in particular—the transition from acute to chronic pain is thought to be supported by a shift in pain representation from nociceptive to ‘emotional’ circuits, that is, the limbic system and prefrontal cortex [57]. This is supported by a pattern of dissociation between brain systems involved in immediate evoked pain experience and those that seem to track pain chronification. For example, the Neurologic Pain Signature (NPS; [58]), a brain pattern predictive of evoked experimental pain, includes a set of brain regions that overlap with those often considered to be in the ‘pain matrix’ by virtue of their responses to noxious stimuli and correlations with pain ratings ([[59], [60], [61],1],). Like the ‘pain matrix,’ in the NPS, activity in the anterior cingulate cortex (ACC), insula, secondary somatosensory cortex (S2), and thalamus is related to a greater pain experiencing, while increased activity in the ventromedial prefrontal cortex (vmPFC) and precuneus is related to less pain experiencing. Indeed, the regions that predict evoked pain as part of the NPS are not the regions that correlate with the intensity of spontaneous fluctuations in chronic back pain [46] nor does activity in these regions predict back pain chronification [62]. The region most heavily implicated in pain chronification is the vmPFC, which changes from being anti-correlated with pain in healthy participants [63] to being positively associated with pain in several patient groups [[48], [49], [50]].

One interpretation of this evidence is that there is a shift in the drivers of pain from systems that encode the immediate, sensory-discriminative aspects of pain experience to affective-motivational information relevant for pain avoidance, which requires linking actions and contexts with pain via associative learning mechanisms [6,[64], [65], [66]]. This is generally adaptive, as actions associated with pain should be avoided in order to prevent harm. However, avoidance can become maladaptive if a wide variety of actions and contexts become linked with pain—particularly if those actions are not harmful and the pain-avoidance system has over-generalized [67].

For example, pain from an injury may be exacerbated by long periods of standing. If a patient is required to stand for long periods of time at work, they may learn to associate their work environment with pain. Indeed, conditioned increases in muscle tension are acquired more rapidly in subacute pain patients at high risk for chronification [68]. That is, those at a higher risk of pain chronification demonstrate quicker associative learning between pain contexts and nociceptive responses. Furthermore, if the patient’s community engages in movement-related hobbies, the patient may learn to expect pain during social events. This may promote social withdrawal and feelings of alienation [69,70]. One patient’s testimony of their experience living with chronic pain elucidates this point:

“In my 10+ years of chronic pain I’ve done many regrettable things, but the thing I regret is something I had no clue I was doing. I began pushing everyone away so that they didn’t have to deal with me or so that I could just quietly decay in my bed without bother. It starts small, you begin missing more and more things and then people stop trying to invite you because they think you’ll say no. I wish I was stronger is the only phrase I want to tell my best friend and how I wish I could have been at your wedding to see you happy.” (Anonymous user on the forum: www.reddit.com/r/chronicpain).

Depressed mood, negative pain beliefs, and early beliefs that the pain may be permanent are also predictive of the chronification of neck and back pain [71]. In this way, various aspects of a person’s life may become entangled with their pain experience, and a widening variety of activities that could promote recovery and wellbeing become threatening and are avoided. That is, chronic pain, unlike acute pain, is conceived as something inseparable from one’s sense of self. This pathological interweaving of pain and self is therefore a promising target for treatment through self-regulatory techniques.