Pain and analgesia: the value of salience circuits

Abstract

Evaluating external and internal stimuli is critical to survival. Potentially tissue-damaging conditions generate sensory experiences that the organism must respond to in an appropriate, adaptive manner (e.g., withdrawal from the noxious stimulus, if possible, or seeking relief from pain and discomfort). The importance we assign to a signal generated by a noxious state, its salience, reflects our belief as to how likely the underlying situation is to impact our chance of survival. Importantly, it has been hypothesized that aberrant functioning of the brain circuits which assign salience values to stimuli may contribute to chronic pain. We describe examples of this phenomenon, including 'feeling pain' in the absence of a painful stimulus, reporting minimal pain in the setting of major trauma, having an 'analgesic' response in the absence of an active treatment, or reporting no pain relief after administration of a potent analgesic medication, which may provide critical insights into the role that salience circuits play in contributing to numerous conditions characterized by persistent pain. Collectively, a refined understanding of abnormal activity or connectivity of elements within the salience network may allow us to more effectively target interventions to relevant components of this network in patients with chronic pain.

Figure 1. Interconnections in the Salience Network

The figure provides a map of connectivity between different brain regions of the salience network. In addition the behavioral context of some of these pathways are also noted (viz. fear, reward, autonomic responses, interoception, memory etc.). Cortical and subcortical areas are differentiated in the figure. Salient stimuli include cognitive (e.g., to prefrontal cortex), sensory (e.g., to thalamus) and emotional (e.g., to amygdala). The Salience Network senses, integrates and produces actions in systems to stabilize the homeostatic challenge (e.g., activation of modulatory circuits in the brainstem through connections for a number of regions that include the cingulate cortex (Stein et al., 2012; Zhang et al., 2005). Some aspects of these networks have been better described than others. For example, the interactions between the anterior insula and the anterior cingulate cortex form a “salience network” that acts to determine hierarchical behavioral responses to stimuli (internal or external). The insula is involved in this function in a number of ways including detection of salient events (e.g., the posterior insula structure is involved in encoding pain intensity (Baumgartner et al., 2006); accessing other networks such as those involved in attention or working memory and also motor networks following detection of a salient stimulus and autonomic modulation in response to salient stimuli (Menon and Uddin, 2010). Although not detailed in this figure, most of the structures interconnect functionally with different components of the salience network (see Seeley and colleagues (Seeley et al., 2007)). For example, the cerebellum (Crus VI) in functional imaging connectivity studies shows connectivity with the caudate, the anterior cingulate, the insula, the red nucleus, and the thalamus (Habas et al., 2009). The regions that are outlined in bright green, and purple represent examples of potential hierarchical organization of the salience network (see Figure 2). Specific known functions of these different regions are noted in Table 1. Brain function at rest and in action trends to a homeostatic baseline that is perturbed by environmental stimuli.

Figure 2. Model of Hierarchical Function in Salience Network Regions

Primary regions include those involved in “sensing” sensory, cognitive and emotional stimuli. Secondary regions are involved in integration of such stimuli while Tertiary regions are involved in homeostatic normalization or stabilization.

Figure 3. Salience Processing in Acute (Experimental) and Chronic Pain

3A: Salience Systems in Healthy Subjects: Three states are shown. Top – normal where a salience response to pain (e.g., heat, sharp object, etc.) results in adaptive changes that sense, evaluate and respond to the stimulus in an adaptive manner (e.g., sense the stimulus as painful or potentially painful and may avoid the stimulus). Middle - Salience Systems in the condition of Perceived Pain but no actual pain. Examples include social or personal empathy for an observed process such as watching a loved-one having pain, or nocebo (increased pain to a normally analgesic drug). Bottom - Salience Systems in the condition of Perceived Pain Relief in the absence of an analgesic medication: Examples include the placebo response where an inert substance produces profound analgesia based on expectancy (placebo effect). 3B: Salience Systems in Chronic Pain Patient: Compared with healthy subjects, salient systems in chronic pain patients may be aberrant to both pain (ongoing or evoked). Abnormal processing in their sense (e.g., cognitive processing (Apkarian et al., 2004), integration (e.g., basal ganglia function ((Borsook et al., 2010);(Maleki et al., 2011); (Starr et al., 2011); (Baliki et al., 2012) and modulatory processing (e.g., periaqueductal gray ((Behbehani, 1995); (Linnman et al., 2012)) is postulated to contribute to such aberrant function of normal homeostatic salience processing. Ongoing background pain and evoked pain with use (particularly in conditions such as osteoarthritis) sets up a process of fear of future events. Such changes, that may be mediated through medial prefrontal -> amygdala circuits may result in “system failure” since it becomes a feed-forward loop that exacerbates the condition. The salience network is now damaged at two levels – its innate state is sensitized to pain-relevant input, and its response to external/salient cues or stimuli in the environment is compromised. Thus avoidance of physical activity for example may lead to further disability and worsening brain state. See Table 2.

Figure 3. Salience Processing in Acute (Experimental) and Chronic Pain

3A: Salience Systems in Healthy Subjects: Three states are shown. Top – normal where a salience response to pain (e.g., heat, sharp object, etc.) results in adaptive changes that sense, evaluate and respond to the stimulus in an adaptive manner (e.g., sense the stimulus as painful or potentially painful and may avoid the stimulus). Middle - Salience Systems in the condition of Perceived Pain but no actual pain. Examples include social or personal empathy for an observed process such as watching a loved-one having pain, or nocebo (increased pain to a normally analgesic drug). Bottom - Salience Systems in the condition of Perceived Pain Relief in the absence of an analgesic medication: Examples include the placebo response where an inert substance produces profound analgesia based on expectancy (placebo effect). 3B: Salience Systems in Chronic Pain Patient: Compared with healthy subjects, salient systems in chronic pain patients may be aberrant to both pain (ongoing or evoked). Abnormal processing in their sense (e.g., cognitive processing (Apkarian et al., 2004), integration (e.g., basal ganglia function ((Borsook et al., 2010);(Maleki et al., 2011); (Starr et al., 2011); (Baliki et al., 2012) and modulatory processing (e.g., periaqueductal gray ((Behbehani, 1995); (Linnman et al., 2012)) is postulated to contribute to such aberrant function of normal homeostatic salience processing. Ongoing background pain and evoked pain with use (particularly in conditions such as osteoarthritis) sets up a process of fear of future events. Such changes, that may be mediated through medial prefrontal -> amygdala circuits may result in “system failure” since it becomes a feed-forward loop that exacerbates the condition. The salience network is now damaged at two levels – its innate state is sensitized to pain-relevant input, and its response to external/salient cues or stimuli in the environment is compromised. Thus avoidance of physical activity for example may lead to further disability and worsening brain state. See Table 2.