It is important to recognize that “stress circuitry,” “reward circuitry” (including nucleus accumbens, amygdala, hippocampus, ventral tegmental area, and orbital prefrontal cortex), and “executive circuitry” are not independent and mutually exclusive entities; they are better conceived of as intersecting and overlapping components of a common 3–dimensional neural network.17,19,20 Disruption in their dynamic balance may give rise to excessive negative emotions, combined with cognitive impairment and withdrawal of hedonic tone. Moreover, anxiety, pain, and depressed mood appear to have a shared capacity to engage autonomic, neuroendocrine, and neuroimmune components of the stress response.21 MDD, GAD,22,23 BD, chronic insomnia,24 and chronic pain25 are all associated with altered sympathetic/parasympathetic balance; neuroendocrine disturbance, manifested by insufficient HPA regulation; and altered immune function, characterized by inhibition of acquired immunity and enhancement of innate inflammatory signaling.1,12,26 In turn, these peripheral responses signal back to neural structures to further drive CNS danger pathway activation; this leads to a maladaptive feed–forward circuit that increasingly appears to be implicated in the production and maintenance of symptoms.

Within the CNS, microglia seem to be the principal recipients of bodily distress/pain signals. Microglia are increasingly implicated in the development of mood (depression and mania)1 and pain symptoms and disorders.27 Indeed, increasing evidence suggests that different patterns of interaction between microglia, astroglia, and neurons may engender diverse symptomatic manifestations (eg, pain, depression). Peripheral distress signals are “amplified” via reverberating communication between microglia, astrocytes, oligodendroglia, and neurons.12,28 The result is suppression of neurotrophic trafficking and an increase in the production and release of proinflammatory cytokines and reactive oxygen and nitrogen species.26 The combined effect of this inflammatory and oxidative “surge” may damage astrocytes and oligodendroglia, thus contributing to demyelination and consequent disruption of CNS regulatory circuits required to restrain peripheral stress/inflammatory responses.12 Thus, the vicious circle closes.

Excessive excitatory glutamatergic transmission and compromised GABA–mediated inhibition (with ensuing excitotoxicity) appear to be common features of anxiety,22 mood,29 sleep,30 and pain disorders.31 Dysregulation in monoamine, substance P, galanin, and opiate–signaling also characterizes GAD, pain syndromes, and MDD. On the other hand, anxiety and mood and pain disorders are characterized by different patterns in the production of neurotrophic factors: depression and mania are characterized by reduced serum levels of brain–derived neurotrophic factor (BDNF), fibromyalgia is associated with increased BDNF,12 while fear and anxiety appear to be accompanied by elevated levels of nerve growth factor.32 Nonetheless, anxiety, pain, stress, and depression have a similar, possibly even synergistic, effect on neurotrophic signaling in the hippocampus, given that all of them are associated with reduced BDNF synthesis in this critical limbic region.33,34 This finding is of particular interest, given that the hippocampus represents a veritable “intersection” of pathways involved in emotional regulation, reward, memory, and coordination of neuroendocrine response.33

MDD, BD, and chronic pain are all associated with neuroplastic changes in the CNS. In pathological pain states, facilitation of pain signaling, presumably on the basis of neuroplastic changes in pain pathways, is often designated as “central sensitization.”35,36 Similarly, the recurrent and progressive nature of MDD and BD is often attributed to “kindling,” which—like central sensitization—reflects neuroplastic changes.37 Given this, MDD, BD,38 and chronic pain39 may all be characterized by adaptive processes gone awry as a result of complex interactions between genetic vulnerabilities and environmental factors. In this scenario, persistent aberrant processing of emotional, painful, and stressful signals eventually becomes “hard–wired,” presumably from ensuing neuroplastic alterations.

In some ways, chronic pain and disorders of sleep, mood, and anxiety share dysfunctional psychosomatic and somatopsychiatric communication patterns—indeed they can be seen as behavioral read–outs for these dysfunctional communication patterns.12 Their synergistic and simultaneous occurrence may give rise to a “symphony” of misery. If we assume that a shared biological underpinning gives origin to the clinical symptoms of MDD, BD, GAD, and chronic pain, it is clear that a full understanding of this “synergy” has critical diagnostic and treatment implications.

Despite these powerful commonalities, however, it is important to realize that diverse underlying biological processes may generate similar symptoms and vice versa; that is, similar pathophysiology may drive diverse clinical manifestations. A synthesis of these dialectical perspectives suggests that understanding shared etiopathogenesis may provide an opportunity for the development of new preventive and treatment strategies that transcend diagnostic boundaries. A full appreciation of each person’s symptoms—as the unique result of interactions between genetic vulnerability, adversity, positive life experiences, individual coping skills, and overall health—offers the clearest way forward in our field’s attempt to develop personalized treatment approaches.
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