Three main results were observed. First, increased activation of the amygdala, anterior insular region and ACC was observed during pain anticipation in MDD subjects, suggesting that depressed individuals experience increased affective processing even before they actually experience painful stimuli. Second, greater right amygdala activation during pain anticipation in MDD was associated with greater levels of perceived helplessness, which was specific to this disorder. Third, for the same perceived intensity of painful stimulation, MDD subjects seemed to show maladaptive activation of a neural network that is involved in pain and emotion modulation 39
. Taken together, these findings extend previous research describing affective biasing of the pain experiences in MDD 22, 23, 40, 41
, and are consistent with the conceptualization of MDD as a disorder of abnormal anticipatory processing and hypervigilance. These findings may also suggest that altered functional responses within a specific neural network during anticipatory processing in MDD may lead to an impaired ability to modulate not only the experience of pain, but also negative affective states.
To our knowledge, this is the first study to examine the neural correlates of anticipatory pain processing in young, unmedicated individuals with current MDD. Cognitive models of depression suggest that depressed individuals negatively bias their expectations, thereby creating conflict with the environment (reviewed in 10
). The increased activation within amygdala, AI and ACC in MDD subjects during anticipation of pain found here is consistent with this cognitive model, and may represent a neural correlate of hypervigilant monitoring 42
of negative information in MDD 43
. Both the ACC and insula receive afferent information via the Lamina I homeostatic pathway 44
. According to recent neuroanatomical and neuroimaging evidence, this pathway subserves all homeostatic emotions, including pain, i.e., feelings and motivations associated with changes in the body’s physiological condition and with the autonomic responses and behaviors that occur in order to restore an optimal balance 44, 45
. Moreover, evidence from rodents and non-human primate studies describes strong anatomical connections between the insula and both the amygdala and ACC 46
. Related functional neuroimaging evidence shows that the AI, ACC and amygdala are also the main nodes within “emotional salience” network that is active during undirected mental activity 47
, further indicating that these structures are directly involved in homeostatic processing. Inappropriately large responses within the brain’s homeostatic and emotional salience network to a stressor or upcoming pain suggest an exaggerated experience of emotional distress or affective biasing in MDD, even before the actual painful stimulation occurs. Interestingly, MDD subjects showed increased affective biasing during anticipation of pain even though the perception of pain intensity was not different. This suggests that the difference between the expected and the actual body state, or the interoceptive error signal, may be higher in MDD. Neuroanatomical and functional neuroimaging evidence shows that the AI plays a major role in detecting the mismatch between cognitive and interoceptive states, reflecting subjects’ awareness of the perceived (and not the actual) interoceptive state 44, 48, 49
. Increased AI activation during anticipation of pain in our MDD subjects is consistent with the idea that the awareness of the interoceptive state during anticipation of impending pain is heightened in MDD. This heightened awareness of the interoceptive state creates a mismatch between the observed and expected body state similar to the ideology behind anxiety disorders 50
. Thus, in much the same way that MDD individuals have a maladaptive interpretation of the environmental cues they also may have impaired interoception.
Cognitive coping styles play an important role in the anticipation and processing of negative emotional information, and the amygdala is directly involved in these processes. Specifically, the amygdala has been linked to “passive coping” strategies, such as helplessness 51
and catastrophizing 52
. For example, a lack of controllability during painful stimulation was associated with increased amygdala activity in healthy human subjects 53
. Likewise, unsolvable cognitive problems that induce a state of learned helplessness in humans are associated with increased amygdala activity 54
. Furthermore, in fibromyalgia patients, passive attitudes toward pain are significantly associated with activity in extended amygdala 52
. Exaggerated activation of the amygdala in our MDD patients during anticipation of pain was significantly predicted by a measure of helplessness towards pain in these patients and this relationship was specific to the MDD patients. Acute antidepressant treatments can significantly diminish resting metabolism and functional activation within amygdala towards negative emotional stimuli and the amount of decrease can predict relapse 55, 56
. Although speculative, the mechanistic relationship between helplessness and amygdala activation found in our study may suggest that the therapeutic effects of cognitive therapy directed toward reducing passive cognitions in depression, may be grounded in the effects of therapy on amygdala functioning.
When dealing with pain, cortical and subcortical modulatory systems are normally activated 57, 58
, which are aimed to elicit adaptive behaviors to stressful exposures. Our findings suggest that MDD is associated with a heightened alarm signal during anticipation of pain. Nevertheless, despite this heightened alarm signal in MDD, the brain shows ineffective or maladaptive recruitment of pain and emotion modulatory pathways during the experience of pain. Studies that have examined the mechanisms of pain and emotion modulation using, for instance, placebo 57, 59
and/or attentional diversion to a secondary task 60, 61
consistently show increased activation within rostral ACC. This region of the ACC is connected to PAG, which, in turn, is one of the main nodes of the endogenous pain inhibitory circuits 58, 62
. Furthermore, regions of the lateral and medial prefrontal cortex play important role in emotion regulation, showing increasing activation as a function of the emotion and pain suppression process (e.g., reappraisal) (reviewed in 37, 39
) or placebo analgesia 36
. In the current study, all of these structures were significantly more activated in healthy compared to MDD subjects during actual pain experience, supporting maladaptive response within pain- and emotion-modulatory circuits in MDD. Furthermore, right DLPFC activation during pain experience in our study showed significant negative correlation with average subjective pain intensity ratings, suggesting that decreased activation of this structure during painful stimulation in MDD might be related to maladaptive cortical pain modulation in this disorder. These findings are consistent with ineffective emotional regulation 63-66
and altered endogenous opioid neurotransmission on mu-opioid receptors in MDD 67
. Deficient endogenous pain modulation has been implicated in chronic and functional pain disorders, including fibromyalgia 68 69
, chronic tension-type headache 70
, irritable bowel syndrome 71
and central post-stroke pain 72
. Deficient endogenous pain modulation is one of the possible mechanisms leading to sensory allodynia in chronic pain disorders, i.e., when stimuli that are normally perceived as non-painful become painful 73
. In our study, groups were matched on the perceived intensity of non-painful and painful stimuli, i.e., the sensory experience of thermal stimuli was not different between the groups. However, as we observed previously 22
, MDD subjects demonstrated “emotional allodynia”, i.e., experiencing non-painful warm stimuli as unpleasant. In fact, a recent study showed that this concept also applies to fibromyalgia patients who rated non-painful muscle sensation as unpleasant or emotional 74
. It is plausible that the decreased activation within the brain’s pain and emotion modulation circuitry observed in our MDD patients is due to ineffective functioning of these systems or a side effect of emotional allodynia. Further studies should examine how decreased activation of endogenous pain/emotion regulatory systems relates to experience of emotional allodynia and whether compromised pain modulation contributes to high vulnerability to chronic pain in depression.
We also observed decreased activation within bilateral precuneus and posterior cingulate cortex in MDD compared to healthy control subjects in our study. This finding is consistent with the notion of competing cognitive networks 75
and prior observations in MDD patients 76, 77
. In addition this region appears responsive to treatment in MDD 76, 77
and can predict prognosis in mild cognitive impairment 78
. Future studies need to examine the role of the posteromedial cortex in pain-depression comorbidity.
Our results are in direct agreement with our own psychophysical observations 22
of increased emotional reactivity to painful stimuli in young depressed adults without comorbid chronic pain condition. Considering increased pain affect to experimental pain in students with increased and/or induced depressive moods 79, 80
, increased affective biasing to daily pain in chronic pain patients with history of depression 81, 82
, as well as increased affective processing in comorbid chronic pain and depression 20
, these results suggest that depression has profound acute, as well as chronic effects on the emotional behavior and brain circuitry. Therefore, even acute changes in the affective state of an individual may significantly influence interoceptive state, which then affectively biases behaviors and feelings towards environmental stimuli. Therapeutic interventions directed towards supporting and restoring interoceptive/homeostatic functioning, by building resilience, for example, have been relatively successful in comorbid depression and chronic pain conditions 83
We would like to acknowledge that our findings are based on a mixed sample of relatively modest size. Although we observed large statistical differences between MDD and CON groups, further studies confirming our results would aid in generalizing the present findings. Future studies examining brain responses to pain stimulation and anticipation in MDD patients of greater diversity without chronic pain and in patients with co-morbid chronic pain and MDD, as well as in older medicated depressed adults would aid in clarifying the relationship between pain and depression. Specifically, future studies should examine how different subpopulations of MDD patients (i.e., older vs. younger age, many vs. few comorbidities and prior episodes, earlier vs. later age of MDD onset) respond to anticipation and receipt of experimental pain.
In summary, using pain as a probe of emotional circuitry, we have shown that unmedicated young adults with recurrent MDD and without comorbid chronic pain conditions show increased affective bias during aversive anticipation in several brain regions, including anterior insular region, ACC and amygdala and decreased response during pain experience in regions responsible for cortical and subcortical pain modulation. The anticipatory brain response may indicate hypervigilance to impending threat, which may lead to increased helplessness and maladaptive modulation during the experience of heat pain. This mechanism could in part explain the high comorbidity of pain and depression when these conditions become chronic. Future studies that directly examine whether maladaptive response to pain in MDD is due to emotional allodynia, maladaptive control responses, lack of resilience, and/or ineffectual recruitment of positive energy resources will further our understanding of pain-depression comorbidity.