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- Supporting Information
Anorexia nervosa (AN) is a debilitating disorder that most commonly affects adolescent females1. AN is often a chronic illness2, 3 that is associated with substantial medical morbidity4 and mortality.5, 6 Individuals with AN have puzzling symptoms that are unique to the disorder, such as restricted eating, a relentless drive to lose weight, body image distortions, and denial of illness. However, there are no FDA approved medications or other treatments that reverse core symptoms,7–10 and little is known about how such symptoms are encoded in the brain.11 Thus a better understanding of the neurobiology of AN is needed in order to develop more efficacious treatments.
Recent theories suggest that AN pathology may relate to a core impairment in interoception,12–14 i.e., perceiving and modulating the physiological condition of the body—a process that serves to maintain homeostasis and facilitate adaptive emotion processing.15 This assertion is bolstered by studies indicating that individuals with AN show altered subjective responses to interoceptive stimuli,16–18 such as food, hunger,19–22 and physical pain.23–28 Moreover, individuals with AN often display behavioral traits that could be related to impaired interoception.29 Specifically, individuals with AN commonly exhibit high levels of alexithymia,30 which relates to difficulty describing and identifying feelings31, 32 raising the possibility that individuals with AN have an impaired ability to effectively use interoceptive information to appropriately value immediate outcomes.
Pain is a uniquely relevant probe for investigating the function of neural systems relevant to AN symptoms. First, as noted above, most, but not all studies show that ill and recovered individuals with AN show maladaptive behavioral responses to experimental pain stimuli. Second, pain is an interoceptive process with well-characterized neuroanatomical pathways,15, 33 and these pathways overlap to a large degree with the neural systems, such as the insula, that are thought to be dysregulated in individuals with AN.14 Third, cued pain has a strong anticipatory component34 that may be particularly relevant to probe affective symptoms of AN.35, 36 Specifically, anxiety and depression are often comorbid with AN and amplified insula response to the upcoming aversive stimulus has been observed in pathological anxiety36, 37 and mood35 disorders.
The purpose of this study was to use functional magnetic resonance imaging (fMRI) to identify the neural correlates of pain anticipation and processing in women recovered from AN (REC AN) relative to healthy control women (CW) with no history of an eating disorder. We examined recovered AN participants to avoid the possible confounding effect of starvation and emaciation on pain responses38 and to minimize the interactive metabolic effects on the observed group differences in brain activation, as done in prior research.39 We hypothesized that REC AN relative to CW would display dysregulated interoceptive processing during anticipation and processing of heat pain, as evidenced by altered activation within insula and related interoceptive brain circuitry.15, 40, 41
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- Supporting Information
Three main findings were observed in this study, which was the first to use neuroimaging to investigate the neural basis of pain anticipation and processing in recovered AN. First, when anticipating painful stimuli, REC AN compared with CW individuals showed more activation of rAI and right dlPFC. Second, when experiencing pain, REC AN compared with CW individuals showed less activation of right posterior insula and more activation of right dlPFC. Third, a positive post hoc correlation between rAI activation and alexithymia (i.e., the inability to identify one's own feelings and emotions) was observed in REC individuals with AN, and not in CW. Taken together, these findings suggest a functional brain basis of altered interoceptive processing in AN.12, 13
As expected,58 both groups activated the rAI during pain anticipation (see Supporting Information), but the activation was significantly greater in the REC AN group. The rAI plays a critical role in health and psychopathology16, 59 by perceiving and modulating the physiological condition of the body, and processing homeostatic emotions such as hunger, thirst, “air hunger,” and pain.15 Neuroanatomical and functional brain imaging studies suggest that the anterior insula is an integrator of interoceptive, cognitive, and emotional experiences, and is a neural substrate for emotional salience,60 as well as interoceptive40 and emotional awareness.15, 16, 41 Therefore, increased rAI activation during anticipation of thermal heat pain in REC AN may suggest an amplified stress response to the upcoming aversive interoceptive stimulus, similar to what is observed in pathological anxiety36, 37, 61, 62 and mood35 disorders. However, our REC AN participants did not rate the upcoming painful stimulation as subjectively more aversive, i.e., subjective experiences during pain anticipation were rated similarly by both groups. Importantly, during pain stimulation, REC AN participants showed less activation in the right midposterior insula, again despite a similar reported subjective experience of painful stimuli. Current evidence suggests that the posterior insula encodes objective thermosensory information, whereas the middle and anterior insula integrate thermosensory information with emotionally salient stimuli from all sensory modalities.15, 16, 41, 63, 64 The observed mismatch between subjective experiences (ratings) and objective responses (brain activation) in REC AN potentially points to the abnormal integration and, possibly, disconnection between reported and actual interoceptive state. This interpretation is consistent with prior research indicating that AN is associated with a reduced capacity to accurately perceive bodily signals,13, 65 a deficit that seems to persist even after recovery.
This interpretation is further supported by our exploratory analyses. While the REC AN did not significantly differ from CW in alexithymic feelings, a positive correlation between alexithymic feelings and rAI activation during pain anticipation was observed in the REC AN group, such that the REC AN participants who displayed the greatest deficits in identifying and describing feelings and emotions also showed the highest anticipatory rAI activation. Furthermore, this relationship was specific to REC AN group and was not evident in the CW group in our study. Prior literature shows negative correlation between activity within anterior insula during emotional processing tasks and alexithymia scores in healthy controls,66, 67 which is consistent with the idea that these individuals have a reduced capacity to experience emotion. However, when a person is classified as highly alexithymic, the correlation between right insula activation and alexithymia scores becomes positive, suggesting that highly alexithymic people are able to experience emotion, in fact, they show hyperarousal to the emotion, but are unable to effectively appraise and identify the emotion.68 We posit that in our REC individuals with AN similar process is taking place, i.e., the REC individuals with AN are more distressed by the upcoming painful stimuli but instead of lack of cognitive awareness of their physiological feedback they intentionally suppress it. Although the results of these exploratory analyses should be interpreted with caution, we think these findings show direct clinical relevance, since treatments directed at improving awareness of emotions may benefit those with anorexia.
DLPFC activation was higher in the REC AN group during pain anticipation and pain processing. The medial and lateral prefrontal cortex is involved in regulating responses to emotional stimuli, as evidenced in prior work by the increased activation of these areas during reappraisal of pain,35, 69, 70 and during placebo analgesia.71 fMRI studies have demonstrated altered prefrontal activation in ill and recovered AN participants. Wagner et al. (2007) found that REC individuals with AN compared with healthy controls showed increased dlPFC activation to a monetary choice task.39 Zastrow et al. (2009)72 reported that ill AN participants showed enhanced responses in dorsal cognitive circuitry during performance of a set-shifting paradigm, suggesting that altered prefrontal activation may be independent of state. Uher et al. (2003) found increased prefrontal activity to food images in participants REC AN compared with currently ill AN patients and to healthy controls.73 Thus, these findings suggest that REC individuals with AN show increased motivation to control stimuli that are perceived as (or expected to be) aversive. Taken together, heightened rAI and dlPFC activation during pain anticipation, potentially due to higher distress of the upcoming pain in REC AN may result in the increased attempts to modulate both anticipatory stress and sensory pain experience in these women. This model is consistent with heightened dlPFC activation and reduced insula activation during pain stimulation. The interpretation that REC AN women may be attempting to control their brain responses to pain in an attempt to achieve a specific subjective experience is consistent with clinical observations of individuals with AN who tend to be overcontrolled and inhibited—behaviors that persist after recovery.74 Our exploratory post hoc correlations are consistent with this notion (see Supporting Information). Interestingly, we observed decreased activation in medial prefrontal cortex and posterior cingulate during pain anticipation in REC AN when compared with CW. These regions correspond closely to the default network, which is often deactivated during cognitively demanding tasks.75 This seems to further support the idea that the REC AN participants were particularly engaged during pain anticipation.
We found that subjective experiences associated with pain anticipation and perception were similar in the REC AN and CW groups. Although we did not measure heat pain thresholds in this study, testing before scanning showed no between group differences in subjective ratings of nonpainful and painful stimuli, thus temperatures used were identical in both groups. There is a substantial, but inconsistent literature, regarding responses to experimental pain in participants with eating disorders. When compared with healthy control participants, individuals currently ill with either AN or bulimia nervosa show decreased thermal pain sensitivity,23–26, 28, 76 and either decreased27 or no change in mechanical pain sensitivity.24, 28 Limited data are available regarding whether abnormal experimental pain perception persists after recovery from AN. One earlier study measured heat pain thresholds in recovered anorexic inpatients and found similar thresholds to those in healthy female controls.77 Another study measured heat pain thresholds in individuals with AN before and immediately after weight gain, then again 6 months after weight restoration and found that thresholds increased 6 months after weight restoration but not upon immediate weight gain.25 Consistent with these two studies, the REC AN women in our study did not show reduced subjective pain perception, as evidenced by equally intense thermal stimuli being rated similarly by both groups. Our data therefore suggest that although subjective experiences during stimulation and anticipation were similar in REC AN and CW, functional activation of neurocircuitry involved in pain perception and anticipation was altered in women REC AN.
This study had several important limitations. First, the sample size of the current study was modest, and therefore, the results require replication. Furthermore, we cannot exclude the possibility that the observed results were partially related to the presence of prior comorbid psychiatric conditions, which were present in most of the REC AN sample in this study. In addition, we did not conduct comprehensive assessment of thermal sensitivity in our participants. Even though we observed no between group differences during brief pretesting of nonpainful and painful stimuli, and the temperatures used during scanning were rated comparably by both groups (Fig. 2), we have no information about pain thresholds in our participants. Finally, we cannot infer from this cross-sectional study whether pain sensitivity changed after recovery or whether the observed alterations in functional brain activity observed in REC individuals with AN represent pre-existing vulnerability factors or residual symptoms of AN. Future longitudinal studies should explore how changes in pain sensitivity and/or emotional awareness relate to one's capacity to recover from anorexia nervosa. Despite these limitations, the current findings may contribute to the neurobiological understanding of AN, and have important implications for the development of new treatments that modify individuals' ability to modify and modulate their interoceptive state.