The predictable and 'annoying' shock (the unconditioned stimuli (US)) elicited activation in several brain regions associated with pain processing [6
], suggesting that stimuli may not need to be perceived as overtly painful to activate the so called 'pain matrix'. Subjects with PTSD had significantly higher BOLD reactivity in the putamen, middle frontal gyrus and parahippocampal gyrus compared with the TENC subjects. The ROI analysis further revealed the amygdala, hippocampus, dorsal ACC, insula and caudate nucleus to be hyperactive in the PTSD US response. These findings are consistent with previous studies indicating higher putamen and insula reactivity to heat pain in PTSD [11
], and increased caudate signaling to heat pain after traumatic memory induction [23
]. Subjects with PTSD displayed hyperactivation of the amygdala and dorsal ACC to the US, findings that are consistent with several previous studies suggesting amygdala and cingulate involvement in processing aversive stimuli [5
] and hyperactivation in PTSD [30
]. Thus, a highly annoying but not overtly painful electrical shock can be used to replicate previous studies indicating alterations in PTSD pain processing. The benefits of using experimental stimuli that are not overtly painful are obvious.
The CS+ led to comparable increases in skin conductance in both the PTSD and the TENC group, suggesting no differences in the fear induced by the conditioned cues. Moreover, there were no differences in the neural response to the CS+, replicating behavioral studies that suggested intact fear learning in PTSD [31
], but other studies have disagreed [36
]. Autonomic responses to the US were of comparable magnitude in PTSD and TENC subjects, as has been previously reported [34
Subjects with PTSD displayed increased putamen reactivity to the US, an effect that was not observed after the omitted US. Moreover, the putamen hyperactivation to the US in the PTSD group remained significant when controlling for responses to the omitted US, (PTSD (US vs. omitted US) vs. TENC (US vs. omitted US); Table ). We therefore interpret the putamen reactivity as driven mostly by sensation rather than alterations in anticipation of the aversive stimulus or a signal of error prediction. It has been shown that learning of the CS-US relationship allows healthy people to engage in endogenous pain inhibition [39
]. When endogenous opioid neurotransmission is blocked with naloxone in healthy subjects, a moderately painful US leads to increased putamen and insular responses [42
], similar to the present findings. There is evidence that people with PTSD have an altered opioidergic system [43
], and the findings in the present study seem to support this.
With regard to the functional connectivity results, two major effects were seen when comparing connectivity at the omitted US and the delivered US: TENC subjects (compared with subjects with PTSD), displayed a larger increase in putamen to temporal lobe/amygdala connectivity at the delivered US compared with the omitted US. Moreover, TENC subjects (compared with subjects with PTSD) displayed an increase in parahippocampal gyrus connectivity to the inferior parietal lobule, the precentral gyrus and the medial frontal gyrus (Figure ). We speculate that the PPI results may be indicative of an altered network processing of aversive stimuli PTSD, but further studies are needed to elucidate how the observed network connectivity changes might relate to the emotional and functional response to aversive stimuli in PTSD.
Higher right anterior insula US reactivity was correlated with higher PTSD symptom severity on the CAPS. This result is consistent with findings of Mickleborough and colleagues [23
], who reported a positive correlation between CAPS scores and insula signaling during heat pain after traumatic memory activation. Dickie and colleagues [46
] reported a positive CAPS-insula correlation with remembered fearful faces. Felmingham and colleagues [47
] reported a positive correlation between CAPS and insula activation to masked fear faces. Thus, this relationship seems to be consistent whether the stimuli are perceived as painful, highly annoying but not painful, encoded as aversive, or subliminally aversive. However, Strigo and colleagues [12
] found the rostral anterior insula reactivity to painful stimulation to be negatively correlated to CAPS avoidance scores. One possible explanation for this discrepancy is that in the Strigo experiment, pain stimulation was delivered without a predictive cue, whereas the study of Mickleborough and the present study entailed a predictive cue.
The putamen is best known as a motor output region [48
], but both nociception [49
] and emotion [51
] are processed in the putamen and the adjacent nucleus accumbens [52
]. Moreover, the putamen is structurally and functionally connected to the medial orbitofrontal cortex and the amygdala [54
], two regions implicated in PTSD. The observed increased putamen activation in PTSD corresponds to regions known to receive projections from the dorsal anterior cingulate and orbital cortex [55
]. Altered basal ganglia function has previously been reported in PTSD for other paradigms: putamen blood flow and reactivity after script-driven imagery in PTSD has been correlated to aspects of flashback intensity and dissociative states [23
], caudate and putamen volume are decreased in people with PTSD with headaches [57
], and people with PTSD display diminished caudate and putamen signal to reward [58
]. Thus, future studies could be aimed at elucidating PTSD alterations in both approach and avoidance behaviors involving corticostriatal circuitry [55
Limitations and alternate interpretations
We have interpreted the neuronal responses and connectivity modulations related to the omitted US as reflecting immediate expectancy ('I am going to get shocked right now'). It could be argued, however, that these results also represent a prediction error and relief signal ('Oh, I guess I did not get shocked'). Our experimental design did not allow us to distinguish between these two responses, thus further studies with higher temporal resolution should be designed and conducted to further examine this point.