This experiment yielded several findings. First, in both ROI and whole brain analyses, both groups activated bilateral anterior insula during anticipation of negative compared to positive stimuli. Second, IPV-PTSD relative to NTC subjects showed greater activation in right anterior/middle insula during anticipation of negative compared to positive stimuli. Third, functional connectivity between activation in bilateral anterior insula and bilateral amygdala, and between right anterior/middle insula and bilateral amygdala were significantly weaker in IPV-PTSD relative to NTC individuals. We also observed within IPV-PTSD subjects had a significant positive correlation between IES-R Hyperarousal scores and activity in left anterior insula. Taken together, these results support the notion that in women with IPV-related PTSD: (1) the anterior and anterior/middle insula are important in cued anticipation of negative stimuli, (2) subregions of the insula, such as the anterior/middle insula, are hyperactivate during negative anticipation, and (3) anterior/middle insula activity may be most strongly related to symptoms of hyperarousal in IPV-related PTSD.
The insula, a part of the extended limbic system, can be subdivided into anterior agranular (Ia), central/middle dysgranular (Id) and posterior granular (Ig) subregions based on function and cytoarchitectural structure (48
). Anterior and middle insula have reciprocal connections with ventral frontal brain regions such as the anterior cingulate and orbital frontal gyrus, as well as with the amygdala, and surrounding, areas, regions that comprise a critical emotion processing circuit. Posterior insula also has reciprocal connections with the frontal cortex, as well as the temporopolar cortex and secondary somatosensory area (61
). Some investigators have suggested that the anterior aspect of the insula (including Ia and part of Id) is more closely linked to the executive control system, which includes the anterior cingulate and the dorsolateral prefrontal cortex, whereas the posterior insula (Ig and caudal aspect of Id) primarily integrates afferent information from unmyelinated C-fibers to provide a global sense of the physiological condition of the body (42
). Further supporting the notion that the insula is critically involved in emotional and interoceptive processing are studies reporting correlations between insula activation and autonomic arousal (62
), anxiety, and visceral changes associated with facial emotion processing (63
), as well as the evidence that aversive physiological reactions are key in the establishment and maintenance of avoidant behavior in the development of phobias (e.g. agoraphobia) (64
). Neuronal measurements in fear conditioning also show strong involvement of the various aspects of the insular cortex (65
). These processes take place in full, and sometimes painful, awareness, which is consistent with the role of the middle/posterior insula in mediating self-awareness (66
). Lesion studies in both humans and animals also support the notion that the entire insular cortex is important for emotional and interoceptive processing (67
). Additionally, although activation across the entire insula has been frequently associated with disgust (68
), there is increasing evidence of a broader role for this brain structure in emotion processing (69
). Similarly, anterior/middle insula activation is thought to be involved in differential positive versus negative emotion processing (70
), in particular fearful face processing (71
), pain perception (72
), and judgments about emotions (73
These findings are consistent with a recent model which explains the critical involvement of the anterior insula in anxiety states and anxiety disorders (46
), which are characterized by altered emotional and interoceptive processing. Prior studies have shown that phobic individuals relative to non-phobic comparison subjects showed increased anterior/middle insula activation during emotionally evocative paradigms that used both pictures (74
) and words (75
) of spider-related stimuli. In a related study, we reported that anxiety prone individuals relative to healthy controls showed exaggerated insula responses during the anticipation of images of spiders and snakes – which are among the most commonly reported phobic stimuli. This evidence is in line with research showing that social phobic individuals show increased activation to fearful faces in the right anterior/middle insula (76
) and to angry faces in the bilateral anterior/middle insula (77
). These, and related studies in which healthy volunteers processed aversive sensory stimuli (37
), are consistent with the notion that anterior insular activity may not only underlie the affective process of emotional distress in normal and phobic individuals, but may also be involved in action planning, i.e., mediation of anxiety-related avoidant behavior (46
Based on this evidence, we speculate that the increased activation in anterior/middle insula observed in IPV subjects with PTSD, in particular on the left side, may represent a neural substrate linking emotional distress, anticipatory processing, and autonomic arousal, which can advance action planning to reduce exposure to the aversive stimuli. Therefore, the anterior/middle insula activation may be interpreted as a “warning signal” that is associated with the anticipation of aversive symptoms such as hyperarousal. This interpretation is supported by the strong functional connectivity between anterior/middle insula and amygdala observed in the current study, and by the strong correlations between activity in the middle insula and the parietal cortex in a prior study (38
The pathways between the insula and the amygdala have been mapped out in great detail in animal studies. The basomedial and basolateral nuclei of the amygdala, areas that are involved with conditioned fear, show connections to the various regions in the insula (78
), particularly the central dysgranular insula (61
). The anterior/middle insula shows the greatest differentiation between groups in the current study, suggesting differential connectivity with the amygdala. This interpretation is consistent with a prior study by Lanius et. al. (25
), which found differential activation in the dorsal anterior cingulate (dACC) between individuals who had experienced trauma and had developed PTSD versus those who had experienced significant trauma but did not develop PTSD. In this study, connectivity with the dACC differed in these two groups in a mostly lateralized way, with the PTSD subjects showing greater activation in the right side and the non-PTSD subjects showing greater activation in the left side. We found strong connectivity with the dorsal MPFC in the current study but this connectivity strength did not differ significantly between groups. To our knowledge, ours is the first study to identify altered insularamygdala connectivity in PTSD.
There are several mechanisms which may explain the functional connectivity in the current study. Due to the varying directionality of amygdala activation in PTSD fMRI studies (34
) the connectivity with the insula may be highly dependent on the stimulus, task, and population. Therefore, it is not expected that this finding will be generalizable to other situation and should be interpreted with great caution. In the current study, this somewhat paradoxical relationship may imply that insula hyperactivation results in compensatory functional weakening with other brain areas, similar to what has been reported elsewhere (38
). Alternatively, the amygdala may receive input from other regions such as the MPFC (19
), which in turn could attenuate the functional connectivity to interoceptive stimuli provided by the anterior/middle insula cortex. These possibilities need to be further investigated with a greater number of subjects that exhibit different insula activation patterns or show significant differences in MPFC. The prevalence of PTSD in females is much higher than in males, which is related to differences in the rates and types of assault (79
) and that the accumulation of traumas makes females more vulnerable to retraumatization (80
). Structural equation modeling has suggested that the symptom cluster of hyperarousal may relate more to the incidence of retraumatization in females (81
). This may suggest that the anterior/middle insula, and subsequent functional correlation findings, may be more pronounced in this population. Combat-related PTSD has received greater investigation in the literature and appears to have higher rates of PTSD subsequent to trauma and potentially reporting compared to other forms of PTSD (82
). However, there is no research to date on the neural differences between IPV and combat -related PTSD.
This study has several limitations. First, this group was comprised of women who had experienced relatively recent IPV. These findings cannot be presumed to extend to males, to those with more chronic PTSD, or to those with PTSD stemming from exposure to other types of trauma (e.g., combat). Second, we cannot determine whether the current findings reflect pre-existing processing differences in individuals who are more susceptible to developing PTSD (e.g., it should be noted that the IPV-PTSD group has slightly lower education levels, which might reflect subtle group differences in pre-trauma cognitive ability, thought to be a risk factor for PTSD development (83
), or are a consequence of the trauma and the post-trauma alterations. Third, future longitudinal studies with individuals exposed to IPV but failing to develop PTSD – a “resilient” comparison group that was lacking from the current study – would help distinguish neural systems involved in trauma exposure from those associated with PTSD, per se. Fourth, the lack of behavioral differences on the CPT task both within and between groups may indicate that the images have only a modest emotional impact. However, due to concerns about distressing subjects we did not include images we deemed too violent. We expect that we may see behavioral differences if stronger images were utilized. Fifth, we used the time series of the entire task as subjects to inspect connectivity rather than just during a single condition. This was done to maximize the within subject power of the connectivity analysis and to see how these networks behaved across anticipatory conditions, thus we do not assert that the functional relationships in this network are highly state dependant.
Anticipation of impending adverse events is potentially a major aspect of the negative effects of PTSD in IPV and may reflect the relationship between hyperarousal and avoidance. Pathological trauma reactions may be perpetuated via increased involvement of the anterior/middle insular cortex in processing negative anticipation, leading to avoidance of affective processing (which may be experienced as “numbing”), as indicated by decreased connectivity with the bilateral amygdala. Important follow up work should determine the heritability (e.g., through twin studies) of this pattern of connectivity and the degree to which treatment may effect this neuronal behavior in individuals with PTSD.