In data from 2 separate fear conditioning experiments, the magnitude of individual's acquired fear responses was correlated with cortical thickness of a region within the posterior insula/temporal operculum, suggesting a role for this region in the expression of conditioned fear. The insula is thought to be critically involved in the representation of aversive experience. The posterior insula receives afferent viscerosensory information about the physiological state of the body via the posterior portion of the ventral medial nucleus of the thalamus (Craig 2002
). This includes nocioceptive information about painful somatic sensations. Consistent with this anatomical connectivity, single-unit recording in monkeys has found neurons within the posterior insula that are responsive to painful stimulation (Robinson and Burton 1980
). Furthermore, microstimulation of regions within the human posterior insula in epileptic patients elicited reports of painful sensation (Ostrowsky et al. 2002
). Thus, evidence across species supports the interpretation that the posterior insula is involved in the representation of pain. The posterior insula, in turn, has reciprocal connections with the amygdala (Reynolds and Zahm 2005
) and is thus well positioned to convey somatosensory information about an aversive US to the amygdala during fear conditioning. Lesion studies in rodents suggest that the posterior insula is part of 1 of 2 parallel pathways responsible for relaying information about the US to the amygdala during conditioning (Shi and Davis 1999
Numerous neuroimaging studies in humans have observed increases in blood oxygen level–dependent (BOLD) activation in the posterior insula in response to painful stimulation (see Peyron et al. 2000
review). Interestingly, many of these studies report increases in insula activation not only in response to the experience of aversive stimulation but also to the anticipation of imminent aversive physical sensation as well. While such anticipatory responses are typically associated with BOLD increases in the anterior insula (Ploghaus et al. 1999
; Jensen et al. 2003
; Wager et al. 2004
), several studies have reported increased posterior insula activation during the anticipation of aversive physical or visual stimuli (Dalton et al. 2005
; Berns et al. 2006
; Simmons et al. 2006
). Models for the formation of associations between stimuli and future salient outcomes have proposed that the prediction of future events involves evaluating a representation of an anticipated outcome against an actual outcome to update expectancies (Rescorla and Wagner 1972
; Schultz et al. 1997
). Research suggests that the insular cortex may be involved in the encoding of anticipatory signals that play a role in aversive learning (Ploghaus et al. 1999
). Based on the observations that the insula is highly responsive to anticipated aversive events and that anxious individuals appear to exhibit altered function in insular cortex, Paulus and Stein (2006)
recently proposed that anxiety-prone individuals may invoke exaggerated representations of predicted aversive events. Our finding that increased fear reactivity in normal healthy subjects was correlated with cortical thickness in insular cortex is consistent with this proposal that differential processing in this region may underlie individual differences in responses to anticipated aversive events.
In addition to its role in representing experienced or anticipated aversive stimulation, the insula is also involved in modulating sympathetic nervous system arousal, including blood pressure, heart rate, and electrodermal activity, via descending projections to autonomic nuclei (Oppenheimer et al. 1992
; Critchley 2002
). Previous studies have observed a positive correlation between BOLD activation in the insula and SCRs while participants are under the threat of shock (Phelps et al. 2001
), as well as in a nonfear-related task (Critchley et al. 2000
). This dual role of the insula suggests a potential mechanism by which anticipatory signals during fear learning may be associated with conditioned arousal.
In conflict with a recent finding that cortical thickness of the dACC correlated with SCR during fear acquisition (Milad et al. 2007
), we did not find any region of the dACC in which thickness correlated with our acquisition measures. One difference between the conditioning paradigm used in the study of Milad et al. and ours was their use of a 100% reinforcement schedule for the US, while both of our experiments used partial reinforcement. A recent study exploring differences in BOLD activation during fear conditioning as a function of reinforcement rate reported that the dACC activation to a CS increases linearly with reinforcement rate, while the insula is maximally responsive to partial reinforced cues (Dunsmoor et al. 2007
). This is consistent with several studies investigating anticipatory activity to certain or uncertain predictors of reinforcement that report greater insula activity to cues indicating increased uncertainty (Huettel et al. 2005
; Brown et al. 2007
; Sarinopoulos et al. 2010
). A recent proposal based on a computational model of fear conditioning is that the dACC computes a prediction of the UCS, while insula activity is better approximated by an attention-modulated representation of the CS, which incorporates factors such as uncertainty (Dunsmoor and Schmajuk 2009
). While the precise computational roles of the regions involved in fear learning have yet to be clarified, there is strong evidence that the neural structures recruited during fear learning may vary depending on the degree of uncertainty about the relationship between the CS and UCS.
Amygdala volume across subjects was not significantly correlated with our fear acquisition measure. However, the observed correlations suggest a trend toward a negative relationship between amygdala volume and the magnitude of subjects' conditioned fear responses. The amygdala is a heterogeneous structure composed of multiple nuclei that are differentially implicated in the acquisition, storage, and expression of conditioned fear (for reviews, see LeDoux 2000
; Maren 2001
; Phelps and LeDoux 2005
). While numerous studies have reported a significant difference in amygdala volumes in individuals with various psychiatric conditions versus normal controls (Szeszko et al. 1999
; Zetzsche et al. 2006
; Rosso et al. 2007
), few have explored the relationship between amygdala volume and differences in affective responding in healthy individuals. A recent study found that strains of mice with smaller basolateral amygdala nucleus (BLA) volume exhibited stronger fear responses to conditioned stimuli when compared with larger BLA groups (Yang et al. 2008
). Furthermore, this variation in BLA volume was unrelated to the display of anxiety or depression-like behavior in individual animals. This is consistent with recent evidence of increased stressor-evoked physiological reactivity in healthy human subjects with reduced amygdala volume (Gianaros et al. 2008
). Although our present data do not provide clear evidence of an inverse relationship between total amygdala volume and subjects' CR during acquisition, future research might examine directly whether variation in BLA volume is more closely related to such individual differences in fear acquisition.
Replicating a previous finding by Milad et al. (2005)
, we observed a positive correlation between cortical thickness in a region of vmPFC and our extinction retention measure. Converging lines of research across species suggest that the vmPFC plays a critical role in the retrieval of extinction learning after consolidation (see Sotres-Bayon et al. 2006
; Quirk and Mueller 2008
for a review). Lesion studies have implicated the infralimbic region of the rodent medial prefrontal cortex as a key region involved in the retention of extinction learning (Morgan and LeDoux 1995
; Milad and Quirk 2002
). In these studies, lesioned animals showed failure to recall extinction memory after a delay. Electrophysiological evidence suggests that the infralimbic region may play a role in inhibiting fear expression during extinction recall. Single-unit recordings from the infralimbic region revealed an inverse correlation between neuronal activity and the expression of conditioned fear, and microstimulation within this same region reduced conditioned freezing in rats that had not undergone extinction learning (Milad and Quirk 2002
). Although direct homology across species is difficult to infer, the subgenual anterior cingulate cortex and medial orbitofrontal cortex have been proposed to be potential human homologues of the rodent infralimbic region (Ongur and Price 2000
). Thus, consistent with the finding that increased activity in the rodent infralimbic region modulates the reduction in fear expression, the fMRI study in humans from which the data in this study were obtained found that increased BOLD signal in the subgenual cingulate region of the vmPFC correlated with the reduction of fear expression during extinction recall (Phelps et al. 2004
; see also Knight et al. 2004
). Our replication of the finding that cortical thickness in a region of vmPFC correlates positively with the retention of extinction learning suggests that individual differences in fear inhibition via extinction retrieval may have a structural basis. Thickness in this cortical region may be tied to one's vulnerability to or resilience against fear-related disorders. Evidence of structural and functional abnormalities in the vmPFC region of PTSD individuals supports this notion (see Rauch et al. 2006
Our analysis did not reveal a relationship between cortical thickness in our prefrontal regions of interest and the reduction of fear via cognitive regulation strategies. This suggests that individual differences in the ability to inhibit conditioned fear using intentional strategies may not have a structural basis or that the present methods used were not sufficient to reveal such a relationship. This may reflect a substantive difference between automatic and controlled processes. Fear expression during acquisition and fear inhibition during extinction retrieval are relatively automatic processes that may be critically influenced by their structural substrates. However, it seems plausible that any executive control processes recruited during the intentional cognitive regulation task may not be specific to affective control and thus might not have a structural basis that is correlated with our physiological arousal measure. Additionally, individual subjects may be using distinct cognitive processes during intentional cognitive regulation, due to the fundamentally subjective nature of the mental imagery task involved in the strategy.
An important finding revealed in this individual differences analysis of fear acquisition and inhibition was that the physiological measures indexing fear reactivity and regulation were uncorrelated within subjects. Individuals displaying larger acquired fear responses were able to reduce these fear responses via extinction learning or intentional cognitive regulation. Correspondingly, we identified distinct regions in the brain in which cortical thickness was correlated with fear acquisition and fear inhibition via extinction retention. This decoupling suggests that fear reactivity and fear reduction have distinct underlying processes and implies that individuals who are highly reactive to cues indicating potential aversive events can adaptively modulate these responses via implicit extinction learning and intentional cognitive regulation strategies.
The mechanism by which cortical thickness might give rise to functional differences is not presently well understood; however, research on the neuroanatomy of the cortex provides a basis for speculation. Neurons within the cerebral cortex are clustered into columns that are oriented perpendicular to the pial surface (Mountcastle 1997
). The radial unit hypothesis, a prominent theory of cortical development, proposes that neurons within a given column migrate from a common origin and that the thickness of cortex is primarily determined by the number of neurons within the column (Rakic 1995
). These columns may function as modular processing units, involved in the transformation of incoming signals (Mountcastle 1997
). Although the functional properties of cortical columns have been questioned (Horton and Adams 2005
), one possibility is that increased cortical thickness, due to the presence of a greater number of neurons within a column, may influence the strength of the excitatory or inhibitory output signals from the region.
An understanding of how the brain generates and regulates emotional expression is of fundamental interest. Emotion regulation is critical for the adaptive behavior of social animals, such as humans. Basic research into how fears are acquired and diminished has important implications for the potential treatment of fear and anxiety related disorders, as well as for the understanding of the normal variation in emotional behavior. Much of the research on the acquisition and reduction of conditioned fear has focused on investigating factors that determine the mean behavior within a group. Though this approach has yielded valuable knowledge about the neural mechanisms underlying classical conditioning, it does not address the considerable variability in emotional expression across individuals. The relationship reported here between cortical thickness measurements and physiological measures of fear acquisition and extinction suggests that brain structure may be an important factor mediating individual differences in affective reactivity and control.