Elsevier

NeuroImage

Volume 26, Issue 1, 15 May 2005, Pages 141-148
NeuroImage

Pathways for fear perception: modulation of amygdala activity by thalamo-cortical systems

https://doi.org/10.1016/j.neuroimage.2005.01.049Get rights and content

Abstract

Effective perception of fear signals is crucial for human survival and the importance of the amygdala in this process is well documented. Animal, lesion and neuroimaging studies indicate that incoming sensory signals of fear travel from thalamus to amygdala via two neural pathways: a direct subcortical route and an indirect pathway via the sensory cortex. Other lines of research have demonstrated prefrontal modulation of the amygdala. However, no study to date has examined the prefrontal modulation of the thalamo-cortico-amygdala pathways in vivo. We used psychophysiological and physiophysiological interactions to examine the functional connectivity within thalamus, amygdala and sensory (inferior occipital, fusiform) cortices, and the modulation of these networks by the anterior cingulate cortex (ACC). Functional magnetic resonance imaging (fMRI) data were acquired for 28 healthy control subjects during a fear perception task, with neutral as the ‘baseline’ control condition. Main effect analysis, using a region of interest (ROI) approach, confirmed that these regions are part of a distributed neural system for fear perception. Psychophysiological interactions revealed an inverse functional connectivity between occipito-temporal visual regions and the left amygdala, but a positive connectivity between these visual region and the right amygdala, suggesting that there is a hemispheric specialization in the transfer of fear signals from sensory cortices to amygdala. Physiophysiological interactions revealed a dorsal–ventral division in ACC modulation of the thalamus–sensory cortex pathway. While the dorsal ACC showed a positive modulation of this pathway, the ventral ACC exhibited an inverse relationship. In addition, both the dorsal and ventral ACC showed an inverse interaction with the direct thalamus–amygdala pathway. These findings suggest that thalamo-amygdala and cortical regions are involved in a dynamic interplay, with functional differentiation in both lateralized and ventral/dorsal gradients. Breakdowns in these interactions may give rise to affect-related symptoms seen in a range of neuropsychiatric disorders.

Introduction

Perception of biologically relevant sensory stimuli is essential for human survival. The importance of the amygdala in modulating responses to salient stimuli has been established in animal and lesion studies (Adolphs et al., 1994, Calder et al., 1996, Davis and Whalen, 2001, LeDoux, 1998, Zald, 2003). In the intact healthy brain, neuroimaging studies have shown that the amygdala is reliably engaged by facial signals of fear (Gur et al., 2002b, Hariri et al., 2000, Morris et al., 1996, Phillips et al., 1998, Williams et al., 2001). Yet, it is becoming increasingly clear that the amygdala is a key component of a distributed neural system for effective perception and regulation of fear, which operates in an interactive synchrony (Davidson et al., 2000, Hariri et al., 2000, Hariri et al., 2003, Phan et al., 2002). Abnormalities in any one of these interactive components may produce the fear-related symptoms of psychotic and anxiety disorders such as paranoid psychosis and posttraumatic stress (Rauch et al., 2000, Williams et al., 2004).

Animal fear conditioning, lesion and neuroimaging studies suggest that sensory input reaches the amygdala via two neural pathways (LeDoux, 1998). It has been proposed that the amygdala receives crude sensory input implicitly via a direct extrageniculostriate (superior colliculus and thalamic pulvinar) pathway (de Gelder et al., 1999, Liddell et al., 2005, Morris et al., 1999, Morris et al., 2001). By contrast, explicit processing of fear signals relies on a geniculostriate system, with input relayed from the thalamus to the amygdala following elaboration in the sensory cortices (Adolphs, 2002, LeDoux, 1998). Neuroimaging studies have reported engagement of the direct extrageniculostriate pathway in response to fearful facial expressions in patients with striate cortex lesions (Morris et al., 2001) and in healthy subjects presented with fearful faces below the threshold for conscious detection (Liddell et al., 2005).

Functional neuroimaging studies have identified the fusiform gyrus (Gf) and the inferior occipital gyrus (GOi) as the key regions of the sensory cortex in response to visual emotion stimuli (Adolphs, 2002) and have investigated the functional correlation of the amygdala with these regions during the processing of positive and negative emotional faces or pictures (Keightley et al., 2003, Morris et al., 1998). Morris et al. (1998) have observed a positive covariation of the left amygdala with the Gf and GOi during processing of fearful (relative to happy) faces, indicating an increase in these visual association cortices with increased amygdala response. A similar positive covariation between the left amygdala and the anterior Gf was observed by Keightley et al. (2003), as well as positive connectivity between the right amygdala and GOi, for both direct and indirect processing of emotional faces and pictures.

Other lines of research have focused on the role of the prefrontal cortex (PFC) in emotion processing and regulation. Neuroimaging studies have reported an inverse relationship between activity in the PFC and amygdala, suggesting that the PFC may provide top-down regulation of the amygdala (Hariri et al., 2000, Hariri et al., 2003, Taylor et al., 2003). While several studies have examined the relationship between the amygdala and the sensory (visual) or prefrontal cortex (Hariri et al., 2000, Hariri et al., 2003, Iidaka et al., 2001, Morris et al., 1998), no study to date has examined prefrontal modulation of the functional connectivity within thalamo-amygdala pathways in vivo.

Within the PFC, the anterior cingulate is the region where attentional and emotional functions are integrated and plays a major role in modulating emotional responses (Damasio, 1994, Yamasaki et al., 2002). Moreover, there is evidence to suggest that the ventral portion of the medial prefrontal cortex, encompassing the anterior cingulate, may have a greater sensitivity to the emotional content of sensory input, whereas the dorsal portion may be more involved in cognitive processing (Bush et al., 2000, Drevets and Raichle, 1998, Lane et al., 1997, Yamasaki et al., 2002). In this study, we used functional magnetic resonance imaging to investigate the engagement of the thalamo-amygdala pathways in a fear perception process, and the modulation of these pathways by the ACC. We focused on the change in the interactions among the nodes of the thalamo-amygdala systems (such as thalamus, amygdala, and sensory (visual) cortex) with the experimental manipulation using psychophysiological interaction and the modulation of the response of these nodes due to thalamo–ACC interactions using physiophysiological interaction analyses (Friston et al., 1997). A psychophysiological interaction shows the change in the contribution of one brain region to another, in relation to the experimental manipulation of interest. Physiophysiological interactions explain the variation in activity in one region as a result of an interaction between two other brain regions. The value of these approaches over traditional fMRI averaging techniques is in providing information about the integration of physiological and experimental influences on brain activity. In this way, interaction analyses allow us to identify variations in functional connectivity over and above the discrete regions of activity. In the present study, three separate analyses were conducted. First, we used regions of interest (ROIs) analysis to confirm that the amygdala, thalamus, ACC and visual (Gf and GOi) cortex are part of a distributed neural system involved in the perception of fear face signals. Second, psychophysiological interaction analysis was conducted to determine changes in the neural connectivity of the amygdala with other ROIs, in response to fear relative to neutral. In a third set of analyses, physiophysiological interaction modeling was applied to investigate the modulatory effect of the ACC on the thalamo-amygdala pathways.

We predicted that fear (relative to neutral) faces would elicit significantly increased activity in each ROI. On the basis of previous neuroimaging evidence (Hariri et al., 2000, Hariri et al., 2003, Iidaka et al., 2001, Morris et al., 1998), we expected that psychophysiological interaction analysis would reveal a positive covariation between the amygdala and the visual (Gf/GOi) cortex during perception of fearful faces. By contrast, we predicted a negative covariation between the amygdala and ACC, reflected in reduced amygdala responses with greater ACC activity. Given that our task required conscious attention, we also expected that the ACC would positively modulate the thalamus–visual association cortex–amygdala pathway but negatively modulate the direct thalamus–amygdala pathway.

Section snippets

Subjects

Twenty-eight predominantly right handed healthy subjects (14 males, 14 females, M = 30.1 years, SD = 10.0) participated in the study (with support from the International Brain Database, http://www.brainresource.com). Exclusion criteria were substance abuse, epilepsy, head injury or other neurological disorders, and previous history of Axis I or genetic disorder (themselves or first-degree relative). Written consent was obtained from all subjects prior to testing in accordance with National

Region of interest analyses

Consistent with our prediction, significantly greater activity was observed in the thalamus, amygdala, ACC, Gf and GOi during fear relative to neutral condition at P < 0.05, small volume corrected. All of these regions showed bilateral activation. While GOi showed uniform bilateral activation Gf activation was predominantly located within the left hemisphere. The activated cluster in the thalamus extended from the left to the right hemisphere. Significant clusters of activity in response to

Discussion

To date, prefrontal modulation of the thalamo-cortico-amygdala pathways engaged during human fear processing has not been examined using neuroimaging. In this study we used psychophysiological and physiophysiological interactions to examine the functional connectivity within thalamo-visual cortex and amygdala networks for fear perception, and their modulation by the medial frontal cortex (defined as anterior cingulate cortex; ACC). The traditional averaged contrast (fear versus neutral)

Acknowledgments

PD was supported by NISAD, utilizing infrastructure funding from NSW Health. LW was supported by a Pharmacia Foundation fellowship and ARC funding (DP0345481), and is an affiliated scientist of NISAD. Analysis infrastructure was supported by University of Sydney SESQUI equipment funding. The authors would like to acknowledge the brain resource international database (BRID, under the auspices of the Brain Resource Co., http://www.brainresource.com) for support and collaboration in data

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