Pathways for fear perception: modulation of amygdala activity by thalamo-cortical systems
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
References (46)
Neural systems for recognizing emotion
Curr. Opin. Neurobiol.
(2002)- et al.
Cognitive and emotional influences in anterior cingulate cortex
Trends Cogn. Sci.
(2000) - et al.
Psychophysiological and modulatory interactions in neuroimaging
NeuroImage
(1997) - et al.
Modeling regional and psychophysiologic interactions in fMRI: the importance of hemodynamic deconvolution
NeuroImage
(2003) - et al.
A method for obtaining 3-dimensional facial expressions and its standardization for use in neurocognitive studies
J. Neurosci. Methods
(2002) - et al.
Brain activation during facial emotion processing
NeuroImage
(2002) - et al.
Neocortical modulation of the amygdala response to fearful stimuli
Biol. Psychiatry
(2003) - et al.
An fMRI study investigating cognitive modulation of brain regions associated with emotional processing of visual stimuli
Neuropsychologia
(2003) - et al.
Activation of the amygdala and anterior cingulate during nonconscious processing of sad versus happy faces
NeuroImage
(2004) - et al.
A direct brainstem–amygdala–cortical ‘alarm’ system for subliminal signals of fear
NeuroImage
(2005)
An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets
NeuroImage
Functional association of the amygdala and ventral prefrontal cortex during cognitive evaluation of facial expressions primed by masked angry faces: an event-related fMRI study
NeuroImage
Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI
NeuroImage
Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study
Biol. Psychiatry
The pulvinar and visual salience
Trends Neurosci.
Subjective rating of emotionally salient stimuli modulates neural activity
NeuroImage
Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain
NeuroImage
Arousal dissociates amygdala and hippocampal fear responses: evidence from simultaneous fMRI and skin conductance recording
NeuroImage
The human amygdala and the emotional evaluation of sensory stimuli
Brain Res. Brain Res. Rev.
Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala
Nature
The amygdala: neurobiological aspects of emotion, memory and mental dysfunction
Facial emotion recognition after bilateral amygdala damage: differentially severe impairment of fear
Cognitive Neuropsychology
Descartes' error: emotion, reason and the human brain
Cited by (142)
Clinical and neuroimaging correlates in a pilot randomized trial of aerobic exercise for major depression
2024, Journal of Affective DisordersSubcortical volume analysis in non-suicidal self-injury adolescents: A pilot study
2023, Psychiatry Research - NeuroimagingNetworks underpinning emotion: A systematic review and synthesis of functional and effective connectivity
2021, NeuroImageCitation Excerpt :MNI coordinates and Brodmann areas for these regions have also been added to Table 1. Twenty seven studies employed tasks that required participants to implicitly or explicitly process the emotional valence of stimuli (Blasi et al., 2009; Breakspear et al., 2015; da Silva et al., 2010; Das et al., 2005; de Marco et al., 2006; Dima et al., 2011, 2015; Fairhall and Ishai, 2006; Fasternath et al., 2014; Furl et al., 2013; Goulden et al., 2012; Hakamata et al., 2016; Hrybouski et al., 2016; Jabbi and Keysers, 2008; Mazzola et al., 2016; Miyahara et al., 2013; Park et al., 2016; Raz et al., 2016; Satterthwaite et al., 2011; Schienle and Scharmuller, 2013; Sladky et al., 2015; Tak et al., 2021; Torrisi et al., 2013; Tschacher et al., 2010; Vai et al., 2015; Williams et al., 2006; Willinger et al., 2019). Twenty of these studies used faces to investigate emotion processing (Blasi et al., 2009; Breakspear et al., 2015; da Silva et al., 2010; Das et al., 2005; de Marco et al., 2006; Dima et al., 2015, 2011; Fairhall and Ishai, 2006; Furl et al., 2013; Goulden et al., 2012; Hakamata et al., 2016; Jabbi and Keysers, 2008; Mazzola et al., 2016; Miyahara et al., 2013; Park et al., 2016; Satterthwaite et al., 2011; Sladky et al., 2015; Torrisi et al., 2013; Vai et al., 2015; Williams et al., 2006).
Neural substrates of human fear generalization: A 7T-fMRI investigation
2021, NeuroImageCitation Excerpt :Analysis of the initial conditioning run revealed a diffuse network of regions – including the insula, inferior parietal lobule, and somatosensory cortices - that exhibited greater activation for the threat versus safety cue; however, when novel generalization stimuli were introduced, only regions within the visual cortex and thalamus exhibited significant generalization, with the BOLD response tracking along the continuum of similarity to the CS+. While many emphasize the amygdala's role in threat detection and arousal (Davis, 1992; LeDoux, 2003), sensory input must first be transmitted to the amygdala along thalamic mediated paths (Das et al., 2005; Shi and Davis, 2001). As such, early perceptual processing plays an important role in fear generalization (Struyf et al., 2015).
Unconscious processing of subliminal stimuli in panic disorder: A systematic review and meta-analysis
2021, Neuroscience and Biobehavioral ReviewsAmygdala connectivity during emotional face perception in psychotic disorders
2021, Schizophrenia Research