Israel Liberzon

Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI.

Neuroimagingstudies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have begun to describe the functional neuroanatomy of emotion. Taken separately, specific studies vary in task dimensions and in type(s) of emotion studied and are limited by statistical power and sensitivity. By examining findings across studies, we sought to determine if common or segregated patterns of activations exist across various emotional tasks. We reviewed 55 PET and fMRI activation studies (yielding 761 individual peaks) which investigated emotion in healthy subjects. Peak activation coordinates were transformed into a standard space and plotted onto canonical 3-D brain renderings. We divided the brain into 20 nonoverlapping regions, and characterized each region by its responsiveness across individual emotions (positive, negative, happiness, fear, anger, sadness, disgust), to different induction methods (visual, auditory, recall/imagery), and in emotional tasks with and without cognitive demand. Our review yielded the following summary observations: (1) The medial prefrontal cortex had a general role in emotional processing; (2) fear specifically engaged the amygdala; (3) sadness was associated with activity in the subcallosal cingulate; (4) emotional induction by visual stimuli activated the occipital cortex and the amygdala; (5) induction by emotional recall/imagery recruited the anterior cingulate and insula; (6) emotional tasks with cognitive demand also involved the anterior cingulate and insula. This review provides a critical comparison of findings across individual studies and suggests that separate brain regions are involved in different aspects of emotion.

The Neurocircuitry of Fear, Stress, and Anxiety Disorders

Anxiety disorders are a significant problem in the community, and recent neuroimaging research has focused on determining the brain circuits that underlie them. Research on the neurocircuitry of anxiety disorders has its roots in the study of fear circuits in animal models and the study of brain responses to emotional stimuli in healthy humans. We review this research, as well as neuroimaging studies of anxiety disorders. In general, these studies have reported relatively heightened amygdala activation in response to disorder-relevant stimuli in post-traumatic stress disorder, social phobia, and specific phobia. Activation in the insular cortex appears to be heightened in many of the anxiety disorders. Unlike other anxiety disorders, post-traumatic stress disorder is associated with diminished responsivity in the rostral anterior cingulate cortex and adjacent ventral medial prefrontal cortex. Additional research will be needed to (1) clarify the exact role of each component of the fear circuitry in the anxiety disorders, (2) determine whether functional abnormalities identified in the anxiety disorders represent acquired signs of the disorders or vulnerability factors that increase the risk of developing them, (3) link the findings of functional neuroimaging studies with those of neurochemistry studies, and (4) use functional neuroimaging to predict treatment response and assess treatment-related changes in brain function.

Valence, gender, and lateralization of functional brain anatomy in emotion: a meta-analysis of findings from neuroimaging

We performed quantitative meta-analyses on 65 neuroimaging studies of emotion. In an earlier report (NeuroImage 16 (2002), 331). we examined the effects of induction method, specific emotions, and cognitive demand in emotional tasks. This paper focuses on the effects of emotional valence (positive vs negative and approach vs withdrawal) and gender on regional brain activations, with particular emphasis on hypotheses concerning lateralization of brain function in emotion. Overall, we found no support for the hypothesis of overall right-lateralization of emotional function, and limited support for valence-specific lateralization of emotional activity in frontal cortex. In addition, we found that males showed more lateralization of emotional activity, and females showed more brainstem activation in affective paradigms. The study provides evidence that lateralization of emotional activity is more complex and region-specific than predicted by previous theories of emotion and the brain.

The contextual brain: implications for fear conditioning, extinction and psychopathology

Contexts surround and imbue meaning to events; they are essential for recollecting the past, interpreting the present and anticipating the future. Indeed, the brains capacity to contextualize information permits enormous cognitive and behavioural flexibility. Studies of Pavlovian fear conditioning and extinction in rodents and humans suggest that a neural circuit including the hippocampus, amygdala and medial prefrontal cortex is involved in the learning and memory processes that enable context-dependent behaviour. Dysfunction in this network may be involved in several forms of psychopathology, including post-traumatic stress disorder, schizophrenia and substance abuse disorders.

Nonstationary cluster-size inference with random field and permutation methods

Because of their increased sensitivity to spatially extended signals, cluster-size tests are widely used to detect changes and activations in brain images. However, when images are nonstationary, the cluster-size distribution varies depending on local smoothness. Clusters tend to be large in smooth regions, resulting in increased false positives, while in rough regions, clusters tend to be small, resulting in decreased sensitivity. Worsley et al. proposed a random field theory (RFT) method that adjusts cluster sizes according to local roughness of images [Worsley, K.J., 2002. Nonstationary FWHM and its effect on statistical inference of fMRI data. Presented at the 8th International Conference on Functional Mapping of the Human Brain, June 2-6, 2002, Sendai, Japan. Available on CD-ROM in NeuroImage 16 (2) 779-780; Hum. Brain Mapp. 8 (1999) 98]. In this paper, we implement this method in a permutation test framework, which requires very few assumptions, is known to be exact [J. Cereb. Blood Flow Metab. 16 (1996) 7] and is robust [NeuroImage 20 (2003) 2343]. We compared our method to stationary permutation, stationary RFT, and nonstationary RFT methods. Using simulated data, we found that our permutation test performs well under any setting examined, whereas the nonstationary RFT test performs well only for smooth images under high df. We also found that the stationary RFT test becomes anticonservative under nonstationarity, while both nonstationary RFT and permutation tests remain valid under nonstationarity. On a real PET data set we found that, though the nonstationary tests have reduced sensitivity due to smoothness estimation variability, these tests have better sensitivity for clusters in rough regions compared to stationary cluster-size tests. We include a detailed and consolidated description of Worsley nonstationary RFT cluster-size test.

Biological studies of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular and molecular levels. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.

Neural correlates of individual ratings of emotional salience: A trial-related fMRI study

Accurate appraisal of meaningful environmental signals involves the interpretation of salient information for their intrinsic emotional value and personal relevance. We examined the neural basis for these components of endogenous salience during such appraisals using trial-related functional magnetic resonance imaging (fMRI). Subjects viewed affective pictures and assessed either the emotional intensity or extent of self-relatedness of the content of those pictures. In a parametric factorial design, individualized subjective ratings of these two dimensions were correlated with brain activity. The nucleus accumbens (NAcc) responded to both increasing emotional intensity and self-relatedness. Activity in the amygdala was specifically related to affective judgments and emotional intensity. The volitional act of appraising the extent of personal association specifically engaged the ventral medial prefrontal cortex (MPFC), and additionally recruited dorsal medial frontal regions and insula as the extent of self-relatedness increased. The findings highlight both overlapping and segregated neural representations of intrinsic value and personal relevance during the appraisal of emotional stimuli.

Functional neuroimaging studies of human emotions.

Neuroimaging studies with positron emission tomography and functional magnetic resonance imaging have begun to describe the functional neuroanatomy of human emotion. Taken separately, specific studies vary in task dimensions and in type(s) of emotion studied, and are limited by statistical power and sensitivity. By examining findings across studies in a meta-analysis, we sought to determine if common or segregated patterns of activations exist in different emotions and across various emotional tasks. We surveyed over 55 positron emission tomography and functional magnetic resonance imaging activation studies, which investigated emotion in healthy subjects. This paper will review observations in several regions of interest in limbic (eg, amygdala, anterior cingulate cortex) and paralimbic (eg, medial prefrontal cortex, insula) brain regions in emotional responding.

Subjective rating of emotionally salient stimuli modulates neural activity.

Studies using emotionally salient stimuli have demonstrated neural activation in limbic and paralimbic brain regions. In some studies, subjects passively perceive evocative stimuli, while in other studies, they perform specific cognitive tasks. Evidence is emerging that even a simple cognitive task performed on emotionally salient stimuli can affect neural activation in emotion-associated brain regions. We tested the hypothesis that rating the subjective experience of an aversive visual stimulus would decrease limbic/paralimbic activation and increase activity in medial frontal regions. Ten healthy subjects underwent (15)O PET scans while they viewed pictures of aversive (AV) and nonaversive (NA) content, taken from the International Affective Picture System. Subjects appraised pictures on a scale of pleasantness/unpleasantness during one set of scans (RTNG), and they passively viewed pictures during another set (PSVW). After each scan, emotional responses were assessed. RTNG was associated with significantly less intensity of sadness and significantly less activation (AV - NA) of the right insula/amygdala and left insula, relative to PSVW. RTNG also activated the dorsal medial prefrontal cortex and the anterior cingulate sulcus, which were not differentially activated during PSVW. For both RTNG and PSVW, subjects activated the left fusiform gyrus. The results support the proposition that task instructions about how subjects should process evocative stimuli can affect neural activity.

Stress-restress: Effects on ACTH and fast feedback

Glucocorticoid secretion is tightly regulated by negative feedback. Glucocorticoid feedback has been found to be altered in depression and post-traumatic stress disorder (PTSD). While hyposensitive glucocorticoid feedback has been found in depression, hypersensitive or enhanced negative feedback was described in PTSD. Enhanced negative feedback, can be seen as a sensitization of the inhibitory elements of HPA axis, and stress-restress or time dependent sensitization (TDS) model, has been suggested as an animal model for PTSD. We have studied the effects of this model on the HPA axis to determine whether it will produce increased sensitivity to negative feedback as found in PTSD patients. Adult Sprague-Dawley male rats were exposed to a single session of prolonged stress (restraint followed by a forced swim and exposure to ether vapors) and briefly restressed 7 days later. The effects of single prolonged stress on plasma ACTH and corticosterone responses (0, 5, and 30 min) and on glucocorticoid fast feedback (cortisol vs. saline pretreatment) were assessed in two studies. Animals exposed to single prolonged stress showed enhanced negative feedback in comparison to naive animals (F = 4.6371, df = 3, p = .0107), but there was no difference in ACTH or corticosterone responses during the restress. Pretreatment with cortisol, in the first stress session, did not prevent the development of the enhanced fast feedback when restressed. This can be seen as a sensitization of the inhibitory elements of HPA axis, suggesting that stress-restress paradigm might serve as a good animal model for HPA abnormalities found in PTSD patients.