Although there are many imaging studies on traditional ROI-based amygdala volumetry, there are very few studies on modeling amygdala shape variations. This paper presents a unified computational and statistical framework for modeling amygdala shape variations in a clinical population. The weighted spherical harmonic representation is used to parameterize, smooth out, and normalize amygdala surfaces. The representation is subsequently used as an input for multivariate linear models accounting for nuisance covariates such as age and brain size difference using the SurfStat package that completely avoids the complexity of specifying design matrices. The methodology has been applied for quantifying abnormal local amygdala shape variations in 22 high functioning autistic subjects.
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The prefrontal cortex (PFC) has been well known for its role in higher order cognition, affect regulation and social reasoning. Although the precise underpinnings have not been sufficiently described, increasing evidence also supports a prefrontal involvement in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis. Here we investigate the PFC's role in HPA axis regulation during a psychosocial stress exposure in 14 healthy humans. Regional brain metabolism was assessed using positron emission tomography (PET) and injection of fluoro-18-deoxyglucose (FDG). Depending on the exact location within the PFC, increased glucose metabolic rate was associated with lower or higher salivary cortisol concentration in response to a psychosocial stress condition. Metabolic glucose rate in the rostral medial PFC (mPFC) (Brodman area (BA) 9 and BA 10) was negatively associated with stress-induced salivary cortisol increases. Furthermore, metabolic glucose rate in these regions was inversely coupled with changes in glucose metabolic rate in other areas, known to be involved in HPA axis regulation such as the amygdala/hippocampal region. In contrast, metabolic glucose rate in areas more lateral to the mPFC was positively associated with saliva cortisol. Subjective ratings on task stressfulness, task controllability and self-reported dispositional mood states also showed positive and negative associations with the glucose metabolic rate in prefrontal regions. These findings suggest that in humans, the PFC is activated in response to psychosocial stress and distinct prefrontal metabolic glucose patterns are linked to endocrine stress measures as well as subjective ratings on task stressfulness, controllability as well as dispositional mood states.
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Echo-Planar functional magnetic resonance imaging (EP-fMRI) was used to study the activity of the amygdala while three normal female subjects viewed alternating blocks of affectively neutral and affectively negative still pictures. Bilateral activation in the amygdala that was significantly correlated with the changing valence of the visual stimuli was found in all three subjects. These findings are consistent with the large corpus of data from non-human studies suggesting that the amygdala is a key structure for extracting the affective significance from external stimuli. This is the first known report of phasic amygdala activation detected with EP-fMRI in normal human subjects responding to affective stimuli.
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Neurosurgical treatment of psychiatric disorders has been influenced by evolving neurobiological models of symptom generation. The advent of functional neuroimaging and advances in the neurosciences have revolutionized understanding of the functional neuroanatomy of psychiatric disorders. This article reviews neuroimaging studies of depression from the last 3 decades and describes an emerging neurocircuitry model of mood disorders, focusing on critical circuits of cognition and emotion, particularly those networks involved in the regulation of evaluative, expressive and experiential aspects of emotion. The relevance of this model for neurotherapeutics is discussed, as well as the role of functional neuroimaging of psychiatric disorders.
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Using functional magnetic resonance imaging, we examined whether individual differences in amygdala activation in response to negative relative to neutral information are related to differences in the speed with which such information is evaluated, the extent to which such differences are associated with medial prefrontal cortex function, and their relationship with measures of trait anxiety and psychological well-being (PWB). Results indicated that faster judgments of negative relative to neutral information were associated with increased left and right amygdala activation. In the prefrontal cortex, faster judgment time was associated with relative decreased activation in a cluster in the ventral anterior cingulate cortex (ACC, BA 24). Furthermore, people who were slower to evaluate negative versus neutral information reported higher PWB. Importantly, higher PWB was strongly associated with increased activation in the ventral ACC for negative relative to neutral information. Individual differences in trait anxiety did not predict variation in judgment time or in amygdala or ventral ACC activity. These findings suggest that people high in PWB effectively recruit the ventral ACC when confronted with potentially aversive stimuli, manifest reduced activity in subcortical regions such as the amygdala, and appraise such information as less salient as reflected in slower evaluative speed.
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To monitor the environment for social threat humans must build affective evaluations of others. These evaluations are malleable and to a high degree shaped by responses engendered by specific social encounters. The precise neuronal mechanism by which these evaluations are constructed is poorly understood. We tested a hypothesis that conjoint activity in amygdala and fusiform gyrus would correlate with acquisition of social stimulus value. We tested this using a reinforcement learning algorithm, Q-learning, that assigned values to faces as a function of a history of pairing, or not pairing, with aversive shocks. Behaviourally, we observed a correlation between conditioning induced changes in skin conductance response (SCR) and subjective ratings for likeability of faces. Activity in both amygdala and fusiform gyrus (FG) correlated with the output of the reinforcement learning algorithm parameterized by these ratings. In amygdala, this effect was greater for averted than direct gaze faces. Furthermore, learning-related activity change in these regions correlated with SCR and subjective ratings. We conclude that amygdala and fusiform encode affective value in a manner that closely approximates a standard computational solution to learning.
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The role of the amygdala in major depression was investigated. Resting regional cerebral metabolic rate (rCMRglu) was measured with [18F]fluorodeoxyglucose positron emission tomography (PET) in two samples of subjects using two different PET cameras. The samples consisted of 10 and 17 medication-free depressives and 11 and 13 controls, respectively. Using coregistration of PET and magnetic resonance images, regions were individually delineated for the amygdala and thalamus, the latter of which was used as a control region. Within the depressed groups, right amygdalar rCMRglu was positively correlated with negative affect. Thalamic rCMRglu was not related to negative affect, and amygdalar rCMRglu accounted for a significant portion of variance in depressives' negative affect scores over and above the contribution of thalamic rCMRglu.
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Lesion and neuroimaging studies suggest the amygdala is important in the perception and production of negative emotion; however, the effects of emotion regulation on the amygdalar response to negative stimuli remain unknown. Using event-related fMRI, we tested the hypothesis that voluntary modulation of negative emotion is associated with changes in neural activity within the amygdala. Negative and neutral pictures were presented with instructions to either "maintain" the emotional response or "passively view" the picture without regulating the emotion. Each picture presentation was followed by a delay, after which subjects indicated how they currently felt via a response keypad. Consistent with previous reports, greater signal change was observed in the amygdala during the presentation of negative compared to neutral pictures. No significant effect of instruction was found during the picture presentation component of the trial. However, a prolonged increase in signal change was observed in the amygdala when subjects maintained the negative emotional response during the delay following negative picture offset. This increase in amygdalar signal due to the active maintenance of negative emotion was significantly correlated with subjects' self-reported dispositional levels of negative affect. These results suggest that consciously evoked cognitive mechanisms that alter the emotional response of the subject operate, at least in part, by altering the degree of neural activity within the amygdala.
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Anxiety is a debilitating symptom of many psychiatric disorders including generalized anxiety disorder, mood disorders, schizophrenia, and autism. Anxiety involves changes in both central and peripheral biology, yet extant functional imaging studies have focused exclusively on the brain. Here we show, using functional brain and cardiac imaging in sequential brain and cardiac magnetic resonance imaging (MRI) sessions in response to cues that predict either threat (a possible shock) or safety (no possibility of shock), that MR signal change in the amygdala and the prefrontal and insula cortices predicts cardiac contractility to the threat of shock. Participants with greater MR signal change in these regions show increased cardiac contractility to the threat versus safety condition, a measure of the sympathetic nervous system contribution to the myocardium. These findings demonstrate robust neural-cardiac coupling during induced anxiety and indicate that individuals with greater activation in brain regions identified with aversive emotion show larger magnitude cardiac contractility increases to threat.
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This article reviews the modern literature on two key aspects of the central circuitry of emotion - the prefrontal cortex (PFC) and the amygdala. There are several different functional divisions of the PFC including the dorsolateral, ventromedial and orbitofrontal sectors. Each of these regions plays some role in affective processing that shares the feature of representing affect in the absence of immediate rewards and punishments as well as in different aspects of emotional regulation. The amygdala appears to be crucial for the learning of new stimulus-threat contingencies and also appears to be important in the expression of cue-specific fear. Individual differences in both tonic activation and phasic reactivity in this circuit play an important role in governing affective style. Emphasis is placed upon affective chronometry, or the time course of emotional responding, as a key attribute of emotion that varies across individuals and is regulated by this circuitry.
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Children with an anxious temperament (AT) are at risk for developing psychiatric disorders along the internalizing spectrum, including anxiety and depression. Like these disorders, AT is a multidimensional phenotype and children with extreme anxiety show varying mixtures of physiological, behavioral, and other symptoms. Using a well-validated juvenile monkey model of AT, we addressed the degree to which this phenotypic heterogeneity reflects fundamental differences or similarities in the underlying neurobiology. The rhesus macaque is optimal for studying AT because children and young monkeys express the anxious phenotype in similar ways and have similar neurobiology. Fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET) in 238 freely behaving monkeys identified brain regions where metabolism predicted variation in three dimensions of the AT phenotype: hypothalamic-pituitary-adrenal (HPA) activity, freezing behavior, and expressive vocalizations. We distinguished brain regions that predicted all three dimensions of the phenotype from those that selectively predicted a single dimension. Elevated activity in the central nucleus of the amygdala and the anterior hippocampus was consistently found across individuals with different presentations of AT. In contrast, elevated activity in the lateral anterior hippocampus was selective to individuals with high levels of HPA activity, and decreased activity in the motor cortex (M1) was selective to those with high levels of freezing behavior. Furthermore, activity in these phenotype-selective regions mediated relations between amygdala metabolism and different expressions of anxiety. These findings provide a framework for understanding the mechanisms that lead to heterogeneity in the clinical presentation of internalizing disorders and set the stage for developing improved interventions.
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OBJECTIVE: The purpose of this study was to use functional magnetic resonance imaging (fMRI) to probe the neural circuitry associated with reactivity to negative and positive affective stimuli in patients with major depressive disorder before treatment and after 2 and 8 weeks of treatment with venlafaxine. Relations between baseline neural activation and response to treatment were also evaluated.
METHOD: Patients with major depressive disorder (N=12) and healthy comparison subjects (N=5) were scanned on three occasions, during which trials of alternating blocks of affective and neutral pictorial visual stimuli were presented. Symptoms were evaluated at each testing occasion, and both groups completed self-report measures of mood. Statistical parametric mapping was used to examine the fMRI data with a focus on the group-by-time interactions.
RESULTS: Patients showed a significant reduction in depressive symptoms with treatment. Group-by-time interactions in response to the negative versus neutral stimuli were found in the left insular cortex and the left anterior cingulate. At baseline, both groups showed bilateral activation in the visual cortices, lateral prefrontal cortex, and amygdala in response to the negative versus neutral stimuli, with patients showing greater activation in the visual cortex and less activation in the left lateral prefrontal cortex. Patients with greater relative anterior cingulate activation at baseline in response to the negative versus neutral stimuli showed the most robust treatment response.
CONCLUSIONS: The findings underscore the importance of the neural circuitry activated by negative affect in depression and indicate that components of this circuitry can be changed within 2 weeks of treatment with antidepressant medication.
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In children, behavioral inhibition (BI) in response to potential threat predicts the development of anxiety and affective disorders, and primate lesion studies suggest involvement of the orbitofrontal cortex (OFC) in mediating BI. Lesion studies are essential for establishing causality in brain-behavior relationships, but should be interpreted cautiously because the impact of a discrete lesion on a complex neural circuit extends beyond the lesion location. Complementary functional imaging methods assessing how lesions influence other parts of the circuit can aid in precisely understanding how lesions affect behavior. Using this combination of approaches in monkeys, we found that OFC lesions concomitantly alter BI and metabolism in the bed nucleus of stria terminalis (BNST) region and that individual differences in BNST activity predict BI. Thus it appears that an important function of the OFC in response to threat is to modulate the BNST, which may more directly influence the expression of BI.
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Social relations between humans critically depend on our affective experiences of others. Oxytocin enhances prosocial behavior, but its effect on humans' affective experience of others is not known. We tested whether oxytocin influences affective ratings, and underlying brain activity, of faces that have been aversively conditioned. Using a standard conditioning procedure, we induced differential negative affective ratings in faces exposed to an aversive conditioning compared with nonconditioning manipulation. This differential negative evaluative effect was abolished by treatment with oxytocin, an effect associated with an attenuation of activity in anterior medial temporal and anterior cingulate cortices. In amygdala and fusiform gyrus, this modulation was stronger for faces with direct gaze, relative to averted gaze, consistent with a relative specificity for socially relevant cues. The data suggest that oxytocin modulates the expression of evaluative conditioning for socially relevant faces via influences on amygdala and fusiform gyrus, an effect that may explain its prosocial effects.
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Temperamentally anxious individuals can be identified in childhood and are at risk to develop anxiety and depressive disorders. In addition, these individuals tend to have extreme asymmetric right prefrontal brain activity. Although common and clinically important, little is known about the pathophysiology of anxious temperament. Regardless, indirect evidence from rodent studies and difficult to interpret primate studies is used to support the hypothesis that the amygdala plays a central role. In previous studies using rhesus monkeys, we characterized an anxious temperament endophenotype that is associated with excessive anxiety and fear-related responses and increased electrical activity in right frontal brain regions. To examine the role of the amygdala in mediating this endophenotype and other fearful responses, we prepared monkeys with selective fiber sparing ibotenic acid lesions of the amygdala. Unconditioned trait-like anxiety-fear responses remained intact in monkeys with >95% bilateral amygdala destruction. In addition, the lesions did not affect EEG frontal asymmetry. However, acute unconditioned fear responses, such as those elicited by exposure to a snake and to an unfamiliar threatening conspecific were blunted in monkeys with >70% lesions. These findings demonstrate that the primate amygdala is involved in mediating some acute unconditioned fear responses but challenge the notion that the amygdala is the key structure underlying the dispositional behavioral and physiological characteristics of anxious temperament.
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Although once considered disruptive, self-conscious emotions are now theorized to be fundamentally involved in the regulation of social behavior. The present study examined the social regulation function of self-conscious emotions by comparing healthy participants with a neuropsychological population--patients with orbitofrontal lesions--characterized by selective regulatory deficits. Orbitofrontal patients and healthy controls participated in a series of tasks designed to assess their social regulation and self-conscious emotions. Another task assessed the ability to infer others' emotional states, an appraisal process involved in self-conscious emotion. Consistent with the theory that self-conscious emotions are important for regulating social behavior, the findings show that deficient behavioral regulation is associated with inappropriate self-conscious emotions that reinforce maladaptive behavior. Additionally, deficient behavioral regulation is associated with impairments in interpreting the self-conscious emotions of others.
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Given the central role of the amygdala in fear perception and expression and its likely abnormality in affective disorders and autism, there is great demand for a technique to measure differences in neurochemistry of the human amygdala. Unfortunately, it is also a technically complex target for magnetic resonance spectroscopy (MRS) due to a small volume, high field inhomogeneity and a shared boundary with hippocampus, which can undergo opposite changes in response to stress. We attempted to achieve reliable PRESS-localized single-voxel MRS at 3T of the isolated human amygdala by using anatomy to guide voxel size and location. We present data from 106 amygdala-MRS sessions from 58 volunteers aged 10 to 52 years, including two tests of one-week stability and a feasibility study in an adolescent sample. Our main outcomes were indices of spectral quality, repeated measurement variability (within- and between-subject standard deviations), and sensitivity to stable individual differences measured by intra-class correlation (ICC). We present metrics of amygdala-MRS reliability for n-acetyl-aspartate, creatine, choline, myo-Inositol, and glutamate+glutamine (Glx). We found that scan quality suffers an age-related difference in field homogeneity and modified our protocol to compensate. We further identified an effect of anatomical inclusion near the endorhinal sulcus, a region of high synaptic density, that contributes up to 29% of within-subject variability across 4 sessions (n=14). Remaining variability in line width but not signal-to-noise also detracts from reliability. Statistical correction for partial inclusion of these strong neurochemical gradients decreases n-acetyl-aspartate reliability from an intraclass correlation of 0.84 to 0.56 for 7-minute acquisitions. This suggests that systematic differences in anatomical inclusion can contribute greatly to apparent neurochemical concentrations and could produce false group differences in experimental studies. Precise, anatomically-based prescriptions that avoid age-related sources of inhomogeneity and use longer scan times may permit study of individual differences in neurochemistry throughout development in this late-maturing structure.
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Numerous studies demonstrate that the rhesus monkey is an excellent species with which to investigate mechanisms underlying human emotion and psychopathology. To examine the role of the central nucleus of the amygdala (CeA) in mediating the behavioral and physiological responses associated with fear and anxiety, we used rhesus monkeys to assess the effects of excitotoxic lesions of the CeA. Behavioral and physiological responses of nine monkeys with bilateral CeA destruction (ranging from 46 to 98%) were compared with five animals with asymmetric lesions (42-86.5% destruction on the most affected side) and with 16 unoperated controls. Results suggest that similar to rodent species, the primate CeA plays a role in mediating fear- and anxiety-related behavioral and endocrine responses. Compared with controls and the asymmetric-lesion group, bilaterally lesioned monkeys displayed significantly less fear-related behavior when exposed to a snake and less freezing behavior when confronted by a human intruder. In addition, bilaterally lesioned monkeys had decreased levels of CSF corticotrophin-releasing factor (CRF), and both lesioned groups had decreased plasma ACTH concentrations. In contrast to these findings, patterns of asymmetric frontal brain electrical activity, as assessed by regional scalp EEG, did not significantly differ between control and lesioned monkeys. These findings suggest that in primates, the CeA is involved in mediating fear- and anxiety-related behavioral and pituitary-adrenal responses as well as in modulating brain CRF activity.
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The serotonin transporter (5-HTT) plays a critical role in regulating serotonergic neurotransmission and is implicated in the pathophysiology of anxiety and affective disorders. Positron emission tomography scans using [(11)C]DASB [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile] to measure 5-HTT availability (an index of receptor density and binding) were performed in 34 rhesus monkeys in which the relationship between regional brain glucose metabolism and anxious temperament was previously established. 5-HTT availability in the amygdalohippocampal area and bed nucleus of the stria terminalis correlated positively with individual differences in a behavioral and neuroendocrine composite of anxious temperament. 5-HTT availability also correlated positively with stress-induced metabolic activity within these regions. Collectively, these findings suggest that serotonergic modulation of neuronal excitability in the neural circuitry associated with anxiety mediates the developmental risk for affect-related psychopathology.
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