To test the effects of cortisol on affective experience, the authors orally administered a placebo, 20 mg cortisol, or 40 mg cortisol to 85 men. Participants' affective responses to negative and neutral stimuli were measured. Self-reported affective state was also assessed. Participants in the 40-mg group (showing extreme cortisol elevations within the physiological range) rated neutral stimuli as more highly arousing than did participants in the placebo and 20-mg groups. Furthermore, within the 20-mg group, individuals with higher cortisol elevations made higher arousal ratings of neutral stimuli. However, cortisol was unrelated to self-reported affective state. Thus, findings indicate that acute cortisol elevations cause heightened arousal in response to objectively nonarousing stimuli, in the absence of effects on mood.
Considerable evidence exists to support an association between psychological states and immune function. However, the mechanisms by which such states are instantiated in the brain and influence the immune system are poorly understood. The present study investigated relations among physiological measures of affective style, psychological well being, and immune function. Negative and positive affect were elicited by using an autobiographical writing task. Electroencephalography and affect-modulated eye-blink startle were used to measure trait and state negative affect. Participants were vaccinated for influenza, and antibody titers after the vaccine were assayed to provide an in vivo measure of immune function. Higher levels of right-prefrontal electroencephalographic activation and greater magnitude of the startle reflex reliably predicted poorer immune response. These data support the hypothesis that individuals characterized by a more negative affective style mount a weaker immune response and therefore may be at greater risk for illness than those with a more positive affective style.
Among younger adults, the ability to willfully regulate negative affect, enabling effective responses to stressful experiences, engages regions of prefrontal cortex (PFC) and the amygdala. Because regions of PFC and the amygdala are known to influence the hypothalamic-pituitary-adrenal axis, here we test whether PFC and amygdala responses during emotion regulation predict the diurnal pattern of salivary cortisol secretion. We also test whether PFC and amygdala regions are engaged during emotion regulation in older (62- to 64-year-old) rather than younger individuals. We measured brain activity using functional magnetic resonance imaging as participants regulated (increased or decreased) their affective responses or attended to negative picture stimuli. We also collected saliva samples for 1 week at home for cortisol assay. Consistent with previous work in younger samples, increasing negative affect resulted in ventral lateral, dorsolateral, and dorsomedial regions of PFC and amygdala activation. In contrast to previous work, decreasing negative affect did not produce the predicted robust pattern of higher PFC and lower amygdala activation. Individuals demonstrating the predicted effect (decrease < attend in the amygdala), however, exhibited higher signal in ventromedial prefrontal cortex (VMPFC) for the same contrast. Furthermore, participants displaying higher VMPFC and lower amygdala signal when decreasing compared with the attention control condition evidenced steeper, more normative declines in cortisol over the course of the day. Individual differences yielded the predicted link between brain function while reducing negative affect in the laboratory and diurnal regulation of endocrine activity in the home environment.
Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we studied a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution (18)F-labelled deoxyglucose positron-emission tomography (FDG-PET) was selected as the imaging modality because it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Here we demonstrate that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. We also show significant heritability of the AT phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, we reveal significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT is not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differ from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk of developing anxiety and depression.
The amygdalae are important, if not critical, brain regions for many affective, attentional and memorial processes, and dysfunction of the amygdalae has been a consistent finding in the study of clinical depression. Theoretical models of the functional neuroanatomy of both normal and psychopathological affective processes which posit cortical hemispheric specialization of functions have been supported by both lesion and functional neuroimaging studies in humans. Results from human neuroimaging studies in support of amygdalar hemispheric specialization are inconsistent. However, recent results from human lesion studies are consistent with hemispheric specialization. An important, yet largely ignored, feature of the amygdalae in the primate brain--derived from both neuroanatomical and electrophysiological data--is that there are virtually no direct interhemispheric connections via the anterior commissure (AC). This feature stands in stark contrast to that of the rodent brain wherein virtually all amygdalar nuclei have direct interhemispheric connections. We propose this feature of the primate brain, in particular the human brain, is a result of influences from frontocortical hemispheric specialization which have developed over the course of primate brain evolution. Results consistent with this notion were obtained by examining the nature of human amygdalar interhemispheric connectivity using both functional magnetic resonance imaging (FMRI) and positron emission tomography (PET). We found modest evidence of amygdalar interhemispheric functional connectivity in the non-depressed brain, whereas there was strong evidence of functional connectivity in the depressed brain. We interpret and discuss the nature of this connectivity in the depressed brain in the context of dysfunctional frontocortical-amygdalar interactions which accompany clinical depression.
OBJECTIVE: The anticipation of adverse outcomes, or worry, is a cardinal symptom of generalized anxiety disorder. Prior work with healthy subjects has shown that anticipating aversive events recruits a network of brain regions, including the amygdala and anterior cingulate cortex. This study tested whether patients with generalized anxiety disorder have alterations in anticipatory amygdala function and whether anticipatory activity in the anterior cingulate cortex predicts treatment response. METHOD: Functional magnetic resonance imaging (fMRI) was employed with 14 generalized anxiety disorder patients and 12 healthy comparison subjects matched for age, sex, and education. The event-related fMRI paradigm was composed of one warning cue that preceded aversive pictures and a second cue that preceded neutral pictures. Following the fMRI session, patients received 8 weeks of treatment with extended-release venlafaxine. RESULTS: Patients with generalized anxiety disorder showed greater anticipatory activity than healthy comparison subjects in the bilateral dorsal amygdala preceding both aversive and neutral pictures. Building on prior reports of pretreatment anterior cingulate cortex activity predicting treatment response, anticipatory activity in that area was associated with clinical outcome 8 weeks later following treatment with venlafaxine. Higher levels of pretreatment anterior cingulate cortex activity in anticipation of both aversive and neutral pictures were associated with greater reductions in anxiety and worry symptoms. CONCLUSIONS: These findings of heightened and indiscriminate amygdala responses to anticipatory signals in generalized anxiety disorder and of anterior cingulate cortex associations with treatment response provide neurobiological support for the role of anticipatory processes in the pathophysiology of generalized anxiety disorder.
Functional MRI resting state and connectivity studies of brain focus on neural fluctuations at low frequencies which share power with physiological fluctuations originating from lung and heart. Due to the lack of automated software to process physiological signals collected at high magnetic fields, a gap exists in the processing pathway between the acquisition of physiological data and its use in fMRI software for both physiological noise correction and functional analyses of brain activation and connectivity. To fill this gap, we developed an open source, physiological signal processing program, called PhysioNoise, in the python language. We tested its automated processing algorithms and dynamic signal visualization on resting monkey cardiac and respiratory waveforms. PhysioNoise consistently identifies physiological fluctuations for fMRI noise correction and also generates covariates for subsequent analyses of brain activation and connectivity.
Background A key to successful adaptation is the ability to regulate emotional responses in relation to changing environmental demands or contexts. Methods High-resolution PET 18fluoro-deoxyglucose (FDG) scanning in rhesus monkeys was performed during two contexts (alone, and human intruder with no eye contact) during which the duration of anxiety related freezing behavior was assessed. Correlations between individual differences in freezing duration and brain activity were performed for each of the two conditions, as well as for the contextual regulation between the two conditions. Results In both conditions, activity in the basal forebrain, including the bed nucleus of the stria terminalis and the nucleus accumbens were correlated with individual differences in freezing duration. In contrast, individual differences in the ability to regulate freezing behavior between contexts were correlated with activity in the dorsal anterior cingulate cortex, the thalamus and the dorsal raphe nucleus. Conclusions These findings demonstrate differences in the neural circuitry mediating the expression compared to the contextual regulation of freezing behavior. These findings are relevant since altered regulatory processes may underlie anxiety disorders.
In primates, during times of need, calling for help is a universal experience. Calling for help recruits social support and promotes survival. However, calling for help also can attract predators, and it is adaptive to inhibit calls for help when a potential threat is perceived. Based on this, we hypothesized that individual differences in calling for help would be related to the activity of brain systems that mediate goal-directed behavior and the detection of threat. By using high-resolution positron emission tomography in rhesus monkeys undergoing social separation, we demonstrate that increased [18F]-fluoro-2-deoxy-d-glucose uptake in the right dorsolateral prefrontal cortex and decreased uptake in the amygdala independently predict individual differences in calling for help. When taken together, these two regions account for 76% of the variance in calling for help. This result suggests that the drive for affiliation and the perception of threat determine the intensity of an individual's behavior during separation. These findings in monkeys are relevant to humans and provide a conceptual neural framework to understand individual differences in how primates behave when in need of social support.
Children with anxious temperament (AT) are particularly sensitive to new social experiences and have increased risk for developing anxiety and depression. The young rhesus monkey is optimal for studying the origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. In vivo imaging in young monkeys demonstrated that central nucleus of the amygdala (Ce) metabolism is relatively stable across development and predicts AT. Transcriptome-wide gene expression, which reflects combined genetic and environmental influences, was assessed within the Ce. Results support a maladaptive neurodevelopmental hypothesis linking decreased amygdala neuroplasticity to early-life dispositional anxiety. For example, high AT individuals had decreased mRNA expression of neurotrophic tyrosine kinase, receptor, type 3 (NTRK3). Moreover, variation in Ce NTRK3 expression was inversely correlated with Ce metabolism and other AT-substrates. These data suggest that altered amygdala neuroplasticity may play a role the early dispositional risk to develop anxiety and depression.
Some children show emotion that is not consistent with normative appraisal of the context and can therefore be defined as context inappropriate (CI). The authors used individual growth curve modeling and hierarchical multiple regression analyses to examine whether CI anger predicts differences in hypothalamic-pituitary-adrenal axis activity, as manifest in salivary cortisol measures. About 23% of the 360 children (ages 6-10 years, primarily 7-8) showed at least 1 expression of CI anger in situations designed to elicit positive affect. Expression of anger across 2 positive assessments was less common (around 4%). CI anger predicted the hypothesized lower levels of cortisol beyond that attributed to context appropriate anger. Boys' CI anger predicted lower morning cortisol and flatter slopes. Results suggest that this novel approach to studying children's emotion across varying contexts can provide insight into affective style.
The putative association between fear-related behaviors and peripheral sympathetic and neuroendocrine reactivity has not been replicated consistently. This inconsistency was addressed in a reexamination of the characterization of children with extreme fearful reactions by focusing on the match between distress behaviors and the eliciting context. Eighty 24-month-old children were observed in 4 mildly threatening contexts, and the relations among different measures of fear-related behaviors, reactive and basal cortisol levels, and baseline cardiac measures of heart rate, respiratory sinus arrhythmia, and preejection period (PEP) were examined. The hypothesis that only behaviors under the less threatening context would be associated with higher cortisol and sympathetic cardiac activity was confirmed; only task-specific freezing behavior predicted higher reactive and basal cortisol levels and resting PEP measured 1 week later. Implications for the conceptualization of dysregulated fear behaviors in the classification of extremely fearful children are discussed.
In a test of the effects of cortisol on emotional memory, 90 men were orally administered placebo or 20 or 40 mg cortisol and presented with emotionally arousing and neutral stimuli. On memory tests administered within 1 hr of stimulus presentation, cortisol elevations caused a reduction in the number of errors committed on free-recall tasks. Two evenings later, when cortisol levels were no longer manipulated, inverted-U quadratic trends were found for recognition memory tasks, reflecting memory facilitation in the 20-mg group for both negative and neutral information. Results suggest that the effects of cortisol on memory do not differ substantially for emotional and neutral information. The study provides evidence of beneficial effects of acute cortisol elevations on explicit memory in humans.
Early life stress (ELS) and function of the hypothalamic-pituitary-adrenal axis predict later psychopathology. Animal studies and cross-sectional human studies suggest that this process might operate through amygdala-ventromedial prefrontal cortex (vmPFC) circuitry implicated in the regulation of emotion. Here we prospectively investigated the roles of ELS and childhood basal cortisol amounts in the development of adolescent resting-state functional connectivity (rs-FC), assessed by functional connectivity magnetic resonance imaging (fcMRI), in the amygdala-PFC circuit. In females only, greater ELS predicted increased childhood cortisol levels, which predicted decreased amygdala-vmPFC rs-FC 14 years later. For females, adolescent amygdala-vmPFC functional connectivity was inversely correlated with concurrent anxiety symptoms but positively associated with depressive symptoms, suggesting differing pathways from childhood cortisol levels function through adolescent amygdala-vmPFC functional connectivity to anxiety and depression. These data highlight that, for females, the effects of ELS and early HPA-axis function may be detected much later in the intrinsic processing of emotion-related brain circuits.
Neuroanatomists posit that the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST) comprise two major nodes of a macrostructural forebrain entity termed the extended amygdala. The extended amygdala is thought to play a critical role in adaptive motivational behavior and is implicated in the pathophysiology of maladaptive fear and anxiety. Resting functional connectivity of the Ce was examined in 107 young anesthetized rhesus monkeys and 105 young humans using standard resting-state functional magnetic resonance imaging (fMRI) methods to assess temporal correlations across the brain. The data expand the neuroanatomical concept of the extended amygdala by finding, in both species, highly significant functional coupling between the Ce and the BST. These results support the use of in vivo functional imaging methods in nonhuman and human primates to probe the functional anatomy of major brain networks such as the extended amygdala.
Although depressed mood is a normal occurrence in response to adversity in all individuals, what distinguishes those who are vulnerable to major depressive disorder (MDD) is their inability to effectively regulate negative mood when it arises. Investigating the neural underpinnings of adaptive emotion regulation and the extent to which such processes are compromised in MDD may be helpful in understanding the pathophysiology of depression. We report results from a functional magnetic resonance imaging study demonstrating left-lateralized activation in the prefrontal cortex (PFC) when downregulating negative affect in nondepressed individuals, whereas depressed individuals showed bilateral PFC activation. Furthermore, during an effortful affective reappraisal task, nondepressed individuals showed an inverse relationship between activation in left ventrolateral PFC and the amygdala that is mediated by the ventromedial PFC (VMPFC). No such relationship was found for depressed individuals, who instead show a positive association between VMPFC and amygdala. Pupil dilation data suggest that those depressed patients who expend more effort to reappraise negative stimuli are characterized by accentuated activation in the amygdala, insula, and thalamus, whereas nondepressed individuals exhibit the opposite pattern. These findings indicate that a key feature underlying the pathophysiology of major depression is the counterproductive engagement of right prefrontal cortex and the lack of engagement of left lateral-ventromedial prefrontal circuitry important for the downregulation of amygdala responses to negative stimuli.
Context: Emotion regulation is critically disrupted in depression and use of paradigms tapping these processes may uncover essential changes in neurobiology during treatment. In addition, as neuroimaging outcome studies of depression commonly utilize solely baseline and endpoint data – which is more prone to week-to week noise in symptomatology – we sought to use all data points over the course of a six month trial. Objective: To examine changes in neurobiology resulting from successful treatment. Design: Double-blind trial examining changes in the neural circuits involved in emotion regulation resulting from one of two antidepressant treatments over a six month trial. Participants were scanned pretreatment, at 2 months and 6 months posttreatment. Setting: University functional magnetic resonance imaging facility. Participants: 21 patients with Major Depressive Disorder and without other Axis I or Axis II diagnoses and 14 healthy controls. Interventions: Venlafaxine XR (doses up to 300mg) or Fluoxetine (doses up to 80mg). Main Outcome Measure: Neural activity, as measured using functional magnetic resonance imaging during performance of an emotion regulation paradigm as well as regular assessments of symptom severity by the Hamilton Rating Scale for Depression. To utilize all data points, slope trajectories were calculated for rate of change in depression severity as well as rate of change of neural engagement. Results: Those depressed individuals showing the steepest decrease in depression severity over the six months were those individuals showing the most rapid increases in BA10 and right DLPFC activity when regulating negative affect over the same time frame. This relationship was more robust than when using solely the baseline and endpoint data. Conclusions: Changes in PFC engagement when regulating negative affect correlate with changes in depression severity over six months. These results are buttressed by calculating these statistics which are more reliable and robust to week-to-week variation than difference scores.
A current limitation for imaging of brain function is the potential confound of anatomical differences or registration error, which may manifest via apparent functional "activation" for between-subject analyses. With respect to functional activations, underlying tissue mismatches can be regarded as a nuisance variable. We propose adding the probability of gray matter at a given voxel as a covariate (nuisance variable) in the analysis of voxelwise multisubject functional data using standard statistical techniques. A method is presented to assess the extent to which a functional activation can reliably be explained by underlying anatomical differences, and simultaneously, to assess the component of the functional activation which cannot be attributed to anatomical difference and thus is likely due to functional difference alone. Extension of the method to other intermodal imaging applications is discussed. Two exemplary data sets, one PET and one fMRI, are used to demonstrate the implementation and utility of this method, which apportions the relative contributions of anatomy and function for an apparent functional activation. The examples show two distinct types of results. First, a so-called functional activation may actually be caused by a systematic anatomical difference which, when modeled, diminishes the functional effect. In the second result type, including the anatomical differences in the model can account for a large component of otherwise unmodeled variance, yielding an increase in the functional effect cluster size and/or magnitude. In either case, ignoring the readily available structural information can lead to misinterpretation of functional results.
The medial prefrontal cortex (mPFC), hippocampus, and amygdala are implicated in the regulation of affect and physiological processes, including hypothalamic-pituitary-adrenal (HPA) axis function. Anhedonia is likely associated with dysregulation of these processes. Dense-array resting electroencephalographic and cortisol were obtained from healthy and anhedonic groups. Low-resolution electromagnetic tomography was used to compute intracerebral current density. For the control group, voxelwise analyses found a relationship between current density in beta and gamma bands and steeper cortisol slope (indicative of more adaptive HPA axis functioning) in regions of the hippocampus, parahippocampal gyrus, and mPFC. For the anhedonic group, the mPFC finding was absent. Anhedonia may be characterized by disruptions of mPFC-mediated neuroendocrine regulation, which could constitute a vulnerability to the development of stress-related disorders.
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.
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.
BACKGROUND: Anxious temperament (AT) is identifiable early in life and predicts the later development of anxiety disorders and depression. Neuropeptide Y (NPY) is a putative endogenous anxiolytic neurotransmitter that adaptively regulates responses to stress and might confer resilience to stress-related psychopathology. With a well-validated nonhuman primate model of AT, we examined expression of the NPY system in the central nucleus (Ce) of the amygdala, a critical neural substrate for extreme anxiety. METHODS: In 24 young rhesus monkeys, we measured Ce messenger RNA (mRNA) levels of all members of the NPY system that are detectable in the Ce with quantitative real time polymerase chain reaction. We then examined the relationship between these mRNA levels and both AT expression and brain metabolism. RESULTS: Lower mRNA levels of neuropeptide Y receptor 1 (NPY1R) and NPY5R but not NPY or NPY2R in the Ce predicted elevated AT; mRNA levels for NPY1R and NPY5R in the motor cortex were not related to AT. In situ hybridization analysis provided for the first time a detailed description of NPY1R and NPY5R mRNA distribution in the rhesus amygdala and associated regions. Lastly, mRNA levels for these two receptors in the Ce predicted metabolic activity in several regions that have the capacity to regulate the Ce. CONCLUSIONS: Decreased NPY signaling in the Ce might contribute to the altered metabolic activity that is a component of the neural substrate underlying AT. This suggests that enhancement of NPY signaling might reduce the risk to develop psychopathology.
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.
Anhedonia, the loss of pleasure or interest in previously rewarding stimuli, is a core feature of major depression. While theorists have argued that anhedonia reflects a reduced capacity to experience pleasure, evidence is mixed as to whether anhedonia is caused by a reduction in hedonic capacity. An alternative explanation is that anhedonia is due to the inability to sustain positive affect across time. Using positive images, we used an emotion regulation task to test whether individuals with depression are unable to sustain activation in neural circuits underlying positive affect and reward. While up-regulating positive affect, depressed individuals failed to sustain nucleus accumbens activity over time compared with controls. This decreased capacity was related to individual differences in self-reported positive affect. Connectivity analyses further implicated the fronto-striatal network in anhedonia. These findings support the hypothesis that anhedonia in depressed patients reflects the inability to sustain engagement of structures involved in positive affect and reward.
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