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Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LME INT), (2) LME that models both site-specific random intercepts and age-related random slopes (LME INT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ 2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ 2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ 2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Background: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). Methods: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2–85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis–Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2–148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. Results: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. Conclusions: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = −0.111 to −0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed, which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3,047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1,426 individuals with PTSD and 1,621 controls (2174 males/873 females) between ages 18–83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen’s d=−0.11, p=0.0055). The tapetum connects the left and right hippocampus, structures for which structure and function have been consistently implicated in PTSD. Results remained significant/similar after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Reduced hippocampal volume is frequently observed in posttraumatic stress disorder (PTSD), but the psychological processes associated with these alterations remain unclear. Given hippocampal involvement in memory and contextual representations of threat, we investigated relationships between retrospectively reported combat exposure, perceived threat, and hippocampal volume in trauma-exposed veterans. T1-weighted anatomical MRI scans were obtained from 56 veterans (4 women, 52 men; 39 with elevated PTSD symptoms, “PTSS” group) and hippocampal volume was estimated using automatic segmentation tools in FreeSurfer. Hippocampal volume was regressed on self-reported perceived threat from the Deployment Risk and Resilience Inventory, and combat exposure from the Combat Exposure Scale. As a secondary analysis, hippocampal volume was regressed on Clinician-Administered PTSD Scale (CAPS) symptoms. In veterans with elevated PTSD symptoms, hippocampal volume was inversely related to perceived threat while deployed while controlling for self-reported combat exposure. Hippocampal volume was also inversely correlated with avoidance/numbing CAPS symptoms. Future research should clarify the temporal milieu of these effects and investigate whether individual differences in hippocampal structure and function contribute to heightened threat appraisal at the time of trauma vs. subsequently elevated appraisals of traumatic events.

Previous studies have identified reduced heart rate variability (HRV) in posttraumatic stress disorder (PTSD), which may temporally precede the onset of the disorder. A separate line of functional neuroimaging research in PTSD has consistently demonstrated hypoactivation of the ventromedial prefrontal cortex (vmPFC), a key aspect of a descending neuromodulatory system that exerts inhibitory control over heart rate. No research to date, however, has simultaneously investigated whether altered vmPFC activation is associated with reduced HRV and elevated PTSD symptoms in the same individuals. Here, we collected fMRI data during alternating conditions of threat of shock and safety from shock in 51 male, combat-exposed veterans with either high or low levels of PTSD symptoms. Pulse rate variability (PRV) - an HRV surrogate calculated from pulse oximetry - was assessed during a subsequent resting scan. Correlational analyses tested for hypothesized relationships between reduced vmPFC activation, lower PRV, and elevated PTSD symptomatology. We found that PTSD re-experiencing symptoms were inversely associated with high-frequency (HF)-PRV, thought to primarily reflect parasympathetic control of heart rate, in veterans with elevated PTSD symptoms. Reduced vmPFC activation for the contrast of safety-threat was associated both with lower HF-PRV and elevated PTSD re-experiencing symptoms. These results tie together previous observations of reduced HRV/PRV and impaired vmPFC function in PTSD and call for further research on reciprocal brain-body relationships in understanding PTSD pathophysiology.

Anticipation is an adaptive process, aiding preparatory responses to potentially threatening events. However, excessive anticipatory responding and associated hyper-reactivity in the amygdala and insula are integral to anxiety disorders. Despite the co-occurrence of sleep disruption and anxiety disorders, the impact of sleep loss on affective anticipatory brain mechanisms, and the interaction with anxiety, remains unknown. Here, we demonstrate that sleep loss amplifies preemptive responding in the amygdala and anterior insula during affective anticipation in humans, especially for cues with high predictive certainty. Furthermore, trait anxiety significantly determined the degree of such neural vulnerability to sleep loss: individuals with highest trait anxiety showed the greatest increase in anticipatory insula activity when sleep deprived. Together, these data support a neuropathological model in which sleep disruption may contribute to the maintenance and/or exacerbation of anxiety through its impact on anticipatory brain function. They further raise the therapeutic possibility that targeted sleep restoration in anxiety may ameliorate excessive anticipatory responding and associated clinical symptomatology.

Granger causality analysis of functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent signal data allows one to infer the direction and magnitude of influence that brain regions exert on one another. We employed a method for upsampling the time resolution of fMRI data that does not require additional interpolation beyond the interpolation that is regularly used for slice-timing correction. The mathematics for this new method are provided, and simulations demonstrate its viability. Using fMRI, 17 snake phobics and 19 healthy controls viewed snake, disgust, and neutral fish video clips preceded by anticipatory cues. Multivariate Granger causality models at the native 2-sec resolution and at the upsampled 400-ms resolution assessed directional associations of fMRI data among 13 anatomical regions of interest identified in prior research on anxiety and emotion. Superior sensitivity was observed for the 400-ms model, both for connectivity within each group and for group differences in connectivity. Context-dependent analyses for the 400-ms multivariate Granger causality model revealed the specific trial types showing group differences in connectivity. This is the first demonstration of effective connectivity of fMRI data using a method for achieving 400-ms resolution without sacrificing accuracy available at 2-sec resolution.

Uncertainty is an omnipresent force in peoples’ lives that has been shown to amplify the negative impact of aversive events. This amplified aversiveness, together with the negative attitudes that individuals can have toward uncertainty, suggests that a cue indicating uncertainty about future events might be associated with biased expectancies of negative outcomes or biased contingency estimates, similar to biases that have been observed for traditional fear-relevant cues, such as snakes or spiders. Participants in this study saw three different cues: one that indicated with certainty that an aversive picture would follow, one that indicated with certainty that a neutral picture would follow, and one that indicated uncertainty about whether an aversive or neutral picture would follow. Online self-report data revealed negatively biased expectancies of aversion following uncertain cues. The degree of this online expectancy bias predicted subjects’ estimates, at the conclusion of the experiment, of the relationship between uncertain cues and aversive pictures. Aversive pictures following the uncertain cue (relative to those following the certain cue) were accompanied by increased skin conductance responses and self-reported negative mood. These findings that uncertainty is accompanied by biased expectancies of aversion and heightened responses to aversion warrant extensions of this research in anxiety disorders, given evidence for intolerance of uncertainty and anticipatory dysfunction in the pathology of such disorders.

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.

Like other forms of emotion, anxiety has been theoretically linked to preparation for action. Worry is a type of anticipatory anxiety and the hallmark of generalized anxiety disorder. Research has shown that worry is associated with vigilance to threat cues and increased muscle tension, which may in part be explained by motor facilitation that accompanies preparation for action. This study assessed corticospinal motor responses during worry using transcranial magnetic stimulation (TMS). Participants received TMS during a worry induction, during motor imagery, and during mental arithmetic, while electromyography and force were measured. TMS over the primary motor cortex elicited larger corticospinal motor responses during worry than mental arithmetic and smaller responses than motor imagery of maximum voluntary contraction of targeted muscles. These findings suggest that the association between worry and motor preparation cannot be explained by high cognitive load and provide further support for theoretical accounts emphasizing the role of action preparation in anxiety.

The authors examined the time course of affective responding associated with different affective dimensions--anxious apprehension, anxious arousal, and anhedonic depression--using an emotion-modulated startle paradigm. Participants high on 1 of these 3 dimensions and nonsymptomatic control participants viewed a series of affective pictures with acoustic startle probes presented before, during, and after the stimuli. All groups exhibited startle potentiation during unpleasant pictures and in anticipation of both pleasant and unpleasant pictures. Compared with control participants, symptomatic participants exhibited sustained potentiation following the offset of unpleasant stimuli and a lack of blink attenuation during and following pleasant stimuli. Common and unique patterns of affective responses in the 3 types of mood symptoms are discussed.

The primary taste cortex consists of the insula and operculum. Previous work has indicated that neurons in the primary taste cortex respond solely to sensory input from taste receptors and lingual somatosensory receptors. Using functional magnetic resonance imaging, we show here that expectancy modulates these neural responses in humans. When subjects were led to believe that a highly aversive bitter taste would be less distasteful than it actually was, they reported it to be less aversive than when they had accurate information about the taste and, moreover, the primary taste cortex was less strongly activated. In addition, the activation of the right insula and operculum tracked online ratings of the aversiveness for each taste. Such expectancy-driven modulation of primary sensory cortex may affect perceptions of external events.

Deficits in the initiation and utilization of strategies contribute importantly to memory impairments in depression. Other research on depression has documented memory biases toward negative and away from positive material. This study investigated brain mechanisms accompanying the initiative deficit and negative bias processes affecting memory in depressed individuals. Electroencephalography was recorded prior to and during emotional narratives and correlated with subsequent memory recognition of narrative material. Hypothesized to reflect strategy initiation, bilateral activity of the prefrontal cortex (PFC) preceding a sad narrative was associated with memory performance for that narrative in nondepressed controls only. Negative memory bias in depressed participants was inferred from their association between right prefrontal activity during the sad narrative and memory performance, consistent with research implicating that region in withdrawal-related unpleasant emotions. These results highlight the importance of distinguishing processes that influence memory performance when investigating the neural mechanisms of cognitive deficit and bias in depression.

Positive affect elicited in a mother toward her newborn infant may be one of the most powerful and evolutionarily preserved forms of positive affect in the emotional landscape of human behavior. This study examined the neurobiology of this form of positive emotion and in so doing, sought to overcome the difficulty of eliciting robust positive affect in response to visual stimuli in the physiological laboratory. Six primiparous human mothers with no indications of postpartum depression brought their infants into the laboratory for a photo shoot. Approximately 6 weeks later, they viewed photographs of their infant, another infant, and adult faces during acquisition of functional magnetic resonance images (fMRI). Mothers exhibited bilateral activation of the orbitofrontal cortex (OFC) while viewing pictures of their own versus unfamiliar infants. While in the scanner, mothers rated their mood more positively for pictures of their own infants than for unfamiliar infants, adults, or at baseline. The orbitofrontal activation correlated positively with pleasant mood ratings. In contrast, areas of visual cortex that also discriminated between own and unfamiliar infants were unrelated to mood ratings. These data implicate the orbitofrontal cortex in a mother's affective responses to her infant, a form of positive emotion that has received scant attention in prior human neurobiological studies. Furthermore, individual variations in orbitofrontal activation to infant stimuli may reflect an important dimension of maternal attachment.

Serotonin transporter gene variants are known to interact with stressful life experiences to increase chances of developing affective symptoms, and these same variants have been shown to influence amygdala reactivity to affective stimuli in non-psychiatric populations. The impact of these gene variants on affective neurocircuitry in anxiety and mood disorders has been studied less extensively. Utilizing a triallelic assay (5-HTTLPR and rs25531) to assess genetic variation linked with altered serotonin signaling, this fMRI study investigated genetic influences on amygdala and anterior insula activity in 50 generalized anxiety disorder patients, 26 of whom also met DSM-IV criteria for social anxiety disorder and/or major depressive disorder, and 39 healthy comparison subjects. A Group x Genotype interaction was observed for both the amygdala and anterior insula in a paradigm designed to elicit responses in these brain areas during the anticipation of and response to aversive pictures. Patients who are S/L(G) carriers showed less activity than their L(A)/L(A) counterparts in both regions and less activity than S/L(G) healthy comparison subjects in the amygdala. Moreover, patients with greater insula responses reported higher levels of intolerance of uncertainty, an association that was particularly pronounced for patients with two LA alleles. A genotype effect was not established in healthy controls. These findings link the serotonin transporter gene to affective circuitry findings in anxiety and depression psychopathology and further suggest that its impact on patients may be different from effects typically observed in healthy populations.

Given the limited success of conventional treatments for veterans with posttraumatic stress disorder (PTSD), investigations of alternative approaches are warranted. We examined the effects of a breathing-based meditation intervention, Sudarshan Kriya yoga, on PTSD outcome variables in U.S. male veterans of the Iraq or Afghanistan war. We randomly assigned 21 veterans to an active (n = 11) or waitlist control (n = 10) group. Laboratory measures of eye-blink startle and respiration rate were obtained before and after the intervention, as were self-report symptom measures; the latter were also obtained 1 month and 1 year later. The active group showed reductions in PTSD scores, d = 1.16, 95% CI [0.20, 2.04], anxiety symptoms, and respiration rate, but the control group did not. Reductions in startle correlated with reductions in hyperarousal symptoms immediately postintervention (r =. 93, p

Objective: The anterior cingulate cortex has been implicated in depression. Results are best interpreted by considering anatomic and cytoarchitectonic subdivisions. Evidence suggests depression is characterized by hypoactivity in the dorsal anterior cingulate, whereas hyperactivity in the rostral anterior cingulate is associated with good response to treatment. The authors tested the hypothesis that activity in the rostral anterior cingulate during the depressed state has prognostic value for the degree of eventual response to treatment. Whereas prior studies used hemodynamic imaging, this investigation used EEG. Method: The authors recorded 28-channel EEG data for 18 unmedicated patients with major depression and 18 matched comparison subjects. Clinical outcome was assessed after nortriptyline treatment. Of the 18 depressed patients, 16 were considered responders 4–6 months after initial assessment. A median split was used to classify response, and the pretreatment EEG data of patients showing better (N=9) and worse (N=9) responses were analyzed with low-resolution electromagnetic tomography, a new method to compute three-dimensional cortical current density for given EEG frequency bands according to a Talairach brain atlas. Results: The patients with better responses showed hyperactivity (higher theta activity) in the rostral anterior cingulate (Brodmann’s area 24/32). Follow-up analyses demonstrated the specificity of this finding, which was not confounded by age or pretreatment depression severity. Conclusions: These results, based on electrophysiological imaging, not only support hemodynamic findings implicating activation of the anterior cingulate as a predictor of response in depression, but they also suggest that differential activity in the rostral anterior cingulate is associated with gradations of response.

The 15th Annual Meeting of the Cognitive Neuroscience Society brought together researchers and exhibitors to discuss and present data relevant to the study of the mind using neuroscience methods, especially neuroimaging. A history of interdisciplinary communication, which was the basis of the creation of this society, continues to expand the scope of work presented at the meeting to include research on emotional and social processes as well as various forms of psychopathology. Neurotherapeutics and individual differences in treatment responsivity may be on the horizon.

Uncertainty about a possible future threat disrupts our ability to avoid it or to mitigate its negative impact and thus results in anxiety. Here, we focus the broad literature on the neurobiology of anxiety through the lens of uncertainty. We identify five processes that are essential for adaptive anticipatory responses to future threat uncertainty and propose that alterations in the neural instantiation of these processes result in maladaptive responses to uncertainty in pathological anxiety. This framework has the potential to advance the classification, diagnosis and treatment of clinical anxiety.

Context Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD. Objectives To investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas. Design Participants underwent diffusion-tensor imaging and functional magnetic resonance imaging. Setting University magnetic resonance imaging facility. Participants Forty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education. Main Outcome Measures The mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract-based analysis for diffusion-tensor imaging data. Results Lower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion. Conclusions Reduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus.

The anticipation of future adversity confers adaptive benefits by engaging a suite of preparatory mechanisms, but this process can also be deleterious when carried out in excess. Neuroscientific investigations have largely treated anticipation as a unitary process, but we show here using functional magnetic resonance imaging that distinct stages of aversive anticipation are supported by dissociable neural mechanisms. Immediate anticipatory responses were observed in regions associated with threat detection and early processing of predictive cues, including the orbitofrontal cortex and pregenual anterior cingulate cortex, as well as the amygdala for individuals with elevated anxiety symptoms. Sustained anticipatory activity was observed in the forebrain/bed nucleus of the stria terminalis, anterior insula, anterior mid-cingulate cortex (aMCC), and midbrain/periaqueductal gray, regions associated with anxiety, interoception, and defensive behavior. The aMCC showed increased functional coupling with the midbrain during sustained anticipation of aversion, highlighting a circuit critical for the expression of preparatory fear responses. These data implicate distinct sets of regions that are active during different temporal stages of anticipation, and provide insight into how the human brain faces the future both adaptively and maladaptively.

Uncertainty about potential negative future outcomes can cause stress and is a central feature of anxiety disorders. The stress and anxiety associated with uncertain situations may lead individuals to overestimate the frequency with which uncertain cues are followed by negative outcomes, an example of covariation bias. Using functional magnetic resonance imaging, we found that uncertainty-related expectations modulated neural responses to aversion. Insula and amygdala responses to aversive pictures were larger after an uncertain cue (that preceded aversive or neutral pictures) than a certain cue (that always preceded aversive pictures). Anticipatory anterior cingulate cortex (ACC) activity elicited by the cues was inversely associated with the insula and amygdala responses to aversive pictures following the cues. Nearly 75% of subjects overestimated the frequency of aversive pictures following uncertain cues, and ACC and insula activity predicted this uncertainty-related covariation bias. Findings provide the first evidence of the brain mechanisms of covariation bias and highlight the temporal dynamics of ACC, insula, and amygdala recruitment for processing aversion in the context of uncertainty.

The present study examined EEG gamma (35-70 Hz) spectral power distributions during worry inductions in participants suffering from generalized anxiety disorder (GAD) and in control participants without a history of psychiatric illness. As hypothesized, the EEG gamma band was useful for differentiating worry from baseline and relaxation. During worry induction, GAD patients showed higher levels of gamma activity than control participants in posterior electrode sites that have been previously associated with negative emotion. Gamma fluctuations in these electrode sites were correlated with subjective emotional experience ratings lending additional support to interpretations of negative affect. Following 14 weeks of psychotherapy, the GAD group reported less negative affect with worry inductions and the corresponding gamma sites that previously differentiated the clinical from control groups changed for the GAD patients in the direction of control participants. These findings suggest converging evidence that patients suffering from GAD experience more negative emotion during worry and that the EEG gamma band is useful for monitoring fluctuations in pathological worry expected to follow successful treatment.

Prior research has shown memory is enhanced for emotional events. Key brain areas involved in emotional memory are the amygdala and hippocampus, which are also recruited during aversion and its anticipation. This study investigated whether anticipatory processes signaling an upcoming aversive event contribute to emotional memory. In an event-related functional MRI paradigm, 40 healthy participants viewed aversive and neutral pictures preceded by predictive warning cues. Participants completed a surprise recognition task directly after functional MRI scanning or 2 weeks later. In anticipation of aversive pictures, bilateral dorsal amygdala and anterior hippocampus activations were associated with better immediate recognition memory. Similar associations with memory were observed for activation of those areas in response to aversive pictures. Anticipatory activation predicted immediate memory over and above these associations for picture viewing. Bilateral ventral amygdala activations in response to aversive pictures predicted delayed memory only. We found that previously reported sex differences of memory associations with left amygdala for women and with right amygdala for men were confined to the ventral amygdala during picture viewing and delayed memory. Results support an established animal model elucidating the functional neuroanatomy of the amygdala and hippocampus in emotional memory, highlight the importance of anticipatory processes in such memory for aversive events, and extend neuroanatomical evidence of sex differences for emotional memory.

The experience of aversion is shaped by multiple physiological and psychological factors including one's expectations. Recent work has shown that expectancy manipulation can alter perceptions of aversive events and concomitant brain activation. Accruing evidence indicates a primary role of altered expectancies in the placebo effect. Here, we probed the mechanism by which expectation attenuates sensory taste transmission by examining how brain areas activated by misleading information during an expectancy period modulate insula and amygdala activation to a highly aversive bitter taste. In a rapid event-related fMRI design, we showed that activations in the rostral anterior cingulate cortex (rACC), orbitofrontal cortex (OFC), and dorsolateral prefrontal cortex to a misleading cue that the taste would be mildly aversive predicted decreases in insula and amygdala activation to the highly aversive taste. OFC and rACC activation to the misleading cue were also associated with less aversive ratings of that taste. Additional analyses revealed consistent results demonstrating functional connectivity among the OFC, rACC, and insula. Altering expectancies of upcoming aversive events are shown here to depend on robust functional associations among brain regions implicated in prior work on the placebo effect.

The capacity to anticipate aversive circumstances is central not only to successful adaptation but also to understanding the abnormalities that contribute to excessive worry and anxiety disorders. Forecasting and reacting to aversive events mobilize a host of affective and cognitive capacities and corresponding brain processes. Rapid event-related functional magnetic resonance imaging (fMRI) in 21 healthy volunteers assessed the overlap and divergence in the neural instantiation of anticipating and being exposed to aversive pictures. Brain areas jointly activated by the anticipation of and exposure to aversive pictures included the dorsal amygdala, anterior insula, dorsal anterior cingulate cortex (ACC), right dorsolateral prefrontal cortex (DLPFC), and right posterior orbitofrontal cortex (OFC). Anticipatory processes were uniquely associated with activations in rostral ACC, a more superior sector of the right DLPFC, and more medial sectors of the bilateral OFC. Activation of the right DLPFC in anticipation of aversion was associated with self-reports of increased negative affect, whereas OFC activation was associated with increases in both positive and negative affect. These results show that anticipation of aversion recruits key brain regions that respond to aversion, thereby potentially enhancing adaptive responses to aversive events.

Despite the vast literature that has implicated asymmetric activation of the prefrontal cortex in approach-withdrawal motivation and emotion, no published reports have directly explored the neural correlates of well-being. Eighty-four right-handed adults (ages 57–60) completed self-report measures of eudaimonic well-being, hedonic well-being, and positive affect prior to resting electroencephalography. As hypothesized, greater left than right superior frontal activation was associated with higher levels of both forms of well-being. Hemisphere-specific analyses documented the importance of goal-directed approach tendencies beyond those captured by approach-related positive affect for eudaimonic but not for hedonic well-being. Appropriately engaging sources of appetitive motivation, characteristic of higher left than right baseline levels of prefrontal activation, may encourage the experience of well-being.

Recent theoretical accounts of emotion regulation assign an important role in this process to the prefrontal cortex, yet there is little relevant data available to support this hypothesis. The current study assessed the relation between individual differences in asymmetric prefrontal activation and an objective measure of uninstructed emotion regulation. Forty-seven participants 57 to 60 years old viewed emotionally arousing and neutral visual stimuli while eye-blink startle data were collected. Startle probes were also presented after picture presentation to capture the persistence or attenuation of affect following the offset of an emotional stimulus. Subjects with greater relative left-sided anterior activation in scalp-recorded brain electrical signals displayed attenuated startle magnitude after the offset of negative stimuli. This relation between resting frontal activation and recovery following an aversive event supports the idea of a frontally mediated mechanism involved in one form of automatic emotion regulation.

The present study was undertaken to determine whether aversiveness contributes to startle potentiation in anticipation of affective pictures above and beyond the effects of emotional arousal. Further, participants high in trait anxious apprehension, which is characterized by worry about the future, were expected to show especially pronounced anticipatory startle responses. Startle blink reflex was measured during warning stimuli that predicted the valence of ensuing aversive/unpleasant, pleasant, or neutral pictures. Startle magnitude was larger in anticipation of aversive than of pleasant pictures and smallest in anticipation of neutral pictures. Enhanced startle potentiation was not found in anxious apprehension subjects. These data suggest that the aversive nature of stimuli contribute to the potentiation of startle above and beyond the effects of emotional arousal, which may be a universal phenomenon not modulated by individual differences.

Background: The frontal lobe has been crucially involved in the neurobiology of major depression, but inconsistencies among studies exist, in part due to a failure of considering modulatory variables such as symptom severity, comorbidity with anxiety, and distinct subtypes, as codeterminants for patterns of brain activation in depression. Methods: Resting electroencephalogram was recorded in 38 unmedicated subjects with major depressive disorder and 18 normal comparison subjects, and analyzed with a tomographic source localization method that computes the cortical three-dimensional distribution of current density for standard electroencephalogram frequency bands. Symptom severity and anxiety were measured via self-report and melancholic features via clinical interview. Results: Depressed subjects showed more excitatory (beta3, 21.5–30.0 Hz) activity in the right superior and inferior frontal lobe (Brodmann’s area 9/10/11) than comparison subjects. In melancholic subjects, this effect was particularly pronounced for severe depression, and right frontal activity correlated positively with anxiety. Depressed subjects showed posterior cingulate and precuneus hypoactivity. Conclusions: While confirming prior results implicating right frontal and posterior cingulate regions, this study highlights the importance of depression severity, anxiety, and melancholic features in patterns of brain activity accompanying depression.

▪ Abstract Depression is a disorder of the representation and regulation of mood and emotion. The circuitry underlying the representation and regulation of normal emotion and mood is reviewed, including studies at the animal level, human lesion studies, and human brain imaging studies. This corpus of data is used to construct a model of the ways in which affect can become disordered in depression. Research on the prefrontal cortex, anterior cingulate, hippocampus, and amygdala is reviewed and abnormalities in the structure and function of these different regions in depression is considered. The review concludes with proposals for the specific types of processing abnormalities that result from dysfunctions in different parts of this circuitry and offers suggestions for the major themes upon which future research in this area should be focused.

Significant progress has been made in our understanding of the neural substrates of emotion and its disorders. Neuroimaging methods have been used to characterize the circuitry underlying disorders of emotion. Particular emphasis has been placed on the prefrontal cortex, anterior cingulate, parietal cortex, and the amygdala as critical components of the circuitry that may be dysfunctional in both depression and anxiety.

Prior research has often linked anxiety to attentional vigilance for threat using the dot probe task, which presents probes in spatial locations that were or were not preceded by a putative threat stimulus. The present study investigated the impact of worry on threat vigilance by administering this task during a worry condition and during a mental arithmetic control condition to 56 undergraduate students scoring in the low normal range on a measure of chronic worry. The worry induction was associated with faster responses than arithmetic to probes in the attended location following threat words, indicating the combined influence of worry and threat in facilitating attention. Within the worry condition, responses to probes in the attended location were faster for trials containing threat words than for trials with only neutral words, whereas the converse pattern was observed for responses to probes in the unattended location. This connection between worry states and attentional capture by threat may be central to understanding the impact of hypervigilance on information processing in anxiety and its disorders.