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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.

BackgroundPrevious 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 suggests that the ventromedial prefrontal cortex (vmPFC) — a key aspect of a descending neuromodulatory system that exerts inhibitory control over heart rate — shows functional and structural abnormalities in PTSD. 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.MethodsWe 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 vmPFC activation, PRV, and distinct dimensions of PTSD symptomatology.ResultsRe-experiencing PTSD symptoms were inversely associated with high-frequency (HF)-PRV, thought to primarily reflect parasympathetic control of heart rate, in veterans with elevated PTSD symptoms. Lower HF-PRV was associated with reduced vmPFC activation for the contrast of safety-threat in a region that also showed an inverse relationship with re-experiencing symptoms.ConclusionsReduced vmPFC responses to safety vs. threat were associated with both reduced HF-PRV and increased 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.

BackgroundReduced hippocampal volume is frequently observed in posttraumatic stress disorder (PTSD), but the exact psychological processes associated with these alterations remain unclear. Given the role of the hippocampus in contextual representations of threat and memory, we investigated relationships between retrospectively reported combat exposure, perceived threat, and hippocampal volume in trauma-exposed veterans.MethodsT1-weighted anatomical MRI scans were obtained from 52 male veterans with a broad range of PTSD symptoms. Hippocampal volume was estimated using automatic segmentation tools in FreeSurfer. An index of perceived threat bias was calculated, reflecting the degree of discordance between subjective perceptions of threat while deployed and self-reported combat exposure. Hippocampal volume was regressed on perceived threat bias and PTSD symptoms on the Clinician-Administered PTSD Scale (CAPS).ResultsPerceived threat bias was unrelated to overall CAPS symptoms, but was positively correlated with CAPS avoidance/numbing symptoms and symptoms of depression, anxiety, and worry. The degree of perceived threat bias was inversely correlated with hippocampal volume. Hippocampal volume was also inversely related to avoidance/numbing CAPS symptoms.ConclusionsThese results indicate that volume of the hippocampus, a region involved in contextual threat processing and memory, is related to recalled associations between traumatic events and accompanying subjective threat appraisals. Future research should clarify the precise temporal milieu of these effects and investigate whether individual differences in hippocampal structure and function contribute to exaggerated threat appraisal at the time of trauma, or in subsequently biased memories or appraisals of traumatic events.

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 < .001) and at 1-year follow-up (r = .77, p = .025). This longitudinal intervention study suggests there may be clinical utility for Sudarshan Kriya yoga for PTSD.

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.

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.

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.

Symptom covariation and lack of symptom specificity have proven to be complicating factors in research on the emotional, cognitive, and physiologic characteristics of anxiety and depression. Numerous attempts have been made to investigate the unique and overlapping features of anxiety and depression. Of interest in the present study were potential distinctions among proposed types of anxiety and depression. A variety of self-report measures were administered to 783 college students. Correlational analyses and confirmatory factor analyses converged in suggesting that anxious arousal (somatic anxiety) and anxious apprehension (worry) represent distinct affective dimensions that can be distinguished from depression and negative affect.

The high comorbidity of depression and anxiety is well established empirically but not well understood conceptually, in terms of either psychological or biological mechanisms. A neuropsychological model of regional brain activity in emotion provides contrasting hypotheses for depression and anxiety, with depression associated with a relative decrease and anxiety with a relative increase in right-posterior activity. These hypotheses received support in a comparison of individuals diagnosed with depression and community controls, and also in a separate study of nonpatients administered a measure of perceptual asymmetry. Hierarchical regressions revealed that depression and anxiety were uniquely and jointly associated with perceptual asymmetry. In light of consistent empirical support for the model, implications for conceptualizations of the comorbidity of depression and anxiety are discussed.

Evidence suggests that a distinction between anxious apprehension (worry) and anxious arousal (somatic anxiety) might account for some discrepancies in the literature examining brain activity in anxiety. In the current study, we compared the regional brain activity of groups of anxious apprehension and anxious arousal participants, selected on the basis of self-report measures previously shown to be psychometrically distinct from each other and from a specific measure of depression. Patterns of hemispheric asymmetry in electroencephalogram alpha distinguished the two types of anxiety, with the anxious arousal group showing more right than left activity. No significant asymmetry was found for the anxious apprehension group. The results provide further support for contrasting patterns of brain activity in distinct types of anxiety. Research is needed to specify further the topography and functional significance of this distinction.

The literature on brain activity in depression and anxiety is reviewed with an on highlighting discrepancies and inconsistencies. In particular, and posterior asymmetries have been reported for both depression anxiety, but the magnitude and direction of these asymmetries has been We propose that by identifying subtypes of depression and anxiety of these inconsistencies can be explained. In addition, we review suggesting that issues of comorbidity are important to consider in to account for regional brain activity in depression and anxiety.

Previous studies have reported hemispheric asymmetries in brain activity in anxiety, but the direction of asymmetry has been inconsistent. A distinction between anxious apprehension (e.g., worry) and anxious arousal (e.g., panic), as types of anxiety, may account for some of the discrepancies. To test this proposition, the authors selected participants with self-reported anxious apprehension and experimentally manipulated anxious arousal. Regional brain activity was examined by recording electroencephalograms during rest and during an emotional narrative task designed to elicit anxious arousal. Overall, anxious participants showed a larger asymmetry in favor of the left hemisphere than did controls. In contrast, during the task, anxious participants showed a selective increase in right parietal activity. The results support the hypothesis that anxious apprehension and anxious arousal are associated with different patterns of regional brain activity.

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.

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.

Publisher Summary This chapter reviews cognitive and neuroimaging findings for each of the six anxiety disorders: obsessive‐compulsive disorder, posttraumatic stress disorder, panic disorder, specific phobia, social phobia, and generalized anxiety disorder. Cognitive biases toward threats are common to all six disorders and may correspond to hyperactivation of right hemisphere regions dedicated to threat. Brain structures subserving anxiety pathology include orbital frontal, prefrontal, anterior cingulate, and right parietal cortices, as well as the amygdala, hippocampus, and caudate. Neuropsychological data from extant research on cognitive, affective, and brain processes indicate that anxiety is not a homogenous entity and that attempts to map its neural circuitry must consider symptom variability and comorbidity with other types of psychopathology. This review of the neuroscience findings in anxiety disorders covers a wide array of methods that together provide knowledge of the brain mechanisms involved in the circuitry governing pathological forms of anxiety. The chapter discusses what is known about the neural circuitry of anxiety disorders by examining the relevant cognitive research and structural and functional neuroimaging data, including morphometric magnetic resonance imaging (MRI), functional MRI (f MRI), and positron emission tomography (PET). Various radiotracers are used such as [18F] fluorodeoxyglucose (FDG) for glucose metabolism and 15O‐labeled water for blood flow, single‐ photon emission computed tomography (SPECT) with 133Xenon or 99mTc‐ HMPAO, and scalp‐recorded electroencephalography (EEG).

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.

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.

Generalized anxiety disorder (GAD) patients exhibit heightened anticipatory amygdala activity before presentations of affective pictures (Nitschke et al., 2009). Worrying (experienced chronically in GAD) is a future-oriented thought process (Borkovec, 2002) that may similarly reflect anticipatory anxiety in GAD. GAD severity, indexed by the GAD-Q (Newman et al., 2002) might also overlap significantly with anticipatory anxiety indexed by amygdala activity during the anticipation of aversion.