Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability and spontaneous gamma oscillations, but it is unknown whether these effects are key to ketamine's mechanism of antidepressant action.
Twenty drug-free MDD patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made ≈3 d before and ≈6.5 h after the infusion while patients passively received tactile stimulation to the right and left index fingers, and also while they rested (eyes-closed). Antidepressant response was assessed by percent change in Montgomery-Åsberg Depression Rating Scale scores.
Patients with robust improvements in depressive symptoms 230 m post-infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical (SS ctx) responses increase post-infusion relative to pretreatment responses in responders but not in treatment non-responders. Spontaneous SS ctx gamma-band activity during rest did not change within the same timeframe following ketamine in either responders or non-responders.
These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later, and, thus, may not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to ketamine's antidepressant effect.
cortical excitability; gamma oscillation; ketamine; major depression; magnetoencephalography; NMDA antagonist
An extensive body of research has demonstrated that anxious individuals abnormally process threat-related content. Yet, the manner in which clinical anxiety affects the selection of threatening signals and their maintenance within consciousness is yet to be explored. The present study used an emotional binocular rivalry (e-BR) procedure, in which pictures of faces depicting either fearful or neutral expressions competed with pictures of a house for conscious perception. We assumed that first- or cumulative-preferred perception of faces with fearful over neutral expression (i.e., initial or sustained threat bias, respectively) stand for preferential selection or maintenance of fear content in awareness, correspondingly. Unmedicated patients with social anxiety disorder (SAD) and panic disorder (PAD) were compared to healthy controls for threat-related perceptual biases in the e-BR. At first perception of face, both SAD and PAD patients showed a greater initial threat bias than healthy controls. In contrast, at cumulative dwell-time of face, patient groups demonstrated a diminished sustained threat bias relative to healthy controls, yet in a different manner. SAD patients showed a sustained threat bias, though it was smaller than in healthy controls. Furthermore, increased levels of reported anxiety among SAD patients were associated with enhanced sustained perception of neutral faces. PAD patients, on the other hand, showed no sustained threat bias and a diminished cumulative perception of fearful faces with increased levels of anxiety traits. These findings indicate that anxiety disorders commonly involve an initially enhanced selection of threat signals into awareness, followed by disorder-specific manifestation of diminished preferred maintenance of threat in awareness.
social anxiety disorder; panic disorder; threat bias; binocular rivalry; information processing
Current views of the hippocampus assign this structure, and its prominent theta rhythms, a key role in both cognition and affect. We studied this duality of function in humans, where no direct evidence exists. Whole-head magnetoencephalographic (MEG) data were recorded to measure theta activity while healthy participants (N = 25) navigated two virtual Morris water mazes, one in which they risked receiving aversive shocks without warning to induce anxiety and one in which they were safe from shocks. Results showed that threat of shock elevated anxiety level and enhanced navigation performance compared to the safe condition. MEG source analyses revealed that improved navigation performance during threat was preferentially associated with increased left septal (posterior) hippocampal theta (specifically 4–8 Hz activity), replicating previous research that emphasizes a predominant role of the septal third of the hippocampus in spatial cognition. Moreover, increased self-reported anxiety during threat was preferentially associated with increased left temporal (anterior) hippocampal theta (specifically 2–6 Hz activity), consistent with this region’s involvement in mediating conditioned and innate fear. Supporting contemporary theory, these findings highlight simultaneous involvement of the human hippocampus in spatial cognition and anxiety, and clarify their distinct correlates.
anxiety; hippocampus; magnetoencephalography; spatial cognition; theta oscillation; virtual navigation
According to the emotion-context insensitivity (ECI) hypothesis, major depressive disorder (MDD) is associated with a diminished ability to react emotionally to positive stimuli and with blunting of defensive responses to threat. That defensive responses are blunted in MDD seems inconsistent with the conceptualization and diagnostic nosology of MDD. The present study tested the ECI hypothesis in MDD using a threat of shock paradigm. Twenty-eight patients with MDD (35.5±10.4 years) were compared with 28 controls (35.1±7.4 years). Participants were exposed to three conditions: no shock, predictable shock, and unpredictable shock. Startle magnitude was used to assess defensive responses. Inconsistent with the ECI hypothesis, startle potentiation to predictable and unpredictable shock was not reduced in the MDD group. Rather, MDD patients showed elevated startle throughout testing as well as increased contextual anxiety during the placement of the shock electrodes and in the predictable condition. A regression analysis indicated that illness duration and Beck depression inventory scores explained 37% (p<.005) of the variance in patients’ startle reactivity. MDD is not associated with emotional blunting but rather enhanced defensive reactivity during anticipation of harm. These results do not support a strong version of the ECI hypothesis. Understanding the nature of stimuli or situations that lead to blunted or enhanced defensive reactivity will provide better insight into dysfunctional emotional experience in MDD.
Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short-duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphé-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders.
ATD; serotonin; anxiety; startle; depression; biological psychiatry; serotonin; mood/anxiety/stress disorders; psychiatry & behavioral sciences; ATD; anxiety; startle
Anxiety impairs the ability to think and concentrate, suggesting that the interaction between emotion and cognition may elucidate the debilitating nature of pathological anxiety. Using a verbal n-back task that parametrically modulated cognitive load, we explored the effect of experimentally-induced anxiety on task performance and the startle reflex. Findings suggest there is a crucial inflection point between moderate and high cognitive load, where resources shift from anxious apprehension to focus on task demands. Specifically, we demonstrate that anxiety impairs performance under low-load, but is reduced when subjects engage in a difficult task that occupies executive resources. We propose a two-component model of anxiety that describes a cognitive mechanism behind performance impairment and an automatic response that supports sustained anxiety-potentiated startle. Implications for therapeutic interventions and emotional pathology are discussed.
Anxiety is typically considered an impediment to cognition. We propose anxiety-related impairments in cognitive-behavioral performance are the consequences of enhanced stimulus-driven attention. Accordingly, reflexive, habitual behaviors that rely on stimulus-driven mechanisms should be facilitated in an anxious state, while novel, flexible behaviors that compete with the former should be impaired. To test these predictions, healthy adults (N=17) performed a mixed-saccade task, which pits habitual actions (pro-saccades) against atypical ones (anti-saccades), under anxiety-inducing threat of shock and safe conditions. Whole-head magnetoencephalography (MEG) captured oscillatory responses in the preparatory interval preceding target onset and saccade execution. Results showed threat-induced anxiety differentially impacted response times based on the type of saccade initiated, slowing anti-saccades but facilitating erroneous pro-saccades on anti-saccade trials. MEG source analyses revealed that successful suppression of reflexive pro-saccades and correct initiation of anti-saccades during threat was marked by increased theta power in right ventrolateral prefrontal cortical and midbrain regions (superior colliculi) implicated in stimulus-driven attention. Theta activity may delay stimulus-driven processes to enable generation of an anti-saccade. Moreover, compared to safety, threat reduced beta desynchronization in inferior parietal cortices during anti-saccade preparation but increased it during pro-saccade preparation. Differential effects in inferior parietal cortices indicate a greater readiness to execute anti-saccades during safety and to execute pro-saccades during threat. These findings suggest that, in an anxiety state, reduced cognitive-behavioral flexibility may stem from enhanced stimulus-driven attention, which may serve the adaptive function of optimizing threat detection.
anxiety; beta oscillation; magnetoencephalography; saccade; stimulus-driven attention; theta oscillation
Functionally, anxiety serves to increase vigilance towards aversive stimuli and improve the ability to detect and avoid danger. We have recently shown, for instance, that anxiety increases the ability to a) detect and b) instigate defensive responses towards aversive and not appetitive face stimuli in healthy individuals. This is arguably the key adaptive function of anxiety, yet the neural circuitry underlying this valence-specific effect is unknown. In the present translational study, we sought evidence for the proposition that dorsomedial regions of the prefrontal (DMPFC) and cingulate cortex constitute the human homologue of the rodent prelimbic and are thus associated with increased amygdala responding during this adaptive threat bias in anxiety. To this end, we applied a novel functional connectivity analysis to healthy subjects (N=20) identifying the emotion of fearful and happy faces in an fMRI scanner under anxious (threat of unpredictable foot shock) and non-anxious (safe) conditions. We showed that anxiety significantly increased positive DMPFC-amygdala connectivity during the processing of fearful faces. This effect was a) valence-specific (it was not seen for happy faces), b) paralleled by faster behavioral response to fearful faces, and c) correlated positively with trait anxiety. As such we provide the first experimental support for an anxiety-mediated, valence-specific, DMPFC-amygdala aversive amplification mechanism in healthy humans. This may be homologous to the rodent prelimbic-amygdala circuit and may, given the relationship with trait anxiety, underlie vulnerability to anxiety disorders. This study thus pinpoints a key neural mechanism in adaptive anxiety and highlights its potential link to maladaptive anxiety.
amygdala; dMPFC; functional connectivity; prelimbic; anxiety; threat bias
Anxiety has wide reaching effects on cognition; evidenced most prominently by the “difficulties concentrating” seen in anxiety disorders, and by adaptive harm-avoidant behaviors adopted under threatening circumstances. Despite having critical implications for daily-living, the precise impact of anxiety on cognition is as yet poorly quantified. Here we attempt to clarify the impact of anxiety on sustained attention and response inhibition via a translational anxiety induction in healthy individuals (N = 22). Specifically, in a within-subjects design, participants completed the Sustained Attention to Response Task (SART) in which subjects withhold responses to infrequent no-go stimuli under threat of unpredictable electrical shock (anxious) and safe (non-anxious) conditions. Different studies have argued that this task measures either (1) attention lapses due to off-task thinking or (2) response inhibition; two cognitive functions which are likely impacted by anxiety. We show that threat of shock significantly reduces errors of commission on the no-go trials relative to the safe condition whilst having no effect on go trials or overall reaction time (RT). We suggest that this is because threat of shock during SART promotes response inhibition. In particular we argue that, by virtue of frequency, subjects acquire a habitual bias toward a go response which impairs no-go performance and that threat of shock improves the ability to withhold these prepotent responses. This improved response inhibition likely falls within the range of adaptive cognitive functions which promote cautious harm avoidance under threatening conditions, although a range of alternative explanations for this effect is discussed.
anxiety; threat; threat of shock; response inhibition; mind-wandering
Anxiety can be distracting, disruptive, and incapacitating. Despite problems with empirical replication of this phenomenon, one fruitful avenue of study has emerged from working memory (WM) experiments where a translational method of anxiety induction (risk of shock) has been shown to disrupt spatial and verbal WM performance. Performance declines when resources (e.g., spatial attention, executive function) devoted to goal-directed behaviors are consumed by anxiety. Importantly, it has been shown that anxiety-related impairments in verbal WM depend on task difficulty, suggesting that cognitive load may be an important consideration in the interaction between anxiety and cognition. Here we use both spatial and verbal WM paradigms to probe the effect of cognitive load on anxiety-induced WM impairment across task modality. Subjects performed a series of spatial and verbal n-back tasks of increasing difficulty (1, 2, and 3-back) while they were safe or at risk for shock. Startle reflex was used to probe anxiety. Results demonstrate that induced-anxiety differentially impacts verbal and spatial WM, such that low and medium-load verbal WM is more susceptible to anxiety-related disruption relative to high-load, and spatial WM is disrupted regardless of task difficulty. Anxiety impacts both verbal and spatial processes, as described by correlations between anxiety and performance impairment, albeit the effect on spatial WM is consistent across load. Demanding WM tasks may exert top-down control over higher-order cortical resources engaged by anxious apprehension, however high-load spatial WM may continue to experience additional competition from anxiety-related changes in spatial attention, resulting in impaired performance. By describing this disruption across task modalities, these findings inform current theories of emotion–cognition interactions and may facilitate development of clinical interventions that seek to target cognitive impairments associated with anxiety.
anxiety; working memory; cognition; startle; electromyography; performance
Anxiety disorders constitute a sizeable worldwide health burden with profound social and economic consequences. The symptoms are wide-ranging; from hyperarousal to difficulties with concentrating. This latter effect falls under the broad category of altered cognitive performance which is the focus of this review. Specifically, we examine the interaction between anxiety and cognition focusing on the translational threat of unpredictable shock paradigm; a method previously used to characterize emotional responses and defensive mechanisms that is now emerging as valuable tool for examining the interaction between anxiety and cognition. In particular, we compare the impact of threat of shock on cognition in humans to that of pathological anxiety disorders. We highlight that both threat of shock and anxiety disorders promote mechanisms associated with harm avoidance across multiple levels of cognition (from perception to attention to learning and executive function)—a “hot” cognitive function which can be both adaptive and maladaptive depending upon the circumstances. This mechanism comes at a cost to other functions such as working memory, but leaves some functions, such as planning, unperturbed. We also highlight a number of cognitive effects that differ across anxiety disorders and threat of shock. These discrepant effects are largely seen in “cold” cognitive functions involving control mechanisms and may reveal boundaries between adaptive (e.g., response to threat) and maladaptive (e.g., pathological) anxiety. We conclude by raising a number of unresolved questions regarding the role of anxiety in cognition that may provide fruitful avenues for future research.
anxiety; cognition; threat of shock; anxiety disorders; perception; attention; learning and memory; executive function
Fearful faces readily activate the amygdala. Yet, whether fearful faces evoke fear is unclear. Startle studies show no potentiation of startle by fearful faces, suggesting that such stimuli do not activate defense mechanisms. However, the response to biologically relevant stimuli may be sensitized by anxiety. The present study tested the hypothesis that startle would not be potentiated by fearful faces in a safe context, but that startle would be larger during fearful faces compared to neutral faces in a threat-of-shock context. Subjects viewed fearful and neutral faces in alternating periods of safety and threat of shock. Acoustic startle stimuli were presented in the presence and absence of the faces. Startle was transiently potentiated by fearful faces compared to neutral faces in the threat periods. This suggests that although fearful faces do not prompt behavioral mobilization in an innocuous context, they can do so in an anxiogenic one.
Fear; Anxiety; Startle reflex; Fearful face
Major questions remain about the specific role of testosterone in human spatial navigation. We tested 10 boys (mean age 11.65 years) with an extremely rare disorder of androgen excess (Familial Male Precocious Puberty, FMPP) and 40 healthy boys (mean age 12.81 years) on a virtual version of the Morris Water Maze task. In addition, anatomical magnetic resonance images were collected for all patients and a subsample of the controls (n=21) after task completion. Behaviourally, no significant differences were found between both groups. However, in the MRI analyses, grey matter volume (GMV) was correlated with performance using voxel-based morphometry (VBM). Group differences in correlations of performance with GMV were apparent in medial regions of the prefrontal cortex as well as the middle occipital gyrus and the cuneus. By comparison, similar correlations for both groups were found in the inferior parietal lobule. These data provide novel insight into the relation between testosterone and brain development and suggest that morphological differences in a spatial navigation network covary with performance in spatial ability.
testosterone; spatial navigation; development; familial male precocious puberty; VBM; virtual water maze
A detailed understanding of how individuals diagnosed with social anxiety disorder (SAD) respond physiologically under social-evaluative threat is lacking. We aimed to isolate the specific components of public speaking that trigger fear in vulnerable individuals and best discriminate among SAD and healthy individuals.
Sixteen individuals diagnosed with SAD and 16 healthy individuals were asked to prepare and deliver a short speech in a virtual reality (VR) environment. The VR environment simulated standing center stage before a live audience and allowed us to gradually introduce social cues during speech anticipation. Startle eye-blink responses were elicited periodically by white noise bursts presented during anticipation, speech delivery, and recovery in VR, as well as outside VR during an initial habituation phase.
SAD individuals reported greater distress and state anxiety than healthy individuals across the entire procedure (ps < .005). Analyses of startle reactivity revealed a robust group difference during speech anticipation in VR, specifically as audience members directed their eye gaze and turned their attention toward participants (p < .05, Bonferroni corrected).
The VR environment is sufficiently realistic to provoke fear and anxiety in individuals highly vulnerable to socially threatening situations. SAD individuals showed potentiated startle, indicative of a strong phasic fear response, specifically when they perceived themselves as occupying the focus of others' attention as speech time approached. Potentiated startle under social-evaluative threat indexes SAD-related fear of negative evaluation.
Research has highlighted the need for new methods to assess emotions in children on multiple levels in order to gain better insight into the complex processes of emotional development. The startle reflex is a unique translational tool that has been utilized to study physiological processes during fear and anxiety in rodents and in human subjects. However, it has been challenging to implement developmentally-appropriate startle experiments in children. This paper describes a procedure that uses predictable and unpredictable aversive events to distinguish between phasic fear and sustained anxiety in children and adolescents. We investigated anxious responses, as measured with the startle reflex, in youth (N = 36, mean age[range] = 12.63 [7–17]) across three conditions: no aversive events (N), predictable aversive events (P), and unpredictable aversive events (U). Short-duration cues were presented several times in each condition. Aversive events were signaled by the cues in P, but were presented randomly in U. Participants showed fear-potentiated startle to the threat cue in P. Startle responses were also elevated between cues in U compared to N, suggesting that unpredictable aversive events can evoke a sustained state of anxiety in youth. This latter effect was influenced by sex, being greater in girls compared to boys. These findings indicate the feasibility of this experimental induction of the startle reflex in response to predictable and unpredictable events in children and adolescents, enabling future research on inter-individual differences in fear and anxiety and their development in youth.
fear; anxiety; unpredictability; psychophysiology; startle reflex; sex differences
Preclinical evidence implicates several neurotransmitter systems in the extinction of conditioned fear. These results are of great interest, because the reduction of acquired fear associations is critical in therapies for anxiety disorders. We tested whether findings with respect to the N-methyl-D-aspartate (NMDA) and cannabinoid receptor (CB) systems in animals carry over to healthy human subjects. To that end, we administered selected doses of D-cycloserine (partial NMDA receptor agonist, 250 mg), delta-9-tetrahydrocannabinol (THC, CB1 receptor agonist, 10 mg), or placebo prior to the extinction session of a 3-day conditioning protocol. D-cycloserine did not affect within-session extinction, or the retention of extinction in healthy human participants, in contrast with patient data but in line with previous reports in healthy volunteers. During extinction training, Δ9-THC reduced conditioned skin conductance responses, but not fear-potentiated startle. This effect was not retained at the retention test 2 days later, suggesting it was dependent on acute effects of the drug. Our findings implicate that facilitation of the CB1 or NMDA system with the substances used in this study does not affect conditioned fear extinction lastingly in healthy humans. The apparent discrepancy between these findings and the results from (pre-) clinical trials is discussed in terms of room for improvement in these systems in healthy volunteers, and the lack of specificity of THC as a CB1 agonist.
Δ9-THC; d-cycloserine; extinction; fear conditioning; fear-potentiated startle; human
The threat of predictable and unpredictable aversive events was developed to assess short-duration (fear) and long-duration (anxiety) aversive states in humans. A typical experiment consists of three conditions: a safe condition (neutral (N)), during which participants are safe from aversive stimuli, and two threat conditions—one in which aversive events are administered predictably (P) (i.e., signaled by a threat cue), and one in which aversive stimuli are administered unpredictably (U). During the so-called NPU -threat test, ongoing change in aversive states is measured with the startle reflex. The NPU -threat test has been validated in pharmacological and clinical studies and can be implemented in children and adults. Similar procedures have been applied in animal models, making the NPU -threat test an ideal tool for translational research. The procedure is relatively short (35 min), simple to implement and generates consistent results with large effect sizes.
Amygdala reactivity to threat-related distractor stimuli can be abolished in perceptually-demanding contexts. Premised on the biological imperative to respond swiftly to threat, we demonstrate, however, that when participants are threatened by shock, greater amygdala responses to fearful compared to neutral distractor faces is preserved under conditions of high attentional demand. Lateral prefrontal cortices also showed selective responding to fearful distractor faces under these conditions, suggesting that threat-related distractor stimuli engaged attentional control mechanisms. We conclude that anxiety elicited by looming threat promotes neurocognitive processes that broaden attention and enhance sensitivity to potential danger cues, even when perceptual systems are taxed.
amygdala; anxiety; attention; fearful faces; perceptual load; prefrontal cortices
Anxious individuals exhibit threat biases at multiple levels of information processing. From a developmental perspective, abnormal safety learning in childhood may establish threat-related appraisal biases early, which may contribute to chronic disorders in adulthood. The current review illustrates how the interface among attention, threat appraisal, and fear learning can generate novel insights for outcome prediction. This review summarizes data on amygdala function, as it relates to learning and attention, highlights the importance of examining threat appraisal, and introduces a novel imaging paradigm to investigate the neural correlates of threat appraisal and threat-sensitivity during extinction recall. This novel paradigm can be used to investigate key questions relevant to prognosis and treatment.
fear conditioning; generalization; attention; amygdala; ventromedial prefrontal cortex
In the conditioned fear paradigm, repeated pairing of an aversive unconditioned stimulus (US) (e.g. electric shock) with a neutral conditioned stimulus (CS) (e.g. bright light) results in a conditioned fear response to the light alone. Animal studies have shown that the amygdala plays a critical role in acquisition of conditioned fear responses, while the medial prefrontal cortex (including anterior cingulate), through inhibition of amygdala responsiveness, has been hypothesized to play a role in extinction of fear responses. No studies have examined neural correlates of fear conditioning and extinction in patients with post-traumatic stress disorder (PTSD).
Women with early childhood sexual-abuse-related PTSD (n=8) and women without abuse or PTSD (n=11) underwent measurement of psychophysiological (skin conductance) responding as well as positron emission tomographic (PET) measurement of cerebral blood flow during habituation, acquisition and extinction conditions. During habituation subjects were repeatedly exposed to a blue square on a screen. During acquisition, exposure to the blue square (CS) was paired with an electric shock to the forearm (US). With extinction, subjects were again exposed to the blue squares without shock. On a different day subjects went through the same procedure with electric shocks administered randomly in the absence of the blue square.
Skin conductance responding to the CS was consistent with the development of conditioned responses with this paradigm. PTSD patients had increased left amygdala activation with fear acquisition, and decreased anterior cingulate function during extinction, relative to controls.
These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.
Individuals with anxiety disorders demonstrate altered cognitive performance including (1) cognitive biases towards negative stimuli (affective biases) and (2) increased cognitive rigidity (e.g., impaired conflict adaptation) on affective Stroop tasks. Threat of electric shock is frequently used to induce anxiety in healthy individuals, but the extent to which this manipulation mimics the cognitive impairment seen in anxiety disorders is unclear. In this study, 31 healthy individuals completed an affective Stroop task under safe and threat-of-shock conditions. We showed that threat (1) enhanced aversive processing and abolished a positive affective bias but (2) had no effect on conflict adaptation. Threat of shock thus partially models the effects of anxiety disorders on affective Stroop tasks. We suggest that the affective state of anxiety—which is common to both threat and anxiety disorders—modulates the neural inhibition of subcortical aversive processing, whilst pathologies unique to anxiety disorders modulate conflict adaptation.
Anxiety; Threat of shock; Affective bias; Conflict adaptation; Resilience; BIS/BAS
Dysfunction of the hippocampus has long been suspected to be a key component of the pathophysiology of major depressive disorder. Despite evidence of hippocampal structural abnormalities in depressed patients, abnormal hippocampal functioning has not been demonstrated. We aimed to link spatial navigation deficits previously documented in depressed patients to abnormal hippocampal functioning using a virtual reality navigation task.
Whole-head magnetoencephalography (MEG) recordings were collected while participants – 19 patients diagnosed with major depressive disorder and 19 healthy controls, matched by gender and age – navigated a virtual Morris water maze to find a hidden platform, and a visible one as a control condition. Behavioral measures were taken to assess navigation performance. Theta oscillatory activity (4-8 Hz) was mapped across the brain on a voxel-wise basis using a spatial-filtering MEG source analysis technique.
Depressed patients performed worse than controls in navigating to the hidden platform. Robust group differences in theta activity were observed in right medial temporal cortices during navigation, with patients exhibiting less engagement of the anterior hippocampus and parahippocampal cortices compared to controls. Left posterior hippocampal theta activity was positively correlated with individual performance within each group.
Consistent with previous findings, depressed patients showed impaired spatial navigation. Dysfunction of right anterior hippocampus and parahippocampal cortices may underlie this deficit and stem from structural abnormalities commonly found in depressed patients.
The debilitating effects of chronic glucocorticoids excess are well-known, but comparatively little is understood about the role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration aversive states, such as “anxiety,” but not relatively similar, briefer aversive states, such as “fear.” However, no prior experimental studies in humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but dissociable aversive states. The current study examines these effects, as instantiated with short- and long-duration threats.
Healthy volunteers (n = 18) received placebo or a low (20 mg) or a high (60 mg) dose of hydrocortisone in a double-blind crossover design. Subjects were exposed repeatedly to three 150-sec duration conditions: no shock; predictable shocks, in which shocks were signaled by a short-duration threat cue; and unpredictable shocks. Aversive states were indexed by acoustic startle. Fear was operationally defined as the increase in startle reactivity during the threat cue in the predictable condition (fear-potentiated startle). Anxiety was operationally defined as the increase in baseline startle from the no shock to the two threat conditions (anxiety-potentiated startle).
Hydrocortisone affected neither baseline nor short-duration, fear-potentiated startle but increased long-duration anxiety-potentiated startle.
These results suggest that hydrocortisone administration in humans selectively increases anxiety but not fear. Possible mechanisms implicated are discussed in light of prior data in rodents. Specifically, hydrocortisone might increase anxiety via sensitization of corticotrophin-releasing hormones in the bed nucleus of the stria terminalis.
Amygdala; anxiety; BNST; corticotropin-releasing hormone (CRH); cortisol; fear; predictability; startle reflex
Impaired function of the central gamma-aminobutyric acid (GABA) system, which provides the brain’s major inhibitory pathways, is thought to play an important role in the pathophysiology of anxiety disorders. The effect of acute psychological stress on the human GABA-ergic system is still unknown, however. The purpose of this study was to determine the effect of acute stress on prefrontal GABA levels.
A recently developed noninvasive magnetic resonance spectroscopy method was used to measure changes in the GABA concentration of the prefrontal cortex in 10 healthy human subjects during a threat-of-shock condition and during a safe condition (two sessions on different days). The main outcome measure was the mean GABA concentration within a 3×3×2-cm3 voxel selected from the medial prefrontal cortex.
Prefrontal GABA decreased by approximately 18% in the threat-of-shock condition relative to the safe condition. This reduction was specific to GABA, since the concentrations of N-acetyl-aspartate, choline-containing compounds, and glutamate/glutamine levels obtained in the same spectra did not change significantly.
This result appeared compatible with evidence from preclinical studies in rodents, which showed rapid presynaptic down-regulation of GABA-ergic neurotransmission in response to acute psychological stress. The molecular mechanism and functional significance of this reduced inhibitory effect of acute psychological stress in relation to impaired GABA-ergic function in anxiety disorders merit further investigation.
Pregenual anterior cingulate cortex (pgACC) hyperactivity differentiates treatment responders from non-responders to various pharmacological antidepressant interventions, including ketamine, an N-methyl--aspartate receptor antagonist. Evidence of pgACC hyperactivition during non-emotional working memory tasks in patients with major depressive disorder (MDD) highlights the importance of this region for processing both emotionally salient and cognitive stimuli. However, it is unclear whether pgACC activity might serve as a potential biomarker of antidepressant response during working memory tasks as well, in line with previous research with emotionally arousing tasks. This study tested the hypothesis that during the N-back task, a widely used working memory paradigm, low pretreatment pgACC activity, as well as coherence between the pgACC and the amygdala, would be correlated with the clinical improvement after ketamine. Magnetoencephalography (MEG) recordings were obtained from 15 drug-free patients with MDD during working memory performance 1 to 3 days before receiving a single ketamine infusion. Functional activation patterns were analyzed using advanced MEG source analysis. Source coherence analyses were conducted to quantify the degree of long-range functional connectivity between the pgACC and the amygdala. Patients who showed the least engagement of the pgACC in response to increased working memory load showed the greatest symptomatic improvement within 4 h of ketamine administration (r=0.82, p=0.0002, false discovery rate (FDR) <0.05). Pretreatment functional connectivity between the pgACC and the left amygdala was negatively correlated with antidepressant symptom change (r=−0.73, p=0.0021, FDR <0.05).These data implicate the pgACC and its putative interaction with the amygdala in predicting antidepressant response to ketamine in a working memory task context.
major depressive disorder (MDD); magnetoencephalography (MEG); N-back; biomarker; beta desynchronization; Biological Psychiatry; Mood/Anxiety/Stress Disorders; Imaging; Clinical or Preclinical; Glutamate; magnetoencephalography; N-back; beta desynchronization; biomarker