A neural oscillatory signature of sustained anxiety.

BACKGROUND: Anxiety is a sustained response to uncertain threats; yet few studies have explored sustained neurobiological activities underlying anxious states, particularly spontaneous neural oscillations. To address this gap, we reanalysed magnetoencephalographic (MEG) data recorded during induced anxiety to identify differences in sustained oscillatory activity between high- and low-anxiety states. METHODS: We combined data from three previous MEG studies in which healthy adults (total N = 51) were exposed to alternating periods of threat of unpredictable shock and safety while performing a range of cognitive tasks (passive oddball, mixed-saccade or stop-signal tasks). Spontaneous, band-limited, oscillatory activity was extracted from middle and late intervals of the threat and safe periods, and regional power distributions were reconstructed with adaptive beamforming. Conjunction analyses were used to identify regions showing overlapping spectral power differences between threat and safe periods across the three task paradigms. RESULTS: MEG source analyses revealed a robust and widespread reduction in beta (14-30 Hz) power during threat periods in bilateral sensorimotor cortices extending into right prefrontal regions. Alpha (8-13 Hz) power reductions during threat were more circumscribed, with notable peaks in left intraparietal sulcus and thalamus. CONCLUSIONS: Threat-induced anxiety is underpinned by a sustained reduction in spontaneous beta- and alpha-band activity in sensorimotor and parietal cortical regions. This general oscillatory pattern likely reflects a state of heightened action readiness and vigilance to cope with uncertain threats. Our findings provide a critical reference for which to identify abnormalities in cortical oscillatory activities in clinically anxious patients as well as evaluating the efficacy of anxiolytic treatments.

Anxious arousal alters prefrontal cortical control of stopping.

Anxiety heightens vigilance and stimulus-driven attention to the environment, which may in turn disrupt cognitive control processes such as response inhibition. How this unfolds at the neural level is unclear. Previous evidence implicates the right inferior frontal gyrus (IFG) as an important cortical node in both stimulus-driven attention and inhibitory control. Here we used magnetoencephalography (MEG) to investigate the neural mechanisms involved in the relationship between threat-induced anxiety and stopping during a stop-signal task, where a visual go signal was occasionally followed by an auditory stop signal. Healthy individuals (N = 18) performed the task during the threat of unpredictable shocks and safety to modulate anxious arousal. Behaviorally, we observed that stopping was impaired during threat (i.e. slower estimated stop-signal reaction times), indicating that anxious arousal weakens inhibitory control. MEG source analyses revealed that bilateral IFG and right dorsal prefrontal cortex showed increased beta-band activity (14-30 Hz) to the stop signal that varied as a function of successful stopping during nonanxious (safe) conditions only. Moreover, peak beta-band responses from right IFG were inversely correlated with stopping efficiency during nonanxious conditions. These findings support theoretical claims that beta oscillations function to maintain the current sensorimotor state, and that the lack of differential beta-band activity in prefrontal cortices underlies anxiety-related deficits in inhibitory control. We specifically argue that altered right IFG functioning might directly link impaired cognitive control to heightened stimulus-driven responding in anxiety states.

The translational neural circuitry of anxiety.

Anxiety is an adaptive response that promotes harm avoidance, but at the same time excessive anxiety constitutes the most common psychiatric complaint. Moreover, current treatments for anxiety-both psychological and pharmacological-hover at around 50% recovery rates. Improving treatment outcomes is nevertheless difficult, in part because contemporary interventions were developed without an understanding of the underlying neurobiological mechanisms that they modulate. Recent advances in experimental models of anxiety in humans, such as threat of unpredictable shock, have, however, enabled us to start translating the wealth of mechanistic animal work on defensive behaviour into humans. In this article, we discuss the distinction between fear and anxiety, before reviewing translational research on the neural circuitry of anxiety in animal models and how it relates to human neuroimaging studies across both healthy and clinical populations. We highlight the roles of subcortical regions (and their subunits) such as the bed nucleus of the stria terminalis, the amgydala, and the hippocampus, as well as their connectivity to cortical regions such as dorsal medial and lateral prefrontal/cingulate cortex and insula in maintaining anxiety responding. We discuss how this circuitry might be modulated by current treatments before finally highlighting areas for future research that might ultimately improve treatment outcomes for this common and debilitating transdiagnostic symptom.

High-gamma activity in the human hippocampus and parahippocampus during inter-trial rest periods of a virtual navigation task.

In rodents, hippocampal cell assemblies formed during learning of a navigation task are observed to re-emerge during resting (offline) periods, accompanied by high-frequency oscillations (HFOs). This phenomenon is believed to reflect mechanisms for strengthening newly-formed memory traces. Using magnetoencephalography recordings and a beamforming source location algorithm (synthetic aperture magnetometry), we investigated high-gamma (80-140 Hz) oscillations in the hippocampal region in 18 human participants during inter-trial rest periods in a virtual navigation task. We found right hippocampal gamma oscillations mirrored the pattern of theta power in the same region during navigation, varying as a function of environmental novelty. Gamma power during inter-trial rest periods was positively correlated with theta power during navigation in the first task set when the environment was new and predicted greater performance improvement in the subsequent task set two where the environment became familiar. These findings provide evidence for human hippocampal reactivation accompanied by high-gamma activities immediately after learning and establish a link between hippocampal high-gamma activities and subsequent memory performance.

The functional role of human right hippocampal/parahippocampal theta rhythm in environmental encoding during virtual spatial navigation.

Low frequency theta band oscillations (4-8 Hz) are thought to provide a timing mechanism for hippocampal place cell firing and to mediate the formation of spatial memory. In rodents, hippocampal theta has been shown to play an important role in encoding a new environment during spatial navigation, but a similar functional role of hippocampal theta in humans has not been firmly established. To investigate this question, we recorded healthy participants' brain responses with a 160-channel whole-head MEG system as they performed two training sets of a virtual Morris water maze task. Environment layouts (except for platform locations) of the two sets were kept constant to measure theta activity during spatial learning in new and familiar environments. In line with previous findings, left hippocampal/parahippocampal theta showed more activation navigating to a hidden platform relative to random swimming. Consistent with our hypothesis, right hippocampal/parahippocampal theta was stronger during the first training set compared to the second one. Notably, theta in this region during the first training set correlated with spatial navigation performance across individuals in both training sets. These results strongly argue for the functional importance of right hippocampal theta in initial encoding of configural properties of an environment during spatial navigation. Our findings provide important evidence that right hippocampal/parahippocampal theta activity is associated with environmental encoding in the human brain. Hum Brain Mapp 38:1347-1361, 2017. © 2016 Wiley Periodicals, Inc.

Passive avoidance is linked to impaired fear extinction in humans.

Conventional wisdom dictates we must face our fears to conquer them. This idea is embodied in exposure-based treatments for anxiety disorders, where the intent of exposure is to reverse a history of avoidant behavior that is thought to fuel a patient's irrational fears. We tested in humans the relationship between fear and avoidance by combining Pavlovian differential fear conditioning with a novel task for quantifying spontaneous passive avoidant behavior. During self-guided navigation in virtual reality following de novo fear conditioning, we observed participants keeping their distance from the feared object. At the individual level, passive avoidant behavior was highly associated with maladaptive fear expression (fear-potentiated startle) during late extinction training, indicating that extinction learning was impaired following a brief episode of avoidance. Avoidant behavior, however, was not related to initial acquired fear, raising doubt about a straightforward link between physiological fear and behavioral avoidance. We conclude that a deeper understanding of what motivates avoidance may offer a target for early intervention, before fears transition from the rational to the irrational.

A shared threat-anticipation circuit is dynamically engaged at different moments by certain and uncertain threat.

Temporal dynamics play a central role in models of emotion: "fear" is widely conceptualized as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Yet the underlying human neurobiology remains contentious. Leveraging an ethnoracially diverse sample, translationally relevant paradigm, and theory-driven modeling approach, we demonstrate that certain and uncertain threat recruit a shared threat-anticipation circuit. This circuit exhibits persistently elevated activation when anticipating uncertain threat encounters and a transient burst of activation in the moments before certain encounters. For many scientists and clinicians, feelings are the defining feature of human fear and anxiety. Here we used an independently validated brain signature to covertly decode the momentary dynamics of anticipatory distress for the first time. Results mirrored the dynamics of neural activation. These observations provide fresh insights into the neurobiology of threat-elicited emotions and set the stage for more ambitious clinical and mechanistic research.

Distinct contributions of human hippocampal theta to spatial cognition and anxiety.

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 as 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, a benefit and detriment to cognition: behavioral and magnetoencephalographic evidence from a mixed-saccade task.

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.

Negative urgency is related to impaired response inhibition during threatening conditions.

While it has been argued that impulsivity and inhibition are unrelated, previous evidence suggests that the relationship between the two can only be seen when their characteristics are closely matched. The negative urgency subscale of the UPPS-P describes impulsive action during negative affect. This was predicted to correlate more strongly with stop-signal reaction-time (SSRT) during threatening conditions than non-threatening conditions. Healthy participants (N = 68) completed the stop-signal task in threatening (induced by threat-of-shock) and non-threatening conditions after completing the UPPS-P and Spielberg State Trait Anxiety Inventory (STAI) scales. Negative urgency correlated with the difference in SSRT (threat - safe) after controlling for other variables. Conversely, similar correlations were not observed for positive urgency, suggesting threat increases the poorer inhibition seen in those high on negative urgency but not for those high on positive urgency. Additionally, sensation seeking correlated with the difference in SSRT (threat - safe) in the opposite direction, suggesting sensation seeking was related to a reduction in the effect of threat. The findings suggest the relationship between negative urgency and inhibition is facilitated by threatening conditions and that high sensation seekers experience threatening stimuli differently.

A preliminary study of the neural mechanisms of frustration in pediatric bipolar disorder using magnetoencephalography.

BACKGROUND: Irritability is prevalent and impairing in pediatric bipolar disorder (BD) but has been minimally studied using neuroimaging techniques. We used magnetoencephalography (MEG) to study theta band oscillations in the anterior cingulate cortex (ACC) during frustration in BD youth. ACC theta power is associated with attention to emotional stimuli, and the ACC may mediate responses to frustrating stimuli. METHODS: We used the affective Posner task, an attention paradigm that uses rigged feedback to induce frustration, to compare 20 medicated BD youth (14.9+/-2.0 years; 45% male) and 20 healthy controls (14.7+/-1.7 years; 45% male). MEG measured neuronal activity after negative and positive feedback; we also compared groups on reaction time, response accuracy, and self-reported affect. Patients met strict DSM-IV BD criteria and were euthymic. Controls had no psychiatric history. RESULTS: BD youth reported more negative affective responses than controls. After negative feedback, BD subjects, relative to controls, displayed greater theta power in the right ACC and bilateral parietal lobe. After positive feedback, BD subjects displayed lower theta power in the left ACC than did controls. Correlations between MEG, behavior, and affect were nonsignificant. CONCLUSION: In this first MEG study of BD youth, BD youth displayed patterns of theta oscillations in the ACC and parietal lobe in response to frustration-inducing negative feedback that differed from healthy controls. These data suggest that BD youth may display heightened processing of negative feedback and exaggerated self-monitoring after frustrating emotional stimuli. Future studies are needed with unmedicated bipolar youth, and comparison ADHD and anxiety groups.

Gender differences in navigation performance are associated with differential theta and high-gamma activities in the hippocampus and parahippocampus.

Hippocampal rhythms are important for spatial navigation. This study examined whether gender differences in human navigation performance are associated with differences in hippocampal rhythms. We measured brain activities in males and females with whole-head magnetoencephalography (MEG), while they performed a virtual Morris water maze task. Behavioural results showed clear gender differences: males were significantly faster than females; unlike males, females did not show improved navigation performance in a familiar vs. new environment. MEG results showed that the magnitudes of right hippocampal/parahippocampal theta rhythm were similar between the two groups during navigation in a new environment; however, unlike males who exhibited a significant decrease in right hippocampal/parahippocampal theta power in the familiar environment shown before, females showed no change. This result may suggest faster environmental learning in males vs. females. After navigating in the new environment during the inter-trial (ITI) rest periods, males showed significantly higher right hippocampal/parahippocampal high-gamma power than females, suggesting greater consolidation in males. Moreover, right hippocampal/parahippocampal theta power during navigation correlated with navigation performance in both genders; high-gamma power during the ITI was correlated with navigation performance only in males. These associations may provide further support for the functional importance of theta and high-gamma rhythms in navigation. Overall, this study provides new insights into the neurophysiological mechanisms underlying gender differences in spatial navigation.

Functional Connectivity of the Anterior and Posterior Hippocampus: Differential Effects of Glucose in Younger and Older Adults.

The hippocampus features structurally and functionally distinct anterior and posterior segments. Relatively few studies have examined how these change during aging or in response to pharmacological interventions. Alterations in hippocampal connectivity and changes in glucose regulation have each been associated with cognitive decline in aging. A distinct line of research suggests that administration of glucose can lead to a transient improvement in hippocampus-dependent memory. Here, we probe age, glucose and human cognition with a special emphasis on resting-state functional connectivity (rsFC) of the hippocampus along its longitudinal axis to the rest of the brain. Using a randomized, placebo-controlled, double-blind, crossover design 32 healthy adults (16 young and 16 older) ingested a drink containing 25 g glucose or placebo across two counter balanced sessions. They then underwent resting-state functional magnetic resonance imaging (rs-fMRI) and cognitive testing. There was a clear dissociation in the effects of glucose by age. Magnitude change in rsFC from posterior hippocampus (pHPC) to medial frontal cortex (mPFC) was correlated with individual glucose regulation and gains in performance on a spatial navigation task. Our results demonstrate that glucose administration can attenuate cognitive performance deficits in older adults with impaired glucose regulation and suggest that increases in pHPC-mPFC rsFC are beneficial for navigation task performance in older participants.

Human hippocampal and parahippocampal theta during goal-directed spatial navigation predicts performance on a virtual Morris water maze.

The hippocampus and parahippocampal cortices exhibit theta oscillations during spatial navigation in animals and humans, and in the former are thought to mediate spatial memory formation. Functional specificity of human hippocampal theta, however, is unclear. Neuromagnetic activity was recorded with a whole-head 275-channel magnetoencephalographic (MEG) system as healthy participants navigated to a hidden platform in a virtual reality Morris water maze. MEG data were analyzed for underlying oscillatory sources in the 4-8 Hz band using a spatial filtering technique (i.e., synthetic aperture magnetometry). Source analyses revealed greater theta activity in the left anterior hippocampus and parahippocampal cortices during goal-directed navigation relative to aimless movements in a sensorimotor control condition. Additional analyses showed that left anterior hippocampal activity was predominantly observed during the first one-half of training, pointing to a role for this region in early learning. Moreover, posterior hippocampal theta was highly correlated with navigation performance, with the former accounting for 76% of the variance of the latter. Our findings suggest human spatial learning is dependent on hippocampal and parahippocampal theta oscillations, extending to humans a significant body of research demonstrating such a pivotal role for hippocampal theta in animal navigation.

Impaired spatial navigation in pediatric anxiety.

BACKGROUND: Previous theories implicate hippocampal dysfunction in anxiety disorders. Most of the data supporting these theories stem from animal research, particularly lesion studies. The generalization of findings from rodent models to human function is hampered by fundamental inter-species differences. The present work uses a task of spatial orientation, which is known to rely on hippocampal function. Deficits in spatial navigation in anxious children suggest that the hippocampal network involved in spatial orientation is also implicated in anxiety disorders. METHODS: Thirty-four treatment-naive children with an anxiety disorder (mean 11.00 years +/- 2.54) are compared to 35 healthy age- and IQ-matched healthy children (mean 11.95 years +/- 2.36) on a virtual, computer-based equivalent of the Morris Water Maze task. RESULTS: Results indicate that children with anxiety disorder exhibit overall impaired performance relative to the comparison group. Anxious children made more heading direction errors and had worse accuracy in completing trials relative to controls. CONCLUSIONS: The results present novel evidence that spatial orientation deficits occur in pediatric anxiety.

Threat-induced anxiety weakens inhibitory control.

Growing evidence indicates that anxiety impairs cognitive control processes, including inhibitory functioning. However, there are reports of anxiety state-related improvements in response inhibition performance in a go/nogo (GNG) task. Here we employed the stop-signal task (SST) to examine in complementary fashion the link between anticipatory anxiety and inhibitory control. Participants (N = 45) completed the SST under threat of unpredictable shocks and safe conditions while physiological activity (skin conductance and heart rate) was monitored. In addition to increased physiological activity, we found that stop-signal reaction time (SSRT), a robust measure of stopping efficiency, was prolonged during threat compared to safe without any difference in choice reaction times to go stimuli. This finding supports the claim of impaired inhibitory control in anxiety, and by consideration of differences between the SST and GNG tasks, can be reconciled with evidence of improved response inhibition on the latter under similar threat conditions.

Modeling anxiety in healthy humans: a key intermediate bridge between basic and clinical sciences.

Animal models of anxiety disorders are important for elucidating neurobiological defense mechanisms. However, animal models are limited when it comes to understanding the more complex processes of anxiety that are unique to humans (e.g., worry) and to screen new treatments. In this review, we outline how the Experimental Psychopathology approach, based on experimental models of anxiety in healthy subjects, can mitigate these limitations and complement research in animals. Experimental psychopathology can bridge basic research in animals and clinical studies, as well as guide and constrain hypotheses about the nature of psychopathology, treatment mechanisms, and treatment targets. This review begins with a brief review of the strengths and limitations of animal models before discussing the need for human models of anxiety, which are especially necessary to probe higher-order cognitive processes. This can be accomplished by combining anxiety-induction procedures with tasks that probe clinically relevant processes to identify neurocircuits that are potentially altered by anxiety. The review then discusses the validity of experimental psychopathology and introduces a methodological approach consisting of five steps: (1) select anxiety-relevant cognitive or behavioral operations and associated tasks, (2) identify the underlying neurocircuits supporting these operations in healthy controls, 3) examine the impact of experimental anxiety on the targeted operations in healthy controls, (4) utilize findings from step 3 to generate hypotheses about neurocircuit dysfunction in anxious patients, and 5) evaluate treatment mechanisms and screen novel treatments. This is followed by two concrete illustrations of this approach and suggestions for future studies.

Generalization of conditioned fear-potentiated startle in humans: experimental validation and clinical relevance.

Though generalization of conditioned fear has been implicated as a central feature of pathological anxiety, surprisingly little is known about the psychobiology of this learning phenomenon in humans. Whereas animal work has frequently applied methods to examine generalization gradients to study the gradual weakening of the conditioned-fear response as the test stimulus increasingly differs from the conditioned stimulus (CS), to our knowledge no psychobiological studies of such gradients have been conducted in humans over the last 40 years. The current effort validates an updated generalization paradigm incorporating more recent methods for the objective measurement of anxiety (fear-potentiated startle). The paradigm employs 10, quasi-randomly presented, rings of gradually increasing size with extremes serving as CS+ and CS-. The eight rings of intermediary size serve as generalization stimuli (GSs) and create a continuum-of-similarity from CS+ to CS-. Both startle data and online self-report ratings demonstrate continuous decreases in generalization as the presented stimulus becomes less similar to the CS+. The current paradigm represents an updated and efficacious tool with which to study fear generalization--a central, yet understudied conditioning-correlate of pathologic anxiety.

Acute exposure to stress improves performance in trace eyeblink conditioning and spatial learning tasks in healthy men.

The present study investigated the effects of acute stress exposure on learning performance in humans using analogs of two paradigms frequently used in animals. Healthy male participants were exposed to the cold pressor test (CPT) procedure, i.e., insertion of the dominant hand into ice water for 60 sec. Following the CPT or the control procedure, participants completed a trace eyeblink conditioning task followed by a virtual navigation Morris water task (VNMWT). Hypothalamic-pituitary-adrenocortical (HPA) axis and sympathetic autonomic system (SAS) activity were assessed by measuring salivary cortisol, heart rate, and skin conductance at selected timepoints. Results revealed positive effects of stress on performance in both tasks. The stress group showed significantly more conditioned blinks than the control group during acquisition of trace eyeblink conditioning. The stress group also performed significantly better in the VNMWT than the control group, with the former showing significantly fewer failures to locate the hidden platform in the allotted time and smaller heading errors than the latter. Regression analyses revealed positive relationships between HPA axis and SAS activity during stress and eyeblink conditioning performance. Our results directly extend findings from animal studies and suggest potential physiological mechanisms underlying stress and learning.

Non-invasive Investigation of Human Hippocampal Rhythms Using Magnetoencephalography: A Review.

Hippocampal rhythms are believed to support crucial cognitive processes including memory, navigation, and language. Due to the location of the hippocampus deep in the brain, studying hippocampal rhythms using non-invasive magnetoencephalography (MEG) recordings has generally been assumed to be methodologically challenging. However, with the advent of whole-head MEG systems in the 1990s and development of advanced source localization techniques, simulation and empirical studies have provided evidence that human hippocampal signals can be sensed by MEG and reliably reconstructed by source localization algorithms. This paper systematically reviews simulation studies and empirical evidence of the current capacities and limitations of MEG "deep source imaging" of the human hippocampus. Overall, these studies confirm that MEG provides a unique avenue to investigate human hippocampal rhythms in cognition, and can bridge the gap between animal studies and human hippocampal research, as well as elucidate the functional role and the behavioral correlates of human hippocampal oscillations.