Clinical anxiety promotes excessive response inhibition.

BACKGROUND: Laboratory tasks to delineate anxiety disorder features are used to refine classification and inform our understanding of etiological mechanisms. The present study examines laboratory measures of response inhibition, specifically the inhibition of a pre-potent motor response, in clinical anxiety. Data on associations between anxiety and response inhibition remain inconsistent, perhaps because of dissociable effects of clinical anxiety and experimentally manipulated state anxiety. Few studies directly assess the independent and interacting effects of these two anxiety types (state v. disorder) on response inhibition. The current study accomplished this goal, by manipulating state anxiety in healthy and clinically anxious individuals while they complete a response inhibition task. METHOD: The study employs the threat-of-shock paradigm, one of the best-established manipulations for robustly increasing state anxiety. Participants included 82 adults (41 healthy; 41 patients with an anxiety disorder). A go/nogo task with highly frequent go trials was administered during alternating periods of safety and shock threat. Signal detection theory was used to quantify response bias and signal-detection sensitivity. RESULTS: There were independent effects of anxiety and clinical anxiety on response inhibition. In both groups, heightened anxiety facilitated response inhibition, leading to reduced nogo commission errors. Compared with the healthy group, clinical anxiety was associated with excessive response inhibition and increased go omission errors in both the safe and threat conditions. CONCLUSIONS: Response inhibition and its impact on go omission errors appear to be a promising behavioral marker of clinical anxiety. These results have implications for a dimensional view of clinical anxiety.

Reduced optimism and a heightened neural response to everyday worries are specific to generalized anxiety disorder, and not seen in social anxiety.

BACKGROUND: Generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are co-morbid and associated with similar neural disruptions during emotion regulation. In contrast, the lack of optimism examined here may be specific to GAD and could prove an important biomarker for that disorder. METHOD: Unmedicated individuals with GAD (n = 18) and age-, intelligence quotient- and gender-matched SAD (n = 18) and healthy (n = 18) comparison individuals were scanned while contemplating likelihoods of high- and low-impact negative (e.g. heart attack; heartburn) or positive (e.g. winning lottery; hug) events occurring to themselves in the future. RESULTS: As expected, healthy subjects showed significant optimistic bias (OB); they considered themselves significantly less likely to experience future negative but significantly more likely to experience future positive events relative to others (p < 0.001). This was also seen in SAD, albeit at trend level for positive events (p < 0.001 and p < 0.10, respectively). However, GAD patients showed no OB for positive events (t 17 = 0.82, n.s.) and showed significantly reduced neural modulation relative to the two other groups of regions including the medial prefrontal cortex (mPFC) and caudate to these events (p < 0.001 for all). The GAD group further differed from the other groups by showing increased neural responses to low-impact events in regions including the rostral mPFC (p < 0.05 for both). CONCLUSIONS: The neural dysfunction identified here may represent a unique feature associated with reduced optimism and increased worry about everyday events in GAD. Consistent with this possibility, patients with SAD did not show such dysfunction. Future studies should consider if this dysfunction represents a biomarker for GAD.

Learning from other people's fear: amygdala-based social reference learning in social anxiety disorder.

BACKGROUND: Social anxiety disorder involves fear of social objects or situations. Social referencing may play an important role in the acquisition of this fear and could be a key determinant in future biomarkers and treatment pathways. However, the neural underpinnings mediating such learning in social anxiety are unknown. Using event-related functional magnetic resonance imaging, we examined social reference learning in social anxiety disorder. Specifically, would patients with the disorder show increased amygdala activity during social reference learning, and further, following social reference learning, show particularly increased response to objects associated with other people's negative reactions? METHOD: A total of 32 unmedicated patients with social anxiety disorder and 22 age-, intelligence quotient- and gender-matched healthy individuals responded to objects that had become associated with others' fearful, angry, happy or neutral reactions. RESULTS: During the social reference learning phase, a significant group × social context interaction revealed that, relative to the comparison group, the social anxiety group showed a significantly greater response in the amygdala, as well as rostral, dorsomedial and lateral frontal and parietal cortices during the social, relative to non-social, referencing trials. In addition, during the object test phase, relative to the comparison group, the social anxiety group showed increased bilateral amygdala activation to objects associated with others' fearful reactions, and a trend towards decreased amygdala activation to objects associated with others' happy and neutral reactions. CONCLUSIONS: These results suggest perturbed observational learning in social anxiety disorder. In addition, they further implicate the amygdala and dorsomedial prefrontal cortex in the disorder, and underscore their importance in future biomarker developments.

Improvement of polyphenol properties upon glucosylation in a UV-induced skin cell ageing model.

OBJECTIVE: Polyphenols are strong antioxidant molecules allowing prevention of skin photo-ageing damages, but their use is limited due to low solubility and toxicity towards skin cells. We postulated that enzymatic glucosylation could improve their solubility, stability and, consequently, their efficacy. The aim of this work was to study changes induced by addition of a glucose moiety on two polyphenols displaying very different chemical structures [caffeic acid (CA), epigallocatechin-3-gallate (EGCG) and there glucosylated form, Glc-CA and Glc-EGCG] by assessing their cytotoxic properties and their antioxidant and anti-inflammatory activities. METHODS: Their antioxidant effect was assessed first by the classical DPPH radical-scavenging method. Then, a panel of human skin cells (keratinocytes, melanocytes, fibroblasts and endothelial cells) was used to evaluate their effect on cell toxicity and their antioxidant activities. With this aim, a photo-ageing model based on UV irradiation of skin cells was established. Molecule activity was assessed on reactive oxygen species (ROS) production, on superoxide dismutase (SOD) and catalase activities and, finally, on inflammatory factor production IL-6, IL-8 and IL-1ß. RESULTS: In an acellular model, antioxidant activity assessed by DPPH method was strongly reduced for Glc-CA compared to CA, whereas it remained the same for Glc-EGCG compared to EGCG. Glucosylated derivatives did not display more toxic effect on various skin cells. Moreover, toxicity was even strongly reduced for caffeic acid upon glucosylation. The efficacy of glucosyl-compounds against UV-induced ROS production was preserved, both with pre- and post-UV treatments. Particularly, a better antioxidant efficacy was shown by Glc-EGCG, vs. EGCG, on keratinocytes. In addition, an induction of SOD and catalase activity was clearly observed for Glc-CA. Both glucosyl-polyphenols display the same activity as their parent molecule in decreasing inflammatory factor production. CONCLUSION: Our results demonstrated that enzymatic glucosylation of CA and EGCG led to an improved or preserved antioxidant activity in a cellular model of UV-induced skin ageing, despite the decrease in instantaneous antioxidant properties observed for Glc-CA. Glc-EGCG is specifically more active on keratinocytes, suggesting a specific targeting. Such glucosylated polyphenols displaying improved physicochemical and biological properties should be better candidates than natural ones for use in food additives and cosmetics.

Depressed mood enhances anxiety to unpredictable threat.

BACKGROUND: Depression and anxiety disorders (ADs) are highly co-morbid, but the reason for this co-morbidity is unclear. One possibility is that they predispose one another. An informative way to examine interactions between disorders without the confounds present in patient populations is to manipulate the psychological processes thought to underlie the pathological states in healthy individuals. In this study we therefore asked whether a model of the sad mood in depression can enhance psychophysiological responses (startle) to a model of the anxiety in ADs. We predicted that sad mood would increase anxious anxiety-potentiated startle responses. METHOD: In a between-subjects design, participants (n=36) completed either a sad mood induction procedure (MIP; n=18) or a neutral MIP (n=18). Startle responses were assessed during short-duration predictable electric shock conditions (fear-potentiated startle) or long-duration unpredictable threat of shock conditions (anxiety-potentiated startle). RESULTS: Induced sadness enhanced anxiety- but not fear-potentiated startle. CONCLUSIONS: This study provides support for the hypothesis that sadness can increase anxious responding measured by the affective startle response. This, taken together with prior evidence that ADs can contribute to depression, provides initial experimental support for the proposition that ADs and depression are frequently co-morbid because they may be mutually reinforcing.

Methylphenidate modulates interactions of anxiety with cognition.

While a large body of literature documents the impairing effect of anxiety on cognition, performing a demanding task was shown to be effective in reducing anxiety. Here we explored the mechanisms of this anxiolytic effect by examining how a pharmacological challenge designed to improve attentional processes influences the interplay between the neural networks engaged during anxiety and cognition. Using a double-blind between-subject design, we pharmacologically manipulated working memory (WM) using a single oral dose of 20 mg methylphenidate (MPH, cognitive enhancer) or placebo. Fifty healthy adults (25/drug group) performed two runs of a WM N-back task in a 3 T magnetic resonance imaging scanner. This task comprised a low (1-Back) and high (3-Back) WM load, which were performed in two contexts, safety or threat of shocks (induced-anxiety). Analyses revealed that (1) WM accuracy was overall improved by MPH and (2) MPH (vs. placebo) strengthened the engagement of regions within the fronto-parietal control network (FPCN) and reduced the default mode network (DMN) deactivation. These MPH effects predominated in the most difficult context, i.e., threat condition, first run (novelty of the task), and 3-Back task. The facilitation of neural activation can be interpreted as an expansion of cognitive resources, which could foster both the representation and integration of anxiety-provoking stimuli as well as the top-down regulatory processes to protect against the detrimental effect of anxiety. This mechanism might establish an optimal balance between FPCN (cognitive processing) and DMN (emotion regulation) recruitment.

Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH).

Major questions remain about the exact role of hormones in cognition. Furthermore, the extent to which early perturbation in steroid function affects human brain development continues to be a wide open area of research. Congenital adrenal hyperplasia (CAH), a genetic disorder of steroid dysfunction characterized in part by in utero over-production of testosterone, was used as a natural model for addressing this question. Here, CAH (n=54, mean age=17.53, 31 female) patients were compared to healthy age- and sex-matched individuals (n=55, mean age=19.02, 22 female) on a virtual equivalent of the Morris Water Maze task [Morris, R., 1984. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47-60], an established measure of sex differences in spatial cognition in rodents. Findings revealed that females with CAH with the most severe form of the disease and expected highest level of in utero exposure to androgens were found to perform similarly to both healthy males and CAH males, whereas strong sex differences were apparent in milder forms of the disorder and in controls. Moreover, advanced bone age, an indicator of long-term childhood exposure to testosterone was correlated with improved performance. The results indicate that individuals exposed to both excess androgens prenatally and prolonged exposure during childhood may manifest long-lasting changes in cognitive function. Such finding suggests a pivotal role of hormonal function on brain development in humans, mirroring results from the animal literature.

Activation of the left amygdala to a cognitive representation of fear.

We examined the neural substrates involved when subjects encountered an event linked verbally, but not experientially, to an aversive outcome. This instructed fear task models a primary way humans learn about the emotional nature of events. Subjects were told that one stimulus (threat) represents an aversive event (a shock may be given), whereas another (safe) represents safety (no shock will be given). Using functional magnetic resonance imaging (fMRI), activation of the left amygdala was observed in response to threat versus safe conditions, which correlated with the expression of the fear response as measured by skin conductance. Additional activation observed in the insular cortex is proposed to be involved in conveying a cortical representation of fear to the amygdala. These results suggest that the neural substrates that support conditioned fear across species have a similar but somewhat different role in more abstract representations of fear in humans.

Anxiety-potentiated amygdala-medial frontal coupling and attentional control.

Anxiety disorders can be treated both pharmacologically and psychologically, but many individuals either fail to respond to treatment or relapse. Improving outcomes is difficult, in part because we have incomplete understanding of the neurobiological mechanisms underlying current treatments. In a sequence of studies, we have identified 'affective bias-related' amygdala-medial cortical coupling as a candidate substrate underlying adaptive anxiety (that is, anxiety elicited by threat of shock in healthy individuals) and shown that it is also chronically engaged in maladaptive anxiety disorders. We have provided evidence that this circuit can be modulated pharmacologically, but whether this mechanism can be shifted by simple psychological instruction is unknown. In this functional magnetic resonance imaging study, we extend a previously used translational anxiety induction (threat of shock) in healthy subjects (N=43) and cognitive task to include an element of instructed attentional control. Replicating our previous findings, we show that induced anxiety engages 'affective bias-related' amygdala-dorsal medial frontal coupling during the processing of emotional faces. By contrast, instructing subjects to attend to neutral shapes (and ignore faces) disengages this circuitry and increases putative 'attentional control-related' coupling between the amygdala and a more rostral prefrontal region. These neural coupling changes are accompanied by corresponding modulation of behavioural performance. Taken together, these findings serve to further highlight the potential role of amygdala-medial frontal coupling in the pathogenesis of anxiety and highlight a mechanism by which it can be modulated via psychological instructions. This, in turn, generates hypotheses for future work exploring the mechanisms underlying psychological therapeutic interventions for anxiety.

Gating and habituation of the startle reflex in schizophrenic patients.

Schizophrenic patients exhibit impairments in both sensorimotor gating and habituation in a number of paradigms. Through human and animal model research, these fundamental cognitive deficits have well-described neurobiologic bases and offer insights into the neuroanatomic and neurotransmitter abnormalities that characterize patients with schizophrenic spectrum disorders. In this context, the startle response is particularly interesting, because it is a cross-species response to strong stimuli that is plastic or alterable using experimental and neurobiologic manipulations. Thirty-nine medicated schizophrenic patients and 37 normal control subjects were studied in a new electromyography based startle response paradigm in which both prepulse inhibition (an operational measure of sensorimotor gating) and habituation (the normal decrease in response magnitude to repeated stimuli over time) can be separated and assessed in one test session. The results indicate that schizophrenic patients have extensive deficits in both intramodal and cross-modal sensorimotor gating and a trend to show acoustic startle habituation deficits. The deficit in prepulse inhibition of startle amplitude exhibited by schizophrenic patients was evident when an acoustic prepulse stimulus preceded either an acoustic or a tactile startle stimulus. No deficit was observed in the prepulse-induced facilitation of startle latencies, indicating that the failure of gating was not due to a failure of stimulus detection. These findings suggest centrally mediated deficits in sensorimotor gating in schizophrenic patients.

Increased distractibility in schizophrenic patients. Electrophysiologic and behavioral evidence.

The inability of schizophrenics to filter irrelevant information has often been implicated in the psychopathology of schizophrenia. Despite numerous attempts at characterizing the behavior of schizophrenics in the presence of distractors, evidence of increased distractibility has been equivocal due to the difficulty of assessing simultaneously the behavioral and neurophysiological effects of distracting stimuli. We report the results of an experiment in which event-related potential and performance measures were used to assess distractibility during reaction time tasks under different distracting conditions. The results supported the view of an increased distractibility in schizophrenic patients. Event-related potential data suggested that in schizophrenic patients, a reduced amount of processing resources is allocated to process external stimuli and attention is abnormally apportioned to task-irrelevant vs task-relevant stimuli.

Abnormal mismatch negativity in women with sexual assault-related posttraumatic stress disorder.

BACKGROUND: Disturbances in sensory processing have been hypothesized in individuals with posttraumatic stress disorder (PTSD). The authors investigated this possibility by using mismatch negativity (MMN), an event-related potential (ERP) that reflects the operation of a preconscious cortical detector of stimulus change. METHODS: Thirteen medication-free women with sexual assault-related PTSD were compared with 16 age-matched, healthy comparison women without PTSD. ERPs were elicited by regularly presented "standard" auditory stimuli and by infrequently occurring "deviant" auditory stimuli, which differed slightly in frequency. The MMN was identified in the subtraction waveforms as the difference between ERPs elicited by the deviant and standard stimuli. Group comparisons of P50, N1, P2, and N2 to the standard and to the deviant stimuli, and of the MMN in the subtraction waveform were performed. RESULTS: The amplitude of the MMN was significantly greater in the PTSD compared to the non-PTSD women. MMN was significantly correlated with the total Mississippi PTSD Symptom Scale score in the PTSD group. No significant group differences were noted in P50, N1, or P2 responding. Significant group differences in N2 were due to the increased MMN in PTSD subjects. CONCLUSIONS: The data provide evidence for abnormalities in preconscious auditory sensory memory in PTSD, whereas earlier studies have reported abnormalities in conscious processing. These data suggest an increased sensitivity to stimulus changes in PTSD and implicate the auditory cortex in the pathophysiology of the disorder.

Fear-potentiated startle: relationship to the level of state/trait anxiety in healthy subjects.

The startle reflex is potentiated during experimentally induced anxiety (fear-potentiated startle). It is also increased in various anxiety disorders. The present study investigated the relationship between individual differences in fear and anxiety, and startle modulation. The eyeblink component of the acoustic startle reflex was measured in a paradigm involving the anticipation of electric shocks in 22 healthy men who were volunteers. Each subject's fear of shock was assessed with the state portion of the State-Trait Anxiety Inventory (STAI; Spielberger 1983). Fear-potentiated startle, but not baseline startle, differed in the low and high fear subjects. The magnitude of fear-potentiated startle was larger in the high-fear group as compared to the low-fear group. The time-course of startle modulation suggested a longer duration of anticipatory anxiety in the high-fear group. Trait anxiety, which was assessed with the trait portion of the STAI, did not relate to individual differences in either baseline or fear-potentiated startle.

N400 and semantic categorization in schizophrenia.

The N400 component of event-related potentials (ERPs) was investigated in medicated schizophrenic patients and normal controls in a semantic categorization task. The subjects' task was to indicate whether pairs of words were semantically related or unrelated. The ERPs to the unrelated second words of the pairs contained a negative component, N400, which was reduced and delayed in the patients. However, inspection of individual subjects' data indicated that N400 was abnormal only in a subgroup of schizophrenics. Abnormalities in the amplitude of N400 suggest impairments in semantic expectancies, whereas abnormalities in the latency of N400 suggest a delay in information processing.

Fear-potentiated startle in adolescent offspring of parents with anxiety disorders.

BACKGROUND: The startle reflex and its potentiation by aversive states was used as a possible vulnerability marker for anxiety disorders in adolescent offspring of parents with this condition. METHODS: The participants were 39 low-risk adolescents (16 male/23 female) with a parental history of no psychiatric disorder and 35 high-risk adolescents (18 male/17 female) with a parental history of anxiety disorders. The magnitude of startle was examined at baseline and during anticipation of an aversive stimulus (fear-potentiated startle). RESULTS: Startle was found to discriminate between children at high and low risk for anxiety disorders; however, different abnormalities for high-risk male and female subjects were observed. Startle levels, overall, were elevated among high-risk female subjects, whereas high-risk male subjects exhibited greater magnitude of startle potentiation during aversive anticipation. CONCLUSIONS: Startle reactivity may serve as a vulnerability marker for the development of anxiety disorders. With its basic grounding in animal and human behavioral research, startle may enhance our understanding of the underlying neurobiological bases of human anxiety states.

Baseline and fear-potentiated startle in panic disorder patients.

The present study investigated whether patients with panic disorder had an increase in the startle response and whether this effect, if present, was specific to anticipatory anxiety. The eyeblink component of the acoustic startle reflex was measured in a paradigm involving the anticipation of electric shocks (fear-potentiated startle) in 34 patients with panic disorder and 49 healthy controls. Startle was also recorded in the absence of specific threat at the beginning and at the end of the testing. The testing consisted of three phases: adaptation, fear-potentiated startle, and recovery. In the adaptation and recovery phases, startle stimuli were delivered in the absence of threat. In the fear-potentiated startle phase, startle stimuli were delivered in threat conditions, when subjects anticipated shocks, and in safe conditions that predicted the absence of shocks. Startle was larger in the younger patients (age < 40 years old) compared to the younger controls throughout the testing. The difference reached significance only during the fear-potentiated startle phase, however. Startle was nonsignificantly reduced in the older patients (age > or = 39 years old), compared to the older controls. The results are discussed in terms of the contextual effects of the experimental setting.

Darkness facilitates the acoustic startle reflex in humans.

The effects of darkness on startle reactivity and prepulse inhibition were investigated in two studies with 25 subjects participating in each study. Acoustic startle stimuli that were or were not preceded by an acoustic prepulse were delivered in alternating periods of complete darkness or light. In both studies, darkness significantly increased the magnitude of startle but did not affect prepulse inhibition (PPI). The PPI results suggest that darkness did not increase attention to the auditory modality, so that the startle facilitation in the dark probably did not result from an attentional process. The increased startle in the dark was significantly correlated with the intensity of subjects' fear of the dark as children based on retrospective rating scales. It is hypothesized that the startle facilitation in the dark results from a change in affect rather than from a change in attention.

Effects of experimental context and explicit threat cues on acoustic startle in Vietnam veterans with posttraumatic stress disorder.

BACKGROUND: The hypothesis that exaggerated startle in Vietnam veterans with posttraumatic stress disorder (PTSD) reflects an anxiogenic response to stressful contexts was tested. METHODS: Thirty-four nonmedicated Vietnam veterans with PTSD, and 17 combat and 14 civilian non-PTSD controls participated in two testing sessions over separate days. Acoustic startle stimuli were delivered alone or in a test of prepulse inhibition. In the first session, startle was assessed without experimental stress. In the second session, startle was investigated during a stressful "threat of shock" experiment, when subjects anticipated the administration of shocks during threat periods and during safe periods when no shocks were anticipated. RESULTS: The magnitude of startle did not differ significantly among the three groups in the first session, but was increased throughout the threat of shock experiment in the PTSD veterans in the second session. The actual increase in startle in the threat compared to the safe condition did not significantly differ among the three groups. Prepulse inhibition was reduced in the PTSD veterans, compared to the non-PTSD civilians, but not compared to the non-PTSD veterans. CONCLUSION: Exaggerated startle in Vietnam veterans with PTSD reflects an anxiogenic response to an environment that is experienced as stressful.

Vulnerability factors among children at risk for anxiety disorders.

BACKGROUND: The high-risk strategy is one of the most powerful approaches for identifying premorbid risk factors and reducing etiologic and phenotypic heterogeneity characteristic of the major psychiatric disorders. METHODS: This paper reviews the methods of high-risk research and findings from previous high-risk studies of anxiety. The preliminary results of the 6-8 year follow-up of a high-risk study of 192 offspring of probands with anxiety disorders, substance abuse, and unaffected controls are presented. The key study measures include comprehensive diagnostic interviews, symptom ratings, indirect measures of brain functioning (neuropsychologic, neurologic and psychophysiologic function), developmental measures, and family functioning measures. RESULTS: The major findings reveal that there is specificity of familial aggregation of anxiety disorders among parents and children; children at high risk for anxiety have increased startle reflex, autonomic reactivity, and stress reactivity, higher verbal IQ, and deficits in paired associative learning as compared to other children. CONCLUSIONS: The finding that family environment and parenting do not differ between children at risk for anxiety disorders and other children, when taken together with the strong degree of specificity of transmission of anxiety disorders, suggests that there may be temperamental vulnerability factors for anxiety disorders in general that may already manifest in children prior to puberty.