The mediating role of parenting behaviors in the relationship between early and late adolescent levels of anxiety: Specificity and informant effects.

INTRODUCTION: The role of parenting behavior is often highlighted in the development of anxiety in youth. However, previous reports are limited in terms of the specificity of relationships between different types of anxiety and parenting behaviors, informant effects on these relationships, and direction of effects. METHODS: This study investigates these questions using longitudinal data from 1350 Swedish adolescents and their parents. Adolescents' self-reports of six dimensions of anxiety and adolescents' and parents' reports of six dimensions of parenting behaviors were used in the analyses. Parallel multiple mediation models were employed to analyze specificity and informant effects within a reciprocal effects model. RESULTS: Overall, and irrespective of informant, this study found little support for a mediating role of parenting behaviors in the relationship between early and late adolescent levels of anxiety. Evidence for specificity within the parenting-anxiety relationship was scarce with specific mediating effects observed only for panic/agoraphobia and total anxiety through the parenting dimension of rejection. CONCLUSIONS: The findings of this study concern the un-conditional mediating role of parenting. Parenting behaviors may be more influential among some adolescents, depending on individual differences in other factors related to the development and course of adolescent anxiety. Thus, further research on moderating factors of the influence of parenting on adolescent anxiety is warranted.

Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study.

The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [(11)C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori-defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important.

Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder.

Patients with anxiety disorders exhibit excessive neural reactivity in the amygdala, which can be normalized by effective treatment like cognitive behavior therapy (CBT). Mechanisms underlying the brain's adaptation to anxiolytic treatments are likely related both to structural plasticity and functional response alterations, but multimodal neuroimaging studies addressing structure-function interactions are currently missing. Here, we examined treatment-related changes in brain structure (gray matter (GM) volume) and function (blood-oxygen level dependent, BOLD response to self-referential criticism) in 26 participants with social anxiety disorder randomly assigned either to CBT or an attention bias modification control treatment. Also, 26 matched healthy controls were included. Significant time × treatment interactions were found in the amygdala with decreases both in GM volume (family-wise error (FWE) corrected P(FWE) = 0.02) and BOLD responsivity (P(FWE) = 0.01) after successful CBT. Before treatment, amygdala GM volume correlated positively with anticipatory speech anxiety (P(FWE)=0.04), and CBT-induced reduction of amygdala GM volume (pre-post) correlated positively with reduced anticipatory anxiety after treatment (P(FWE) ⩽ 0.05). In addition, we observed greater amygdala neural responsivity to self-referential criticism in socially anxious participants, as compared with controls (P(FWE) = 0.029), before but not after CBT. Further analysis indicated that diminished amygdala GM volume mediated the relationship between decreased neural responsivity and reduced social anxiety after treatment (P=0.007). Thus, our results suggest that improvement-related structural plasticity impacts neural responsiveness within the amygdala, which could be essential for achieving anxiety reduction with CBT.

Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning.

Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual's long-term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52% (12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% (confidence interval 95% 73.2-97.6). This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale-Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC-amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC-amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual.

Increased neurokinin-1 receptor availability in the amygdala in social anxiety disorder: a positron emission tomography study with [11C]GR205171.

The neurokinin-1 (NK1) receptor is abundantly expressed in the fear circuitry of the brain, including the amygdala, where it modulates stress and anxiety. Despite its proposed involvement in psychopathology, only a few studies of NK1 receptor availability in human subjects with anxiety disorders exist. Here, we compared NK1 receptor availability in patients with social anxiety disorder (SAD; n = 17) and healthy controls (n = 17) using positron emission tomography and the radiotracer [11C]GR205171. The Patlak Graphical plot using a cerebellar reference region was used to model the influx parameter, Ki measuring NK1 receptor availability. Voxel-wise statistical parametric mapping analyses revealed increased NK1 receptor availability specifically in the right amygdala in SAD patients relative to controls. Thus, we demonstrate that exaggerated social anxiety is related to enhanced NK1 receptor availability in the amygdala. This finding supports the contribution of NK1 receptors not only in animal models of stress and anxiety but also in humans with anxiety disorders.

Cerebral blood flow in subjects with social phobia during stressful speaking tasks: a PET study.

OBJECTIVE: The central nervous system representation of social phobia (social anxiety disorder) is largely unknown. The aim of this study was to examine brain activity during symptom provocation in social phobics. METHOD: Positron emission tomography with the use of (15)O water was used to measure regional cerebral blood flow (rCBF) in 18 subjects with DSM-IV-defined social phobia and a nonphobic comparison group while they were speaking in front of an audience and in private. Heart rate and subjective anxiety were also recorded. RESULTS: During public versus private speaking, subjective anxiety increased more in the social phobics than in the comparison group. Increased anxiety was accompanied by enhanced rCBF in the amygdaloid complex in the social phobics relative to the comparison subjects. Cortically, brain blood flow decreased in the social phobics and increased in the comparison subjects more during public than private speaking in the orbitofrontal and insular cortices as well as in the temporal pole and increased less in the social phobics than in the comparison group in the parietal and secondary visual cortices. Furthermore, rCBF increased in the comparison group, but not in the social phobics, in the perirhinal and retrosplenial cortices. CONCLUSIONS: An rCBF pattern of relatively increased cortical rather than subcortical perfusion was observed in the nonphobic subjects, indicating that cortical evaluative processes were taxed by public performance. In contrast, the social phobia symptom profile was associated with increased subcortical activity. Thus, the functional neuroanatomy of social phobia involves the activation of a phylogenetically older danger-recognition system.

Fear conditioning and brain activity: a positron emission tomography study in humans.

Regional cerebral blood flow (rCBF) was measured with H2 (15)O positron emission tomography in 8 healthy women before and after fear conditioning (i.e., paired shocks) and unpaired shocks to videotape cues. Conditioning was supported by enhanced peripheral nervous system recordings and subjective ratings. Fear conditioning increased rCBF in the central gray of the midbrain; bilaterally in the hypothalamus, the thalamus, and the left striatum; and in the right and left anterior cingulate and right prefrontal cortices. Regional CBF was attenuated bilaterally in the right and left prefrontal, temporal (including the amygdala), parietal, and occipital cortices, and in the left orbitofrontal cortex. When compared with unpaired shock presentations, fear conditioning resulted in elevated rCBF in the left cerebellum. Hence, in the present paradigm, only neural activity in the left cerebellum solely reflected processes associated with true Pavlovian conditioning.

Dispositional pessimism and amygdala activity: a PET study in healthy volunteers.

The present study used scores from Seligman's Attribution Style Questionnaire and [15O] water positron emission tomographic measurements of regional cerebral blood flow (rCBF) to investigate the relation between individual differences in dispositional pessimism and amygdala activity. During scanning 13 healthy non-snake-phobic females passively viewed a snake videotape. Using one-tailed tests, significant negative correlations were evident between pessimism scores, with low scores reflecting relatively more pessimism, and right (r=-0.60; p=0.014) and left amygdala rCBF (r=-0.53; p=0.032). These results extend previous neuroimaging findings in healthy subjects indicating a role for the amygdala in transient negative emotional states, and suggest that this multimodal brain region also is involved in more durable negative affects such as dispositional pessimism.

Brain representation of habituation to repeated complex visual stimulation studied with PET.

To investigate CNS habituation (i.e. response decrement due to stimulus repetition) the present study used positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) in eight healthy women during two repetitions of complex visual stimuli. Repeated visual stimulation resulted in neural habituation bilaterally in the secondary visual cortex and in the right medial temporal cortex including the amygdala and the hippocampus. Regional CBF in the left thalamus was elevated as a function of repeated stimuli presentations. Thus, repeated presentation of complex visual stimuli result in rCBF habituation in later stages of the visual processing chain. The elevated neural activity in the thalamus might be associated with interruption of further neural transmission related to suppression of non-meaningful behavior.

The amygdala and individual differences in human fear conditioning.

While animal research on fear conditioning suggests crucial involvement of the amygdala, this has not been corroborated in humans when using subtractive neuroimaging methodology. Correlation analyses might be more able to reveal relations between individual differences in conditionability and central neural activity. Hence, we performed a directed search for amygdalar participation in human fear conditioning by correlating central and autonomic nervous activity. [15O]Butanol positron emission tomography evaluated regional cerebral blood flow (rCBF) in six subjects before and after aversive conditioning to visual snake stimuli. Non-specific electrodermal fluctuations (EDA) were recorded simultaneously. A significant positive correlation was obtained between conditioned EDA and conditioned rCBF in the right amygdala (r = 0.75, p < 0.05), supporting involvement of the amygdala in human fear conditioning.

Brain correlates of an unexpected panic attack: a human positron emission tomographic study.

Previous brain imaging studies on symptom provocation in panic anxiety have used either drug-infusions or sensory related stimulation to induce panic attacks. We here report positron emission tomographic measurements of regional cerebral blood flow (rCBF) during an unexpected panic attack in a healthy female volunteer participating in a fear conditioning study. During a first but not a second run with electric shock presentations the woman unexpectedly experienced a panic attack that fulfilled the DSM-IV criteria. Panic was associated with decreased rCBF in the right orbitofrontal (Brodmann area 11), prelimbic (area 25), anterior cingulate (area 32) and anterior temporal cortices (area 15). These findings suggest that neural activity in brain regions previously associated with symptom provocation in specific phobics and subjects with posttraumatic stress disorder also are involved during panic in healthy individuals.

Social phobia and avoidant personality disorder as related to parental history of social anxiety: a general population study.

Using a validated and DSM-IV compatible questionnaire, the present study related family history of excessive social anxiety to social phobia and avoidant personality disorder (APD) in epidemiologically identified probands in the general population. Probands met diagnostic criteria for social phobia with or without APD and APD with or without social phobia. A two- to three-fold increased relative risk of social anxiety was observed for all diagnostic groups. Increasing severity in probands by varying diagnostic criteria did not affect the relative risk. Because familial aggregation of social anxiety was not modulated by Axis I or II diagnosis or diagnostic cut-off levels, data imply that social phobia and APD may represent a dimension of social anxiety rather than separate disorders. Thus, having an affected family member is associated with a two- to three-fold risk increase for both social phobia and APD.

One-session group therapy of spider phobia: direct versus indirect treatments.

Forty-six patients with spider phobia, fulfilling the DSM-IV criteria for specific phobia, were assessed with behavioral, physiological and self-report measures. They were randomly assigned to three group treatment conditions: (1) direct treatment; (2) direct observation; and (3) indirect observation. All treatments were carried out in large groups of eight patients, and consisted of one 3 hr session of massed exposure and modelling. The results showed that on the behavioral test, measures and the specific self-report measures of spider phobia the direct treatment was significantly better than direct observation and indirect observation, which did not differ. On the physiological measures and the psychopathology self-report measures there were significant pre-post improvements, but no differences between the groups. The effects were maintained or furthered at the one year follow-up assessment. The proportion of clinically significantly improved patients were, at post-treatment, 75% in the direct treatment, 7% in the direct observation, and 31% in the indirect observation group. At follow-up, the corresponding figures were 75, 14, and 44%, respectively. The conclusion that can be drawn is that direct treatment is the treatment of choice.

Personality traits in social phobia.

The purpose was to assess personality traits in subjects with a DSM-IV diagnosis of social phobia. Thirty-two subjects were administered the Structured Clinical Interview for DSM-IV for Axes I and II disorders (SCID I and II). Personality traits were assessed by means of the Karolinska Scales of Personality (KSP). Current and lifetime axis I co-morbidity was diagnosed in 28% and 53% of the subjects, respectively. In total, 59% had at least one personality disorder and 47% were diagnosed with an avoidant personality disorder. The social phobics scored significantly higher than a Swedish normative sample on the KSP measuring anxiety proneness, irritability, detachment, and indirect aggression but lower on the scales for socialisation and social desirability. The presence as compared to absence of avoidant personality disorder in the social phobics was associated with significantly higher psychic anxiety and inhibition of aggression. In addition, symptom severity was higher in social phobics with an avoidant personality disorder. Generally, the results support the view that social phobia and avoidant personality disorder reflect different aspects of a social anxiety spectrum.

Regional cerebral blood flow during tinnitus: a PET case study with lidocaine and auditory stimulation.

Brain imaging of tinnitus has suggested central correlates of tinnitus perception. This study presents positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF) in a female tinnitus patient with bilateral left dominant tinnitus. Lidocaine infusion (75 mg during 5 min (0.2 mg/kg/min)) resulted in a 75% reduction of tinnitus and a temporary abolition of the dominant tinnitus in her left ear. Regional CBF was measured in four conditions: i) at rest while concentrating on tinnitus, ii) following maximum effect of lidocaine, iii) during sound stimulation, and iv) the following day at rest while concentrating on tinnitus. Subtraction analyses showed that tinnitus was associated with increased rCBF in the left parieto-temporal auditory cortex, including the primary and secondary auditory cortex with a focus in the parietal cortex (Brodmann areas 39, 41, 42, 21, 22). Activations were also found in right frontal paralimbic areas (Brodmann areas 47, 49 and 15). Sound stimulation resulted in bilateral activation of auditory areas. It is suggested that tinnitus is processed in primary, secondary and integrative auditory cortical areas. Tinnitus perception may involve areas related to auditory attention, while emotional processing relates to temporofrontal paralimbic areas.

Association between amygdala reactivity and a dopamine transporter gene polymorphism.

Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [(15)O]water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.

Altered fusiform connectivity during processing of fearful faces in social anxiety disorder.

Social anxiety disorder (SAD) has been associated with hyper-reactivity in limbic brain regions like the amygdala, both during symptom provocation and emotional face processing tasks. In this functional magnetic resonance imaging study we sought to examine brain regions implicated in emotional face processing, and the connectivity between them, in patients with SAD (n=14) compared with healthy controls (n=12). We furthermore aimed to relate brain reactivity and connectivity to self-reported social anxiety symptom severity. SAD patients exhibited hyper-reactivity in the bilateral fusiform gyrus in response to fearful faces, as well as greater connectivity between the fusiform gyrus and amygdala, and decreased connectivity between the fusiform gyrus and ventromedial prefrontal cortex. Within the SAD group, social anxiety severity correlated positively with amygdala reactivity to emotional faces, amygdala-fusiform connectivity and connectivity between the amygdala and superior temporal sulcus (STS). These findings point to a pivotal role for the fusiform gyrus in SAD neuropathology, and further suggest that altered amygdala-fusiform and amygdala-STS connectivity could underlie previous findings of aberrant socio-emotional information processing in this anxiety disorder.

Human fear reconsolidation and allelic differences in serotonergic and dopaminergic genes.

Fear memory persistence, central for the development and maintenance of anxiety disorders, is partially genetically controlled. Recently, consolidation and reconsolidation processes have been reported to affect fear memory stability and integrity. This study explored the impact of reconsolidation processes and genetic make-up on fear reacquisition by manipulating reconsolidation, using extinction performed outside or inside a reconsolidation interval. Reacquisition measured by skin conductance responses was stronger in individuals that extinguished outside (6 h) than inside (10 min) the reconsolidation interval. However, the effect was predominantly present in val/val homozygotes of the functional val158met polymorphism of the catechol O-methyltransferase (COMT) enzyme and in short-allele carriers of the serotonin-transporter length 5-HTTLPR polymorphism. These results demonstrate that reconsolidation of human fear memory is influenced by dopamine and serotonin-related genes.

Outcome predictors in guided and unguided self-help for social anxiety disorder.

Internet-based self-help with therapist guidance has shown promise as an effective treatment and may increase access to evidence-based psychological treatment for social anxiety disorder (SAD). Although unguided self-help has been suggested primarily as a population-based preventive intervention, some studies indicate that patients with SAD may profit from unguided self-help. Gaining knowledge about predictors of outcome in guided and unguided self-help for SAD is important to ensure that these interventions can be offered to those who are most likely to respond. Utilizing a sample of 245 patients who received either guided or unguided self-help for SAD, the present study examined pre-treatment symptoms and program factors as predictors of treatment adherence and outcome. The results were in line with previous findings from the face-to-face treatment literature: namely, the intensity of baseline SAD symptoms, but not depressive symptoms, predicted treatment outcomes in both unguided and guided self-help groups. Outcomes were unrelated to whether a participant has generalized versus specific SAD. Furthermore, for the unguided self-help group, higher credibility ratings of the treatment program were associated with increased treatment adherence. The findings suggest that guided and unguided self-help may increase access to SAD treatment in a population that is more heterogeneous than previously assumed.