Kevin Hilbert

Neural structures, functioning and connectivity in Generalized Anxiety Disorder and interaction with neuroendocrine systems: A systematic review

BACKGROUND Research on the neurobiological basis of Generalized Anxiety Disorder (GAD) has considerably expanded in recent years. However, many studies investigated different domains and used different methods and paradigms. Therefore, this review aims to integrate the findings to date and to identify the core correlates of neurobiological underpinnings of GAD discovered so far. METHODS We conducted a systematic review of original papers investigating neural correlates, connectivity, or structural changes as well as reporting changes in the serotonergic system, noradrenergic system and cortisol levels in DSM-IV-defined GAD samples until December 2013. RESULTS Studies have identified abnormal amygdala and prefrontal cortex activation in patients and decreased functional connectivity between these areas. Furthermore, studies showed increased gray matter volume and decreased structural connectivity between these structures. Neuroendocrine findings are less consistent, but increased reactivity of the noradrenergic system and perpetuations in the cortisol secretion have been reported. LIMITATIONS Only studies on DSM-IV defined Generalized Anxiety Disorder which employed a group comparison were included. CONCLUSIONS Current research suggests a distinct set of neurobiological alterations in Generalized Anxiety Disorder. However, future research on the interaction between these structures and systems and on the specificity of these findings in relation to other mental disorders is urgently needed.

Neural substrates of defensive reactivity in two subtypes of specific phobia

Depending on threat proximity, different defensive behaviours are mediated by a descending neural network involving forebrain (distal threat) vs midbrain areas (proximal threat). Compared to healthy subjects, it can be assumed that phobics are characterized by shortened defensive distances on a behavioural and neural level. This study aimed at characterizing defensive reactivity in two subtypes of specific phobia [snake (SP) and dental phobics (DP)]. Using functional magnetic resonance imaging (fMRI), n = 39 subjects (13 healthy controls, HC; 13 SP; 13 DP) underwent an event-related fMRI task employing an anticipation (5-10 s) and immediate perception phase (phobic pictures and matched neutral stimuli; 1250 ms) to modulate defensive distance. Although no differential brain activity in any comparisons was observed in DP, areas associated with defensive behaviours (e.g. amygdala, hippocampus, midbrain) were activated in SP. Decreasing defensive distance in SP was characterized by a shift to midbrain activity. Present findings substantiate differences between phobia types in their physiological and neural organization that can be expanded to early stages of defensive behaviours. Findings may contribute to a better understanding of the dynamic organization of defensive reactivity in different types of phobic fear.

Gray and white matter volume abnormalities in generalized anxiety disorder by categorical and dimensional characterization.

Increasing efforts have been made to investigate the underlying pathophysiology of generalized anxiety disorder (GAD), but only limited consistent information is available on gray (GM) and white matter (WM) volume changes in affected adults. Additionally, few studies employed dimensional approaches to GAD pathology. This study compares structural brain imaging data from n=19 GAD subjects and n=24 healthy comparison (HC) subjects, all medication-free and matched on age, sex and education. Separate categorical and dimensional models were employed using voxel-based morphometry for GM and WM. Significantly higher GM volumes were found in GAD subjects mainly in basal ganglia structures and less consistently in the superior temporal pole. For WM, GAD subjects showed significantly lower volumes in the dlPFC. Largely consistent findings in dimensional and categorical models point toward these structural alterations being reliable and of importance for GAD. While lower volume in the dlPFC could reflect impaired emotional processing and control over worry in GAD, basal ganglia alterations may be linked to disturbed gain and loss anticipation as implicated in previous functional GAD studies. As perturbations in anticipation processes are central to GAD, these areas may warrant greater attention in future studies.

Fear Processing in Dental Phobia during Crossmodal Symptom Provocation: An fMRI Study

While previous studies successfully identified the core neural substrates of the animal subtype of specific phobia, only few and inconsistent research is available for dental phobia. These findings might partly relate to the fact that, typically, visual stimuli were employed. The current study aimed to investigate the influence of stimulus modality on neural fear processing in dental phobia. Thirteen dental phobics (DP) and thirteen healthy controls (HC) attended a block-design functional magnetic resonance imaging (fMRI) symptom provocation paradigm encompassing both visual and auditory stimuli. Drill sounds and matched neutral sinus tones served as auditory stimuli and dentist scenes and matched neutral videos as visual stimuli. Group comparisons showed increased activation in the insula, anterior cingulate cortex, orbitofrontal cortex, and thalamus in DP compared to HC during auditory but not visual stimulation. On the contrary, no differential autonomic reactions were observed in DP. Present results are largely comparable to brain areas identified in animal phobia, but also point towards a potential downregulation of autonomic outflow by neural fear circuits in this disorder. Findings enlarge our knowledge about neural correlates of dental phobia and may help to understand the neural underpinnings of the clinical and physiological characteristics of the disorder.

Neurostructural correlates of two subtypes of specific phobia: A voxel-based morphometry study

The animal and blood-injection-injury (BII) subtypes of specific phobia are both characterized by subjective fear but distinct autonomic reactions to threat. Previous functional neuroimaging studies have related these characteristic responses to shared and non-shared neural underpinnings. However, no comparative structural data are available. This study aims to fill this gap by comparing the two subtypes and also comparing them with a non-phobic control group. Gray and white matter data of 33 snake phobia subjects (SP), 26 dental phobia subjects (DP), and 37 healthy control (HC) subjects were analyzed with voxel-based morphometry. Especially DP differed from HC and SP by showing significantly increased grey matter volumes in widespread areas including the right subgenual anterior cingulate gyrus, left insula, left orbitofrontal and left prefrontal (PFC) cortices. In addition, white matter volume was significantly increased in the left PFC in DP compared with SP. These results are in line with functional changes observed in dental phobia and point toward those brain circuits associated with emotional processing and regulation. Future studies should aim to further delineate functional and structural connectivity alterations in specific phobia.

Sleep-amount differentially affects fear-processing neural circuitry in pediatric anxiety: A preliminary fMRI investigation

Insufficient sleep, as well as the incidence of anxiety disorders, both peak during adolescence. While both conditions present perturbations in fear-processing-related neurocircuitry, it is unknown whether these neurofunctional alterations directly link anxiety and compromised sleep in adolescents. Fourteen anxious adolescents (AAs) and 19 healthy adolescents (HAs) were compared on a measure of sleep amount and neural responses to negatively valenced faces during fMRI. Group differences in neural response to negative faces emerged in the dorsal anterior cingulate cortex (dACC) and the hippocampus. In both regions, correlation of sleep amount with BOLD activation was positive in AAs, but negative in HAs. Follow-up psychophysiological interaction (PPI) analyses indicated positive connectivity between dACC and dorsomedial prefrontal cortex, and between hippocampus and insula. This connectivity was correlated negatively with sleep amount in AAs, but positively in HAs. In conclusion, the presence of clinical anxiety modulated the effects of sleep-amount on neural reactivity to negative faces differently among this group of adolescents, which may contribute to different clinical significance and outcomes of sleep disturbances in healthy adolescents and patients with anxiety disorders.

Psychophsyiological reactivity during uncertainty and ambiguity processing in high and low worriers

BACKGROUND AND OBJECTIVES Intolerance of uncertainty (IU) has been linked to Generalized Anxiety Disorder (GAD), but studies experimentally manipulating uncertainty have mostly failed to find differences between GAD patients and controls, possible due to a lack of distinction between uncertainty and ambiguity. This study therefore investigated reactivity to ambiguity in addition to uncertainty in high worriers (HW) and low worriers (LW). We hypothesized an interpretation bias between the groups during ambiguity tasks, while uncertainty would facilitate threat processing of subsequent aversive stimuli. METHODS HW (N = 23) and LW (N = 23) completed a paradigm comprising the anticipation and perception of pictures with dangerous, safe, or ambiguous content. Anticipatory cues were certain (always correct information about the following picture) or uncertain (no information). Subjective ratings, reaction times and skin conductance responses (SCRs) were recorded. RESULTS HW rated particularly ambiguous pictures as more aversive and showed longer reaction times to all picture conditions compared to LW. SCRs were also larger in HW compared to LW, particularly during uncertain but also safe anticipation. No group differences were observed during perception of stimuli. LIMITATIONS All participants were female. HW was used as subclinical phenotype of GAD. CONCLUSIONS Intolerance of ambiguity seems to be related to individual differences in worry and possibly to the development of GAD. Threat-related interpretations differentiating HW and LW occurred particularly for ambiguous pictures but were not accompanied by increased autonomic arousal during the picture viewing. This disparity between subjective rating and arousal may be the result of worrying in response to intolerance of uncertainty, restraining physiological responses.

Separating generalized anxiety disorder from major depression using clinical, hormonal, and structural MRI data: A multimodal machine learning study

Generalized anxiety disorder (GAD) is difficult to recognize and hard to separate from major depression (MD) in clinical settings. Biomarkers might support diagnostic decisions. This study used machine learning on multimodal biobehavioral data from a sample of GAD, MD and healthy subjects to differentiate subjects with a disorder from healthy subjects (case‐classification) and to differentiate GAD from MD (disorder‐classification).

Self-reported volitional control in adolescents and young adults from a community cohort: Associations with current, past and future mental disorders

Alterations in volitional control have been found for various mental disorders. However, it remains unclear to which degree such alterations vary by type of psychopathology and constitute preceding vulnerabilities or correlates of mental disorders. DSM-IV mental disorders were assessed among adolescents and young adults from the community at baseline (age 14-24) and in up to 3 follow-up assessments over 10 years (n = 2515) using a standardized diagnostic interview (DIA-X/M-CIDI). Self-reported volitional control was assessed at second follow-up (T2) when subjects were aged 17-28 using the German version of the Short Form of the Volitional Components Inventory. Linear regressions adjusted for sex, age and lifetime disorders revealed that anxiety and affective disorders were associated with widespread alterations in self-reported volitional control (lower self regulation, higher self inhibition and volitional inhibition), while substance use disorders were specifically associated with higher volitional inhibition. Logistic regressions adjusted for sex, age and prior lifetime psychopathology revealed that lower self-reported volitional control at T2 predicted incident panic, social phobia and substance use at T3 (follow-up interval M = 4.8 years). Findings point toward at least partly disorder-specific alterations in volitional control in mental disorders, which might be antecedent vulnerability factors and thus useful to guide early recognition and prevention.

Networks of phobic fear: Functional connectivity shifts in two subtypes of specific phobia

Anxiety disorders can be conceptualized by an abnormal interplay of emotion-processing brain circuits; however, knowledge of brain connectivity measures in specific phobia is still limited. To explore functional interactions within selected fear-circuitry structures (anterior cingulate cortex (ACC), amygdala, insula), we re-examined three task-based fMRI studies using a symptom provocation approach (n=94 subjects in total) on two different phobia subtypes (animal subtype as represented by snake phobia (SP) and blood-injection-injury subtype as represented by dental phobia (DP)), and a non-phobic healthy control group (HC). Functional connectivity (FC) analyses detected a negative coupling between the amygdala and the ACC in HC for both classes of phobic stimuli, while SP and DP lacked this inhibitory relationship during visual stimulus presentation. However, a negative FC between the insula and the amygdala was observed in DP during visual symptom provocation, which reversed to a positive FC under auditory symptom provocation pointing to effects depending on stimulus modality in DP. SP showed significantly higher FC towards snake-anxiety eliciting stimuli than HC on an average measure of FC, while DP showed a similar pattern under auditory stimulation only. These findings altogether indicate FC shifts during symptom provocation in specific phobia possibly reflecting impaired emotion regulation processes within fear-circuitry networks. FC hence could represent a prime target for neuroscience-informed augmentation strategies when treating pathological forms of fear.