Dissociation between amygdala and bed nucleus of the stria terminalis during threat anticipation in female post-traumatic stress disorder patients.

Feelings of uncontrollability and anxiety regarding possibly harmful events are key features of post-traumatic stress disorder (PTSD) symptomatology. Due to a lack of studies, the neural correlates of anticipatory anxiety in PTSD are still poorly understood. During functional magnetic resonance imaging, female PTSD patients with interpersonal violence trauma and healthy controls (HC) anticipated the temporally unpredictable presentation of aversive (human scream) or neutral sounds. Based on separate analysis models, we investigated phasic and sustained brain activations. PTSD patients reported increased anxiety during anticipation of aversive versus neutral sounds. Furthermore, we found both increased initial, phasic amygdala activation and increased sustained activation of the bed nucleus of the stria terminalis (BNST) during anticipation of aversive versus neutral sounds in PTSD patients in comparison to HC. PTSD patients as compared with HC also showed increased phasic responses in mid-cingulate cortex (MCC), posterior cingulate cortex (PCC), mid-insula and lateral prefrontal cortex (PFC) as well as increased sustained responses in MCC, PCC, anterior insula and lateral and medial PFC. Our results demonstrate a relationship between anticipatory anxiety in PTSD patients and hyperresponsiveness of brain regions that have previously been associated with PTSD symptomatology. Additionally, the dissociation between amygdala and BNST indicates distinct temporal and functional characteristics and suggests that phasic fear and sustained anxiety responses are enhanced during unpredictable anticipation of aversive stimuli in PTSD. Hum Brain Mapp 38:2190-2205, 2017. © 2017 Wiley Periodicals, Inc.

Phasic and sustained brain responses in the amygdala and the bed nucleus of the stria terminalis during threat anticipation.

Several lines of evidence suggest that the amygdala and the bed nucleus of the stria terminalis (BNST) are differentially involved in phasic and sustained fear. Even though, results from neuroimaging studies support this distinction, a specific effect of a temporal dissociation with phasic responses to onset versus sustained responses during prolonged states of threat anticipation has not been shown yet. To explore this issue, we investigated brain activation during anticipation of threat in 38 healthy participants by means of functional magnetic resonance imaging. Participants were presented different visual cues indicated the temporally unpredictable occurrence of a subsequent aversive or neutral stimulus. During the onset of aversive versus neutral anticipatory cues, results showed a differential phasic activation of amygdala, anterior cingulate cortex (ACC), and ventrolateral prefrontal cortex (PFC). In contrast, activation in the BNST and other brain regions, including insula, dorsolateral PFC, ACC, cuneus, posterior cingulate cortex, and periaqueductal grey was characterized by a sustained response during the threat versus neutral anticipation period. Analyses of functional connectivity showed phasic amygdala response as positively associated with activation, mainly in sensory cortex areas whereas sustained BNST activation was negatively associated with activation in visual cortex and positively correlated with activation in the insula and thalamus. These findings suggest that the amygdala is responsive to the onset of cues signaling the unpredictable occurrence of a potential threat while the BNST in concert with other areas is involved in sustained anxiety. Furthermore, the amygdala and BNST are characterized by distinctive connectivity patterns during threat anticipation.

Implicit emotion regulation in the presence of threat: neural and autonomic correlates.

Efficient emotion regulation is essential for social interaction and functioning in human society and often happens without direct intention and conscious awareness. Cognitive labeling of stimuli based on certain characteristics has been assumed to represent an effective strategy of implicit emotional regulation whereas processing based on simple perceptual characteristics (e.g., matching) has not. Evidence exists that the ventrolateral prefrontal cortex (VLPFC) might be of functional relevance during labeling by down-regulating limbic activity in the presence of threatening stimuli. However, it remained unclear whether this VLPFC activation was particularly specific to threat because previous studies focused exclusively on threatening stimuli. In the current study, 35 healthy participants labeled or matched both threatening and neutral pictures while undergoing 52-channel functional near-infrared spectroscopy. Results showed increased VLPFC activation during labeling of threatening but not neutral pictures. No increase in prefrontal activation was detected during matching. Moreover, skin conductance increased equally for both valence conditions during initial phases of labeling whereas during matching stronger increases were found for threatening stimuli. Although a general inverse relationship between VLPFC function and skin conductance was not confirmed, both were negatively correlated during matching of threatening pictures in subjects with high state anxiety. It was concluded that the VLPFC plays an essential role during implicit emotion regulation. Further, even simple perceptual processing seems to engage regulatory top-down activation in anxious individuals.

Prefrontal correlates of approach preferences for alcohol stimuli in alcohol dependence.

An approach bias for alcohol stimuli (i.e. faster approach than avoidance reactions) might facilitate relapses in alcohol dependence. Neurobiological models suggest hypersensitivity in the reward system [inter alia nucleus accumbens and orbitofrontal cortex (OFC)] to cause pathologically enhanced approach impulses towards alcohol stimuli. At the same time, in alcohol dependence, these structures are only insufficiently controlled by a hypoactive dorsolateral prefrontal cortex (DLPFC). The present study investigated the cortical aspects of this model with functional near-infrared spectroscopy in 21 alcohol-dependent in-patients and 21 healthy controls (HC; comparable in age, gender and education) during performance of the Approach-Avoidance Task (AAT) for the first time. Complementing previous findings, in reaction times (RTs), patients showed stronger approach preferences for alcohol than non-alcohol stimuli. For non-alcohol stimuli, patients even displayed avoidance preferences. The reversed pattern was found in HC. Group differences in activity of the OFC were identical to those in RTs, revealing patients to assign higher subjective value to approaching alcohol stimuli. In both groups, regulatory activity in the right DLPFC was stronger during avoiding than approaching alcohol pictures. Probable awareness of the behavioural hypotheses due to explicit task instructions and patients' deficient prefrontal function might account for this equally aligned pattern. Results are discussed with regard to recent findings revealing a reduced behavioural approach bias and risk for relapse by applying a retraining version of the AAT. Functional measurements might serve as a method for monitoring the corresponding neurobiological changes and-possibly-predicting the success of such a training.

Neuropeptide S receptor gene: fear-specific modulations of prefrontal activation.

Since central administration of neuropeptide S (NPS) has been shown to exert anxiolytic effects on rodent behavior in a number of studies, genetic variants of its cognate G-protein coupled receptor (NPSR1) became the focus of several recent human studies on anxiety and anxiety disorders. The T allele of rs324981, which goes along with enhanced receptor function, was associated with panic disorder, increased anxiety sensitivity in healthy subjects, attenuated prefrontal brain activation and elevated amygdala responses to fear-relevant stimuli. To investigate whether prefrontal attenuations in rs324981 T allele carriers are specific to fear-relevant stimulus content and cannot be attributed to a generally higher interference of emotional stimuli, 92 subjects performed a combined cognitive and emotional Stroop task while oxygenation changes in the prefrontal cortex were recorded using functional near-infrared spectroscopy. Results showed a specific NPSR1 gene activation modulation in response to fear-relevant word stimuli. Only A-homozygotes displayed an emotional Stroop effect in terms of increased activation to fear-relevant stimuli in medial and dorsolateral prefrontal cortex. Specifically, activation in the fear-relevant condition was higher in A-homozygotes as compared to T allele carriers while no group differences were found during neutral, congruent or highly interfering incongruent color word presentation. The current results are in line with earlier imaging genetic studies and suggest a potential protective function of the NPSR1 rs324981 A/A genotype against pathologically enhanced anxiety that might be explained by stronger reflective prefrontal regulation over the subcortical fear response.

Inhibitory transcranial magnetic theta burst stimulation attenuates prefrontal cortex oxygenation.

Recent studies highlighted the great potential of newly established theta burst stimulation (TBS) protocols for non-invasive human brain stimulation studies using transcranial magnetic stimulation (TMS). While intermittent TBS over the primary motor cortex was found to potentiate motor evoked potentials, continuous TBS led to profound attenuations. Although numerous studies investigated the impact of TBS on motor cortex function, yet, only few imaging studies focused on its effects in other brain areas. Particularly for the prefrontal cortex, it is unclear whether TBS has similar effects compared to application over motor areas. In the current study continuous TBS was applied to either the left or right dorsolateral prefrontal cortex in a sample of healthy subjects. Changes in prefrontal oxygenation were measured during an emotional Stroop task by means of functional multi-channel near-infrared spectroscopy (fNIRS) before and after stimulation. Results showed bilaterally decreased prefrontal oxygenation following inhibitory stimulation of the left prefrontal cortex but no behavioral effect. No such alterations were observed following right-hemispheric or sham stimulation. The results of the current study are in line with earlier findings and additionally demonstrate that also prefrontal oxygenation can be impaired by continuous TBS.

Revise the revised? New dimensions of the neuroanatomical hypothesis of panic disorder.

In 2000, Gorman et al. published a widely acknowledged revised version of their 1989 neuroanatomical hypothesis of panic disorder (PD). Herein, a 'fear network' was suggested to mediate fear- and anxiety-related responses: panic attacks result from a dysfunctional coordination of 'upstream' (cortical) and 'downstream' (brainstem) sensory information leading to heightened amygdala activity with subsequent behavioral, autonomic and neuroendocrine activation. Given the emergence of novel imaging methods such as fMRI and the publication of numerous neuroimaging studies regarding PD since 2000, a comprehensive literature search was performed regarding structural (CT, MRI), metabolic (PET, SPECT, MRS) and functional (fMRI, NIRS, EEG) studies on PD, which will be reviewed and critically discussed in relation to the neuroanatomical hypothesis of PD. Recent findings support structural and functional alterations in limbic and cortical structures in PD. Novel insights regarding structural volume increase or reduction, hyper- or hypoactivity, laterality and task-specificity of neural activation patterns emerged. The assumption of a generally hyperactive amygdala in PD seems to apply more to state than trait characteristics of PD, and involvement of further areas in the fear circuit, such as anterior cingulate and insula, is suggested. Furthermore, genetic risk variants have been proposed to partly drive fear network activity. Thus, the present state of knowledge generally supports limbic and cortical prefrontal involvement as originally proposed in the neuroanatomical hypothesis. Some modifications might be suggested regarding a potential extension of the fear circuit, genetic factors shaping neural network activity and neuroanatomically informed clinical subtypes of PD potentially guiding future treatment decisions.

Neural correlates of spontaneous panic attacks.

In this report, we present two anxiety disorder patients who spontaneously experienced a panic attack during an fMRI examination and subsequently aborted the measurement. We analyzed the functional data gathered up to that point in relation to the patients' subsequent verbal reports of the course of the panic attacks. Within prominent structures of the fear network (amygdala, insula, prefrontal cortex) neural dynamics mirrored the description of the attack very well for one of the patients. For the other patient who experienced a less intense attack and who was treated pharmacologically at the time of measurement, the relation was limited to the prefrontal cortex. Investigating the temporal dynamics of neural activation in an ecologically valid situation may point to the potentially different roles of the amygdala and the insula as well as the prefrontal cortex prior to and during a panic attack.

Medial prefrontal cortex stimulation modulates the processing of conditioned fear.

The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS-) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS- discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT).

N1 and N2 ERPs reflect the regulation of automatic approach tendencies to positive stimuli.

The Approach-Avoidance Task (AAT) measures automatic approach-avoidance tendencies and their regulation: compatible reactions (approach positive, avoid negative) are faster than incompatible ones (approach negative, avoid positive). The present study assessed event-related potentials (ERPs) in 15 healthy persons for depicting neuropsychological sub-processes of such stimulus-response compatibility (SRC) effects. Early attention allocation preparing efficient stimulus classification (N1 ERP) and response inhibition on the level of response representations (N2 ERP) were found to underlie the solution of the AAT-conflict. For positive stimuli, these processes were enhanced during the incompatible condition avoid positive compared to the compatible condition approach positive. Source localization analysis revealed activity in right occipital areas (N1 ERP), and in left DLPFC and insula (N2 ERP) to be neuronal generators of these electrophysiological SRC effects. This neuronal regulation resulted in no influence of incompatibility at the behavioural level. For negative pictures, we found the reversed pattern: there were no electrophysiological SRC effects, but clear behavioural SRC effects in both RTs and error frequency, i.e. participants were faster and made fewer errors during avoiding than approaching negative pictures. These valence-specific differences are in line with previous studies indicating negative stimuli - probably due to higher importance for survival - to more strongly influence behaviour.

Prefrontal activation patterns of automatic and regulated approach-avoidance reactions - a functional near-infrared spectroscopy (fNIRS) study.

INTRODUCTION: The present pilot study investigated cortical processes during automatic and regulated approach-avoidance reactions for the first time. METHODS 1: In 15 healthy volunteers, prefrontal activity was measured with functional near-infrared spectroscopy (fNIRS) during performance of a joystick version of the Approach-Avoidance Task (AAT). In experiment 1, participants approached (pulled towards their body) and avoided (pushed away from their body) positive and negative pictures. RESULTS 1: Incompatible, regulated reactions (avoid positive, approach negative) compared to compatible, automatic reactions (approach positive, avoid negative) caused stronger activation in terms of a decrease of deoxygenated haemoglobin (HHb) in right dorsolateral prefrontal cortex (DLPFC) (i.e., in one of the main instances for behavioural control in humans). METHODS 2: In the context of pathologically enhanced approach tendencies in addiction disorders and of planned future studies, we presented alcohol and non-alcohol pictures in experiment 2. RESULTS 2: Here, left anterior lateral orbitofrontal cortex as part of the general reward system processing secondary rewards showed stronger activation in terms of increased oxygenated haemoglobin (O(2)Hb) during approaching compared to avoiding alcohol pictures. This difference was positively correlated with participants' expectation about beneficial effects of alcohol in terms of emotional regulation. DISCUSSION: Despite some limitations due to the pilot character of the study, our results suggest that further combinations of the AAT and functional imaging methods will reveal detailed insight into neuronal mechanisms constituting approach-avoidance as basic behavioural principles and into specifically altered sub-processes in alcohol dependence.

Differential prefrontal and frontotemporal oxygenation patterns during phonemic and semantic verbal fluency.

Movement artifacts are still considered a problematic issue for imaging research on overt language production. This motion-sensitivity can be overcome by functional near-infrared spectroscopy (fNIRS). In the present study, 50 healthy subjects performed a combined phonemic and semantic overt verbal fluency task while frontal and temporal cortex oxygenation was recorded using multi-channel fNIRS. Results showed a partial dissociation for phonemic and semantic word generation with equally increased oxygenation in frontotemporal cortices for both types of tasks whereas anterior and superior prefrontal areas were exclusively activated during phonemic fluency. Also, a general left-lateralization was found being more pronounced during semantic processing. These findings line up with earlier imaging and lesion studies emphasizing a crucial role of the temporal lobe for semantic word production, whereas phonemic processing seems to depend on intact frontal lobe function.