Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been proposed as a feasible treatment for major depressive disorder (MDD). However, meta-analytic evidence is heterogenous and data from multicentre trials are scarce. We aimed to assess the efficacy of tDCS versus sham stimulation as an additional treatment to a stable dose of selective serotonin reuptake inhibitors (SSRIs) in adults with MDD. METHODS: The DepressionDC trial was triple-blind, randomised, and sham-controlled and conducted at eight hospitals in Germany. Patients being treated at a participating hospital aged 18-65 years were eligible if they had a diagnosis of MDD, a score of at least 15 on the Hamilton Depression Rating Scale (21-item version), no response to at least one antidepressant trial in their current depressive episode, and treatment with an SSRI at a stable dose for at least 4 weeks before inclusion; the SSRI was continued at the same dose during stimulation. Patients were allocated (1:1) by fixed-blocked randomisation to receive either 30 min of 2 mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks, or sham stimulation at the same intervals. Randomisation was stratified by site and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score (ie, <31 or ≥31). Participants, raters, and operators were masked to treatment assignment. The primary outcome was change on the MADRS at week 6, analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one treatment session. The trial was registered with ClinicalTrials.gov (NCT02530164). FINDINGS: Between Jan 19, 2016, and June 15, 2020, 3601 individuals were assessed for eligibility. 160 patients were included and randomly assigned to receive either active tDCS (n=83) or sham tDCS (n=77). Six patients withdrew consent and four patients were found to have been wrongly included, so data from 150 patients were analysed (89 [59%] were female and 61 [41%] were male). No intergroup difference was found in mean improvement on the MADRS at week 6 between the active tDCS group (n=77; -8·2, SD 7·2) and the sham tDCS group (n=73; -8·0, 9·3; difference 0·3 [95% CI -2·4 to 2·9]). Significantly more participants had one or more mild adverse events in the active tDCS group (50 [60%] of 83) than in the sham tDCS group (33 [43%] of 77; p=0·028). INTERPRETATION: Active tDCS was not superior to sham stimulation during a 6-week period. Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD. FUNDING: German Federal Ministry of Education and Research.

[VR-supported therapy for anxiety and posttraumatic stress disorder: current possibilities and limitations]. / VR-gestützte Therapie bei Angst und posttraumatischer Belastungsstörung: aktuelle Möglichkeiten und Grenzen.

BACKGROUND: Virtual reality (VR) is increasingly used in psychotherapy, and the speed of development of therapeutic VR tools is continuously increasing. OBJECTIVE: This narrative review provides an overview of the state of the art regarding VR applications for psychotherapy. MATERIAL AND METHODS: The current state of VR therapy research for anxiety disorders and posttraumatic stress disorder (PTSD) is summarized. The focus lies on VR exposure therapy. Current developments in the field are outlined. RESULTS: For anxiety disorders, especially phobic disorders, there are already positive recommendations in the current German S3 guidelines. For PTSD, the development of VR therapy tools is still in a relatively early stage. CONCLUSION: The development of mobile cost-effective VR solutions in recent years has enabled entirely new applications for VR. The empirical challenges of these new developments are considerable. Nevertheless, the chances for an improvement of psychotherapeutic routine care are good.

Virtuelle Realität bei Angsterkrankungen ­ vom experimentellen Tool zur klinischen Praxis.

Anxiety disorders are among the most frequent psychiatric disorders. According to national and international guidelines, psychopharmacological as well as psychotherapeutic approaches are recommended as first-choice treatments, depending on diagnosis and severity. Among psychotherapeutic approaches, cognitive-behavioral therapy (CBT) has been investigated most. Here, exposure is of special relevance as the core element of treatment. The technology of virtual reality (VR) has been increasingly investigated as a possible add-on strategy or alternative to conventional exposure therapy. Numerous studies of VR exposure for anxiety disorders have been published. Further, the comparison of exposure treatment in vivo vs. in VR has been investigated in meta-analyses. The results are promising overall, however they do not yet justify a general recommendation of this treatment. There is still the need for more research, especially regarding treatment efficacy in large-scale studies with larger patient samples.

[Development of virtual reality as an exposure technique]. / Die Entwicklung virtueller Realität als Expositionsverfahren.

BACKGROUND: Virtual reality (VR) has been investigated as a medium for exposure therapy of anxiety disorders for 20 years. Various meta-analyses have provided convincing evidence of the therapeutic efficacy of exposure therapy in VR. OBJECTIVE: In recent years VR technology and its applications have considerably improved. Therefore, the current state of the art of VR exposure therapy is presented. MATERIAL AND METHODS: This article provides a narrative review of current research on VR exposure therapy for anxiety disorders and major directions of development in this area. RESULTS: After an almost exclusive focus on specific phobias in the early days, research on more complex anxiety disorders (particularly on social anxiety disorder) is increasing. In addition, VR has become established as an experimental method to probe psychopathological processes and to elucidate the mechanism of action of (VR) exposure therapy. CONCLUSION: There is still a need for more research into VR exposure therapy, especially in complex anxiety disorders (e. g. panic disorder, agoraphobia and social anxiety disorder) and trauma-related disorders. Furthermore, VR has become established as a research tool. The rapid technological development gives reason to expect a continuing increase in VR research, in clinical as well as basic research.

[Evaluation of a neuropsychological test battery with psychiatric and psychosomatic patients]. / Evaluation einer neuropsychologischen Testbatterie an psychiatrischen und psychosomatischen Patienten.

Neuropsychological assessment should be an integral component of clinical psychiatric diagnostics. Yet, the commonly used tests have not been investigated adequately for this population so far. The current study evaluated a clinically approved neuropsychological test battery by analyzing data on 226 mentally ill patients using factor and regression analyses. The extraction of three factors (Speed, Memory, and Executive Functions) proved to be adequate as the tests could be allocated properly. Regression analysis revealed an economical basis assessment consisting of three tests (TAP Alertness, VLMT, and Matrices Test). Based on acceptance, economy, and factorial structure aspects, we recommend the investigated test battery for neuropsychological assessment of psychiatric and psychosomatic patients.

Diaphragmatic breathing during virtual reality exposure therapy for aviophobia: functional coping strategy or avoidance behavior? a pilot study.

BACKGROUND: Although there is solid evidence for the efficacy of in vivo and virtual reality (VR) exposure therapy for a specific phobia, there is a significant debate over whether techniques promoting distraction or relaxation have impairing or enhancing effects on treatment outcome. In the present pilot study, we investigated the effect of diaphragmatic breathing (DB) as a relaxation technique during VR exposure treatment. METHOD: Twenty-nine patients with aviophobia were randomly assigned to VR exposure treatment either with or without diaphragmatic breathing (six cycles per minute). Subjective fear ratings, heart rate and skin conductance were assessed as indicators of fear during both the exposure and the test session one week later. RESULTS: The group that experienced VR exposure combined with diaphragmatic breathing showed a higher tendency to effectively overcome the fear of flying. Psychophysiological measures of fear decreased and self-efficacy increased in both groups with no significant difference between the groups. CONCLUSIONS: Our findings indicate that diaphragmatic breathing during VR exposure does not interfere with the treatment outcome and may even enhance treatment effects of VR exposure therapy for aviophobic patients. TRIAL REGISTRATION: Retrospectively registered. ClinicalTrials.gov NCT02990208 . Registered 07 December 2016.

Emotional processing and rTMS: does inhibitory theta burst stimulation affect the human startle reflex?

Repetitive transcranial magnetic stimulation (rTMS) enables the local and non-invasive modulation of cortical activity and has proved to achieve antidepressant effects. To a lesser extent, rTMS is investigated as a treatment option for anxiety disorders. As the prefrontal cortex and the amygdala represent key components of human emotion regulation, we investigated how prefrontally applied rTMS affects the responsiveness of the subcortical amygdala during a fear-relevant study paradigm to examine potential cortico-limbic effects. Sham-controlled, randomised inhibitory rTMS (continuous theta burst stimulation, TBS) was applied to 102 healthy subjects (female = 54) over the right dorsolateral prefrontal cortex. Subsequently, the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) acoustic startle response was investigated. Subjective anxiety ratings (anxiety sensitivity, trait and state anxiety) were considered. Picture category affected the startle magnitude as expected for both TBS intervention groups (highest startle response for unpleasant, lowest for pleasant pictures). However, no modulatory effects of TBS on startle potentiation were discerned. No significant interaction effects of TBS intervention, subjective anxiety ratings, and gender were identified. Interestingly, startle habituation was influenced by TBS intervention on a trend-level, with verum TBS leading to an accelerated habituation. We found no evidence for the hypothesis that prefrontal inhibitory TBS affects the responsiveness of the amygdala during the presentation of emotionally relevant stimuli in healthy subjects. Instead, we found accelerated habituation under verum TBS on a statistical trend-level. Hence, some preliminary hints for modulatory effects of inhibitory TBS on basic learning mechanisms could be found.

Dopamine D3 receptor gene variation: impact on electroconvulsive therapy response and ventral striatum responsiveness in depression.

Dysfunction of dopamine D3 receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D3 receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D3 receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a sample of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent samples of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02-0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009; corrected p=0.045) and rs3773679 (uncorrected p=0.009; corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (sample 1: cluster-corrected p=0.002; sample 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli.

Distraction versus focusing during VR exposure therapy for acrophobia: A randomized controlled trial.

BACKGROUND AND OBJECTIVES: The therapeutic mechanisms of exposure therapy are not well understood. Research suggests that focusing on the most feared aspect might not be necessary, and that distraction with a low cognitive load (e.g., conversation) might enhance exposure. We aimed at systematically testing the efficacy of exposure therapy with focusing vs. conversational distraction, hypothesizing that distracted exposure would yield superior effects. METHODS: Thirty-eight patients with acrophobia (specific phobia of heights; clinician-determined) (free from relevant somatic or other mental disorders) were randomly assigned (1:1) to one virtual reality (VR) session of either focused (n = 20) or distracted exposure (n = 18). This monocentric trial took place at a psychiatric university hospital. RESULTS: Both conditions resulted in a significant reduction of acrophobic fear and avoidance, and a significant increase of self-efficacy (primary outcome variables). However, condition did not have a significant effect on any of these variables. Effects were stable at four-week follow-up. Heart rate and skin conductance level indicated significant arousal, but did not differ between conditions. LIMITATIONS: Eye-tracking was unavailable, nor did we assess emotions other than fear. Power was limited due to sample size. CONCLUSIONS: A balanced exposure protocol combining attention to fear cues with conversational distraction, while not being superior, might be as effective as focused exposure for acrophobia, at least during the initial stages of exposure therapy. These results support previous findings. This study demonstrates how VR can be exploited for therapy process research, as VR supports dismantling designs and the incorporation of online process measures.

Driving-related cognitive skills during antidepressant transcranial direct current stimulation: results in a subsample from the DepressionDC trial.

Therapeutic transcranial direct current stimulation (tDCS) is a well-tolerated neuromodulatory intervention. However, there are currently no data on its impact on driving skills. Therefore, we conducted a validated assessment of driving-related cognitive skills in participants of the DepressionDC trial, a multicenter, randomized-controlled trial investigating the antidepressant effects of 6-week prefrontal tDCS in patients with major depressive disorder (MDD). Twenty-one patients (12 women, active tDCS, n = 11, sham, n = 10) underwent an assessment of driving-related cognitive skills before and after the intervention. Using a Bayesian analysis approach, we found no group differences between active tDCS and sham tDCS in the pre-post treatment changes for visual perception (estimated median difference: 3.41 [-3.17, 10.55 89%-CI], BF01: 2.1), stress tolerance (estimated median difference: 0.77 [-2.40, 4.15 89%-CI], BF01: 1.6), and reaction time (estimated median difference: 2.06 [-12.33, 16.83 89%-CI], BF01: 6.5). Our results indicate that repeated sessions of a conventional bifrontal tDCS protocol do not negatively impact driving-related cognitive skills in patients with MDD.

Fear, psychophysiological arousal, and cognitions during a virtual social skills training in social anxiety disorder while manipulating gaze duration.

The use of virtual reality (VR) is an option for social skills training and exposure in Social Anxiety Disorder (SAD). In addition, virtual social situations are an ideal tool to study the influence of a counterpart's social behavior, e. g. eye contact. We developed two scenarios in VR that enable users to practice to assert their rights. The participants' tasks were to ask a passenger to release their reserved seat in a virtual train and to cancel a trip in a virtual travel agency. In a randomized, crossover design, we compared the effect of a large (during 80% of the conversation time) and a small (20%) amount of direct gaze by the virtual conversational partners in 41 patients with SAD and 21 healthy controls (HCs). We expected fear and psychophysiological arousal to be higher in patients than in HCs and higher in the 80% eye contact condition. The scenarios provoked an increase of fear and psychophysiological arousal over baseline in patients and in HCs. Gaze duration of the virtual agent had no influence on fear and psychophysiological arousal, but affected the experience of presence. Our results suggest a suitability of our scenarios for social skills training and exposure therapy in SAD. The lack of influence of gaze duration on parameters of fear might be explained by the fact that participants did not consciously detect the differences in gaze duration. However, the impact on some parameters (e. g. presence) suggests that participants noticed differences in gaze duration on a subliminal level.

COMT val158met influence on electroconvulsive therapy response in major depression.

There is strong evidence for a genetic contribution to the pathogenesis of depression, with the functional catechol-O-methyltransferase (COMT) val158met polymorphism having been suggested as a potential susceptibility factor. In the present study, the effect of COMT val158met on response to electroconvulsive therapy (ECT) was analyzed in a sample of 104 Caucasian patients (f = 71, m = 33) with pharmacologically treatment-resistant Major Depression. The higher active COMT 158val allele was found to be associated with (1) higher pre-ECT severity of depression and (2) better treatment response to ECT particularly regarding the core symptoms of depression as well as sleep-related symptoms. These findings were restricted to the female subgroup of patients. In summary, the present study supports a potentially gender-specific significant impact of COMT gene variation on electroconvulsive therapy response, with COMT 158val risk allele carriers suffering from more severe, pharmacologically less efficiently treatable depression and thus possibly deriving greater benefit from ECT in the first place.

Neurobiological and clinical effects of fNIRS-controlled rTMS in patients with panic disorder/agoraphobia during cognitive-behavioural therapy.

BACKGROUND: A relevant proportion of patients with panic disorder (PD) does not improve even though they receive state of the art treatment for anxiety disorders such as cognitive-behavioural therapy (CBT). At the same time, it is known, that from a neurobiological point of view, PD patients are often characterised by prefrontal hypoactivation. Intermittent Theta Burst Stimulation (iTBS) is a non-invasive type of neurostimulation which can modulate cortical activity and thus has the potential to normalise prefrontal hypoactivity found in PD. We therefore aimed at investigating the effects of iTBS as an innovative add-on to CBT in the treatment for PD. METHODS: In this double-blind, bicentric study, 44 PD patients, randomised to sham or verum stimulation, received 15 sessions of iTBS over the left prefrontal cortex (PFC) in addition to 9 weeks of group CBT. Cortical activity during a cognitive as well as an emotional (Emotional Stroop) paradigm was assessed both at baseline and post-iTBS treatment using functional near-infrared spectroscopy (fNIRS) and compared to healthy controls. RESULTS: In this manuscript we only report the results of the emotional paradigm; for the results of the cognitive paradigm please refer to Deppermann et al. (2014). During the Emotional Stroop test, PD patients showed significantly reduced activation to panic-related compared to neutral stimuli for the left PFC at baseline. Bilateral prefrontal activation for panic-related stimuli significantly increased after verum iTBS only. Clinical ratings significantly improved during CBT and remained stable at follow-up. However, no clinical differences between the verum- and sham-stimulated group were identified, except for a more stable reduction of agoraphobic avoidance during follow-up in the verum iTBS group. LIMITATIONS: Limitations include insufficient blinding, the missing control for possible state-dependent iTBS effects, and the timing of iTBS application during CBT. CONCLUSION: Prefrontal hypoactivity in PD patients was normalised by add-on iTBS. Clinical improvement of anxiety symptoms was not affected by iTBS.

Fear and physiological arousal during a virtual height challenge--effects in patients with acrophobia and healthy controls.

Virtual reality (VR) exposure therapy is becoming increasingly established, but the mode of action is not well understood. One potential efficacy factor might be physiological arousal. To investigate arousal during VR exposure, we exposed 40 patients with acrophobia and 40 matched healthy controls to a VR height challenge and assessed subjective (fear ratings) and physiological (heart rate, skin conductance level, salivary cortisol) fear reactions. Patients experienced a significant increase of subjective fear, heart rate and skin conductance level. Unexpectedly, controls, who reported no subjective fear, also showed an increase in heart rate and skin conductance. There was no increase in salivary cortisol levels in either group. Physiological arousal in acrophobic patients, in contrast to subjective fear, might not be stronger than that of controls confronted with height cues in VR, indicating marked discordance across symptom domains. The lack of a cortisol response in a clearly stressful paradigm warrants further study.

Trier Social Stress Test in vivo and in virtual reality: Dissociation of response domains.

The Trier Social Stress Test (TSST) is considered a reliable paradigm for inducing psychosocial stress. Virtual reality (VR) has successfully been applied to ensure a greater degree of efficiency and standardization in the TSST. Studies using the TSST in VR (VR-TSST) have reported significant stress reactions, with subjective and peripheral physiological reactions comparable to those in response to the in vivo TSST and with lower cortisol reactions. The current study examined whether an additional virtual competitive factor triggers larger stress responses than a standard VR-TSST. Forty-five male participants were randomly assigned to either in vivo TSST, VR-TSST (VR) or VR-TSST with a virtual competitor (VR+). A significant increase of self-reported stress, electrodermal activity, and heart rate indicated a pronounced stress reaction with no differences between groups. For salivary cortisol, however, responder rates differed significantly between groups, with in vivo participants showing overall higher response rates (86%) than participants of both VR groups (VR: 33%, VR+: 47%). In contrast, participants of both VR groups judged the task significantly more challenging than did in vivo TSST participants. In sum, our results indicate successful stress induction in all experimental conditions, and a marked dissociation of salivary cortisol levels on the one hand, and the physiological and psychological stress reactions on the other hand. The competitive scenario did not significantly enhance stress reactions. VR technology may serve as a standardized tool for inducing social stress in experimental settings, but further research is needed to clarify why the stress reaction as assessed by cortisol differs from peripheral and subjective stress reactions in VR.

Representation of Patients' Hand Modulates Fear Reactions of Patients with Spider Phobia in Virtual Reality.

Embodiment (i.e., the involvement of a bodily representation) is thought to be relevant in emotional experiences. Virtual reality (VR) is a capable means of activating phobic fear in patients. The representation of the patient's body (e.g., the right hand) in VR enhances immersion and increases presence, but its effect on phobic fear is still unknown. We analyzed the influence of the presentation of the participant's hand in VR on presence and fear responses in 32 women with spider phobia and 32 matched controls. Participants sat in front of a table with an acrylic glass container within reaching distance. During the experiment this setup was concealed by a head-mounted display (HMD). The VR scenario presented via HMD showed the same setup, i.e., a table with an acrylic glass container. Participants were randomly assigned to one of two experimental groups. In one group, fear responses were triggered by fear-relevant visual input in VR (virtual spider in the virtual acrylic glass container), while information about a real but unseen neutral control animal (living snake in the acrylic glass container) was given. The second group received fear-relevant information of the real but unseen situation (living spider in the acrylic glass container), but visual input was kept neutral VR (virtual snake in the virtual acrylic glass container). Participants were instructed to touch the acrylic glass container with their right hand in 20 consecutive trials. Visibility of the hand was varied randomly in a within-subjects design. We found for all participants that visibility of the participant's hand increased presence independently of the fear trigger. However, in patients, the influence of the virtual hand on fear depended on the fear trigger. When fear was triggered perceptually, i.e., by a virtual spider, the virtual hand increased fear. When fear was triggered by information about a real spider, the virtual hand had no effect on fear. Our results shed light on the significance of different fear triggers (visual, conceptual) in interaction with body representations.

The impact of perception and presence on emotional reactions: a review of research in virtual reality.

Virtual reality (VR) has made its way into mainstream psychological research in the last two decades. This technology, with its unique ability to simulate complex, real situations and contexts, offers researchers unprecedented opportunities to investigate human behavior in well controlled designs in the laboratory. One important application of VR is the investigation of pathological processes in mental disorders, especially anxiety disorders. Research on the processes underlying threat perception, fear, and exposure therapy has shed light on more general aspects of the relation between perception and emotion. Being by its nature virtual, i.e., simulation of reality, VR strongly relies on the adequate selection of specific perceptual cues to activate emotions. Emotional experiences in turn are related to presence, another important concept in VR, which describes the user's sense of being in a VR environment. This paper summarizes current research into perception of fear cues, emotion, and presence, aiming at the identification of the most relevant aspects of emotional experience in VR and their mutual relations. A special focus lies on a series of recent experiments designed to test the relative contribution of perception and conceptual information on fear in VR. This strand of research capitalizes on the dissociation between perception (bottom-up input) and conceptual information (top-down input) that is possible in VR. Further, we review the factors that have so far been recognized to influence presence, with emotions (e.g., fear) being the most relevant in the context of clinical psychology. Recent research has highlighted the mutual influence of presence and fear in VR, but has also traced the limits of our current understanding of this relationship. In this paper, the crucial role of perception on eliciting emotional reactions is highlighted, and the role of arousal as a basic dimension of emotional experience is discussed. An interoceptive attribution model of presence is suggested as a first step toward an integrative framework for emotion research in VR. Gaps in the current literature and future directions are outlined.

Virtual reality exposure in anxiety disorders: impact on psychophysiological reactivity.

OBJECTIVES: Anxiety disorders are among the most frequently encountered psychiatric disorders. Recommended treatments include cognitive behavioural therapy (CBT) and/or medication. In recent years, beneficial effects of virtual reality (VR) exposure therapy have been shown, making this technique a promising addition to CBT. However, the ability of VR to mimic threatening stimuli in a way comparable to in vivo cues has been discussed. In particular, it has been questioned whether VR is capable of provoking psychophysiological symptoms of anxiety. Since psychophysiological arousal is considered a prerequisite for effective exposure treatment, this systematic review aims to evaluate the evidence for the potential of VR exposure to evoke and modulate psychophysiological fear reactions. METHODS: PubMed and PsycINFO/Academic Search Premier databases were searched. Thirty-eight studies investigating challenge or habituation effects were included. RESULTS: VR exposure does provoke psychophysiological arousal, especially in terms of electrodermal activity. Results on psychophysiological habituation in VR are inconclusive. Study design and methodological rigour vary widely. CONCLUSIONS: Despite several limitations, this review provides evidence that VR exposure elicits psychophysiological fear reactions in patients and healthy subjects, rendering VR a promising treatment for anxiety disorders, and a potent research tool for future investigations of psychophysiological processes and their significance during exposure treatment.

Does rTMS alter neurocognitive functioning in patients with panic disorder/agoraphobia? An fNIRS-based investigation of prefrontal activation during a cognitive task and its modulation via sham-controlled rTMS.

OBJECTIVES: Neurobiologically, panic disorder (PD) is supposed to be characterised by cerebral hypofrontality. Via functional near-infrared spectroscopy (fNIRS), we investigated whether prefrontal hypoactivity during cognitive tasks in PD-patients compared to healthy controls (HC) could be replicated. As intermittent theta burst stimulation (iTBS) modulates cortical activity, we furthermore investigated its ability to normalise prefrontal activation. METHODS: Forty-four PD-patients, randomised to sham or verum group, received 15 iTBS-sessions above the left dorsolateral prefrontal cortex (DLPFC) in addition to psychoeducation. Before first and after last iTBS-treatment, cortical activity during a verbal fluency task was assessed via fNIRS and compared to the results of 23 HC. RESULTS: At baseline, PD-patients showed hypofrontality including the DLPFC, which differed significantly from activation patterns of HC. However, verum iTBS did not augment prefrontal fNIRS activation. Solely after sham iTBS, a significant increase of measured fNIRS activation in the left inferior frontal gyrus (IFG) during the phonological task was found. CONCLUSION: Our results support findings that PD is characterised by prefrontal hypoactivation during cognitive performance. However, verum iTBS as an "add-on" to psychoeducation did not augment prefrontal activity. Instead we only found increased fNIRS activation in the left IFG after sham iTBS application. Possible reasons including task-related psychophysiological arousal are discussed.

Acute shift in glutamate concentrations following experimentally induced panic with cholecystokinin tetrapeptide--a 3T-MRS study in healthy subjects.

According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate+glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary-adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17)=149.41; p<0.0001; PSS: F(1,17)=88.03; p<0.0001) and heart rate (HR: F(1,17)=72.79; p<0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17)=15.94; p=0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11)=8.68; p=0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both APImax (r=0.598; p=0.009) and maximum heart rate (HR(max)) during challenge (r=0.519; p=0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks.