Functional and clinical outcomes of FMRI-based neurofeedback training in patients with alcohol dependence: a pilot study.

Identifying treatment options for patients with alcohol dependence is challenging. This study investigates the application of real-time functional MRI (rtfMRI) neurofeedback (NF) to foster resistance towards craving-related neural activation in alcohol dependence. We report a double-blind, placebo-controlled rtfMRI study with three NF sessions using alcohol-associated cues as an add-on therapy to the standard treatment. Fifty-two patients (45 male; 7 female) diagnosed with alcohol dependence were recruited in Munich, Germany. RtfMRI data were acquired in three sessions and clinical abstinence was evaluated 3 months after the last NF session. Before the NF training, BOLD responses and clinical data did not differ between groups, apart from anger and impulsiveness. During NF training, BOLD responses of the active group were decreased in medial frontal areas/caudate nucleus, and increased, e.g. in the cuneus/precuneus and occipital cortex. Within the active group, the down-regulation of neuronal responses was more pronounced in patients who remained abstinent for at least 3 months after the intervention compared to patients with a relapse. As BOLD responses were comparable between groups before the NF training, functional variations during NF cannot be attributed to preexisting distinctions. We could not demonstrate that rtfMRI as an add-on treatment in patients with alcohol dependence leads to clinically superior abstinence for the active NF group after 3 months. However, the study provides evidence for a targeted modulation of addiction-associated brain responses in alcohol dependence using rtfMRI.

Correlations Between the DMN and the Smoking Cessation Outcome of a Real-Time fMRI Neurofeedback Supported Exploratory Therapy Approach: Descriptive Statistics on Tobacco-Dependent Patients.

The aim of this study was to explore the potential of default mode network (DMN) functional connectivity for predicting the success of smoking cessation in patients with tobacco dependence in the context of a real-time function al MRI (RT-fMRI) neurofeedback (NF) supported therapy.Fifty-four tobacco-dependent patients underwent three RT-fMRI-NF sessions including resting-state functional connectivity (RSFC) runs over a period of 4 weeks during professionally assisted smoking cessation. Patients were randomized into two groups that performed either active NF of an addiction-related brain region or sham NF. After preprocessing, the RSFC baseline data were statistically evaluated using seed-based ROI (SBA) approaches taking into account the smoking status of patients after 3 months (abstinence/relapse).The results of the real study group showed a widespread functional connectivity in the relapse subgroup (n = 10) exceeding the DMN template and mainly low correlations and anticorrelations in the within-seed analysis. In contrast, the connectivity pattern of the abstinence subgroup (n = 8) primarily contained the core DMN in the seed-to-whole-brain analysis and a left lateralized correlation pattern in the within-seed analysis. Calculated Multi-Subject Dictionary Learning (MSDL) matrices showed anticorrelations between DMN regions and salience regions in the abstinence group. Concerning the sham group, results of the relapse subgroup (n = 4) and the abstinence subgroup (n = 6) showed similar trends only in the within-seed analysis.In the setting of a RT-fMRI-NF-assisted therapy, a widespread intrinsic DMN connectivity and a low negative coupling between the DMN and the salience network (SN) in patients with tobacco dependency during early withdrawal may be useful as an early indicator of later therapy nonresponse.

Effects of binaural and monaural beat stimulation on attention and EEG.

Nowadays a popular technique to improve mood and cognition is auditory beat stimulation (ABS), which is thought to induce a frequency-following response of brainwaves. The main types of ABS are monaural beats (MB) and binaural beats (BB). BB involves the presentation of a specific frequency to one ear and another frequency to the other ear which may induce neural entrainment. A difference between the frequencies of 40 Hz is assumed to improve cognition. The present study examined the effect of 40 Hz binaural beats (BB) and monaural beats (MB) on attention and electroencephalography (EEG). A total of 25 first-year psychology students (11 males, 14 females) performed a Flanker task while EEG was recorded during the 5 min-presentation of pink noise (PN), MB and BB. With respect to attention, as measured by the Flanker task, the number of false responses in the BB condition was smaller than that in the PN condition while the number of false responses in the MB condition was larger as compared to the PN condition. As there was no association of BB with a consistent increase in absolute 40 or 45 Hz power compared to PN or MB, EEG recordings could not confirm the hypothesized neural entrainment in the brain. Overall, the current findings show that listening to 40 Hz BB improves attention but do not show the occurrence of neural entrainment. Future research is recommended to include a larger sample, to use a broader cognitive test battery and to present auditory beats with a longer duration.

Just "Like Coffee" or Neuroenhancement by Stimulants?

Introduction: Pharmacological neuroenhancement (PN) is a topic of increasing importance and prevalence among students. However, there is a lack of differentiating PN substances, according to their psychoactive effects. In particular, there is a lack of data about PN by caffeinated drinks, even if coffee is a common and broadly used Neuroenhancer because of its cognitively enhancing effects regarding wakefulness, alertness and concentration. Materials and Methods: A web-survey was developed for German students and alumni about the non-medical use of caffeine for PN contained questions about coffee, caffeinated drinks and energy drinks, caffeine pills and methylxanthine tea regarding frequency and further contextual factors. Results: Six hundred and eighty-three participants completed the survey. Nearly all participants knew about PN (97.7%). 88.1% admitted using some over-the-counter substances. For PN purposes, coffee was used by 72.9% followed by energy drinks (68.2%) and cola drinks (62.4%). Methylxanthine containing tea was used for PN purposes, too (black tea 52.3%, green tea 51.7%). 1.8% admitted using illegal substances or prescription drugs, too. Discussion: Using legal methylxanthine containing drinks for PN seems to be extremely common with coffee and energy drinks being the preferred substances, while illegal and prescription drugs are only minimally used. Further studies should investigate the awareness of methylxanthine containing drinks as well as its character to be a flavoring drink or a neuroenhancer.

[Efficacy and safety of medicinal cannabis: results of the CaPRis study]. / Wirksamkeit und Sicherheit von Cannabisarzneimitteln: Ergebnisse der CaPRis-Studie.

In the 1990s, the endocannabinoid system was discovered as part of the human physiology. Since then, the effects of cannabis as a medicine have been researched more systematically. To summarize the scientific knowledge, the German Federal Ministry of Health commissioned an expertise.The project "Cannabis: Potential and Risks: a Scientific Analysis" (CaPRis), which started in 2016, aimed at analyzing the potential of medicinal cannabis and the risks of recreational cannabis use. A search of systematic reviews (SRs) and randomized-controlled trials (RCTs) were conducted in five international databases (publication date: 2006-2017). For the medical use of cannabis 16 SRs (of 186 RCTs) were included from a global search and nine further RCTs were comprised from a de novo search. All studies were methodologically assessed.Evidence for the efficacy of cannabis medicine (given as an adjunct to other medication) was found in patients with chronic pain and spasticity due to multiple sclerosis. Benefits were also found for appetite stimulation, improvement of nausea, and weight gain in patients with cancer, HIV/AIDS or in palliative care. Effects were often small. For other physical or mental disorders, only few or no controlled human studies are available. Adverse effects of cannabis medicine are often reported; severe adverse effects were mentioned in single cases only.To provide reliable treatment recommendations for clinicians and patients, more large-sized RCTs with follow-up assessments, consistent outcome measures, and active comparisons are needed.

Correction to: How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

The article "How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review", written by Eva Hoch, was originally published Online First without open access. After publication in volume 269, issue 1, page 87-105 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders. Five data bases were systematically searched (2006-August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a  meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists. THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.

Modulation of Craving Related Brain Responses Using Real-Time fMRI in Patients with Alcohol Use Disorder.

LITERATURE: One prominent symptom in addiction disorders is the strong desire to consume a particular substance or to display a certain behaviour (craving). Especially the strong association between craving and the probability of relapse emphasises the importance of craving in the therapeutic process. Neuroimaging studies have shown that craving is associated with increased responses, predominantly in fronto-striatal areas. AIM AND METHODS: The aim of the present study is the modification of craving-related neuronal responses in patients with alcohol addiction using fMRI real-time neurofeedback. For that purpose, patients with alcohol use disorder and healthy controls participated once in neurofeedback training; during the sessions neuronal activity within an individualized cortical region of interest (ROI) (anterior cingulate cortex, insula, dorsolateral prefrontal cortex) was evaluated. In addition, variations regarding the connectivity between brain regions were assessed in the resting state. RESULTS AND DISCUSSION: The results showed a significant reduction of neuronal activity in patients at the end of the training compared to the beginning, especially in the anterior cingulate cortex, the insula, the inferior temporal gyrus and the medial frontal gyrus. Furthermore, the results show that patients were able to regulate their neuronal activities in the ROI, whereas healthy subjects achieved no significant reduction. However, there was a wide variability regarding the effects of the training within the group of patients. After the neurofeedback-sessions, individual craving was slightly reduced compared to baseline. The results demonstrate that it seems feasible for patients with alcohol dependency to reduce their neuronal activity using rtfMRI neurofeedback. In addition, there is some evidence that craving can be influenced with the help of this technique. FUTURE PROSPECTS: In future, real-time fMRI might be a complementary neurophysiological-based strategy for the psychotherapy of patients with psychiatric or psychosomatic diseases. For that purpose, the stability of this effect and the generalizability needs to be assessed.

Serum levels of brain-derived neurotrophic factor are unchanged after transcranial direct current stimulation in treatment-resistant depression.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays an important role in differentiation and repair of neurons in the adult brain. BDNF serum levels have been found to be lower in depressed patients than in healthy subjects. In a couple of studies, effective antidepressant treatment including electroconvulsive therapy led to an increase in BDNF serum levels. As transcranial direct current stimulation (tDCS) is currently discussed as novel therapeutic intervention in major depression, we investigated BDNF serum levels during tDCS in therapy-resistant depression. METHODS: Twenty-two patients with a major depressive episode participated in a double-blind placebo-controlled trial and received randomized cross over treatment with 2 weeks active and 2 weeks sham tDCS (1 or 2 mA for 20 min, anode over the left dorsolateral prefrontal cortex, cathode right supraorbital cortex). RESULTS: Clinical assessment only showed a modest and non-significant improvement in HAMD, BDI and CGI in both groups. BDNF serum levels were measured at baseline, after 2 and after 4 weeks. There was neither a significant change of BDNF levels following active tDCS, nor were severity of depressive symptoms and BDNF levels correlated. LIMITATIONS: The small sample size, its heterogeneity, the short observation period and a cross-over design without an interval between both conditions. CONCLUSIONS: tDCS did not change BDNF serum levels unlike other established antidepressant interventions in this treatment resistant sample. However, larger studies are needed.

Effects of acute detoxification of the herbal blend 'Spice Gold' on dopamine D2/3 receptor availability: a [18F]fallypride PET study.

We carried out dynamic [(18)F]fallypride PET scans to measure cerebral dopamine D2/3 receptor availability in a 23-year old patient experiencing a severe withdrawal syndrome upon voluntary abstinence from "Spice", a pre-packaged herbal smoking thought to contain synthetic cannabinoids. Upon admission to the clinic, the patient experienced craving, affective symptoms and a range of somatic complaints, which resolved after several days' monitored abstinence. PET scans were performed on the day of admission, and one week later. Estimates of [(18)F]fallypride binding potential (BPND) were obtained in striatal and extrastriatal brain regions, and compared to results of age-matched healthy control subjects. Upon admission, [(18)F]fallypride BPND was reduced by 20% in the patient's striatum and also in extra-striatal regions. During short-term follow-up upon detoxification, the BPND increased to normal values. This study shows substantial short-term alterations of dopamine D2/3 receptor availability in a patient before and after acute detoxification from "Spice Gold", thus providing first evidence of reversible effects on dopamine receptors of heavy use of a herbal smoking blend.

Evaluation of sham transcranial direct current stimulation for randomized, placebo-controlled clinical trials.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been investigated as therapeutic intervention in various psychiatric and neurologic disorders. As placebo responses to technical interventions may be pronounced in many clinical conditions, it is important to thoroughly develop placebo conditions which meet the requirements for application in randomized double-blind controlled trials. OBJECTIVE: The two-part experiment reported here aims at evaluating a new sham tDCS condition in healthy subjects and device operators. Sham or active tDCS is delivered after entering a number code to the device and allows blinding of the operator before and during tDCS. The sham mode has no short stimulation period. METHODS: The experimental sequence was as follows: 1) Evaluation of successful blinding by comparing placebo to active stimulation at prefrontal sites based on the rating of subjects undergoing tDCS, 2) Evaluation of successful blinding by comparing placebo to active stimulation at prefrontal sites based on the operator/observer ratings. RESULTS: Subjects were not able to distinguish between active and sham tDCS for prefrontal stimulation. Overall there was no relevant discomfort and tDCS was well tolerated. Operators/observers were able to identify sham stimulation based on skin reddening after active, but not after sham tDCS. CONCLUSIONS: The tDCS sham condition investigated here may be suitable for placebo-controlled trials keeping subjects blind to treatment conditions. However, operators can easily be aware of the condition applied and they should not get involved in rating outcome measures during the course of high standard placebo-controlled trials.

Loudness dependence of auditory evoked potentials in patients with borderline personality disorder--impact of psychopathology.

Alterations of the central serotonergic system are considered to be involved in the pathophysiology of borderline personality disorder (BPD). The loudness dependence of the N1/P2 component of auditory evoked potentials (LD) has been shown to indirectly reflect central serotonergic activity. The aim of this study was to investigate LD in patients with BPD compared to healthy controls, and to evaluate the association between LD and psychopathology such as anxiety, anger or impulsiveness. Female patients with BPD were included and compared to age- and sex-matched healthy subjects. Self-rating instruments, such as the State-Trait Anxiety Inventory (STAI), State-Trait Anger Expression Inventory (STAXI), and the Barratt Impulsiveness Scale (BIS) were used to assess clinical scores of anxiety, anger, and impulsiveness. Evoked potentials were recorded following the application of acoustic stimuli with increasing intensities; the LD was analysed using dipole source analysis. The mean LD was significantly higher in patients with BPD compared to controls. In the entire sample there were significant positive correlations of LD with state anxiety scores and STAXI subscores. The data contribute to the knowledge of neurophysiological alterations in patients with BPD, supporting the hypothesis of serotonergic dysregulation in the pathophysiology of the disorder. The significant clinical correlations suggest monoaminergic modulations of psychopathology on the symptom level.

Alterations of the early auditory evoked gamma-band response in first-degree relatives of patients with schizophrenia: hints to a new intermediate phenotype.

BACKGROUND: There is growing evidence of abnormalities of high-frequency oscillations in the gamma-range of the electroencephalography in schizophrenia. The generation of neural activity in the gamma-band was shown to be critically related to a glutamatergic and GABAergic microcircuit which is also known to be involved in the pathophysiology of schizophrenia. Recently, a reduction of the early auditory evoked gamma-band response (eGBR) in schizophrenic patients was reported. In order to investigate the possible applicability of this neurophysiological marker as an intermediate phenotype for schizophrenia, this is the main question of our investigation: Is the early eGBR decreased regarding evoked power and phase locking in first-degree relatives of patients with schizophrenia? METHODS: We investigated the early eGBR in 17 unaffected first-degree relatives of patients with schizophrenia and in age-, gender- and education-matched groups of schizophrenic patients and healthy controls using an auditory reaction task. RESULTS: First-degree relatives of patients with schizophrenia and schizophrenic patients showed a significant reduction of evoked power and phase locking of the early eGBR compared to healthy controls. CONCLUSION: This study shows significantly reduced evoked power and phase locking of the early auditory eGBR in first-degree relatives of patients with schizophrenia pointing to the applicability of this marker as a heritable intermediate phenotype for schizophrenia. The findings are in line with the hypothesis of a disturbed GABAergic interneural modulation of pyramidal cells in schizophrenia and findings of different schizophrenia risk genes associated with transmission at glutamatergic and GABAergic synapses.

Attention to emotion: auditory-evoked potentials in an emotional choice reaction task and personality traits as assessed by the NEO FFI.

Several studies suggest that attention to emotional content is related to specific changes in central information processing. In particular, event-related potential (ERP) studies focusing on emotion recognition in pictures and faces or word processing have pointed toward a distinct component of the visual-evoked potential, the EPN ('early posterior negativity'), which has been shown to be related to attention to emotional content. In the present study, we were interested in the existence of a corresponding ERP component in the auditory modality and a possible relationship with the personality dimension extraversion-introversion, as assessed by the NEO Five-Factors Inventory. We investigated 29 healthy subjects using three types of auditory choice tasks: (1) the distinction of syllables with emotional intonation, (2) the identification of the emotional content of adjectives and (3) a purely cognitive control task. Compared with the cognitive control task, emotional paradigms using auditory stimuli evoked an EPN component with a distinct peak after 170 ms (EPN 170). Interestingly, subjects with high scores in the personality trait extraversion showed significantly higher EPN amplitudes for emotional paradigms (syllables and words) than introverted subjects.

Anterior cingulum volumetry, auditory P300 in schizophrenia with negative symptoms.

The anterior cingulate cortex (ACC) is located at the rostum of the corpus callosum and involved in both cognitive and emotional brain processes. It has been suggested to be involved in P300 event-related potential generation. A large sample of schizophrenia inpatients and controls was examined in order to assess the potential relationship between ACC volumes and P300 characteristics in patients with more pronounced negative symptoms. In 50 male schizophrenia patients and 50 matched controls, auditory P300 and structural magnetic resonance imaging volume measurements of the ACC were obtained. Patients' negative symptoms were assessed using the PANSS (Positive and Negative Syndrome Scale). Volumetry of ACC subregions revealed a volume reduction in patients with schizophrenia compared with controls in right hemispheric rostral ACC subregions that were most pronounced in more negative schizophrenia patients. There was a positive correlation between PZ P300 amplitude and total ACC volume in the right hemisphere in schizophrenia patients with less negative symptoms. The results support the assumption that structural changes of the ACC are more pronounced in subgroups of schizophrenia patients with more negative psychopathology. In addition, while right hemisphere ACC volumes significantly differ between schizophrenia subgroups, combining measures of event-related potential (ERP) and ACC volumetry does not add additional information.

Serotonergic functioning as measured by the loudness dependence of auditory evoked potentials is related to a haplotype in the brain-derived neurotrophic factor (BDNF) gene.

OBJECTIVES: The serotonergic system plays an important pathophysiological role in various psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is involved in the differentiation and survival of serotonergic neurons. A previous study showed that low serum BDNF levels were associated with strong loudness dependence of auditory evoked potentials (LDAEP) as a reflection of low central serotonergic activity. To evaluate the genetic basis of this relationship, we studied whether the LDAEP is correlated with genetic variants within the BDNF gene. METHODS: Ninety five healthy subjects (41 males, 54 females) received electrophysiological recording of LDAEP and blood drawing for BDNF genotyping. Three BDNF markers (including the single nucleotide polymorphism rs6265(Val66Met)) were analyzed. RESULTS: Haplotype analysis revealed stronger LDAEP values in carriers of the G(Val)-C-T [rs6265(Val66Met)-rs2030324-rs1491850] haplotype within the BDNF gene in comparison to other haplotype carriers. These findings were demonstrated for the LDAEP of both left and right primary auditory cortices as well as for the vertex electrode (Cz). CONCLUSION: Subjects with the BDNF haplotype G(Val)-C-T seem to be characterized by low serotonergic activity as well as possibly by low serum BDNF levels. These findings need replication in independent samples.

Avoiding the ballistocardiogram (BCG) artifact of EEG data acquired simultaneously with fMRI by pulse-triggered presentation of stimuli.

Simultaneous acquisition of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data could offer a much deeper understanding of brain function, e.g. in the analysis of tempo-spatial dynamics of brain activity in cognitive processing. However, more sophisticated analysis methods such as single-trial coupling of EEG and fMRI are often handicapped by the limited quality of EEGs acquired in the MRI scanner. In particular, the ballistocardiogram (BCG) artifact is still a relevant problem. Methods that are currently available typically remove the BCG artifact either in post-recording or real-time signal processing. Here, we would like to suggest a new strategy to avoid BCG artifacts during data acquisition. In our proposal, stimuli are presented pulse-triggered (PT), thus avoiding interference of BCG artifacts with the evoked potentials investigated during EEG recording. This method is based on the observation that the main influence of the BCG artifact is generally limited to the time interval of 150-500 ms post-QRS complex. Based on real measurements, we simulated different signal presentation methods relative to the onset of the BCG artifact for 14 subjects. Stimuli were either presented independently of the BCG artifact or pulse-triggered at fixed time-points (280 ms, 480 ms and 680 ms post-QRS complex) and with a jitter (short: 120 ms or long: 240 ms). In combination with an averaged artifact subtraction method signal distortion was reduced at best by 47%.

Reduced early auditory evoked gamma-band response in patients with schizophrenia.

BACKGROUND: There is growing evidence for abnormalities of certain gamma-aminobutyric acid (GABA)-ergic interneurons and their interaction with glutamatergic pyramidal cells in schizophrenia. These interneurons are critically involved in generating neural activity in the gamma-band (30-100 Hz) of the electroencephalogram. One example of such gamma oscillations is the early auditory evoked gamma-band response (GBR). Although auditory processing is obviously disturbed in schizophrenia, there is no direct evidence providing a reduced early auditory evoked GBR so far. We addressed two questions: 1) Is the early auditory evoked GBR decreased regarding power and phase-locking in schizophrenic patients?; and 2) Is this possible decrease a result of reduced activity in the auditory cortex and/or the anterior cingulate cortex (ACC), which were identified as sources of the GBR previously? METHODS: We investigated the early auditory evoked GBR and its sources in the ACC and the auditory cortex in 90 medicated patients with schizophrenia and in age-, gender-, and education-matched healthy control subjects with an auditory reaction task. RESULTS: Patients with schizophrenia showed a significant reduction of power and phase-locking of the early auditory evoked GBR. This effect was due to a reduced activity in the auditory cortex and the ACC/medial frontal gyrus region (low-resolution brain electromagnetic tomography analysis). CONCLUSIONS: Generally, these findings are in line with earlier reports on the impaired ability of schizophrenic patients in generating gamma activity. In addition, this is the first study to demonstrate disturbance of gamma activity in auditory processing as assessed by the early auditory GBR power.

Impact of loudness dependency of auditory evoked potentials on the panic response to CCK-4.

RATIONALE: Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder. In line with the serotonin (5-HT)-hypothesis of panic disorder it has been suggested that the panicogenic effects of CCK-4 are mediated in part through the 5-HT system. The analysis of the loudness dependency of the auditory evoked potentials (LDAEP) is a valid non-invasive indicator of central serotonergic activity. METHODS: We investigated the correlation between LDAEP and behavioral, cardiovascular and neuroendocrine panic responses to CCK-4in 77 healthy volunteers and explored whether differences in LDAEP paralleled subjective panic severity. Behavioral panic responses were measured with the panic symptom scale (PSS). Heart rate and ACTH/cortisol plasma concentrations were assessed concomitantly. RESULTS: LDAEP did not differ between panickers and nonpanickers. Furthermore, LDAEP did not correlate with the behavioral panic response. However, a significant positive correlation between LDAEP and CCK-4 induced HPA-axis activation, which was uniform in panickers and nonpanickers, could be detected. CONCLUSIONS: The psychological effects of CCK-4 rather are mediated by neurotransmitters others than the endogenous 5-HT system. However, the extent of the neuroendocrine activation related to the CCK-4 panic provocation was correlated with the LDAEP, thereby suggesting that central 5-HT mechanisms are involved in the HPA-axis activation during this challenge paradigm.