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Research on the involvement of the cerebellum in social behavior and its relationship with social mentalizing has just begun. Social mentalizing is the ability to attribute mental states such as desires, intentions, and beliefs to others. This ability involves the use of social action sequences which are believed to be stored in the cerebellum. In order to better understand the neurobiology of social mentalizing, we applied cerebellar transcranial direct cur-rent stimulation (tDCS) on 23 healthy participants in the MRI scanner, immediately followed by measuring their brain activity during a task that required to generate the correct sequence of social actions involving false (i.e., outdated) and true beliefs, social routines and non-social (control) events. The results revealed that stimulation decreased task performance along with decreased brain activation in mentalizing areas, including the temporo-parietal junction and the precuneus. This decrease was strongest for true belief sequences compared to the other sequences. These findings support the functional impact of the cerebellum on the mentalizing network and belief mentalizing, contributing to the understanding of the role of the cerebellum in social sequences.

Background: Trauma-based psychotherapy is a first line treatment for post-traumatic stress disorder (PTSD) but not all patients achieve long-term remission. Transcranial direct current stimulation (tDCS) received considerable attention as a neuromodulation method that may improve trauma-based psychotherapy. Objective: We explored the effects of repeated anodal tDCS over the prefrontal cortex (PFC) on fear extinction in mice as a preclinical model for trauma-based psychotherapy. Methods: We performed auditory fear conditioning with moderate or high shock intensity on C57BL6/J mice. Next, mice received anodal tDCS (0.2 mA, 20 min) or sham stimulation over the PFC twice daily for five consecutive days. Extinction training was performed by repeatedly exposing mice to the auditory cue the day after the last stimulation session. Early and late retention of extinction were evaluated one day and three weeks after extinction training respectively. Results: We observed no significant effect of tDCS on the acquisition or retention of fear extinction in mice subjected to fear conditioning with moderate intensity. However, when the intensity of fear con-ditioning was high, tDCS significantly lowered freezing during the acquisition of extinction, regardless of the extinction protocol. Moreover, when tDCS was combined with a strong extinction protocol, we also observed a significant improvement of early extinction recall. Finally, we found that tDCS reduced generalized fear induced by contextual cues when the intensity of conditioning is high and extinction training limited. Conclusions: Our data provide a rationale to further explore anodal tDCS over the PFC as potential support for trauma-based psychotherapy for PTSD. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This review focuses on autistic adults and serves 4 purposes: (1) providing an overview of their difficulties regarding mentalizing (understanding others' mental states) and narrative coherence (structured storytelling), (2) highlighting the relations between both skills by examining behavioral observations and shared neural substrates, (3) providing an integrated perspective regarding novel diagnostic tools and support services, and (4) raising awareness of adult autism. We suggest that mentalizing and narrative coherence are related at the behavioral level and neural level. In addition to the traditional mentalizing network, the cerebellum probably serves as an important hub in shared cerebral networks implicated in mentalizing and narrative coherence. Future autism research and support services should tackle new questions within a framework of social cerebellar (dys)functioning.

Introduction Prior resting state fMRI studies have revealed that elevated connectivity between the default mode network (DMN) and subgenual prefrontal cortex (sgPFC) connectivity may underly maladaptive rumination, which is a major risk factor for depression. To further evaluate such relationship, we investigated whether posterior regions of the DMN, showed elevated connectivity with the sgPFC in remitted depressed patients (rMDD) and whether this connectivity was related to maladaptive rumination. Methods We examined whether rMDD (N = 20) had elevated EEG posterior DMN – sgPFC functional connectivity when compared to age and sex matched healthy controls (N = 17), and whether this posterior DMN – sgPFC connectivity positively correlated with rumination. Using minimum norm as the source estimation method, we extracted current density maps from six regions of interest (ROIs) within the posterior DMN. EEG source-space functional connectivity was calculated using the Amplitude Envelope Correlation method. Results Relative to controls, rMDD showed increased posterior cingulate cortex (PCC) – sgPFC connectivity in the beta-3 (25–30 Hz) band. As hypothesized, PCC – sgPFC connectivity was positively associated with rumination for rMDD, even after controlling for depression and anxiety. Limitations The absence of an MDD patient group and the relatively small sample size can limit the generalizability of the results. Conclusions EEG resting state PCC – sgPFC functional connectivity is significantly elevated in rMDD and is associated with rumination, suggesting that EEG PCC – sgPFC connectivity may be useful as a neural marker to identify individuals at risk for depression.

Accelerated high-frequency repetitive transcranial magnetic stimulation (aHF-rTMS) was proven to produce fast clinical effects in humans suffering from psychiatric illnesses. Although dogs also frequently present behavioral symptoms similar to mental illness, rTMS treatment was not yet investigated in this species. The aim of this study was to apply an aHF-rTMS treatment over the frontal cortex in an anxious aggressive dog. Because aHF-rTMS is used to treat anxiety and mood disorders in humans and shows changes in neuronal activity and on monoamine concentrations, it was hypothesized that the dog's behavior would improve after such a treatment. This improvement was expected to be accompanied by alterations in regional cerebral blood flow (rCBF) as well as in monoamine levels in cerebrospinal fluid (CSF) and serum. An aHF-rTMS protocol was applied twice (3 weeks separated) over the left frontal cortex (5 sessions, 20 Hz, 110% cortical motor threshold) in a 5-year-old neutered male Belgian Malinois dog showing anxious aggressive behavior. Each protocol was preceded and followed by a behavior assessment and a d,1 hexamethylpropylene amine oxime single-photon emission computed tomography scan. A Z-score for each volume of interest at each time point was obtained, whereby a |Z|-score > 3.09 (P-value of 0.001) indicated significant differences. Monoamines and their metabolites were quantified in CSF and serum using liquid chromatography coupled to electrochemical detection. An improvement of the dog's aggressive behavior was detected. At baseline, only a decreased rCBF of the left frontal cortex was noticeable (Z-score = −3.87). Twenty-four hours after the first protocol, the perfusion in the left frontal cortex was normalized and decreased in subcortical region (Z-score = −6.97). Three weeks after each stimulation protocol, no deviations in the rCBF were found. Parallel time-dependent changes of 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations in serum and CSF were observed. This case study demonstrates that a single day aHF-rTMS treatment reduces a dog's anxious/aggressive behavior. This behavioral change was accompanied by immediate and long-lasting alterations in the rCBF and DOPAC concentration. This study confirms the interaction between the frontal cortex and the subcortical region in canine anxiety. Finally, DOPAC is put forward as a possible biomarker for the improvement of this behavior.

In humans, determining the cortical motor threshold (CMT) is a critical step in successfully applying a transcranial magnetic stimulation (TMS) treatment. Stimulus intensity, safety and efficacy of a TMS treatment are dependent of the correct assessment of the CMT. Given that TMS in dogs could serve as a natural animal model, an accurate and reliable technique for the measurement of the CMT should be available for dogs. Using a visual descending staircase paradigm (Rossini paradigm), the CMT repeatability was assessed and compared to the electromyographic (EMG) variant. The influence of a HF-rTMS treatment on the CMT was examined. Subsequently, the CMT was measured under sedation and general anaesthesia. Finally, the coil-cortex distance was associated with the CMT, weight, age and gender. During one year the CMT was measured three times, during which it remained constant, although a higher CMT was measured (40% higher machine output) when using EMG (P-value

Subanaesthetic ketamine has recently been established as an effective and rapid treatment for major depressive disorder showing antidepressant effects for up to 1 week on average. The use of repeated ketamine infusions has been put forward to augment and to prolong the antidepressant response and increase the remission rates. The underlying neurobiological mechanisms responsible for ketamine's antidepressant effects remain unclear. Nevertheless, it has been shown, both in dogs and humans, that ketamine can alter neuronal perfusion and therefore neuronal function in brain regions involved in psychiatric and behavioural disorders. Consequently, the aim of the current placebo controlled study was to assess the long-term effects on cerebral perfusion of single and repeated subanaesthetic ketamine infusions in dogs. Twelve healthy, laboratory dogs were scanned at six different time points following single and repeated ketamine administration, using Single Photon Emission Computed Tomography with the radiotracer 99mTc-hexamethylpropylene amine oxime. We hypothesised that repeated infusions could lead to more prolonged perfusion alterations in brain regions critical for behaviour regulation. We found that repeated subanaesthetic ketamine administration did not result in more prolonged cerebral perfusion alterations compared to a single ketamine administration.

There is a growing interest in applying double-dose repetitive transcranial Magnetic Stimulation (rTMS) as a therapeutic tool for stress-related psychiatric disorders. Such stimulation protocols may shorten the treatment duration and may result in faster symptom improvement. Currently, theta-burst stimulation (TBS) protocols have gained attention because of their significantly reduced treatment duration, compared to conventional rTMS. However, the effect of one or twice daily rTMS sessions remains unclear in relation to stress. Using a two-period cross-over design, we examined the impact of double-dosed intermittent (TBS) over the left dorsolateral prefrontal cortex on stress responses (salivary cortisol) in thirty-eight healthy participants after being stressed by a validated psychosocial stress task: the Trier Social Stress Test. After the first active iTBS session, as contrasted to sham, no differential effects on salivary output were observed. However, after the second active session, there was a significantly smaller decrease of salivary cortisol concentrations in the active iTBS condition compared to sham. Our results suggest that double-dosed iTBS after being stressed might differently affect stress recovery compared to a single session of iTBS.

Background Refractory major depressive disorder (MDD) is a severe mental disorder, chronic and difficult to treat. Although generalized anxiety disorder (GAD) is frequently observed as a comorbid diagnosis, little is known on the comorbid neurobiological substrate. Better insights may improve adequate treatment algorithms. Objective To examine this poorly understood clinical question, we recruited 52 individuals to participate in a [ 18 F] FDG PET brain imaging study. Methods Twenty-two refractory MDD patients were diagnosed with and 15 refractory MDD patients without comorbid GAD. To compare to the none-depressed state a sample of 15 age and gender matched never-depressed individuals were included. Results Compared to healthy control subjects, all patients showed significantly higher metabolic activity in the bilateral parahippocampal areas. Compared to MDD patients, healthy subjects displayed significant higher metabolic activity in distinct (bi)frontotemporal and parietal cortices. Refractory MDD patients without comorbid GAD showed significant higher metabolic activity in the dorsomedial parts of the frontal cortex (dmFC). Conclusions The impaired dmFC metabolic activity observed in comorbid GAD within refractory MDD may be indicative of specific emotional dysfunctional top-down processing in this subgroup, conform the anxiety state. Additional psychotherapeutic interventions may be warranted.

Objective Although accelerated repetitive transcranial magnetic stimulation (rTMS) designs seem to be able to alleviate mood over a relatively short period of time, no studies yet examined the cellular effects on neurochemicals with regard to working mechanisms, safety and neural integrity. Methods Eighteen right-handed antidepressant-free unipolar treatment resistant depressed (TRD) patients participated in this sham-controlled accelerated high frequency (aHF)-rTMS 1 H MR spectroscopy study applied to the left dorsolateral prefrontal cortex (DLPFC). Baseline measurements were compared to eighteen age- and gender-matched healthy controls. We explicitly focused on neurochemical concentrations in the bilateral DLPFC and rostral anterior cingulate cortex (rACC). Results Compared to healthy individuals, TRD patients displayed significantly lower baseline glutamatergic (sum absolute concentrations glutamate and glutamine) concentrations in the left DLPFC. aHF-rTMS does not significantly alter neurochemical concentrations in the three predefined brain regions. Clinical improvement was related to significant GABA concentration increases in the left DLPFC. Conclusions Accelerated HF-rTMS treatment did not affect neural integrity in the examined regions. The observed GABA concentration increases suggest that the immediate therapeutic effects of aHF-rTMS could be mediated through a locally increased GABAergic inhibitory neurotransmission. Significance Although more statistical power is needed for reaching firm conclusions, aHF-rTMS does not appear to negatively influence neural integrity.

Suicide plans are a major risk factor for suicide, which is a devastating outcome of depression. While structural and functional brain changes have been demonstrated in relation to suicidal thoughts and behaviour, brain mechanisms underlying suicide plans have not yet been studied. Here, we studied changes in regional cerebral metabolic activity in association with suicide plans in depressed individuals. Using (18)FDG-PET, a comparative study of regional cerebral glucose metabolism (rCMRglu) was carried out in depressed individuals with suicidal thoughts and suicide plans, depressed individuals with only suicidal thoughts, depressed individuals without suicide thoughts and plans, and healthy controls. When compared to the other groups, depressed individuals with suicide plans showed relative hypometabolism in the right middle frontal gyrus and the right inferior parietal lobe (Brodmann areas 10 and 39). Suicide plans in depressed individuals appear to be associated with reduced activity in brain areas that are involved in decision-making and choice, more particularly in exploratory behaviour.

Introduction A recent study showed hypoactivity in the beta/gamma band in female suicide ideators and suicide attempters diagnosed with depression, relative to a low-risk group. The current study aimed to conceptually replicate these results. Methods In the iSPOT-D sub-sample (n = 402), suicide ideators and low-risk individuals were identified. Confining analyses to females only, differences between low-risk individuals and suicide ideators were tested for using the electroencephalogram (EEG) frequency bands SMR (Sensori-Motor-Rhythm; 12−15 Hz), beta (14.5−30 Hz), beta I (14.5−20 Hz), beta II (20−25 Hz), beta III (25−30 Hz), gamma I (31−49 Hz) using LORETA-software. Results None of the tested frequency bands showed to be significantly different between suicide ideators and low-risk individuals. Conclusions The current study could not conceptually replicate the earlier published results. Several reasons could explain this non-replication, among which possible electromyographic (EMG) contamination in the beta/gamma band in the original study. Trial Registration ClinicalTrials.gov identifier: NCT00693849. URL: http://clinicaltrials.gov/ct2/show/NCT00693849 .

Emotional Context Insensitivity (ECI) is a psychological feature observed in depressed patients characterized by a decreased emotional reactivity when presented to positive- and negative valence-loaded stimuli. Given that fronto-cingulate-limbic circuits are implicated in abnormal reactivity to valence-loaded stimuli, neurocognitive treatments engaging the prefrontal cortex may be able to modulate this emotional blunting observed in MDD. Therefore, our goal was to evaluate emotional reactivity in depressed patients before and after a combination of neurocognitive interventions that engage the prefrontal cortex (cognitive control training and/or transcranial direct current stimulation). In line with the premises of the ECI framework, before the start of the antidepressant intervention, patients showed blunted emotional reactivity after exposure to negative valence-loaded stimuli. This emotional reactivity pattern changed after 9 sessions of the intervention: positive affect decreased and negative affect increased after watching a series of negative valence-loaded stimuli (i.e. images). Interestingly, higher emotional reactivity (as indexed by a larger increase in negative affect after watching the valence-loaded stimuli) at baseline predicted reductions in depression symptoms after the intervention. On the other hand, higher emotional reactivity (as indexed by a decrease in positive affect) after the intervention was marginally associated with reductions in depression symptoms. To conclude, emotional reactivity increased after the neurocognitive antidepressant intervention and it was directly associated to the degree of depression improvement.

The prefrontal cortex, and especially the Dorsolateral Prefrontal Cortex (DLPFC), plays an inhibitory role in the regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis under stressful situations. Moreover, recent evidence suggests that a sustained DLPFC activation is associated with adaptive stress regulation in anticipation of a stressful event, leading to a reduced stress-induced amygdala response, and facilitating the confrontation with the stressor. However, studies using experimental manipulation of the activity of the DLPFC before a stressor are scarce, and more research is needed to understand the specific role of this brain area in the stress-induced physiological response. This pre-registered study investigated the effect on stress regulation of a single excitatory high frequency (versus sham) repetitive transcranial magnetic stimulation (HF-rTMS) session over the left DLPFC applied before the Trier Social Stress Test in 75 healthy young women (M = 21.05, SD = 2.60). Heart rate variability (HRV) and salivary cortisol were assessed throughout the experimental protocol. The active HF-rTMS and the sham group showed a similar cognitive appraisal of the stress task. No differences in HRV were observed during both the anticipation and the actual confrontation with the stress task and therefore, our results did not reflect DLPFC-related adaptive anticipatory adjustments. Importantly, participants in the active HF-rTMS group showed a lower cortisol response to stress. The effect of left prefrontal HF-rTMS on the stress system provides further critical experimental evidence for the inhibitory role played by the DLPFC in the regulation of the HPA axis.

An exacerbated physiological response to stress is associated with the development of stress-related disorders (e.g., depression and anxiety disorders). Recently, it has been proposed that individuals with high expectancies of being able to deal with stressful situations will activate regulatory mechanisms during the anticipation of the stressful event that would improve stress regulation. To test this hypothesis, 52 women in young adulthood (M = 21.06; SD = 2.58) anticipated and performed a laboratory-based stress task after receiving positive or negative bogus feedback on their abilities to deal with stressful events. Heart rate variability and salivary cortisol were assessed throughout the experimental protocol. Participants receiving positive bogus feedback (i.e., High Expectancy group) showed a more positive anticipatory cognitive stress appraisal (i.e., they anticipated the stress task as less threatening/challenging, and they perceived that they were more able to deal with it), and they showed a lower cortisol response to stress. Moreover, a more positive anticipatory cognitive stress appraisal was associated with better anticipatory stress regulation (indexed as less decrease in heart rate variability), leading to a lower cortisol response. Our results indicate that people with positive expectancy initiate mechanisms of anticipatory stress regulation that enhance the regulation of the physiological stress response. Expectancy and anticipatory stress regulation may be key mechanisms in the development and treatment of stress-related disorders.

ispartof: Lancet Psychiatry vol:6 issue:11 pages:894-895 ispartof: location:England status: published

Introduction Obsessive Compulsive Disorder (OCD) is a disabling psychiatric disorder with a prevalence of approximately 1–3%. Next to disruptions within the orbitofronto-subcortical loops, regions within the salience network (SN) are related to specific OCD symptoms. Of interest, non-invasive brain stimulation has been documented to modulate SN cortical-subcortical loop disturbances. Therefore medial prefrontal regions (supplementary motor area (SMA), pre-SMA and the dorsomedial prefrontal cortex (dmPFC)) could be promising targets. Because accelerated rTMS (arTMS) has been showing fast clinical responses in depression, we applied arTMS (LF) in OCD patients. Methods Seven patients (4 M, 3F, mean age: 33 years) with severe treatment resistant OCD, under treatment with stable medication regimen were enrolled. Patients received 20 sessions of 1 Hz rTMS (1200 pulses) in an accelerated protocol (2 sessions a day) during 10 weekdays. Change from baseline to endpoint and to delayed endpoint (14 days after treatment) on the Y-BOCS were the primary outcome measure. Change as a direct and delayed effect on the IDS-SR were the secondary outcome measure. Side effects were carefully monitored. Results We found statistically significant reductions of the Y-BOCS scores from baseline to endpoint and to the delayed endpoint, however, without achieving clinical response (decline of ≥ 35% at Y-BOCS). We also found a significant reduction on depression severity scores. The treatment was generally well tolerated. Headache was a common adverse effect. No epileptic insult occurred. Conclusion To our knowledge, this is the first accelerated rTMS protocol of the dmPFC in patients with OCD. These preliminary results indicate that accelerated rTMS may be safe, well-tolerated and capable of achieving significant improvement. Because this study is limited due to lack of sham condition and lack of power, further investigation is warranted.

Vagus nerve stimulation (VNS) is a proposed neuromodulatory treatment for medically refractory major depression. Although VNS is already used in clinical practice, the underlying mechanism of action remains unknown. The present review provides an overview of the preclinical VNS studies in view of two major hypotheses in depression research: the monoaminergic and the neural plasticity hypothesis of depression.

Background: Although one of the most frequent diagnosed mental illnesses worldwide, it appears to be challenging to successfully treat major depressive disorder (MDD). Although the phenomenon of treatment-resistant depression (TRD) still remains unclear, the subgenual anterior cingulate cortex (sgACC) has been put forward as a possible neurobiological marker to evaluate clinical effects of a variety of antidepressant treatments, including repetitive transcranial magnetic stimulation (rTMS). Accelerated high-frequency (HF)-rTMS may have the potential to rapidly result in beneficial clinical outcomes in TRD. No studies yet examined the clinical effects of such accelerated stimulation treatment paradigms on sgACC regional glucose metabolism (CMRglc), nor the predictive value of the latter for clinical outcome. Objective: First, we investigated the predictive value of baseline sgACC metabolic activity for clinical outcome. Second, we hypothesized that in clinical responders only accelerated HF-rTMS treatment would result in significant metabolic decreases. Methods: We recruited right-handed antidepressant-free unipolar melancholic TRD patients to participate in a two-week randomized sham-controlled crossover HF-rTMS treatment study. Stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC). Fifteen patients underwent 18FDG PET (CMRglc) at baseline (T0), after the first week (T1) of accelerated HF-rTMS and at the end of the treatment after the second week (T2). Results: Higher baseline sgACC metabolic activity may indicate beneficial clinical outcome to this kind of accelerated HF-rTMS treatment. Moreover, clinical response resulted in a significant decrease in sgACC CMRglc. Non-response did not affect sgACC CMRglc. Conclusions: Our results add to the sgACC as a specific neurobiological marker for anti-depressive response in accelerated HF-rTMS treatment paradigms. Such protocols may not only have the ability to result in fast clinical responses but they may also have potential to acutely modulate a dysfunctional sgACC.

Although well-defined predictors of response are still unclear, clinicians refer a variety of depressed patients for a repetitive Transcranial Magnetic Stimulation (rTMS) treatment. It has been suggested that personality features such as Harm Avoidance (HA) and self-directedness (SD) might provide some guidance for a classical antidepressant treatment outcome. However, to date no such research has been performed in rTMS treatment paradigms. In this open study, we wanted to examine whether these temperament and character scores in particular would predict clinical outcome in refractory unipolar depressed patients when a typical high-frequency (HF)-rTMS treatment protocol is applied. Thirty six unipolar right-handed antidepressant-free treatment resistant depressed (TRD) patients, all of the melancholic subtype, received 10 HF-rTMS sessions applied to the left dorsolateral prefrontal cortex (DLPFC). All patients were classified as at least stage III TRD and were assessed with the Temperament and Character Inventory (TCI) before a HF-rTMS treatment. Only the individual scores on SD predicted clinical outcome. No other personality scales were found to be a predictor of this kind of application. Our results suggest that refractory MDD patients who score higher on the character scale SD may be more responsive to the HF-rTMS treatment. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Objective Although left dorsolateral prefrontal cortical (DLPFC) repetitive Transcranial Magnetic Stimulation (rTMS) is used to treat major depression, its underlying neurophysiological working mechanism remains to be determined. Prior research suggested that the clinical effects could be mediated by affecting the hypothalamic−pituitary−adrenal (HPA) system, but experimental studies in healthy individuals did not yield clear results. However, in healthy individuals, the influence of HF-rTMS on the HPA-system may only be detected when it is challenged. Methods In 30 rTMS naive healthy females we evaluated the effect of one sham-controlled high frequency (HF)-rTMS session applied to the left DLPFC on the stress hormone cortisol by collecting salivary cortisol samples. In order to increase stress levels, 5 min after stimulation, all participants performed the Critical Feedback Task (CFT), during which they were criticized on their performance. To take possible mood influences into account, all participants were also assessed with Visual Analogue Scales (VAS). Results The experimental procedure did not affect mood differently in the real or sham stimulation. Area under the curve ( AUCi ) analysis showed that one real HF-rTMS session significantly influenced HPA-system sensitivity, as demonstrated by a decrease in cortisol concentrations. The sham procedure yielded no effects. Conclusions In line with former observations in major depression, one real left DLPFC HF-rTMS session significantly influenced HPA-system sensitivity in experimentally stressed females, resulting in decreases in cortisol levels.

Although the serotonergic system has been implicated in healthy as well as in pathological emotional states, knowledge about its involvement in personality is limited. Earlier research on this topic suggests that post-synaptic 5-HT2A receptors could be involved in particular in frontal cortical areas. In drug-naïve healthy individuals, we examined the relationship between these 5-HT2A receptors and the temperament dimension harm avoidance (HA) using (123)I-5-I-R91150 single photon emission computed tomography (SPECT). HA is a personality feature closely related to stress, anxiety and depression proneness, and it is thought to be mediated by the serotonergic system. We focused on the prefrontal cortices as these regions are frequently implicated in cognitive processes related to a variety of affective disorders. We found a positive relationship between dorsal prefrontal cortical (DPFC) 5-HT2A receptor binding indices (BI) and individual HA scores. Further, our results suggest that those individuals with a tendency to worry or to ruminate are particularly prone to display significantly higher 5-HT2A receptor BI in the left DPFC. Although we only examined psychologically healthy individuals, this relationship suggests a possible vulnerability for affective disorders.

Introduction The application of repetitive transcranial magnetic stimulation (rTMS) to prevent relapse in alcohol addiction is currently being evaluated. However, how rTMS may influence the related brain processes is far from clear. Here we wanted to investigate whether baseline grey matter volume (GMV) can predict relapse and whether 15 accelerated high-frequency (HF)-rTMS sessions may influence GMV in areas related to relapse. Methods Voxel based morphometric (VBM) measurements were used to compare baseline GMV of twenty-two detoxified hospitalized alcohol-dependent patients with 22 age and gender matched healthy control subjects. Only patients received 15 accelerated HF-rTMS sessions at the right dorsolateral prefrontal cortex (DLPFC) followed by VBM measurements. Relapse rates were assessed 4 weeks after the end of the stimulation protocol. Results At baseline, alcohol-dependent patients overall showed less GMV in diffuse brain areas compared to healthy controls. Relapsers compared to abstainers displayed larger GMV decreases, especially in brain midline structures, insular, hippocampal, and amygdala areas. Accelerated HF-rTMS treatment had no significant effect on GMV in alcohol-dependent patients, regardless of the relapse state. Conclusion Although an accelerated HF-rTMS treatment protocol did not influence GMV in alcohol-dependent patients, baseline GMV predicted future relapse.

Non-invasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have shown high treatment potential for a broad variety of neuropsychiatric disorders. However, the application of ‘standard’ protocols results in high inter-individual differences in the responses and reduce the overall efficacy. In this symposium, individual characteristics that are linked to the clinical outcome of stimulation treatment will be highlighted. It can be hypothesized that inter-individual differences in responses to stimulation can be assigned to variations in individual neurocircuitries. Therefore, the first two presentations will focus on functional connectivities (FC) on network level. Firstly, the use of graph analysis to study the effect of accelerated intermittent theta burst stimulation (aiTBS) is explained (n = 50, major depressive disorder patients). Also it will be shown that baseline graph measures can predict the clinical efficacy of this stimulation protocol. Clinical efficacy in this case was derived from the 17-item Hamilton questionnaire. Secondly, the influence of different stimulation positions, derived from FC within two different networks, on the effect of one iTBS session on an n-back task will be presented (n = 12, healthy subjects). Being more or less vulnerable to psychopathology can also affect the outcome of NIBS. For example, the tendency to ruminate in daily life influences the outcome of iTBS (n = 38, healthy subjects). Here, the effect of iTBS was quantified using cortisol recovery. Moreover, the application of prefrontal tDCS before listening to self-referent criticism affects FC between the left dorsal anterior cingulate cortex and the right dorsomedial prefrontal cortex distinctively in healthy women low versus high in perceived criticism (n = 46). In conclusion, this symposium will show that individual mechanisms play a role in the effect of NIBS. Therefore, in future protocols, personalized characteristics might enhance clinical efficacy.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique increasingly used to modulate neural activity in the living brain. In order to establish the neurophysiological, cognitive or clinical effect of tDCS, most studies compare the effects of active tDCS to those observed with a sham tDCS intervention. In most cases, sham tDCS consists in delivering an active stimulation for a few seconds to mimic the sensations observed with active tDCS and keep participants blind to the intervention. However, to date, sham-controlled tDCS studies yield inconsistent results, which might arise in part from sham inconsistencies. Indeed, even if most studies report using similar approaches as described in an early study by Gandiga et al. (2006,) [1] , the original protocol (i.e., 10 s ramp-up followed by 30 s of active stimulation at 1 mA before manually turning off the stimulator) has been largely modified, adjusting (a) the intensity and duration of active current being delivered (from “no current” to 2 minutes at 1 mA), (b) the duration of ramp-in and ramp-out phases (e.g. 5–30 s), and (c) the number of ramps done throughout the stimulation. Therefore, this multiplicity of sham stimulation protocols, used in the tDCS research field, might have different biological effects beyond the intended transient sensations. Here, we seek to enlighten the scientific community to this possible confounding factor in order to increase reproducibility of neurophysiological, cognitive and clinical tDCS studies.

Objectives Quite a number of patients diagnosed with major depression are resistant to several well carried-out psychopharmacological interventions. It remains unclear as to how the serotonergic system is implicated in the phenomenon of treatment-resistance. Methods We examined the involvement of post-synaptic 5-HT 2A receptors in the pathophysiology of treatment-resistance in unipolar melancholic major depression with 123 I-5-I-R91150 SPECT. 15 antidepressant-naive (ADN) first-episode depressed patients, 15 antidepressant-free treatment-resistant depressed (TRD) patients and 15 never-depressed individuals, matched for age and gender were studied. Results Compared to ADN patients and healthy controls, TRD patients displayed significantly lower 5-HT 2A receptor binding index (BI) in the dorsal regions of the prefrontal and the anterior cingulate cortex. No significant 5-HT 2A receptor BI differences between ADN patients and controls were observed. Conclusions At the cortical level, 5-HT 2A receptor BI does not significantly differ in first-episode melancholic depressed patients compared to healthy controls. This observation might imply a limited short-term impact on the serotonergic system in first episode depression. Our results also suggest that when encountered with treatment-resistance, the 5-HT 2A receptors in the DPFC-ACC axis are significantly down-regulated. However, whether this assumed underlying pathophysiological mechanism is due solely to abnormalities in the serotonergic system remains to be answered. This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Background Currently, the underlying neurobiological mechanism as to how repetitive transcranial magnetic stimulation (rTMS) can alter depressive states remains unclear. Animal data suggest that its influence could occur at the neurotransmitter level, such as modulation of the serotonin system. Methods Twenty-one antidepressant-free medication-resistant unipolar depressed patients, and 21 age- and gender-matched healthy subjects were studied. We examined the neurobiologic impact of 10 high-frequent (HF)-rTMS sessions applied to the left dorsolateral prefrontal cortex (DLPFC) on postsynaptic 5-HT 2A receptor binding indices (BI) measured with 123 I-5-I-R91150 single photon emission computed tomography (SPECT) only in patients. Results Compared with the control group, patients displayed significantly less bilateral dorsolateral prefrontal cortical and significantly higher left hippocampal baseline 5-HT 2A receptor BI. Successful HF-rTMS treatment correlated positively with 5-HT 2A receptor BI in the DLPFC bilaterally and correlated negatively with right hippocampal 5-HT 2A receptor uptake values. Conclusions Our results indicate that HF-rTMS treatment affect the serotonergic system. Our data also suggest that this kind of treatment affects 5-HT 2A receptor BI in the DLPFC and in the hippocampus in different ways.

Although negative results have been reported, an important aspect of the physiology of repetitive transcranial magnetic stimulation (rTMS) could be related to the endocrinological response of the hypothalamic-pituitary-adrenal (HPA) axis, such as cortisol secretion. Because endocrinological responses are influenced by anxiety states, this could influence the effect of rTMS in healthy individuals. In this sham-controlled, "single blind" crossover study, we examined whether one session of HF-rTMS could affect the HPA-system, when taking into account individual state anxiety scores based on the State-Trait Anxiety Inventory (STAI). Twenty-four healthy rTMS naïve females received one sham-controlled high frequency (HF)-rTMS session delivered on the right dorsolateral prefrontal cortex (DLPFC). The Profile of Mood States (POMS) questionnaire, together with salivary cortisol samples, was collected before, just after and 30 min post HF-rTMS. To examine whether state anxiety could influence endocrinological outcome measurements, we administered the STAI-state just before each HF-rTMS experiment started. Based on the POMS questionnaire, no mood changes were observed. Without taking individual state anxiety scores into account, one sham-controlled right-sided HF-rTMS session did not influence the HPA-system. When taking into account individual STAI-state scores, we found that healthy women scoring higher on the STAI-state displayed a significantly more sensitive HPA-system, resulting in salivary cortisol concentration increases after real HF-rTMS, compared to those scoring lower on this anxiety scale. Our results indicate that healthy women scoring high on state anxiety display a more sensitive HPA-system when receiving one right-sided HF-rTMS session. Our findings suggest that the incorporation of individual anxiety states in experimental rTMS research could add further information about its neurobiological influences on the HPA-system.

Objective High Frequency repetitive Transcranial Magnetic Stimulation (HF-rTMS) has yielded divergent results concerning its effect on mood in normal volunteers. In a former study, we were unable to demonstrate negative mood effects after one session of HF-rTMS on the left dorsolateral prefrontal cortex (DLPFC) in a large group of healthy female volunteers: researchers had focused mainly on negative mood changes, overlooking a possible positive mood induction, while no studies had yet examined mood effects of HF-rTMS delivered on the right prefrontal cortex. In this study, we have tried to replicate our previous HF-rTMS findings on the left DLPFC in a new (large) group of healthy female subjects, and we focused especially on positive mood changes. We also extended our former research by stimulating the right DLPFC in a different but comparable (large) group of healthy female volunteers with the same HF-rTMS parameters. Methods In this sham-controlled, single blind, crossover HF-rTMS study, stimulus parameters were an exact copy of our previous healthy volunteer study. To exclude individual anatomical differences, the left and right DLPFC were targeted under magnetic resonance (MRI) guidance. To examine subjective mood changes we used Visual Analogue Scales (VAS), the Profile of Mood States (POMS), and the Positive Affect and Negative Affect Schedule (PANAS), the latter to assure assessment of positive emotions. To detect any delayed mood changes, assessments were also re-administered 30 min post-HF-rTMS. Results We were unable to demonstrate immediate or delayed mood changes after one single active HF-rTMS session on the left or right DLPFC. Conclusions Although we took into account several methodological problems which might have confounded previous rTMS mood induction studies, the hypothesis that one single session of HF-rTMS on the left or on the right DLPFC can influence mood in healthy female volunteers was not supported. Significance One HF-rTMS session has no effect on subjective mood in healthy female volunteers.

Introduction Thetaburst stimulation (TBS) is a repetitive transcranial magnetic stimulation (rTMS) protocol that may induce long lasting neuroplasticity. Continuous TBS (cTBS), a cortical excitability reducing protocol, would be the stimulation protocol of choice for the treatment of epilepsy. The lower stimulation intensity and number of pulses compared to conventional rTMS may imply superiority with regards to safety, tolerability and applicability in the clinic. Methods Two patients with refractory focal epilepsy due to a low-grade tumor in the rolandic area were treated with cTBS and followed-up for effect on seizure frequency and adverse effects. The stimulation protocol consisted of 5 spaced cTBS trains (600 pulses/train, 80% resting motor threshold) during 4 consecutive days delivered over the ictal onset zone using online neuronavigation. Seizure frequency was assessed over a 4 week baseline period, a 1 week treatment period and an 8 week follow-up period. Results Patient 1 suffered from simple partial motor seizures (SPS), often leading to falls and post-ictal paresis, and myoclonic seizures of the left leg. During baseline 3 SPS and 12 myoclonic seizures occurred. In the first week following cTBS, the patient solely experienced isolated auras consisting of a descending sensation towards the left leg. No SPS occurred. Thereafter, overall SPS frequency was unchanged during follow-up, but the patient reported diminished seizure severity with regards to duration, jerking and paresis. This gradually returned to baseline during follow-up. Notably, myoclonic seizures were completely suppressed for a duration of 6 weeks. Patient 2 suffered from frequent SPS with jerking of the right truncal muscles, spreading to the right arm, head and less often the right leg. Sixteen SPS occurred during baseline, whereas the patient remained seizure-free throughout the treatment week and 13 days thereafter, for a total of nearly three weeks. Follow-up is ongoing at the moment of this report. Stimulation with cTBS was well-tolerated and did not induce adverse effects in either of the patients. Conclusion This case report describes safety and potential anti-epileptic effects of cTBS. Both patients experienced a period of diminished seizure frequency, for a duration of 3–6 weeks following a cTBS treatment protocol.

Although electroconvulsive shock therapy (ECT) remains a successful treatment strategy in medication-resistant bipolar disorder, not all patients respond well. Here, we report on a successful high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) therapy in a highly treatment-resistant bipolar I patient during a mixed episode. This case illustrates that “combative” HF-rTMS therapy could be a safe and valid treatment alternative for refractory bipolar I patients with mixed episodes.