Nicotine reduces discrimination between threat and safety in the hippocampus, nucleus accumbens and amygdala.

Nicotine intake is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in rodents and humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n = 88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to enhanced physiological arousal to learned threats and overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.

Frontal theta oscillations during emotion regulation in people with borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is a severe psychiatric disorder conceptualised as a disorder of emotion regulation. Emotion regulation has been linked to a frontolimbic network comprising the dorsolateral prefrontal cortex and the amygdala, which apparently synchronises its activity via oscillatory coupling in the theta frequency range. AIMS: To analyse whether there are distinct differences in theta oscillatory coupling in frontal brain regions between individuals with BPD and matched controls during emotion regulation by cognitive reappraisal. METHOD: Electroencephalogram (EEG) recordings were performed in 25 women diagnosed with BPD and 25 matched controls during a cognitive reappraisal task in which participants were instructed to downregulate negative emotions evoked by aversive visual stimuli. Between- and within-group time-frequency analyses were conducted to analyse regulation-associated theta activity (3.5-8.5 Hz). RESULTS: Oscillatory theta activity differed between the participants with BPD and matched controls during cognitive reappraisal. Regulation-associated theta increases were lower in frontal regions in the BPD cohort compared with matched controls. Functional connectivity analysis for regulation-associated changes in the theta frequency band revealed a lower multivariate interaction measure (MIM) increase in frontal brain regions in persons with BPD compared with matched controls. CONCLUSIONS: Our findings support the notion of alterations in a frontal theta network in BPD, which may be underlying core symptoms of the disorder such as deficits in emotion regulation. The results add to the growing body of evidence for altered oscillatory brain dynamics in psychiatric populations, which might be investigated as individualised treatment targets using non-invasive stimulation methods.

Reduced frontocingulate theta connectivity during emotion regulation in major depressive disorder.

BACKGROUND: Cognitive reappraisal is an essential emotion regulation skill for social life and psychological health. However, individuals with major depressive disorder (MDD) cannot use this skill effectively. Successful cognitive reappraisal in healthy controls (HC) has been shown to be associated with theta activity in a frontal and subcortical network. In the present study, we investigated whether MDD patients are characterized by altered theta power and connectivity pattern during cognitive reappraisal compared to HC. METHODS: Using EEG and eLORETA, we examined both theta activity and connectivity when 25 controls and 24 patients with MDD were asked to complete the emotion cognitive reappraisal task of viewing neutral and negative pictures and reappraise negative pictures. Habitual use of emotion regulation skills was collected using the Cognitive Emotion Regulation Questionnaire (CERQ). RESULTS: The results showed that MDD patients had (1) reduced theta activity in the left dorsolateral (dlPFC), dorsomedial prefrontal (dmPFC), and rostral-ventral cingulate cortices (rvACC), as well as (2) reduced dlPFC-rvACC theta connectivity than HC during reappraisal. In addition, left dlPFC-rvACC theta connectivity was positively correlated with self-reported cognitive reappraisal in HC. This relation was not observed in MDD. In contrast, CERQ revealed significantly greater use of inadequate regulations skills and significantly lower use of adaptive skills in MDD. LIMITATION: Sample size, limited solution space to cortical grey matter excluding regions such as the amygdala. CONCLUSION: This study may indicate a putative frontocingulate dysfunction leading either to an increased use of inadequate emotion regulation or a decreased use of skills that serve to boost positive emotion.

Comparison of transcranial brain stimulation approaches: prefrontal theta alternating current stimulation enhances working memory performance.

Introduction: One of the most important cognitive functions in our everyday life is the working memory (WM). In several neuropsychiatric diseases such as ADHD or schizophrenia WM deficits can be observed, making it an attractive target for non-invasive brain stimulation methods like transcranial electrical stimulation (tES). However, the literature shows rather heterogeneous results of tES effects on WM performance. fMRI meta-analyses have identified a WM network including frontoparietal brain areas such as the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC). Neurophysiological studies revealed oscillatory activity in the theta band frequency range to be of crucial functional relevance for WM processes. Based on this, transcranial alternating current stimulation (tACS) in the theta frequency range targeting DLPFC and PPC in a spatially optimized way might further improve effects of tES on WM performance. Methods: Sixteen healthy subjects were stimulated with varying stimulation settings on four different days in a counterbalanced within-subject design. These setups included the application of (1) tACS with a frequency of 5 Hz (theta frequency range) over the left DLPFC and (2) the right superior parietal cortex, (3) transcranial direct current stimulation (tDCS) of the DLPFC and (4) a sham stimulation condition during the online performance of a visual delayed-match-to-sample task with varying working memory load. We introduce a procedure to calculate an optimal tES model revealing optimized high-density setups for the present study for 3 cathodes and 1 anode and stimulation currents of 1.5 mA. Results: A significant interaction effect of stimulation type and load condition on working memory capacity was found. This was reflected by a significant improvement of WM performance in the high load condition during tACS over the left DLPFC compared with sham stimulation, which was not the case for our parietal tACS or tDCS setup. Discussion: Working memory performance can be improved with optimized high-definition tACS with a frequency of 5 Hz over the left DLPFC. The conception of different mechanisms underlying transcranial electrical stimulation with alternating and direct currents is supported by these results. Patients suffering from working memory impairments due to neuropsychiatric diseases might potentially benefit from this brain stimulation approach.

Daring to Feel: Emotion-Focused Psychotherapy Increases Amygdala Activation and Connectivity in Euthymic Bipolar Disorder-A Randomized Controlled Trial.

BACKGROUND: In bipolar disorder (BD), the alternation of extreme mood states indicates deficits in emotion processing, accompanied by aberrant neural function of the emotion network. The present study investigated the effects of an emotion-centered psychotherapeutic intervention on amygdala responsivity and connectivity during emotional face processing in BD. METHODS: In a randomized controlled trial within the multicentric BipoLife project, euthymic patients with BD received one of two interventions over 6 months: an unstructured, emotion-focused intervention (FEST), where patients were guided to adequately perceive and label their emotions (n = 28), or a specific, structured, cognitive behavioral intervention (SEKT) (n = 31). Before and after interventions, functional magnetic resonance imaging was conducted while patients completed an emotional face-matching paradigm (final functional magnetic resonance imaging sample of patients completing both measurements: SEKT, n = 17; FEST, n = 17). Healthy control subjects (n = 32) were scanned twice after the same interval without receiving any intervention. Given the focus of FEST on emotion processing, we expected FEST to strengthen amygdala activation and connectivity. RESULTS: Clinically, both interventions stabilized patients' euthymic states in terms of affective symptoms. At the neural level, FEST versus SEKT increased amygdala activation and amygdala-insula connectivity at postintervention relative to preintervention time point. In FEST, the increase in amygdala activation was associated with fewer depressive symptoms (r = 0.72) 6 months after intervention. CONCLUSIONS: Enhanced activation and functional connectivity of the amygdala after FEST versus SEKT may represent a neural marker of improved emotion processing, supporting the FEST intervention as an effective tool in relapse prevention in patients with BD.

Opposite Modulation of the NMDA Receptor by Glycine and S-Ketamine and the Effects on Resting State EEG Gamma Activity: New Insights into the Glutamate Hypothesis of Schizophrenia.

NMDA-receptor hypofunction is increasingly considered to be an important pathomechanism in schizophrenia. However, to date, it has not been possible to identify patients with relevant NMDA-receptor hypofunction who would respond to glutamatergic treatments. Preclinical models, such as the ketamine model, could help identify biomarkers related to NMDA-receptor function that respond to glutamatergic modulation, for example, via activation of the glycine-binding site. We, therefore, aimed to investigate the effects of opposing modulation of the NMDA receptor on gamma activity (30-100 Hz) at rest, the genesis of which appears to be highly dependent on NMDA receptors. The effects of subanesthetic doses of S-ketamine and pretreatment with glycine on gamma activity at rest were examined in twenty-five healthy male participants using 64-channel electroencephalography. Psychometric scores were assessed using the PANSS and the 5D-ASC. While S-ketamine significantly increased psychometric scores and gamma activity at the scalp and in the source space, pretreatment with glycine did not significantly attenuate any of these effects when controlled for multiple comparisons. Our results question whether increased gamma activity at rest constitutes a suitable biomarker for the target engagement of glutamatergic drugs in the preclinical ketamine model. They might further point to a differential role of NMDA receptors in gamma activity generation.

The decoupling of structural and functional connectivity of auditory networks in individuals at clinical high-risk for psychosis.

OBJECTIVES: Disrupted auditory networks play an important role in the pathophysiology of psychosis, with abnormalities already observed in individuals at clinical high-risk for psychosis (CHR). Here, we examine structural and functional connectivity of an auditory network in CHR utilising state-of-the-art electroencephalography and diffusion imaging techniques. METHODS: Twenty-six CHR subjects and 13 healthy controls (HC) underwent diffusion MRI and electroencephalography while performing an auditory task. We investigated structural connectivity, measured as fractional anisotropy in the Arcuate Fasciculus (AF), Cingulum Bundle, and Superior Longitudinal Fasciculus-II. Gamma-band lagged-phase synchronisation, a functional connectivity measure, was calculated between cortical regions connected by these tracts. RESULTS: CHR subjects showed significantly higher structural connectivity in the right AF than HC (p < .001). Although non-significant, functional connectivity between cortical areas connected by the AF was lower in CHR than HC (p = .078). Structural and functional connectivity were correlated in HC (p = .056) but not in CHR (p = .29). CONCLUSIONS: We observe significant differences in structural connectivity of the AF, without a concomitant significant change in functional connectivity in CHR subjects. This may suggest that the CHR state is characterised by a decoupling of structural and functional connectivity, possibly due to abnormal white matter maturation.

Smokers show increased fear responses towards safety signals during fear generalization, independent from acute smoking.

Smoking is highly prevalent among patients with anxiety disorders. Previous studies suggest that smokers show altered fear learning as compared to non-smokers. To test the effect of acute smoking on fear learning and generalization, we conducted a fear learning experiment online. 202 healthy subjects learned to differentiate a danger and a safe cue on day 1 and were tested for generalization of threat responses 24 h later. To see if the timing of smoking impacts fear learning, we formed three smoker groups with manipulations of acute smoking and withdrawal at different time-points (each group: n = 46) and one non-smoker control group (n = 64). Smoking manipulations contained a 6 h withdrawal after fear learning, smoking directly before or after fear learning. We found no group differences between smoker manipulation groups for fear learning or generalization. However, we found differences in fear generalization between smokers and non-smokers. Smokers showed increased fear ratings towards the stimulus that has been learned as safe and higher US expectancy to stimuli similar to the safe stimulus, when compared to non-smokers. Smoking might constitute a risk factor for impaired discrimination between danger and safety and smoking restrictions could be an effective way to reduce the risks of development or maintenance of anxiety disorders.

Acquisition of threat responses are associated with elevated plasma concentration of endocannabinoids in male humans.

Endocannabinoids (eCBs) are involved in buffering threat and stress responses. Elevation of circulating eCBs in humans was reported to strengthen inhibition (i.e., extinction) of threat responses and to reduce effects of stressors. However, it remains unclear whether the acquisition of threat responses involves a physiological change in circulating eCBs. Here, we demonstrate in male human volunteers that the plasma concentration of the eCB N-arachidonoylethanolamine (AEA) and its metabolite arachidonic acid (AA) are increased during acquisition of threat responses. Furthermore, elevated responses to a learned threat cue (e.g., rating of fear) were associated with individual increases in plasma concentration of the eCB 2-arachidonoylglycerol (2-AG). In complementing these observations, we found individual increases in AEA associated with elevated neural responses during threat learning in the amygdala. Our results thereby suggest that physiological increases in circulating eCB levels are part of a response mechanism to learned threats.

Placebo induced expectations of mood enhancement generate a positivity effect in emotional processing.

A perceptual bias towards negative emotions is a consistent finding in mood disorders and a major target of therapeutic interventions. Placebo responses in antidepressant treatment are substantial, but it is unclear whether and how underlying expectancy effects can modulate response biases to emotional inputs. In a first attempt to approach this question, we investigated how placebo induced expectation can shape the perception of specific emotional stimuli in healthy individuals. In a controlled cross-over design, positive treatment expectations were induced by verbal instructions and a hidden training manipulation combined with an alleged oxytocin nasal spray before participants performed an emotion classification task on happy and fearful facial expressions with varying intensity. Analyses of response criterion and discrimination ability as derived from emotion-specific psychometric functions demonstrate that expectation specifically lowered participants' threshold for identifying happy emotions in general, while they became less sensitive to subtle differences in emotional expressions. These indications of a positivity bias were directly correlated with participants' treatment expectations as well as subjective experiences of treatment effects and went along with a significant mood enhancement. Our findings show that expectations can induce a perceptual positivity effect in healthy individuals which is probably modulated by top-down emotion regulation and which may be able to improve mood state. Clinical implications of these promising results now need to be explored in studies of expectation manipulation in patients with mood disorders.

Glycine attenuates impairments of stimulus-evoked gamma oscillations in the ketamine model of schizophrenia.

Although a substantial number of studies suggests some clinical benefit concerning negative symptoms in schizophrenia through the modulation of NMDA-receptor function, none of these approaches achieved clinical approval. Given the large body of evidence concerning glutamatergic dysfunction in a subgroup of patients, biomarkers to identify those with a relevant clinical benefit through glutamatergic modulation are urgently needed. A similar reduction of the early auditory evoked gamma-band response (aeGBR) as found in schizophrenia patients can be observed in healthy subjects following the application of an NMDA-receptor antagonist in the ketamine-model, which addresses the excitation / inhibition (E/I) imbalance of the disease. Moreover, this oscillatory change can be related to the emergence of negative symptoms. Accordingly, this study investigated whether glycine-related increases of the aeGBR, through NMDA-receptor co-agonism, accompany an improvement concerning negative symptoms in the ketamine-model. The impact of subanesthetic ketamine doses and the pretreatment with glycine was examined in twenty-four healthy male participants while performing a cognitively demanding aeGBR paradigm with 64-channel electroencephalography. Negative Symptoms were assessed through the PANSS. S-Ketamine alone caused a reduction of the aeGBR amplitude associated with more pronounced negative symptoms compared to placebo. Pretreatment with glycine attenuated both, the ketamine-induced alterations of the aeGBR amplitude and the increased PANSS negative scores in glycine-responders, classified based on relative aeGBR increase. Thus, we propose that the aeGBR represents a possible biomarker for negative symptoms in schizophrenia related to insufficient glutamatergic neurotransmission. This would allow to identify patients with negative symptoms, who might benefit from glutamatergic treatment.

Simultaneous EEG-fMRI reveals theta network alterations during reward feedback processing in borderline personality disorder.

Previous studies using imaging techniques such as electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) have identified neurophysiological markers of impaired feedback processing in patients with Borderline Personality Disorder (BPD). These mainly include reduced oscillatory activity in the theta frequency range in the EEG and altered activations in frontal and striatal regions in fMRI studies. The aim of the present study is to integrate these results using a coupling of simultaneously recorded EEG and fMRI. Simultaneous EEG (64-channel) and fMRI (3-Tesla Siemens Prisma) was recorded whilst participants (19 BPD patients and 18 controls) performed a gambling task. Data was analysed for the two imaging techniques separately as well as in a single-trial coupling of both modalities. Evoked theta oscillatory power as a response to loss feedback was reduced in BPD patients. EEG-fMRI coupling revealed an interaction between feedback valence and group in prefrontal regions centering in the dorsolateral prefrontal cortex (dlPFC), with healthy controls showing stronger modulation by theta responses during loss when compared to gain feedback and the opposite effect in BPD patients. Our results show multiple alterations in the processing of feedback in BPD, which were partly linked to impulsivity. The dlPFC was identified as the seed of theta-associated activation differences.

Sex-Related Differences in White Matter Asymmetry and Its Implications for Verbal Working Memory in Psychosis High-Risk State.

Objective: Sexual dimorphism has been investigated in schizophrenia, although sex-specific differences among individuals who are at clinical high-risk (CHR) for developing psychosis have been inconclusive. This study aims to characterize sexual dimorphism of language areas in the brain by investigating the asymmetry of four white matter tracts relevant to verbal working memory in CHR patients compared to healthy controls (HC). HC typically show a leftward asymmetry of these tracts. Moreover, structural abnormalities in asymmetry and verbal working memory dysfunctions have been associated with neurodevelopmental abnormalities and are considered core features of schizophrenia. Methods: Twenty-nine subjects with CHR (17 female/12 male) for developing psychosis and twenty-one HC (11 female/10 male) matched for age, sex, and education were included in the study. Two-tensor unscented Kalman filter tractography, followed by an automated, atlas-guided fiber clustering approach, were used to identify four fiber tracts related to verbal working memory: the superior longitudinal fasciculi (SLF) I, II and III, and the superior occipitofrontal fasciculus (SOFF). Using fractional anisotropy (FA) of tissue as the primary measure, we calculated the laterality index for each tract. Results: There was a significantly greater right>left asymmetry of the SLF-III in CHR females compared to HC females, but no hemispheric difference between CHR vs. HC males. Moreover, the laterality index of SLF-III for CHR females correlated negatively with Backward Digit Span performance, suggesting a greater rightward asymmetry was associated with poorer working memory functioning. Conclusion: This study suggests increased rightward asymmetry of the SLF-III in CHR females. This finding of sexual dimorphism in white matter asymmetry in a language-related area of the brain in CHR highlights the need for a deeper understanding of the role of sex in the high-risk state. Future work investigating early sex-specific pathophysiological mechanisms, may lead to the development of novel personalized treatment strategies aimed at preventing transition to a more chronic and difficult-to-treat disorder.

Ketamine Alters Functional Gamma and Theta Resting-State Connectivity in Healthy Humans: Implications for Schizophrenia Treatment Targeting the Glutamate System.

Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo (p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system.

Gamma-band synchronisation in a frontotemporal auditory information processing network.

Neural oscillations are fundamental mechanisms of the human brain that enable coordinated activity of different brain regions during perceptual and cognitive processes. A frontotemporal network generated by means of gamma oscillations and comprising the auditory cortex (AC) and the anterior cingulate cortex (ACC) has been shown to be involved in the cognitively demanding auditory information processing. This study aims to reveal patterns of functional and effective connectivity within this network in healthy subjects by means of simultaneously recorded electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). We simultaneously recorded EEG and fMRI in 28 healthy subjects during the performance of a cognitively demanding auditory choice reaction task. Connectivity between the ACC and AC was analysed employing EEG and fMRI connectivity measures. We found a significant BOLD signal correlation between the ACC and AC, a significant task-dependant increase of fMRI connectivity (gPPI) and a significant increase in functional coupling in the gamma frequency range between these regions (LPS), which was increased in top-down direction (granger analysis). EEG and fMRI connectivity measures were positively correlated. The results of these study point to a role of a top-down influence of the ACC on the AC executed by means of gamma synchronisation. The replication of fMRI connectivity patterns in simultaneously recorded EEG data and the correlation between connectivity measures from both domains found in our study show, that brain connectivity based on the synchronisation of gamma oscillations is mirrored in fMRI connectivity patterns.

Cellular and extracellular white matter alterations indicate conversion to psychosis among individuals at clinical high-risk for psychosis.

OBJECTIVES: It is important to find biomarkers associated with transition to illness in individuals at clinical high-risk for psychosis (CHR). Here, we use free-water imaging, an advanced diffusion MRI technique, to identify white matter alterations in the brains of CHR subjects who subsequently develop psychosis (CHR-P) compared to those who do not (CHR-NP). METHODS: Twenty-four healthy controls (HC) and 30 CHR individuals, 8 of whom converted to schizophrenia after a mean follow-up of 15.16 months, received baseline MRI scans. Maps of fractional anisotropy (FA), FA of cellular tissue (FAT), and extracellular free-water (FW) were extracted using tract-based spatial statistics after which voxel-wise non-parametric group statistics and correlations with symptom severity were performed. RESULTS: There were no significant differences between HCs and the combined CHR group. However, prior to conversion, CHR-P showed widespread lower FA compared to CHR-NP (pFWE < 0.05). FA changes in CHR-P were associated with significantly lower FAT and higher FW, compared to CHR-NP. Positive symptoms correlated significantly with diffusion parameters in similar regions as those discriminating CHR-P from CHR-NP. CONCLUSIONS: Our study suggests that cellular (FAT) and extracellular (FW) white matter alterations are associated with positive symptom severity and indicate an elevated illness risk among CHR individuals.

Alterations of oscillatory neuronal activity during reward processing in schizophrenia.

OBJECTIVES: Reward system dysfunctions are considered to be a pathophysiological mechanism in schizophrenia. Electrophysiological studies of reward system functions have identified frequency-specific brain networks for the processing of positive (high-beta frequency) and negative (theta frequency) events. Remarkably, midbrain dopaminergic signalling also includes theta and high-beta frequency modes, which have been assumed to reflect tonic and phasic dopamine responses, respectively. The aim of the present study was to identify alterations of oscillatory responses to reward feedback in patients with schizophrenia. METHODS: Seventeen patients with schizophrenia and 18 healthy controls performed a gambling task during recording of 64-channel electroencephalography. The theta and high-beta band total power were investigated in response to feedback events depending on feedback valence (loss or gain) and magnitude (5 vs. 25 points). RESULTS: Both the increase of theta oscillatory activity in response to loss feedback (compared to gain feedback) and the increase of high-beta oscillatory activity in response to gain feedback (compared to loss feedback) were reduced in patients. The difference in high-beta responses to gain versus loss feedback in patients was associated with the severity of negative symptoms. CONCLUSIONS: Our findings are consistent with current models of reward system dysfunction in schizophrenia, and indicate deficits in both cortical tonic and subcortical phasic dopamine activity, consistent with the complex dopaminergic abnormalities in schizophrenia.

Altered Oscillatory Responses to Feedback in Borderline Personality Disorder are Linked to Symptom Severity.

Several studies using electroencephalography (EEG) demonstrate that the processing of feedback in patients suffering from borderline personality disorder (BPD) is altered in comparison to healthy controls. Differences occur in the theta (ca. 5 Hz) and high-beta frequency-ranges (ca. 20 Hz) of oscillations in response to negative and positive feedback, respectively. However, alpha (ca. 10 Hz) and low-beta (ca. 15 Hz) oscillations have also been shown to be involved in feedback processing. We hypothesized that additional alterations might occur in these frequency ranges in BPD. Eighteen patients with BPD and twenty-two healthy controls performed a gambling task while 64-channel-EEG was recorded. Induced oscillatory responses to positive (i.e. gain) and negative (i.e. loss) feedback in the alpha and low-beta frequency range were investigated. No significant differences were found in the alpha frequency range. Regarding the low-beta frequency range a significant Group (i.e. BPD vs. healthy controls) × Valence (i.e. gain vs. loss) interaction in the time frame between 600 and 700 milliseconds after feedback was found. This effect showed a significant correlation with symptom severity (assessed with the BSL-23). The results indicate that feedback processing in BPD could be more heavily altered than previously expected, with more severe symptomatology being linked to stronger alterations in oscillatory responses to feedback in the low-beta range.

The role of effective connectivity between the task-positive and task-negative network for evidence gathering [Evidence gathering and connectivity].

Reports linking a 'jumping-to-conclusions' bias to delusions have led to growing interest in the neurobiological correlates of probabilistic reasoning. Several brain areas have been implicated in probabilistic reasoning; however, findings are difficult to integrate into a coherent account. The present study aimed to provide additional evidence by investigating, for the first time, effective connectivity among brain areas involved in different stages of evidence gathering. We investigated evidence gathering in 25 healthy individuals using fMRI and a new paradigm (Box Task) designed such as to minimize the effects of cognitive effort and reward processing. Decisions to collect more evidence ('draws') were contrasted to decisions to reach a final choice ('conclusions') with respect to BOLD activity. Psychophysiological interaction analysis was used to investigate effective connectivity. Conclusion events were associated with extensive brain activations in widely distributed brain areas associated with the task-positive network. In contrast, draw events were characterized by higher activation in areas assumed to be part of the task-negative network. Effective connectivity between the two networks decreased during draws and increased during conclusion events. Our findings indicate that probabilistic reasoning may depend on the balance between the task-positive and task-negative network, and that shifts in connectivity between the two may be crucial for evidence gathering. Thus, abnormal connectivity between the two systems may significantly contribute to the jumping-to-conclusions bias.

EEG-Informed fMRI Reveals a Disturbed Gamma-Band-Specific Network in Subjects at High Risk for Psychosis.

OBJECTIVES: Abnormalities of oscillatory gamma activity are supposed to reflect a core pathophysiological mechanism underlying cognitive disturbances in schizophrenia. The auditory evoked gamma-band response (aeGBR) is known to be reduced across all stages of the disease. The present study aimed to elucidate alterations of an aeGBR-specific network mediated by gamma oscillations in the high-risk state of psychosis (HRP) by means of functional magnetic resonance imaging (fMRI) informed by electroencephalography (EEG). METHODS: EEG and fMRI were simultaneously recorded from 27 HRP individuals and 26 healthy controls (HC) during performance of a cognitively demanding auditory reaction task. We used single trial coupling of the aeGBR with the corresponding blood oxygen level depending response (EEG-informed fMRI). RESULTS: A gamma-band-specific network was significantly lower active in HRP subjects compared with HC (random effects analysis, P < .01, Bonferroni-corrected for multiple comparisons) accompanied by a worse task performance. This network involved the bilateral auditory cortices, the thalamus and frontal brain regions including the anterior cingulate cortex, as well as the bilateral dorsolateral prefrontal cortex. CONCLUSIONS: For the first time we report a reduced activation of an aeGBR-specific network in HRP subjects brought forward by EEG-informed fMRI. Because the HRP reflects the clinical risk for conversion to psychotic disorders including schizophrenia and the aeGBR has repeatedly been shown to be altered in patients with schizophrenia the results of our study point towards a potential applicability of aeGBR disturbances as a marker for the prediction of transition of HRP subjects to schizophrenia.