Reduced activity and connectivity of left amygdala in patients with schizophrenia treated with clozapine or olanzapine.

Obsessive-compulsive symptoms (OCS) in patients with schizophrenia are a common co-occurring condition, often associated with additional impairments. A subgroup of these patients develops OCS during treatment with second-generation antipsychotics (SGAs), most importantly clozapine and olanzapine. So far, little is known about possible neural mechanism of these SGAs, which seem to aggravate or induce OCS. To investigate the role of SGA treatment on neural activation and connectivity during emotional processing, patients were stratified according to their monotherapy into two groups (group I: clozapine or olanzapine, n = 20; group II: amisulpride or aripiprazole, n = 20). We used an fMRI approach, applying an implicit emotion recognition task. Group comparisons showed significantly higher frequency and severity of comorbid OCS in group I than group II. Task specific activation was attenuated in group I in the left amygdala. Furthermore, functional connectivity from left amygdala to right ventral striatum was reduced in group I. Reduced amygdala activation was associated with OCS severity. Recent literature suggests an involvement of an amygdala-cortico-striatal network in the pathogenesis of obsessive-compulsive disorder. The observed differential activation and connectivity pattern of the amygdala might thus indicate a neural mechanism for the development of SGA-associated OCS in patients with schizophrenia. Further neurobiological research and interventional studies are needed for causal inferences.

Increased orbitofrontal cortex activation associated with "pro-obsessive" antipsychotic treatment in patients with schizophrenia.

BACKGROUND: Patients with schizophrenia have an approximately 10-fold higher risk for obsessive-compulsive symptoms (OCS) than the general population. A large subgroup seems to experience OCS as a consequence of second-generation antipsychotic agents (SGA), such as clozapine. So far little is known about underlying neural mechanisms. METHODS: To investigate the role of SGA treatment on neural processing related to OCS in patients with schizophrenia, we stratified patients according to their monotherapy into 2 groups (group I: clozapine or olanzapine; group II: amisulpride or aripiprazole). We used an fMRI approach, applying a go/no-go task assessing inhibitory control and an n-back task measuring working memory. RESULTS: We enrolled 21 patients in group I and 19 patients in group II. Groups did not differ regarding age, sex, education or severity of psychotic symptoms. Frequency and severity of OCS were significantly higher in group I and were associated with pronounced deficits in specific cognitive abilities. Whereas brain activation patterns did not differ during working memory, group I showed significantly increased activation in the orbitofrontal cortex (OFC) during response inhibition. Alterations in OFC activation were associated with the severity of obsessions and mediated the association between SGA treatment and co-occurring OCS on a trend level. LIMITATIONS: The main limitation of this study is its cross-sectional design. CONCLUSION: To our knowledge, this is the first imaging study conducted to elucidate SGA effects on neural systems related to OCS. We propose that alterations in brain functioning reflect a pathogenic mechanism in the development of SGA-induced OCS in patients with schizophrenia. Longitudinal studies and randomized interventions are needed to prove the suggested causal interrelations.

Application of high-frequency repetitive transcranial magnetic stimulation to the DLPFC alters human prefrontal-hippocampal functional interaction.

Neural plasticity is crucial for understanding the experience-dependent reorganization of brain regulatory circuits and the pathophysiology of schizophrenia. An important circuit-level feature derived from functional magnetic resonance imaging (fMRI) is prefrontal-hippocampal seeded connectivity during working memory, the best established intermediate connectivity phenotype of schizophrenia risk to date. The phenotype is a promising marker for the effects of plasticity-enhancing interventions, such as high-frequency repetitive transcranial magnetic stimulation (rTMS), and can be studied in healthy volunteers in the absence of illness-related confounds, but the relationship to brain plasticity is unexplored. We recruited 39 healthy volunteers to investigate the effects of 5 Hz rTMS on prefrontal-hippocampal coupling during working memory and rest. In a randomized and sham-controlled experiment, neuronavigation-guided rTMS was applied to the right dorsolateral prefrontal cortex (DLPFC), and fMRI and functional connectivity analyses [seeded connectivity and psychophysiological interaction (PPI)] were used as readouts. Moreover, the test-retest reliability of working-memory related connectivity markers was evaluated. rTMS provoked a significant decrease in seeded functional connectivity of the right DLPFC and left hippocampus during working memory that proved to be relatively time-invariant and robust. PPI analyses provided evidence for a nominal effect of rTMS and poor test-retest reliability. No effects on n-back-related activation and DLPFC-hippocampus resting-state connectivity were observed. These data provide the first in vivo evidence for the effects of plasticity induction on human prefrontal-hippocampal network dynamics, offer insights into the biological mechanisms of a well established intermediate phenotype linked to schizophrenia, and underscores the importance of the choice of outcome measures in test-retest designs.

Test-retest reliability of fMRI-based graph theoretical properties during working memory, emotion processing, and resting state.

The investigation of the brain connectome with functional magnetic resonance imaging (fMRI) and graph theory analyses has recently gained much popularity, but little is known about the robustness of these properties, in particular those derived from active fMRI tasks. Here, we studied the test-retest reliability of brain graphs calculated from 26 healthy participants with three established fMRI experiments (n-back working memory, emotional face-matching, resting state) and two parcellation schemes for node definition (AAL atlas, functional atlas proposed by Power et al.). We compared the intra-class correlation coefficients (ICCs) of five different data processing strategies and demonstrated a superior reliability of task-regression methods with condition-specific regressors. The between-task comparison revealed significantly higher ICCs for resting state relative to the active tasks, and a superiority of the n-back task relative to the face-matching task for global and local network properties. While the mean ICCs were typically lower for the active tasks, overall fair to good reliabilities were detected for global and local connectivity properties, and for the n-back task with both atlases, smallworldness. For all three tasks and atlases, low mean ICCs were seen for the local network properties. However, node-specific good reliabilities were detected for node degree in regions known to be critical for the challenged functions (resting-state: default-mode network nodes, n-back: fronto-parietal nodes, face-matching: limbic nodes). Between-atlas comparison demonstrated significantly higher reliabilities for the functional parcellations for global and local network properties. Our findings can inform the choice of processing strategies, brain atlases and outcome properties for fMRI studies using active tasks, graph theory methods, and within-subject designs, in particular future pharmaco-fMRI studies.

Amygdala habituation: a reliable fMRI phenotype.

Amygdala function is of high interest for cognitive, social and psychiatric neuroscience, emphasizing the need for reliable assessments in humans. Previous work has indicated unsatisfactorily low within-subject reliability of amygdala activation fMRI measures. Based on basic science evidence for strong habituation of amygdala response to repeated stimuli, we investigated whether a quantification of habituation provides additional information beyond the usual estimate of the overall mean activity. We assessed the within-subject reliability of amygdala habituation measures during a facial emotion matching paradigm in 25 healthy subjects. We extracted the amygdala signal decrement across the course of the fMRI run for the two test-retest measurement sessions and compared reliability estimates with previous findings based on mean response amplitude. Retest-reliability of the session-wise amygdala habituation was significantly higher than the evoked amygdala mean amplitude (intraclass correlation coefficients (ICC)=0.53 vs. 0.16). To test the task-specificity of this finding, we compared the retest-reliability of amygdala habituation across two different tasks. Significant amygdala response decrement was also seen in a cognitive task (n-back working memory) that did not per se activate the amygdala, but was totally unreliable in that context (ICC~0.0), arguing for task-specificity. Together the results show that emotion-dependent amygdala habituation is a robust and considerably more reliable index than the mean amplitude, and provides a robust potential endpoint for within-subject designs including pharmaco-fMRI studies.

Induction and quantification of prefrontal cortical network plasticity using 5 Hz rTMS and fMRI.

Neuronal plasticity is crucial for flexible interaction with a changing environment and its disruption is thought to contribute to psychiatric diseases like schizophrenia. High-frequency repetitive transcranial magnetic stimulation (rTMS) is a noninvasive tool to increase local excitability of neurons and induce short-time functional reorganization of cortical networks. While this has been shown for the motor system, little is known about the short-term plasticity of networks for executive cognition in humans. We examined 12 healthy control subjects in a crossover study with fMRI after real and sham 5 Hz rTMS to the right dorsolateral prefrontal cortex (DLPFC). During scanning, subjects performed an n-back working memory (WM) task and a flanker task engaging cognitive control. Reaction times during the n-back task were significantly shorter after rTMS than after sham stimulation. RTMS compared with sham stimulation caused no activation changes at the stimulation site (right DLPFC) itself, but significantly increased connectivity within the WM network during n-back and reduced activation in the anterior cingulate cortex during the flanker task. Reduced reaction times after real stimulation support an excitatory effect of high-frequency rTMS. Our findings identified plastic changes in prefrontally connected networks downstream of the stimulation site as the substrate of this behavioral effect. Using a multimodal fMRI-rTMS approach, we could demonstrate changes in cortical plasticity in humans during executive cognition. In further studies this approach could be used to study pharmacological, genetic and disease-related alterations.

The Early Recognition Inventory ERIraos detects at risk mental states of psychosis with high sensitivity.

The identification of patients carrying an increased risk of psychosis is one of the most important demands in schizophrenia research. Currently used diagnostic instruments mainly focus on either attenuated psychotic symptoms and brief limited intermittent psychotic symptoms or solely cognitive basic symptoms. The "Early Recognition Inventory based on IRAOS" (ERIraos) has been developed as a comprehensive assessment of both symptom groups within one scale. We compared the results obtained by ERIraos with an international standard instrument, the "Comprehensive Assessment of At Risk Mental States" (CAARMS) and applied both scales in a sample of 121 outpatients positively tested on a screening checklist for at risk mental states (ARMS). Subsamples were classified as first episode of psychosis, late ARMS with prevalent attenuated psychotic symptoms and/or brief limited intermittent psychotic symptoms, earlier stages of ARMS presenting cognitive basic symptoms as well as a vulnerability group, also differing regarding mean age and psychosocial functioning. Our results point to a higher sensitivity of ERIraos compared to scales that mainly focus on attenuated psychotic symptoms and brief limited intermittent psychotic symptoms. A detailed assessment of cognitive basic symptoms seems to be important in early detection, might be an important focus for therapeutic interventions in ARMS patients and might sustain attempts to alleviate cognitive dysfunction in schizophrenia.

Hippocampal function in healthy carriers of the CLU Alzheimer's disease risk variant.

Alzheimer's disease is a devastating, common, progressive dementia with considerable heritability. Recently, a genetic variant associated with the disease was discovered at CLU (rs11136000) with genome-wide support. Here we show, using an imaging genetics approach in a large genotyped sample, that healthy carriers of the variant exhibit altered coupling between hippocampus and prefrontal cortex during memory processing, mirroring clinical evidence of disturbed connectivity in patients and providing a neurogenetic mechanism for CLU-associated risk and protection.

Genetic variation in CYP2D6 impacts neural activation during cognitive tasks in humans.

The drug metabolizing cytochrome P450 2D6 enzyme (CYP2D6) is highly expressed in brain and potentially involved in neurotransmitter biotransformation. Here, we report the effect of the CYP2D6 genotype on brain activation during a working memory and an emotional face matching task measured with fMRI. Subjects were taken from an ongoing large scale multicenter imaging genetic study. CYP2D6 genotyping of the alleles *2, *3, *4, *5, *6, *9, *10, *17, *35, *41 and the duplication was performed in N=114 healthy drug free individuals. All individuals had completed two tasks in functional brain imaging: an n-back working memory task and an implicit emotional face matching task. Contrast images were analyzed in second-level random effects models with CYP2D6 enzyme activity levels as regressor of interest and age, sex and scanning site as covariates. In the working memory task, a significant effect of CYP2D6 genotype was found in the fusiform gyrus and the precuneus. In the emotional face matching task, an effect was detected in the cuneus. No significant activation results were found in the thalamus. A conjunction analysis confirmed a significant joint effect of the CYP2D6 association in both regions. In both tasks activation increased with increasing CYP2D6 activity. In conclusion, we confirmed a central nervous system effect of CYP2D6 activity in a large independent sample using a different imaging modality, and provide evidence that basic cognitive processes related to such as alertness may be impacted.

Test-retest reliability of evoked BOLD signals from a cognitive-emotive fMRI test battery.

Even more than in cognitive research applications, moving fMRI to the clinic and the drug development process requires the generation of stable and reliable signal changes. The performance characteristics of the fMRI paradigm constrain experimental power and may require different study designs (e.g., crossover vs. parallel groups), yet fMRI reliability characteristics can be strongly dependent on the nature of the fMRI task. The present study investigated both within-subject and group-level reliability of a combined three-task fMRI battery targeting three systems of wide applicability in clinical and cognitive neuroscience: an emotional (face matching), a motivational (monetary reward anticipation) and a cognitive (n-back working memory) task. A group of 25 young, healthy volunteers were scanned twice on a 3T MRI scanner with a mean test-retest interval of 14.6 days. FMRI reliability was quantified using the intraclass correlation coefficient (ICC) applied at three different levels ranging from a global to a localized and fine spatial scale: (1) reliability of group-level activation maps over the whole brain and within targeted regions of interest (ROIs); (2) within-subject reliability of ROI-mean amplitudes and (3) within-subject reliability of individual voxels in the target ROIs. Results showed robust evoked activation of all three tasks in their respective target regions (emotional task=amygdala; motivational task=ventral striatum; cognitive task=right dorsolateral prefrontal cortex and parietal cortices) with high effect sizes (ES) of ROI-mean summary values (ES=1.11-1.44 for the faces task, 0.96-1.43 for the reward task, 0.83-2.58 for the n-back task). Reliability of group level activation was excellent for all three tasks with ICCs of 0.89-0.98 at the whole brain level and 0.66-0.97 within target ROIs. Within-subject reliability of ROI-mean amplitudes across sessions was fair to good for the reward task (ICCs=0.56-0.62) and, dependent on the particular ROI, also fair-to-good for the n-back task (ICCs=0.44-0.57) but lower for the faces task (ICC=-0.02-0.16). In conclusion, all three tasks are well suited to between-subject designs, including imaging genetics. When specific recommendations are followed, the n-back and reward task are also suited for within-subject designs, including pharmaco-fMRI. The present study provides task-specific fMRI reliability performance measures that will inform the optimal use, powering and design of fMRI studies using comparable tasks.

Test-retest reliability of resting-state connectivity network characteristics using fMRI and graph theoretical measures.

Characterizing the brain connectome using neuroimaging data and measures derived from graph theory emerged as a new approach that has been applied to brain maturation, cognitive function and neuropsychiatric disorders. For a broad application of this method especially for clinical populations and longitudinal studies, the reliability of this approach and its robustness to confounding factors need to be explored. Here we investigated test-retest reliability of graph metrics of functional networks derived from functional magnetic resonance imaging (fMRI) recorded in 33 healthy subjects during rest. We constructed undirected networks based on the Anatomic-Automatic-Labeling (AAL) atlas template and calculated several commonly used measures from the field of graph theory, focusing on the influence of different strategies for confound correction. For each subject, method and session we computed the following graph metrics: clustering coefficient, characteristic path length, local and global efficiency, assortativity, modularity, hierarchy and the small-worldness scalar. Reliability of each graph metric was assessed using the intraclass correlation coefficient (ICC). Overall ICCs ranged from low to high (0 to 0.763) depending on the method and metric. Methodologically, the use of a broader frequency band (0.008-0.15 Hz) yielded highest reliability indices (mean ICC=0.484), followed by the use of global regression (mean ICC=0.399). In general, the second order metrics (small-worldness, hierarchy, assortativity) studied here, tended to be more robust than first order metrics. In conclusion, our study provides methodological recommendations which allow the computation of sufficiently robust markers of network organization using graph metrics derived from fMRI data at rest.

Cognitive state and connectivity effects of the genome-wide significant psychosis variant in ZNF804A.

Alterations of connectivity are central to the systems-level pathophysiology of schizophrenia. One of the best-established genome-wide significant risk variants for this highly heritable disorder, the rs1344706 single nucleotide polymorphism in ZNF804A, was recently shown to modulate connectivity in healthy carriers during working memory (WM) in a pattern mirroring that which was found in overt disease. However, it was unclear whether this finding is specific to WM or if it is present regardless of cognitive state. Therefore, we examined genotype effects on connectivity in healthy carriers during rest and an emotion processing task without WM component. 111 healthy German subjects performed a battery of functional imaging tasks. Functional connectivity with the right dorsolateral prefrontal cortex during rest and an implicit emotion recognition task was determined using the seed voxel method and compared to results during WM. During rest and during the emotional task, a pattern of reduced interhemispheric prefrontal connectivity with increasing number of rs1344706 risk alleles could be seen that was close to identical to that during WM, suggesting a state-independent influence of the genetic variant on interhemispheric processing, possibly through structural effects. By contrast, the abnormal prefronto-hippocampal connectivity was only seen during the WM task, indicating a degree of task specificity in agreement with prior results in patients with schizophrenia. Our findings confirm a key role for disturbed functional connectivity in the genetic risk architecture of schizophrenia and identify cognitive state-dependent and independent components with regard to WM function.

Nicotine increases neural response to unpleasant stimuli and anxiety in non-smokers.

Studies in smokers suggest that nicotine might exert anxiolytic, stress-dampening and mood-enhancing effects and beneficially influences neural processing of affective information. Regarding non-smokers, results are inconsistent, and no data exist on the effect of nicotine on neural emotion processing. We applied functional magnetic resonance imaging (fMRI) to assess the influence of nicotine on brain activation during processing of emotional stimuli in 31 non-smokers with a maximum lifetime cigarette consumption of 20 cigarettes. Participants were subjected to two fMRI scans with event-related presentations of images taken from the International Affective Picture System, receiving nicotine (2 mg) and placebo gums in a double-blinded, randomized cross-over design. Furthermore, subjective affect was assessed. Nicotine increased brain activity in response to unpleasant stimuli in the amygdala, anterior cingulate cortex (ACC) and basal ganglia, whereas processing of pleasant stimuli was not altered. Psychophysiological interaction (PPI) analyses revealed that nicotine increased connectivity between the amygdala and the perigenual ACC (pACC) during processing of unpleasant stimuli and decreased connectivity between those structures during processing of pleasant stimuli. Participants reported higher state anxiety under nicotine than placebo. A single dose of nicotine acted as a stressor in non-smokers, leading to increased anxiety and neural activation elicited by unpleasant stimuli as well as altered connectivity within the amygdala-pACC circuit. Besides the possibility that reactions to nicotine may differ between non-smokers and smokers due to tolerance and neuroadaptive processes that occur during prolonged nicotine use, a priori differences in smokers and non-smokers might potentially explain diverse effects of nicotine on affect and emotional reactivity.

Influence of vigilance and learning on prefrontal activation in schizophrenia.

BACKGROUND: Executive functions, which are neuroanatomically associated with the frontal lobe, are known to be impaired in schizophrenia. It is, however, still unclear whether the underlying functional disturbance is due to a hyper- or a hypoactivation of the dorsolateral prefrontal cortex (DLPFC) or neither. METHODS: To address this question, we examined the brain activation of 21 schizophrenic patients on atypical antipsychotic medication and 21 healthy control subjects during a mental maze task by means of fMRI. RESULTS: We found no significant overall difference in cerebral activation between the groups, but differences in the change in DLPFC activation from the first to the second half of the experiment. In the maze compared to the control task, there was a decrease in activation in the DLPFC in the patients and an almost significant increase in the controls. The change in activation in the patient group correlated with a change in subjective sleepiness, while the increase in activation in the controls could be attributed to learning processes. CONCLUSION: We hypothesized that differential temporal influences on brain activation could lead to either hyper- or hypoactivation of the DLPFC in schizophrenia.

Oxytocin modulates neural circuitry for social cognition and fear in humans.

In non-human mammals, the neuropeptide oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Oxytocin reduces anxiety and impacts on fear conditioning and extinction. Recently, oxytocin administration in humans was shown to increase trust, suggesting involvement of the amygdala, a central component of the neurocircuitry of fear and social cognition that has been linked to trust and highly expresses oxytocin receptors in many mammals. However, no human data on the effects of this peptide on brain function were available. Here, we show that human amygdala function is strongly modulated by oxytocin. We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. Compared with placebo, oxytocin potently reduced activation of the amygdala and reduced coupling of the amygdala to brainstem regions implicated in autonomic and behavioral manifestations of fear. Our results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain and provide a methodology and rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function has been implicated, such as social phobia or autism.

Area-specific information processing in prefrontal cortex during a probabilistic inference task: a multivariate fMRI BOLD time series analysis.

INTRODUCTION: Discriminating spatiotemporal stages of information processing involved in complex cognitive processes remains a challenge for neuroscience. This is especially so in prefrontal cortex whose subregions, such as the dorsolateral prefrontal (DLPFC), anterior cingulate (ACC) and orbitofrontal (OFC) cortices are known to have differentiable roles in cognition. Yet it is much less clear how these subregions contribute to different cognitive processes required by a given task. To investigate this, we use functional MRI data recorded from a group of healthy adults during a "Jumping to Conclusions" probabilistic reasoning task. METHODS: We used a novel approach combining multivariate test statistics with bootstrap-based procedures to discriminate between different task stages reflected in the fMRI blood oxygenation level dependent signal pattern and to unravel differences in task-related information encoded by these regions. Furthermore, we implemented a new feature extraction algorithm that selects voxels from any set of brain regions that are jointly maximally predictive about specific task stages. RESULTS: Using both the multivariate statistics approach and the algorithm that searches for maximally informative voxels we show that during the Jumping to Conclusions task, the DLPFC and ACC contribute more to the decision making phase comprising the accumulation of evidence and probabilistic reasoning, while the OFC is more involved in choice evaluation and uncertainty feedback. Moreover, we show that in presumably non-task-related regions (temporal cortices) all information there was about task processing could be extracted from just one voxel (indicating the unspecific nature of that information), while for prefrontal areas a wider multivariate pattern of activity was maximally informative. CONCLUSIONS/SIGNIFICANCE: We present a new approach to reveal the different roles of brain regions during the processing of one task from multivariate activity patterns measured by fMRI. This method can be a valuable tool to assess how area-specific processing is altered in psychiatric disorders such as schizophrenia, and in healthy subjects carrying different genetic polymorphisms.

Metamemory in schizophrenia: retrospective confidence ratings interact with neurocognitive deficits.

Prior studies with schizophrenia patients described a reduced ability to discriminate between correct and false memories in terms of confidence compared to control groups. This metamemory bias has been associated with the emergence and maintenance of delusions. The relation to neuropsychological performance and other clinical dimensions is incompletely understood. In a cross-sectional study, metamemory functioning was explored in 32 schizophrenia patients and 25 healthy controls. Metamemory was assessed using a verbal recognition task combined with retrospective confidence level ratings. Associations of metamemory performance with six neuropsychological domains (executive functioning/problem solving, speed of processing, working memory, verbal and visual learning, and attention/vigilance) and psychopathological measures were analyzed. Results revealed a significantly smaller discrepancy between confidence ratings for correct and incorrect recognitions in the patient group. Furthermore, patients showed significantly lower recognition accuracy in the metamemory task and marked deficits in all neuropsychological domains. Across all participants, metamemory performance significantly correlated with executive functioning and working memory. No associations with delusions were found. This data confirms prior findings of metamemory biases in schizophrenia. Selective neuropsychological abilities seem to be modulating factors of metamemory functioning. Longitudinal studies in at risk mental state and first-episode patients are needed to reveal causal interrelations.

Reduced activation in ventral striatum and ventral tegmental area during probabilistic decision-making in schizophrenia.

Patients with schizophrenia suffer from deficits in monitoring and controlling their own thoughts. Within these so-called metacognitive impairments, alterations in probabilistic reasoning might be one cognitive phenomenon disposing to delusions. However, so far little is known about alterations in associated brain functionality. A previously established task for functional magnetic resonance imaging (fMRI), which requires a probabilistic decision after a variable amount of stimuli, was applied to 23 schizophrenia patients and 28 healthy controls matched for age, gender and educational levels. We compared activation patterns during decision-making under conditions of certainty versus uncertainty and evaluated the process of final decision-making in ventral striatum (VS) and ventral tegmental area (VTA). We replicated a pre-described extended cortical activation pattern during probabilistic reasoning. During final decision-making, activations in several fronto- and parietocortical areas, as well as in VS and VTA became apparent. In both of these regions schizophrenia patients showed a significantly reduced activation. These results further define the network underlying probabilistic decision-making. The observed hypo-activation in regions commonly associated with dopaminergic neurotransmission fits into current concepts of disrupted prediction error signaling in schizophrenia and suggests functional links to reward anticipation. Forthcoming studies with patients at risk for psychosis and drug-naive first episode patients are necessary to elucidate the development of these findings over time and the interplay with associated clinical symptoms.

Corticothalamic phase synchrony and cross-frequency coupling predict human memory formation.

The anterior thalamic nucleus (ATN) is thought to play an important role in a brain network involving the hippocampus and neocortex, which enables human memories to be formed. However, its small size and location deep within the brain have impeded direct investigation in humans with non-invasive techniques. Here we provide direct evidence for a functional role for the ATN in memory formation from rare simultaneous human intrathalamic and scalp electroencephalogram (EEG) recordings from eight volunteering patients receiving intrathalamic electrodes implanted for the treatment of epilepsy, demonstrating real-time communication between neocortex and ATN during successful memory encoding. Neocortical-ATN theta oscillatory phase synchrony of local field potentials and neocortical-theta-to-ATN-gamma cross-frequency coupling during presentation of complex photographic scenes predicted later memory for the scenes, demonstrating a key role for the ATN in human memory encoding.

Further evidence for the impact of a genome-wide-supported psychosis risk variant in ZNF804A on the Theory of Mind Network.

The single-nucleotide polymorphism (SNP) rs1344706 in ZNF804A is one of the best-supported risk variants for psychosis. We hypothesized that this SNP contributes to the development of schizophrenia by affecting the ability to understand other people's mental states. This skill, commonly referred to as Theory of Mind (ToM), has consistently been found to be impaired in schizophrenia. Using functional magnetic resonance imaging, we previously showed that in healthy individuals rs1344706 impacted on activity and connectivity of key areas of the ToM network, including the dorsomedial prefrontal cortex, temporo-parietal junction, and the posterior cingulate cortex, which show aberrant activity in schizophrenia patients, too. We aimed to replicate these results in an independent sample of 188 healthy German volunteers. In order to assess the reliability of brain activity elicited by the ToM task, 25 participants performed the task twice with an interval of 14 days showing excellent accordance in recruitment of key ToM areas. Confirming our previous results, we observed decreasing activity of the left temporo-parietal junction, dorsomedial prefrontal cortex, and the posterior cingulate cortex with increasing number of risk alleles during ToM. Complementing our replication sample with the discovery sample, analyzed in a previous report (total N=297), further revealed negative genotype effects in the left dorsomedial prefrontal cortex as well as in the temporal and parietal regions. In addition, as shown previously, rs1344706 risk allele dose positively predicted increased frontal-temporo-parietal connectivity. These findings confirm the effects of the psychosis risk variant in ZNF804A on the dysfunction of the ToM network.