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

Interhemispheric auditory connectivity: structure and function related to auditory verbal hallucinations

Auditory verbal hallucinations (AVH) are one of the most common and most distressing symptoms of schizophrenia. Despite fundamental research, the underlying neurocognitive and neurobiological mechanisms are still a matter of debate. Previous studies suggested that hearing voices is associated with a number of factors including local deficits in the left auditory cortex and a disturbed connectivity of frontal and temporoparietal language-related areas. In addition, it is hypothesized that the interhemispheric pathways connecting right and left auditory cortices might be involved in the pathogenesis of AVH. Findings based on Diffusion-Tensor-Imaging (DTI) measurements revealed a remarkable interindividual variability in size and shape of the interhemispheric auditory pathways. Interestingly, schizophrenia patients suffering from AVH exhibited increased fractional anisotropy (FA) in the interhemispheric fibers than non-hallucinating patients. Thus, higher FA-values indicate an increased severity of AVH. Moreover, a dichotic listening (DL) task showed that the interindividual variability in the interhemispheric auditory pathways was reflected in the behavioral outcome: Stronger pathways supported a better information transfer and consequently improved speech perception. This detection indicates a specific structure-function relationship, which seems to be interindividually variable. This review focuses on recent findings concerning the structure-function relationship of the interhemispheric pathways in controls, hallucinating and non-hallucinating schizophrenia patients and concludes that changes in the structural and functional connectivity of auditory areas are involved in the pathophysiology of AVH

The Impact of Inconsistent Responders to Mixed-Worded Scales on Inferences in International Large-Scale Assessments

In education research, mixed-worded questionnaire scales often suffer from issues like unintended multi-dimensionality and low reliability. Part of the problem might be that some responders fail to respond consistently to positively and negatively worded items. The present study aimed to investigate the prevalence and impact of such inconsistent responders in 37 primary education systems participating in the joint PIRLS/TIMSS 2011 assessment. Using the mean absolute difference method and three mixed-worded self-concept scales, we identified 2%–36% of students as inconsistent responders. Consistent with expectations, these students showed lower average achievement scores and had a higher risk of being identified as inconsistent on more than one scale. We also found that the inconsistent responders biased the estimated dimensionality and reliability of the mixed-worded questionnaire scales. The impact on external validity measures was limited and unsystematic. We discuss implications for the use and development of questionnaire scales

The impact of inconsistent responders to mixed-worded scales on inferences in international large-scale assessments

Questionnaire scales that are mixed-worded, i.e. include both positively and negatively worded items, often suffer from issues like low reliability and more complex latent structures than intended. Part of the problem might be that some responders fail to respond consistently to the mixed-worded items. We investigated the prevalence and impact of inconsistent responders in 37 primary education systems participating in the joint PIRLS/TIMSS 2011 assessment. Using the mean absolute difference method and three mixed-worded self-concept scales, we identified between 2%‒36% of students as inconsistent responders across education systems. Consistent with expectations, these students showed lower average achievement scores and had a higher risk of being identified as inconsistent on more than one scale. We also found that the inconsistent responders biased the estimated dimensionality and reliability of the scales. The impact on external validity measures was limited and unsystematic. We discuss implications for the use and development of questionnaire scales

Auditory verbal hallucinations related to altered long-range synchrony of gamma-band oscillations

Our understanding of the neural correlates of auditory-verbal-hallucinations (AVH) has substantially increased during the last few years, but is far from sufficient. One current hypothesis, the interhemispheric miscommunication theory, is based on findings from fMRI, DTI and EEG, but there is only limited evidence so far concerning underlying functional coupling mechanisms. Here we report a 64-channel EEG study using lagged phase synchronization analysis and eLORETA source estimation to examine the functional connectivity between bilateral auditory cortices in the gamma-band in 26 schizophrenia patients (13 with and 13 without AVH) and 26 matched healthy controls (HC) while performing a dichotic listening task. We found a significantly reduced right-ear-advantage (REA) in AVH but not in non-AVH patients compared to HC. The major finding was significantly stronger gamma-band connectivity between bilateral auditory cortices during conscious perception of left (versus right) ear syllables in patients with AVH compared to HC and patients without AVH. A significant positive correlation was found between this connectivity alteration and the AVH symptom score in schizophrenia patients. These findings provide further support for the interhemispheric miscommunication hypothesis of AVH pathophysiology by indicating that aberrant gamma-band coupling between auditory cortices is related to the emergence of AVH in schizophrenia

Investigation of the Serotonergic Activity and the Serotonin Content in Serum and Platelet, and the Possible Role of the Serotonin Transporter in Patients with Depression

According to the monoamine hypothesis, the development of depression is associated with dysfunctions of the serotonergic system. Alterations in the serotonin transporter gene (5-HTTLPR), the serotonergic activity in the brain, and the content of serotonin (5-HT) have been related to depression and were examined separately by previous studies. This study investigates these parameters in 89 depressed patients and 89 healthy participants. We investigated the serotonergic activity measured by the loudness dependence of auditory evoked potentials (LDAEP). In addition to the examination of the serotonin content (serum and platelet), enzyme-linked immunosorbent assays (ELISA) were used and 5-HTTLPR genotypes were analyzed. We observed a lower serotonin content in patients compared to healthy participants. Further, we noticed a correlation between anxiety and depression-associated symptoms with serotonergic activity. Patients treated with SSRI/SNRI showed decreased contents of serum serotonin compared to patients without any psychotropic medication or other psychotropic medications. Since the serotonergic activity, peripheral serotonin content, and 5-HTTLPR were unrelated, the results suggest independent alterations of central and peripheral serotonergic systems in depression. In line with this finding, serotonergic activity was related to anxiety and depression symptoms. Furthermore, the applied medication seems to influence serum serotonin content in patients with depression

The Time Course of Activity within the Dorsal and Rostral-Ventral Anterior Cingulate Cortex in the Emotional Stroop Task

Growing evidence from neuroimaging studies suggest that emotional and cognitive processes are interrelated. Anatomical key structures in this context are the dorsal and rostral-ventral anterior cingulate cortex (dACC and rvACC). However, up to now, the time course of activations within these regions during emotion-cognition interactions has not been disentangled. In the present study, we used event-related potentials (ERP) and standardized low-resolution electromagnetic tomography (sLORETA) region of interest (ROI) source localization analyses to explore the time course of neural activations within the dACC and rvACC using a modified emotional Stroop paradigm. ERP components related to Stroop conflict (N200, N450 and late negativity) were analyzed. The time course of brain activations in the dACC and rvACC was strikingly different with more pronounced initial responses in the rvACC followed by increased dACC activity mainly at the late negativity window. Moreover, emotional valence modulated the earlier N450 stage within the rvACC region with higher neural activations in the positive compared to the negative and neutral conditions. Emotional arousal modulated the late negativity stage; firstly in the significant arousal × congruence ERP effect and then the significant higher current density in the low arousal condition within the dACC. Using sLORETA source localization, substantial differences in the activation time courses in the dACC and rvACC could be found during the emotional Stroop task. We suggest that during late negativity, within the dACC, emotional arousal modulated the processing of response conflict, reflected in the correlation between the ex-Gaussian µ and the current density in the dACC

fMRI correlates of jumping-to-conclusions in patients with delusions: Connectivity patterns and effects of metacognitive training

Background: Reasoning biases such as the jumping-to-conclusions bias (JTC) are thought to contribute to delusions. Interventions targeting these biases such as metacognitive training (MCT) may improve delusions. So far, it is not clear whether JTC depends on dopaminergic reward areas that constitute the main action locus of antipsychotic drugs, or on additional cortical areas. The present study aimed to investigate fMRI activation and functional connectivity patterns underlying JTC, and their changes following MCT, in patients with delusions. Methods: Participants were 25 healthy individuals and 26 patients with current delusions who were either medication-free or on stable medication without sufficient response. We assessed (1) BOLD activity in the task-positive (TPN), task-negative (TNN), and subcortical reward network (RN); (2) Psychophysiological interactions (PPI) of peak activation areas. Results: Presence of JTC (irrespective of group) was associated with lower RN activity during conclusion events, and with increased effective connectivity between TPN and TNN during draw events. Following MCT, changes were observed in TPN activity and in effective connectivity of inferior parietal cortex (part of the TPN) with all three target networks. Conclusion: JTC is associated not only with reward system areas that constitute the main target of antipsychotic drugs, but also with cortical areas, particularly of the TPN. Keywords: Evidence gathering, Prediction error, Schizophrenia, Psychosis, Striatu

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