Linewidth-related bias in modelled concentration estimates from GABA-edited 1H-MRS.

J-difference-edited MRS is widely used to study GABA in the human brain. Editing for low-concentration target molecules (such as GABA) typically exhibits lower signal-to-noise ratio (SNR) than conventional non-edited MRS, varying with acquisition region, volume and duration. Moreover, spectral lineshape may be influenced by age-, pathology-, or brain-region-specific effects of metabolite T2, or by task-related blood-oxygen level dependent (BOLD) changes in functional MRS contexts. Differences in both SNR and lineshape may have systematic effects on concentration estimates derived from spectral modelling. The present study characterises the impact of lineshape and SNR on GABA+ estimates from different modelling algorithms: FSL-MRS, Gannet, LCModel, Osprey, spant and Tarquin. Publicly available multi-site GABA-edited data (222 healthy subjects from 20 sites; conventional MEGA-PRESS editing; TE = 68 ms) were pre-processed with a standardised pipeline, then filtered to apply controlled levels of Lorentzian and Gaussian linebroadening and SNR reduction. Increased Lorentzian linewidth was associated with a 2-5% decrease in GABA+ estimates per Hz, observed consistently (albeit to varying degrees) across datasets and most algorithms. Weaker, often opposing effects were observed for Gaussian linebroadening. Variations are likely caused by differing baseline parametrization and lineshape constraints between models. Effects of linewidth on other metabolites (e.g., Glx and tCr) varied, suggesting that a linewidth confound may persist after scaling to an internal reference. These findings indicate a potentially significant confound for studies where linewidth may differ systematically between groups or experimental conditions, e.g. due to T2 differences between brain regions, age, or pathology, or varying T2* due to BOLD-related changes. We conclude that linewidth effects need to be rigorously considered during experimental design and data processing, for example by incorporating linewidth into statistical analysis of modelling outcomes or development of appropriate lineshape matching algorithms.

GABA, glutamatergic dynamics and BOLD contrast assessed concurrently using functional MRS during a cognitive task.

A recurring issue in functional neuroimaging is how to link task-driven haemodynamic blood oxygen level dependent functional MRI (BOLD-fMRI) responses to underlying neurochemistry at the synaptic level. Glutamate and γ-aminobutyric acid (GABA), the major excitatory and inhibitory neurotransmitters respectively, are typically measured with MRS sequences separately from fMRI, in the absence of a task. The present study aims to resolve this disconnect, developing acquisition and processing techniques to simultaneously assess GABA, glutamate and glutamine (Glx) and BOLD in relation to a cognitive task, at 3 T. Healthy subjects (N = 81) performed a cognitive task (Eriksen flanker), which was presented visually in a task-OFF, task-ON block design, with individual event onset timing jittered with respect to the MRS readout. fMRS data were acquired from the medial anterior cingulate cortex during task performance, using an adapted MEGA-PRESS implementation incorporating unsuppressed water-reference signals at a regular interval. These allowed for continuous assessment of BOLD activation, through T2 *-related changes in water linewidth. BOLD-fMRI data were additionally acquired. A novel linear model was used to extract modelled metabolite spectra associated with discrete functional stimuli, building on well established processing and quantification tools. Behavioural outcomes from the flanker task, and activation patterns from the BOLD-fMRI sequence, were as expected from the literature. BOLD response assessed through fMRS showed a significant correlation with fMRI, specific to the fMRS-targeted region of interest; fMRS-assessed BOLD additionally correlated with lengthening of response time in the incongruent flanker condition. While no significant task-related changes were observed for GABA+, a significant increase in measured Glx levels (~8.8%) was found between task-OFF and task-ON periods. These findings verify the efficacy of our protocol and analysis pipelines for the simultaneous assessment of metabolite dynamics and BOLD. As well as establishing a robust basis for further work using these techniques, we also identify a number of clear directions for further refinement in future studies.

fMRI fluctuations within the language network are correlated with severity of hallucinatory symptoms in schizophrenia.

Although schizophrenia (SZ) represents a complex multiform psychiatric disorder, one of its most striking symptoms are auditory verbal hallucinations (AVH). While the neurophysiological origin of this pervasive symptom has been extensively studied, there is so far no consensus conclusion on the neural correlates of the vulnerability to hallucinate. With a network-based fMRI approach, following the hypothesis of altered hemispheric dominance (Crow, 1997), we expected that LN alterations might result in self-other distinction impairments in SZ patients, and lead to the distressing subjective experiences of hearing voices. We used the independent component analysis of resting-state fMRI data, to first analyze LN connectivity in three groups of participants: SZ patients with and without hallucinations (AVH/D+ and AVH/D-, respectively), and a matched healthy control (HC) group. Then, we assessed the fMRI fluctuations using additional analyses based on fractional Amplitude of Low Frequency-Fluctuations (fALFF), both at the network- and region of interest (ROI)-level. Specific LN nodes were recruited in the right hemisphere (insula and Broca homologous area) for AVH/D+ , but not for HC and AVH/D-, consistent with a left hemisphere deficit in AVH patients. The fALFF analysis at the ROI level showed a negative correlation between fALFF Slow-4 and P1 Delusions PANSS subscale and a positive correlation between the fALFF Slow-5 and P3 Hallucination PANSS subscale for AVH/D+ only. These effects were not a consequence of structural differences between groups, as morphometric analysis did not evidence any group differences. Given the role of language as an emerging property resulting from the integration of many high-level cognitive processes and the underlying cortical areas, our results suggest that LN features from fMRI connectivity and fluctuations can be a marker of neurophysiological features characterizing SZ patients depending on their vulnerability to hallucinate.

Similarities and differences between intermittent and continuous resting-state fMRI.

Introduction: Functional Magnetic Resonance Imaging (fMRI) block-design experiments typically include active ON-blocks with presentation of cognitive tasks which are contrasted with OFF- blocks with no tasks presented. OFF-blocks in between ON-blocks can however, also be seen as a proxy for intermittent periods of resting, inducing temporary resting-states. We still do not know if brain activity during such intermittent periods reflects the same kind of resting-state activity as that obtained during a continuous period, as is typically the case in studies of the classic Default Mode Network (DMN). The purpose of the current study was therefore to investigate both similarities and differences in brain activity between intermittent and continuous resting conditions. Methods: There were 47 healthy participants in the 3T fMRI experiment. Data for the intermittent resting-state condition were acquired from resting-periods in between active task-processing periods in a standard ON-OFF block design, with three different cognitive tasks presented during ON-blocks. Data for the continuous resting-state condition were acquired during a 5 min resting period after the task-design had been presented. Results and discussion: The results showed that activity was overall similar in the two conditions, but with some differences. These differences were within the DMN network, and for the interaction of DMN with other brain networks. DMN maps showed weak overlap between conditions in the medial prefrontal cortex (MPFC), and in particular for the intermittent compared to the continuous resting-state condition. Moreover, DMN showed strong connectivity with the salience network (SN) in the intermittent resting-state condition, particularly in the anterior insula and the supramarginal gyrus. The observed differences may reflect a "carry-over" effect from task-processing to the next resting-state period, not present in the continuous resting-state condition, causing interference from the ON-blocks. Further research is needed to fully understand the extent of differences between intermittent and continuous resting-state conditions.

Analysis of distributions reveals real differences on dichotic listening scores between left- and right-handers.

About 95% of right-handers and 70% of left-handers have a left-hemispheric specialization for language. Dichotic listening is often used as an indirect measure of this language asymmetry. However, while it reliably produces a right-ear advantage (REA), corresponding to the left-hemispheric specialization of language, it paradoxically often fails to obtain statistical evidence of mean differences between left- and right-handers. We hypothesized that non-normality of the underlying distributions might be in part responsible for the similarities in means. Here, we compare the mean ear advantage scores, and also contrast the distributions at multiple quantiles, in two large independent samples (Ns = 1,358 and 1,042) of right-handers and left-handers. Right-handers had an increased mean REA, and a larger proportion had an REA than in the left-handers. We also found that more left-handers are represented in the left-eared end of the distribution. These data suggest that subtle shifts in the distributions of DL scores for right- and left-handers may be at least partially responsible for the unreliability of significantly reduced mean REA in left-handers.

Signatures of exposure to childhood trauma in young adults in the structure and neurochemistry of the superior temporal gyrus.

BACKGROUND: Childhood trauma (CT) has been linked to increased risk for mental illness in adulthood. Although work in experimental animals has shown that early life stressors can affect inhibitory and excitatory neurotransmission in adult rodents, with possible excitotoxic effects on local grey matter volumes (GMV), the neurobiological mechanisms that mediate this relationship in humans remain poorly understood. AIM: To examine glutamate and gamma-aminobutyric acid (GABA) metabolite concentrations and potential excitotoxic effects on GMV, in adults who experienced CT. METHODS: Fifty-six young adults (Mage = 20.41) were assigned to High CT (n = 29) and Low CT (n = 27) groups (by using the CT questionnaire) and underwent magnetic resonance spectroscopy (1H-MRS) to measure temporal lobe metabolite concentrations and volumetric imaging to measure GMV. RESULTS: Glutamate concentrations did not differ between groups; however, relative to the Low CT group, participants in the High CT group had reduced GABA concentrations in the left superior temporal gyrus (STG) voxel. Furthermore, logistic regression showed that participants with low left STG GABA concentrations and low left STG volumes were significantly more likely to be in the high CT group. CONCLUSIONS: This study provides the first evidence that both low GABA concentrations and its interaction with GMV in the left STG are associated with high levels of CT and suggest that altered inhibitory neurotransmission/metabolism may be linked to a lower GMV in the left STG in adults who experienced CT. Future studies are warranted to establish if utilizing these measures can stratify clinical high-risk and predict future clinical outcomes in high CT individuals.

Functional Changes in GABA and Glutamate during Motor Learning.

Functional magnetic resonance spectroscopy (fMRS) of GABA at 3 T poses additional challenges compared with fMRS of other metabolites because of the difficulties of measuring GABA levels; GABA is present in the brain at relatively low concentrations, and its signal is overlapped by higher concentration metabolites. Using 7 T fMRS, GABA levels have been shown to decrease specifically during motor learning (and not during a control task). Though the use of 7 T is appealing, access is limited. For GABA fMRS to be widely accessible, it is essential to develop this method at 3 T. Nine healthy right-handed participants completed a motor learning and a control button-pressing task. fMRS data were acquired from the left sensorimotor cortex during the task using a continuous GABA-edited MEGA-PRESS acquisition at 3 T. We found no significant changes in GABA+/tCr, Glx/tCr, or Glu/tCr levels in either task; however, we show a positive relationship between motor learning and glutamate levels both at rest and at the start of the task. Though further refinement and validation of this method is needed, this study represents a further step in using fMRS at 3 T to probe GABA levels in both healthy cognition and clinical disorders.

High levels of childhood trauma associated with changes in hippocampal functional activity and connectivity in young adults during novelty salience.

Childhood trauma (CT) has been linked to increased risk for psychosis. Moreover, CT has been linked to psychosis phenotypes such as impaired cognitive and sensory functions involved in the detection of novel sensory stimuli. Our objective was to investigate if CT was associated with changes in hippocampal and superior temporal gyrus functional activation and connectivity during a novelty detection task. Fifty-eight young adults were assigned to High-CT (n = 28) and Low-CT (n = 24) groups based on their scores on the childhood trauma questionnaire (CTQ) and underwent functional Magnetic Resonance Imaging during an auditory oddball task (AOT). Relative to the Low CT group, High CT participants showed reduced functional activation in the left hippocampus during the unpredictable tone condition of the AOT. Furthermore, in the High CT group, psychophysiological interaction analysis revealed hypoconnectivity between the hippocampus and temporal and medial regions. The present study indicates both altered hippocampal activation and hippocampal-temporal-prefrontal connectivity during novelty detection in individuals that experienced CT, similarly to that reported in psychosis risk populations. Early stressful experiences and environments may alter hippocampal function during salient events, mediating the relationship between childhood trauma and psychosis risk.

Paracingulate Sulcus Length and Cortical Thickness in Schizophrenia Patients With and Without a Lifetime History of Auditory Hallucinations.

BACKGROUND: It has been theorized that hallucinations, a common symptom of schizophrenia, are caused by failures in reality monitoring. The paracingulate sulcus (PCS) has been implicated as a brain structure supporting reality monitoring with the absence or shorter length of PCS associated with an occurrence of hallucinations in schizophrenia. The absence or shorter length of PCS has been associated with an occurrence of hallucinations. There are inconsistent findings in the literature regarding the role of the asymmetry of this structure for hallucinations. Here, we investigated the length of the PCS and cortical thickness of surrounding structures in patients with a lifetime history of auditory verbal hallucinations (AVH). DESIGN: Seventy-seven patients and twenty-eight healthy controls (HC) underwent an anatomical MRI scan. PCS length and cortical thickness were estimated using Mango brain visualization and FreeSurfer, respectively. Patients with AVH (n = 45) and patients without AVH were compared (n = 32) to the controls. RESULTS: PCS length significantly differed between HC and patient groups (F(2,102) = 3.57, P = .032) in the left but not in the right sulcus. We found significantly longer PCS between HC and AVH group but no difference between patient groups. Similarly, we found significant thinning of cortical structures including structures surrounding anterior parts of PCS between HC and patients either in general or per group, but no significant differences were observed between patient groups. CONCLUSIONS: PCS length in the left hemisphere is shorter in schizophrenia patients with hallucinations as compared to HC subjects. The patient group without hallucinations was in between those 2 groups. Cortical thickness of neighboring areas of PCS is diminished in patient groups relative to the healthy comparison subjects. The role of lateralization and functional involvement of the PCS region in processes underlying hallucinations, such as reality monitoring, needs further clarification.

Neural Activation in the Ventromedial Prefrontal Cortex Precedes Conscious Experience of Being in or out of a Transient Hallucinatory State.

BACKGROUND AND HYPOTHESES: Auditory verbal hallucinations (AVHs) is not only a common symptom in schizophrenia but also observed in individuals in the general population. Despite extensive research, AVHs are poorly understood, especially their underlying neuronal architecture. Neuroimaging methods have been used to identify brain areas and networks that are activated during hallucinations. A characteristic feature of AVHs is, however, that they fluctuate over time, with varying frequencies of starts and stops. An unanswered question is, therefore, what neuronal events co-occur with the initiation and inhibition of an AVH episode. STUDY DESIGN: We investigated brain activation with fMRI in 66 individuals who experienced multiple AVH-episodes while in the scanner. We extracted time-series fMRI-data and monitored changes second-by-second from 10 s before to 15 s after participants indicated the start and stop of an episode, respectively, by pressing a hand-held response-button. STUDY RESULTS: We found a region in the ventromedial prefrontal cortex (VMPFC) which showed a significant increase in activation initiated a few seconds before participants indicated the start of an episode, and a corresponding decrease in activation initiated a few seconds before the end of an episode. CONCLUSIONS: The consistent increase and decrease in activation in this area in advance of the consciously experienced presence or absence of the "voice" imply that this region may act as a switch in turning episodes on and off. The activation is unlikely to be confounded by motor responses. The findings could have clinical implications for brain stimulation treatments, like transcranial magnetic stimulation.

Pilot-RCT Finds No Evidence for Modulation of Neuronal Networks of Auditory Hallucinations by Transcranial Direct Current Stimulation.

BACKGROUND: Transcranial direct current stimulation (tDCS) is used as treatment for auditory verbal hallucinations (AVH). The theory behind the treatment is that tDCS increases activity in prefrontal cognitive control areas, which are assumed to be hypoactive, and simultaneously decreases activity in temporal speech perception areas, which are assumed to be hyperactive during AVH. We tested this hypofrontal/hypertemporal reversal theory by investigating anatomical, neurotransmitter, brain activity, and network connectivity changes over the course of tDCS treatment. METHODS: A double-blind, randomized controlled trial was conducted with 21 patients receiving either sham or real tDCS treatment (2 mA) twice daily for 5 days. The anode was placed over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the left temporo-parietal cortex (TPC). Multimodal neuroimaging as well as clinical and neurocognitive functioning assessment were performed before, immediately after, and three months after treatment. RESULTS: We found a small reduction in AVH severity in the real tDCS group, but no corresponding neuroimaging changes in either DLPFCD or TPC. LIMITATIONS: The study has a small sample size. CONCLUSION: The results suggest that the currently leading theory behind tDCS treatment of AVH may need to be revised, if confirmed by studies with larger N. Tentative findings point to the involvement of Broca's area as a critical structure for tDCS treatment.

Default mode network alterations underlie auditory verbal hallucinations in schizophrenia.

Although alterations of the default mode network (DMN) in schizophrenia (SZ) have been largely investigated, less research has been carried out on DMN alterations in different sub-phenotypes of this disorder. The aim of this pilot study was to compare DMN features among SZ patients with and without auditory verbal hallucinations (AVH). Three groups of 17 participants each were considered: patients with hallucinations (AVH-SZ), patients without hallucinations (nAVH-SZ) and age-matched healthy controls (HC). The DMN spatial pattern was similar between the nAVH-SZ and HC, but the comparison between these two groups and the AVH-SZ group revealed alterations in the left Angular Gyrus (lAG) node of the DMN. Using a novel approach based on normalized fractional Amplitude of Low-Frequency Fluctuations (fALFF), the AVH-SZ subgroup showed altered spectral activity in the DMN compared with the other two groups, especially in the lower-frequency bands (0.017-0.04 Hz). Significant positive correlations were found for both SZ groups collapsed, and for the nAVH-SZ group alone between delusional scores (PANSS-P1) and slow fALFF bands of the DMN. Narrowing the analysis to the ROI centered on the lAG, significant correlations were found in the AVH-SZ group for hallucination scores (PANSS-P3) and Slow-5 and Slow-4 (both positive), and Slow-3 (negative) fALFF bands. Our results reveal the central role of the lAG in relation to hallucinations, an important cortical area connecting auditory cortex with several hubs (including frontal linguistic centers) and involved in auditory process monitoring.

Involvement of the default mode network under varying levels of cognitive effort.

Everyday cognitive functioning is characterized by constant alternations between different modes of information processing, driven by constant fluctuations in environmental demands. At the neural level, this is realized through corresponding dynamic shifts in functional activation and network connectivity. A distinction is often made between resting and task processing and between task-negative and task-positive functional networks. The Default Mode Network (DMN) is classically considered as a resting state (i.e. task-negative) network, upregulated in the absence of cognitive demands. In contrast, task-positive networks have been labelled the Extrinsic Mode Network (EMN). We investigated changes in brain activation and functional network connectivity in an experimental situation of repeated alterations between levels of cognitive effort, following a block-design. Using fMRI and a classic Stroop paradigm, participants switched back and forth between periods of no effort (resting), low effort (word reading, i.e. automatic processing based on learned internal representations and rules) and high effort (color naming, i.e. cognitively controlled perceptual processing of specific features of external stimuli). Results showed an expected EMN-activation for task versus resting contrasts, and DMN-activation for rest versus task contrasts. The DMN was in addition more strongly activated during periods of low effort contrasted with high effort, suggesting a gradual up- and down-regulation of the DMN network, depending on the level of demand and the type of processing required. The often reported "anti-correlation" between DMN and EMN was strongest during periods of low effort, indicating intermittent contributions of both networks. Taken together, these results challenge the traditional view of the DMN as solely a task-negative network. Instead, both the EMN and DMN may contribute to low-effort cognitive processing. In contrast, periods of resting and high effort are dominated by the DMN and EMN, respectively.

Brain pathology and cognitive scores prior to onset of late-life depression.

OBJECTIVES: Understanding the biological changes that occur prior to onset of late-life depression (LLD) is key to its prevention. To investigate potential predictors of LLD, we assessed cognitive scores and neurodegenerative and vascular biomarkers in healthy older adults who later developed depression. METHODS: Longitudinal data from the Alzheimer's Disease Neuroimaging Initiative of 241 cognitively unimpaired and non-depressed older adults aged 56-90 at baseline with at least 4 years of follow-up were included. Participants were classified based on whether they developed an incident depression (n = 96) or not (n = 145). Cognitive measures of memory, executive functioning, and language, and biomarkers proposed to be related to LLD: hippocampal volume, white matter hyperintensity volume (WMH), and cortical and cerebrospinal fluid (CSF) amyloid beta levels, were compared between the incident depression and the never-depressed groups at four time points: at baseline, the visit prior to onset, at onset, and after the onset of depression. RESULTS: In the incident depression group, there was a mild decline in cognitive scores from baseline to the visit before depression onset compared with the never-depressed group. The cognitive differences between the groups became more marked after depression onset. Baseline cortical amyloid burden, CSF amyloid beta levels, and WMH were significant predictors of incident depression. Compared to the non-depressed group, hippocampal volume was not reduced before onset, but was reduced following depression. CONCLUSIONS: Amyloid pathology and WMH can predict future development of LLD in cognitively unimpaired individuals and may be involved in precipitating vulnerability for depression in older adults.

Modular-Level Functional Connectome Alterations in Individuals With Hallucinations Across the Psychosis Continuum.

Functional connectome alterations, including modular network organization, have been related to the experience of hallucinations. It remains to be determined whether individuals with hallucinations across the psychosis continuum exhibit similar alterations in modular brain network organization. This study assessed functional connectivity matrices of 465 individuals with and without hallucinations, including patients with schizophrenia and bipolar disorder, nonclinical individuals with hallucinations, and healthy controls. Modular brain network organization was examined at different scales of network resolution, including (1) global modularity measured as Qmax and Normalised Mutual Information (NMI) scores, and (2) within- and between-module connectivity. Global modular organization was not significantly altered across groups. However, alterations in within- and between-module connectivity were observed for higher-order cognitive (e.g., central-executive salience, memory, default mode), and sensory modules in patients with schizophrenia and nonclinical individuals with hallucinations relative to controls. Dissimilar patterns of altered within- and between-module connectivity were found bipolar disorder patients with hallucinations relative to controls, including the visual, default mode, and memory network, while connectivity patterns between visual, salience, and cognitive control modules were unaltered. Bipolar disorder patients without hallucinations did not show significant alterations relative to controls. This study provides evidence for alterations in the modular organization of the functional connectome in individuals prone to hallucinations, with schizophrenia patients and nonclinical individuals showing similar alterations in sensory and higher-order cognitive modules. Other higher-order cognitive modules were found to relate to hallucinations in bipolar disorder patients, suggesting differential neural mechanisms may underlie hallucinations across the psychosis continuum.

Comparison of seven modelling algorithms for γ-aminobutyric acid-edited proton magnetic resonance spectroscopy.

Edited MRS sequences are widely used for studying γ-aminobutyric acid (GABA) in the human brain. Several algorithms are available for modelling these data, deriving metabolite concentration estimates through peak fitting or a linear combination of basis spectra. The present study compares seven such algorithms, using data obtained in a large multisite study. GABA-edited (GABA+, TE = 68 ms MEGA-PRESS) data from 222 subjects at 20 sites were processed via a standardised pipeline, before modelling with FSL-MRS, Gannet, AMARES, QUEST, LCModel, Osprey and Tarquin, using standardised vendor-specific basis sets (for GE, Philips and Siemens) where appropriate. After referencing metabolite estimates (to water or creatine), systematic differences in scale were observed between datasets acquired on different vendors' hardware, presenting across algorithms. Scale differences across algorithms were also observed. Using the correlation between metabolite estimates and voxel tissue fraction as a benchmark, most algorithms were found to be similarly effective in detecting differences in GABA+. An interclass correlation across all algorithms showed single-rater consistency for GABA+ estimates of around 0.38, indicating moderate agreement. Upon inclusion of a basis set component explicitly modelling the macromolecule signal underlying the observed 3.0 ppm GABA peaks, single-rater consistency improved to 0.44. Correlation between discrete pairs of algorithms varied, and was concerningly weak in some cases. Our findings highlight the need for consensus on appropriate modelling parameters across different algorithms, and for detailed reporting of the parameters adopted in individual studies to ensure reproducibility and meaningful comparison of outcomes between different studies.

Negative valence of hallucinatory voices as predictor of cortical glutamatergic metabolite levels in schizophrenia patients.

OBJECTIVES: Negative emotional valence of auditory verbal hallucinations (AVHs) in schizophrenia can be a source of distress and is considered a strong predictor of illness severity. Previous studies have found glutamate to mediate AVH severity in frontal and temporal brain regions, however, they do not specifically address emotional valence of AVH. The role of glutamate for the experience of negative- versus positive emotional valence of AVH is therefore unknown and was investigated in the current study. METHODS: Using magnetic resonance spectroscopy (MRS), 37 schizophrenia patients had Glx (glutamate+glutamine) measured in the left superior temporal gyrus (STG), and additionally in the anterior cingulate cortex (ACC) and the right STG, or in the left inferior frontal gyrus (IFG). Self-reported emotional valence in AVH was measured with the Beliefs About Voices Questionnaire (BAVQ-R). RESULTS: Results from linear mixed models showed that negative emotional valence was associated with reduced Glx levels across all four measured brain regions in the frontal and temporal lobe. More specifically, voices that were experienced to be omnipotent (p = 0.04) and that the patients attempted to resist (p = 0.04) were related to lower Glx levels. Follow-up analysis of the latter showed that voices that evoked emotional resistance (i.e., fear, sadness, anger), rather than behavioral resistance, was a significant predictor of reduced glutamate (p = 0.02). CONCLUSION: The findings could indicate aberrant glutamatergic signaling, or increased NMDA-receptor hypoactivity in patients who experience their voices to be more emotionally negative. Overall, the study provides support for the glutamate hypothesis of schizophrenia.

Transcranial direct current stimulation (tDCS) enhances internal source monitoring abilities in healthy participants.

Source monitoring refers to the ability to identify the origin of a memory, for example, whether you remember saying something or thinking about it, and confusions of these sources have been associated with the experience of auditory verbal hallucinations (AVHs). Both AVHs and source confusions are reported to originate from dysfunctional brain activations in the prefrontal cortex (PFC) and the superior temporal gyrus (STG); specifically, it is assumed that a hypoactive PFC and a hyperactive STG gives rise to AVHs and source confusions. We set out to test this assumption by trying to mimic this hypertemporal/hypofrontal model in healthy individuals with transcranial direct current stimulation (tDCS): the inhibitory cathode was placed over the left PFC and the excitatory anode over the left dorsolateral STG. Participants completed a reality monitoring task (distinguishing between external and internal memory sources) and an internal source monitoring task (distinguishing between two or more internal memory sources) in two separate experiments (offline vs. online tDCS). In the offline experiment (n = 34), both source monitoring tasks were completed after tDCS stimulation, and in the online experiment (n = 27) source monitoring tasks were completed while simultaneously being stimulated with tDCS. We found that internal source monitoring abilities were significantly enhanced during active online tDCS, while reality monitoring abilities were unaffected by stimulation in both experiments. We speculate, based on combining the present findings with previous studies, that there might be different brain areas involved in reality and internal source monitoring. While internal source monitoring seems to involve speech production areas, specifically Broca's area, as suggested in the present study, reality monitoring seems to rely more on the STG and DLPFC, as shown in other studies of the field.

Olfactory hallucinations in a population-based sample.

Olfactory hallucinations referring to olfactory perceptions in the absence of chemical stimuli, occur in non-clinical and clinical populations. Few studies have investigated their prevalence in the general population and little is known about factors triggering and maintaining them such as substance use, severe life events, and mood. We analyzed self-report data from 2500 community dwelling Norwegians, aged 18-96 years, for occurrence of olfactory hallucinations and co-occurring hallucinations in other modalities (auditory, visual, tactile). Analyses included age, sex, self-reported symptoms of depression and anxiety, mental health status, and experience of severe life-events. The results show that 4.2% (95% CI 3.5-5.1%) reported having experienced olfactory hallucinations, and 56% of individuals experiencing olfactory hallucinations also reported these in combination with hallucinations in other modalities. Prevalence varied significantly in terms of age and sex, in that olfactory hallucinations were most frequently reported by young individuals and females. Self-reported symptoms of anxiety and experience of stressful life events were significantly associated with olfactory hallucinations, suggesting that experiencing olfactory hallucinations may negatively affect functioning and may increase the likelihood of developing psychopathology. Findings underline the need to continue to examine olfactory hallucinations albeit with a more comprehensive assessment in order to increase knowledge on this experience.

Correlates of Hallucinatory Experiences in the General Population: An International Multisite Replication Study.

Hallucinatory experiences can occur in both clinical and nonclinical groups. However, in previous studies of the general population, investigations of the cognitive mechanisms underlying hallucinatory experiences have yielded inconsistent results. We ran a large-scale preregistered multisite study, in which general-population participants (N = 1,394 across 11 data-collection sites and online) completed assessments of hallucinatory experiences, a measure of adverse childhood experiences, and four tasks: source memory, dichotic listening, backward digit span, and auditory signal detection. We found that hallucinatory experiences were associated with a higher false-alarm rate on the signal detection task and a greater number of reported adverse childhood experiences but not with any of the other cognitive measures employed. These findings are an important step in improving reproducibility in hallucinations research and suggest that the replicability of some findings regarding cognition in clinical samples needs to be investigated.