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.

Glutamate- and GABA-Modulated Connectivity in Auditory Hallucinations-A Combined Resting State fMRI and MR Spectroscopy Study.

Background: Auditory verbal hallucinations (AVH) have been linked to aberrant interhemispheric connectivity between the left and the right superior temporal gyrus (STG), labeled the interhemispheric miscommunication theory. The present study investigated if interhemispheric miscommunication is modulated at the neurochemical level by glutamate (Glu) and gamma-aminobutyric acid (GABA) concentrations in temporal and prefrontal lobe areas, as proposed by the theory. Methods: We combined resting-state fMRI connectivity with MR spectroscopy (MRS) in a sample of 81 psychosis patients, comparing patients with high hallucination severity (high-AVH) and low hallucination severity (low-AVH) groups. Glu and GABA concentrations were acquired from the left STG and the anterior cingulate cortex (ACC), an area of cognitive control that has been proposed to modulate STG functioning in AVH. Results: Functional connectivity showed significant interaction effects between AVH Group and ACC-recorded Glu and GABA metabolites. Follow-up tests showed that there was a significant positive association for Glu concentration and interhemispheric STG connectivity in the high-AVH group, while there was a significant negative association for GABA concentration and interhemispheric STG connectivity in the low-AVH group. Conclusion: The results show neurochemical modulation of STG interhemispheric connectivity, as predicted by the interhemispheric miscommunication hypothesis. Furthermore, the findings are in line with an excitatory/inhibitory imbalance model for AVH. By combining different neuroimaging modalities, the current results provide a more comprehensive insight into the neural correlates of AVH.

Comparative morphology of the corpus callosum across the adult lifespan in chimpanzees (Pan troglodytes) and humans.

The human corpus callosum exhibits substantial atrophy in old age, which is stronger than what would be predicted from parallel changes in overall brain anatomy. To date, however, it has not been conclusively established whether this accentuated decline represents a common feature of brain aging across species, or whether it is a specific characteristic of the aging human brain. In the present cross-sectional study, we address this question by comparing age-related difference in corpus callosum morphology of chimpanzees and humans. For this purpose, we measured total midsagittal area and regional thickness of the corpus callosum from T1-weighted MRI data from 213 chimpanzees, aged between 9 and 54 years. The results were compared with data drawn from a large-scale human sample which was age-range matched using two strategies: (a) matching by chronological age (human sample size: n = 562), or (b) matching by accounting for differences in longevity and various maturational events between the species (i.e., adjusted human age range: 13.6 to 80.9 years; n = 664). Using generalized additive modeling to fit and compare aging trajectories, we found significant differences between the two species. The chimpanzee aging trajectory compared with the human trajectory was characterized by a slower increase from adolescence to middle adulthood, and by a lack of substantial decline from middle to old adulthood, which, however, was present in humans. Thus, the accentuated decline of the corpus callosum found in aging humans is not a universal characteristic of the aging brain, and appears to be human-specific.

Glutamatergic modulation of auditory cortex connectivity with attentional brain networks in unpredictable perceptual environment.

In a stable environment the brain can minimize processing required for sensory input by forming a predictive model of the surrounding world and suppressing neural response to predicted stimuli. Unpredicted stimuli lead to a prediction error signal propagation through the perceptual network, and resulting adjustment to the predictive model. The inter-regional plasticity which enables the model-building and model-adjustment is hypothesized to be mediated via glutamatergic receptors. While pharmacological challenge studies with glutamate receptor ligands have demonstrated impact on prediction-error indices, it is not clear how inter-individual differences in the glutamate system affect the prediction-error processing in non-medicated state. In the present study we examined 20 healthy young subjects with resting-state proton MRS spectroscopy to characterize glutamate + glutamine (rs-Glx) levels in their Heschl's gyrus (HG), and related this to HG functional connectivity during a roving auditory oddball protocol. No rs-Glx effects were found within the frontotemporal prediction-error network. Larger rs-Glx signal was related to stronger connectivity between HG and bilateral inferior parietal lobule during unpredictable auditory stimulation. We also found effects of rs-Glx on the coherence of default mode network and frontoparietal network during unpredictable auditory stimulation. Our results demonstrate the importance of Glx in modulating long-range connections and wider networks in the brain during perceptual inference.

Hallucinating schizophrenia patients have longer left arcuate fasciculus fiber tracks: a DTI tractography study.

The arcuate fasciculus (AF) has been implicated in the pathology behind schizophrenia and auditory verbal hallucinations (AVHs). White matter tracts forming the arcuate fasciculus can be quantified and visualized using diffusion tensor imaging (DTI) tractography. Although there have been a number of studies on this topic, the results have been conflicting. Studying the underlying white matter structure of the AF could shed light on the constrains for interaction between temporal and frontal language areas in AVHs. The participants were 66 patients with a schizophrenia diagnosis, where AVHs were defined from the Positive and Negative Syndrome Scale (PANSS), and compared with a healthy control group. DTI was performed on a 3T MR scanner, and tensor estimation was done using deterministic streamline tractography. Statistical analysis of the data showed significantly longer reconstructed tracks along the AF in patients with severe and frequent AVHs, as well as an overall significant asymmetry with longer tracks in the left compared to the right side. In addition, there were significant positive correlations between PANSS scores and track length, track volume, and number of track streamlines for the posterior AF segment on the left side. It is concluded that the present DTI results may have implications for interpretations of functional imaging results.

Dynamic Functional Connectivity Patterns in Schizophrenia and the Relationship With Hallucinations.

There is a wealth of evidence showing aberrant functional connectivity (FC) in schizophrenia but with considerable variability in findings across studies. Dynamic FC is an extension of traditional static FC, in that such analyses allow for explorations of temporal changes in connectivity. Thereby they also provide more detailed information on connectivity abnormalities in psychiatric disorders such as schizophrenia. The current study investigated dynamic FC in a sample of 80 schizophrenia patients and 80 matched healthy control subjects, replicating previous findings of aberrant dwell times in specific FC states, and further supporting a role for default mode network (DMN) dysfunction. Furthermore, relationships with hallucinations, a core symptom of schizophrenia, were explored. Two measures of hallucinations were used, one measure of current hallucination severity assessed on the day of scanning, and one trait-measure where hallucinations were assessed repeatedly over the course of 1 year. Current hallucination severity did not show a significant relationship with dynamic FC. However, the trait-measure of hallucination proneness over 1 year showed a significant relationship with dynamic FC. Patients with high hallucination proneness spent less time in connectivity states characterized by strong anti-correlation between the DMN and task-positive networks. The findings support theoretical models of hallucinations which have proposed an instability of the DMN and impaired cognitive control in patients with hallucinations. Furthermore, the results point to hallucination proneness as a potential marker for identifying distinct subgroups of schizophrenia patients.

Hierarchical modulation of auditory prediction error signaling is independent of attention.

The auditory system is tuned to detect rhythmic regularities in the environment which can occur on different timescales. Event-related potentials such as mismatch negativity (MMN) and P3b are thought to index local and global deviance, respectively. However, it is not clear how these hierarchical levels interact and to what extent attention modulates this interaction. In this EEG study with 17 healthy young adults, we used a hierarchical oddball paradigm with local (sequence-level) and global (block-level) violations in attended and unattended conditions. Amplitude of N2 and P3b were analyzed in a 2*2*2 factorial model (local status, global status, attention condition). We found a significant interaction between the local and global status on the N2 amplitude, while there was no significant three-way interaction with attention, together demonstrating that lower-level prediction error is modulated by detection of higher-order regularity but expressed independently of attention. By contrast, higher-level prediction error, indexed by P3b, was sensitive to global regularity violations if the auditory stream was attended. The results demonstrate the capacity of our auditory perception to preattentively resolve conflicts between different levels of predictive hierarchy even across longer time intervals as indexed by MMN modulation, while P3b represents a different, attention-dependent system.

Age-Related Differences in Functional Asymmetry During Memory Retrieval Revisited: No Evidence for Contralateral Overactivation or Compensation.

Brain asymmetry is inherent to cognitive processing and seems to reflect processing efficiency. Lower frontal asymmetry is often observed in older adults during memory retrieval, yet it is unclear whether lower asymmetry implies an age-related increase in contralateral recruitment, whether less asymmetry reflects compensation, is limited to frontal regions, or predicts neurocognitive stability or decline. We assessed age-related differences in asymmetry across the entire cerebral cortex, using functional magnetic resonance imaging data from 89 young and 76 older adults during successful retrieval, and surface-based methods allowing direct homotopic comparison of activity between cortical hemispheres . An extensive left-asymmetric network facilitated retrieval in both young and older adults, whereas diverse frontal and parietal regions exhibited lower asymmetry in older adults. However, lower asymmetry was not associated with age-related increases in contralateral recruitment but primarily reflected either less deactivation in contralateral regions reliably signaling retrieval failure in the young or lower recruitment of the dominant hemisphere-suggesting that functional deficits may drive lower asymmetry in older brains, not compensatory activity. Lower asymmetry predicted neither current memory performance nor the extent of memory change across the preceding ~ 8 years in older adults. Together, these findings are inconsistent with a compensation account for lower asymmetry during retrieval and aging.

Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu Imbalance: A 1H-MRS Study of the Neurochemistry of Auditory Verbal Hallucinations in Schizophrenia.

Glutamate (Glu), gamma amino-butyric acid (GABA), and excitatory/inhibitory (E/I) imbalance have inconsistently been implicated in the etiology of schizophrenia. Elevated Glu levels in language regions have been suggested to mediate auditory verbal hallucinations (AVH), the same regions previously associated with neuronal hyperactivity during AVHs. It is, however, not known whether alterations in Glu levels are accompanied by corresponding GABA alterations, nor is it known if Glu levels are affected in brain regions with known neuronal hypo-activity. Using magnetic resonance spectroscopy (MRS), we measured Glx (Glu+glutamine) and GABA+ levels in the anterior cingulate cortex (ACC), left and right superior temporal gyrus (STG), and left inferior frontal gyrus (IFG), in a sample of 77 schizophrenia patients and 77 healthy controls. Two MRS-protocols were used. Results showed a marginally significant positive correlation in the left STG between Glx and AVHs, whereas a significant negative correlation was found in the ACC. In addition, high-hallucinating patients as a group showed decreased ACC and increased left STG Glx levels compared to low-hallucinating patients, with the healthy controls in between the 2 hallucinating groups. No significant differences were found for GABA+ levels. It is discussed that reduced ACC Glx levels reflect an inability of AVH patients to cognitively inhibit their "voices" through neuronal hypo-activity, which in turn originates from increased left STG Glu levels and neuronal hyperactivity. A revised E/I-imbalance model is proposed where Glu-Glu imbalance between brain regions is emphasized rather than Glu-GABA imbalance within regions, for the understanding of the underlying neurochemistry of AVHs.

Dynamic up- and down-regulation of the default (DMN) and extrinsic (EMN) mode networks during alternating task-on and task-off periods.

Using fMRI, Hugdahl et al. (2015) reported the existence of a general-domain cortical network during active task-processing which was non-specific to the cognitive task being processed. They labelled this network the extrinsic mode network (EMN). The EMN would be predicted to be negatively, or anti-correlated with the classic default mode network (DMN), typically observed during periods of rest, such that while the EMN should be down-regulated and the DMN up-regulated in the absence of demands for task-processing, the reverse should occur when demands change from resting to task-processing. This would require alternating periods of task-processing and resting and analyzing data continuously when demands change from active to passive periods and vice versa. We were particularly interested in how the networks interact in the critical transition points between conditions. For this purpose, we used an auditory task with multiple cognitive demands in a standard fMRI block-design. Task-present (ON) blocks were alternated with an equal number of task-absent, or rest (OFF) blocks to capture network dynamics across time and changing environmental demands. To achieve this, we specified the onset of each block, and used a finite-impulse response function (FIR) as basis function for estimation of the fMRI-BOLD response. During active (ON) blocks, the results showed an initial rapid onset of activity in the EMN network, which remained throughout the period, and faded away during the first scan of the OFF-block. During OFF blocks, activity in the DMN network showed an initial time-lag where neither the EMN nor the DMN was active, after which the DMN was up-regulated. Studying network dynamics in alternating passive and active periods may provide new insights into brain network interaction and regulation.

Psychosocial characteristics differentiate non-distressing and distressing voices in 10,346 adolescents.

Adolescents hearing non-existent voices may be at risk for psychosis, but the prevalence of voice-hearing (VH) in the general population complicates clinical interpretations. Differentiating between VH with and without distress may aid treatment decisions in psychosis services, but understanding the differences between these two phenomena as they present in the normal adolescent population is necessary to validate this differentiation. The present study compared VH with and without distress in 10,346 adolescents in relation to clinical characteristics, known risk factors, predictors and psychosocial moderators of psychosis. A population-based cohort of Norwegian 16-19 years old adolescents completed a comprehensive web-based questionnaire, including two questions from the extended Launay-Slade Hallucinations Scale: (1) I often hear a voice speaking my thoughts aloud and (2) I have been troubled by hearing voices in my head. Adolescents reporting no VH, non-distressing VH or distressing VH were compared on 14 psychosocial and clinical variables. A multinomial regression model showed that non-disturbing voices were predicted by better school grades, social dysfunction, distractibility, affective symptoms and experience of trauma, while the disturbing voices were predicted by the experience of bullying and trauma, perceived negative self-worth and self-efficacy, less family support, dysregulation of activation, distractibility, self-harm and anxiety. Hearing voices without distress versus being distressed by the voices is related to different constellations of psychosocial variables, suggesting that they represent two separate groups of adolescents. The findings validate the emphasis on distress in clinical practice.

Language Lateralization and Auditory Attention Impairment in Young Adults at Ultra-High Risk for Psychosis: A Dichotic Listening Study.

Objectives: Impaired attention and language functions are common in psychosis, but have been less explored in subjects with ultra-high risk for psychosis (UHR). The aim of the study was to investigate differences in language lateralization and auditory attention in UHR subjects compared to healthy controls with a dichotic listening paradigm. In addition, symptoms from The Structural Interview for Prodromal Syndromes (SIPS) were explored in relation to performance on dichotic listening. Methods: The UHR subjects (n = 46, female = 28, mean age = 17.9) were compared to a group of healthy controls (n = 40, female = 20, mean age = 16.8). A split-plot repeated measures analysis of covariance was conducted with group as between-subjects factor and attention conditions (non-forced, forced-right, forced-left) and side (right ear, left ear) as repeated measures factors (2×3×2 design) using gender, age and handedness as covariates. SIPS symptoms were subjected to Spearman's r correlations with laterality indexes and attentional gain in each ear. Results: There was a statistically significant three-way interaction of group (UHR, healthy controls) × forced condition (non-forced, forced-right, forced-left) × side (right ear, left ear), p = 0.048. The effect was due to an interaction between group × side in the forced-left condition. There were no significant differences between UHR subjects and healthy controls in the non-forced condition. Right ear gain correlated with "Perceptual abnormalities/Hallucinations" (P4), r = 0.486, p = 0.001. Conclusion: UHR subjects demonstrated impairment in top-down attentional mechanisms, but showed no language lateralization abnormalities. Impairment in top-down attentional mechanisms are frequently reported from dichotic listening studies in patients with schizophrenia. Higher levels of perceptual abnormalities and hallucinatory experiences were associated with enhanced report from the right ear in the forced-right condition.

Do adverse life events at first onset of auditory verbal hallucinations influence subsequent voice characteristics? Results from an epidemiological study.

Understanding what happens at first onset of auditory verbal hallucinations (AVHs) is extremely important on a clinical and theoretical level. Previous studies have only focused on age with regard to first onset of AVHs. In the current epidemiological study, we examined a number of aspects relating to first onset of AVHs, such as the role of adverse life events at first onset of AVHs on symptom severity and general mental health. For this purpose, we compared participants who reported adverse life events at first onset of AHVs (adverse-trigger group; N = 76) to those that did not report any specific events at first onset of AVHs (no-adverse-trigger group; N = 59) on a large array of variables. Results showed that AVHs in the adverse-trigger group were experienced as more emotional compared to the no-adverse-trigger group. In addition, the adverse-trigger group more often reported hallucinations in other (non-auditory) sensory modalities (e.g. visual) compared to the no-adverse-trigger group. Furthermore, the adverse-trigger group reported poorer general mental health, reported having contact with mental health professionals more often, and also reported more frequently taking medication for psychological problems in general. The implications of these findings are discussed.

How to get a left-ear advantage: A technical review of assessing brain asymmetry with dichotic listening.

The dichotic-listening paradigm with verbal stimuli is a widely employed behavioral task for the assessment of hemispheric asymmetry for speech and language processing. Participants with assumed left-hemispheric dominance report the right-ear stimulus with higher probability than the left-ear stimulus. However, there is substantial between-subject and trial-to-trial variability observed in the paradigm, motivating scrutiny of the task set-up and theoretical models. Here, we give an in-depth discussion of specific features of stimulus material and experimental parameters, as well as the conditions of stimulus/response selection, which explain a significant proportion of intra- and inter-individual variability. Carefully considering these factors should be at the heart of any experimental planning when using the dichotic-listening paradigm to achieve an optimal testing situation for measuring laterality and avoid confounds in between-subject and between-group comparisons.

No Effects of Anodal tDCS on Local GABA and Glx Levels in the Left Posterior Superior Temporal Gyrus.

A number of studies investigating the biological effects of transcranial direct current stimulation (tDCS) using magnetic resonance spectroscopy (MRS) have found that it may affect local levels of γ-aminobutyric acid (GABA), glutamate and glutamine (commonly measured together as "Glx" in spectroscopy), and N-acetyl aspartate (NAA), however, these effects depend largely on the stimulation parameters used and the cortical area targeted. Given that different cortical areas may respond to stimulation in different ways, the purpose of this experiment was to assess the as yet unexplored biological effects of tDCS in the posterior superior temporal gyrus (pSTG), an area that has attracted some attention as a potential target for the treatment of auditory verbal hallucinations in schizophrenia patients. Biochemical changes were monitored using continuous, online MRS at a field strength of 3 Tesla. Performing intrascanner stimulation, with continuous spectroscopy before, during and after stimulation, permitted the assessment of acute effects of tDCS that would otherwise be lost when simply comparing pre- and post-stimulation differences. Twenty healthy participants underwent a repeated-measures experiment in which they received both active anodal and sham intrascanner stimulation in a stratified, randomized, double-blind experiment. No significant changes in GABA, Glx, or NAA levels were observed as a result of anodal stimulation, or between active and sham stimulation, suggesting that a single session of anodal tDCS to the pSTG may be less effective than in other cortical areas that have been similarly investigated.

Increased MMN amplitude following passive perceptual learning with LTP-like rapid stimulation.

An important feature of perception is plasticity, enabling the acquisition of new perceptual representations to facilitate responding to regular stimuli in the environment. The auditory system has shown capacity for plasticity into adulthood, allowing the perceptual discrimination abilities to be improved by training. It has been suggested that a certain form of passive learning using rapid sensory stimulation can lead to plasticity in the sensory cortex through mechanisms similar to long-term potentiation. Here we demonstrate using electroencephalography that brief rapid auditory stimulation (2 min, 13 Hz) with a sinusoidal tone (1025 Hz) led to increased discriminability of the stimulated tone from a standard tone (1000 Hz) as indexed by mismatch negativity event-related potential. This shows that perceptual learning with brief exposure can cause plastic changes similar to long-term training.

Auditory Cortex Characteristics in Schizophrenia: Associations With Auditory Hallucinations.

BACKGROUND: Neuroimaging studies have demonstrated associations between smaller auditory cortex volume and auditory hallucinations (AH) in schizophrenia. Reduced cortical volume can result from a reduction of either cortical thickness or cortical surface area, which may reflect different neuropathology. We investigate for the first time how thickness and surface area of the auditory cortex relate to AH in a large sample of schizophrenia spectrum patients. METHODS: Schizophrenia spectrum (n = 194) patients underwent magnetic resonance imaging. Mean cortical thickness and surface area in auditory cortex regions (Heschl's gyrus [HG], planum temporale [PT], and superior temporal gyrus [STG]) were compared between patients with (AH+, n = 145) and without (AH-, n = 49) a lifetime history of AH and 279 healthy controls. RESULTS: AH+ patients showed significantly thinner cortex in the left HG compared to AH- patients (d = 0.43, P = .0096). There were no significant differences between AH+ and AH- patients in cortical thickness in the PT or STG, or in auditory cortex surface area in any of the regions investigated. Group differences in cortical thickness in the left HG was not affected by duration of illness or current antipsychotic medication. CONCLUSIONS: AH in schizophrenia patients were related to thinner cortex, but not smaller surface area of the left HG, a region which includes the primary auditory cortex. The results support that structural abnormalities of the auditory cortex underlie AH in schizophrenia.

Behavioral Laterality and Aging: The Free-Recall Dichotic-Listening Right-Ear Advantage Increases With Age.

The effect of aging on brain asymmetry was studied under consideration of possible confounding effects of known age-related decline in higher cognitive functioning. In a sample of 3,680 participants aged 20-79 years, laterality was assessed with a verbal, free-recall dichotic-listening paradigm with one stimulus pair presentation per trial, minimizing working-memory and cognitive-control demands during task performance. Laterality, reflected as right-ear preference for dichotic stimuli, was found to be increased in older age (above 60 years). This effect was due to a reduced report of left-ear stimuli, while the report of right-ear stimuli stayed on comparable levels across all ages.

Prevalence of auditory verbal hallucinations in a general population: A group comparison study.

The present study was specifically designed to investigate the prevalence of auditory verbal hallucinations (AVH) in the general population, and sought to compare similarities and differences regarding socio-demographics, mental health and severe life events between individuals who have never experienced AVH with those who had. The study also aimed to compare those who sought professional help for their experience of AVH with those who had not sought help. Through a postal questionnaire, 2,533 participants ages 18 and over from a national survey completed the Launay-Slade Hallucinations Scale and other measures examining AVH characteristics and other areas related to AVH. In total, 7.3% of the sample reported a life-time prevalence of AVH. Those with AVH were more likely to be single and unemployed, reported higher levels of depression and anxiety, and experienced a higher number of severe life events compared with those without AVH. Only 16% of those who experienced AVH in the general population sought professional help for these experiences. Compared to those who did not seek professional help, participants that had were more likely to experience AVH with a negative content, experience them on a daily basis, undergo negative reactions when experiencing AVH, and resist AVH. In conclusion, the prevalence of AVH was found to be relatively high. The results also revealed higher levels of reduced mental health for individuals who sought professional help, followed by those who did not, compared with those who had never experienced AVH.