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.

Item-specific overlap between hallucinatory experiences and cognition in the general population: A three-step multivariate analysis of international multi-site data.

Hallucinatory experiences (HEs) can be pronounced in psychosis, but similar experiences also occur in nonclinical populations. Cognitive mechanisms hypothesized to underpin HEs include dysfunctional source monitoring, heightened signal detection, and impaired attentional processes. Using data from an international multisite study on non-clinical participants (N = 419), we described the overlap between two sets of variables - one measuring cognition and the other HEs - at the level of individual items. We used a three-step method to extract and examine item-specific signal, which is typically obscured when summary scores are analyzed using traditional methodologies. The three-step method involved: (1) constraining variance in cognition variables to that which is predictable from HE variables, followed by dimension reduction, (2) determining reliable HE items using split-halves and permutation tests, and (3) selecting cognition items for interpretation using a leave-one-out procedure followed by repetition of Steps 1 and 2. The results showed that the overlap between HEs and cognition variables can be conceptualized as bi-dimensional, with two distinct mechanisms emerging as candidates for separate pathways to the development of HEs: HEs involving perceptual distortions on one hand (including voices), underpinned by a low threshold for signal detection in cognition, and HEs involving sensory overload on the other hand, underpinned by reduced laterality in cognition. We propose that these two dimensions of HEs involving distortions/liberal signal detection, and sensation overload/reduced laterality may map onto psychosis-spectrum and dissociation-spectrum anomalous experiences, respectively.

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.

In the twilight zone: An epidemiological study of sleep-related hallucinations.

BACKGROUND: Few studies have investigated hallucinations that occur at the onset/offset of sleep (called hypnagogic/hypnopompic hallucinations; HHHs), despite the fact that their prevalence in the general population is reported to be higher than the prevalence of daytime hallucinations. We utilized data from an epidemiological study to explore the prevalence of HHHs in various modalities. We also investigated phenomenological differences between sleep-related (HHHs) and daytime hallucinations in the auditory modality. We hypothesized that individuals with only HHHs would not differ from controls on a range of mental health and wellbeing measures, but that if they occur together with daytime hallucinations will pose a greater burden on the individual experiencing them. We also hypothesize that HHHs are qualitatively different (i.e. less severe) from daytime hallucinations. METHODS: This study utilized data from a cross-sectional epidemiological study on the prevalence of hallucinations in the Norwegian general population. The sample (n = 2533) was divided into a control group without hallucinations (n = 2303), a group only experiencing sleep-related hallucinations (n = 62), a group only experiencing daytime hallucinations (n = 57), and a group experiencing both sleep-related as well as daytime hallucinations (n = 111). Prevalence rates were calculated and groups were compared using analyses of variance and chi-square tests where applicable. RESULTS: The prevalence for HHHs in the auditory domain was found to be 6.8%, whereas 12.3% reported multimodal HHHs, and 32.2% indicated out-of-body experiences at the onset/offset of sleep. Group comparisons of hallucinations in the auditory modality showed that individuals that experienced only auditory HHHs scored significantly (p < 0.05) lower than those who also experienced daytime auditory hallucinations on a range of variables including mental health, anxiety, childhood happiness, and wellbeing. In addition, individuals with only auditory HHHs reported significantly (p < 0.05) less frequent hallucinations, less disturbing hallucinations, more neutral (in terms of content) hallucinations, hallucinations with less influence over their behavior, and less hallucination-related interference with social life compared to those individuals that experience daytime hallucinations. We also found that purely auditory HHHs had a significantly higher age of first onset of hallucinations than the purely daytime and the combined daytime and auditory HHHs groups (28.2 years>20.9 > 19.1). CONCLUSIONS: Sleep-related hallucinations are common experiences in the general population, with the auditory modality being the least common. They occur mostly in combination with daytime hallucinations. However, some individuals (2.4%) experience only (auditory) sleep-related hallucinations and this group can be seen as more closely related, on a range of health-related factors, to non-hallucinating individuals than individuals who experience daytime hallucinations. Finally, there is a clear need for more research in this field, and ideas for future studies are presented.

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.

Feasibility and Acceptability of Using a Mobile Phone App for Characterizing Auditory Verbal Hallucinations in Adolescents With Early-Onset Psychosis: Exploratory Study.

BACKGROUND: Auditory verbal hallucinations (AVH) are the most frequent symptom in early-onset psychosis (EOP) and a risk factor for increased suicide attempts in adolescents. Increased knowledge of AVH characteristics can lead to better prediction of risk and precision of diagnosis and help identify individuals with AVH who need care. As 98% of Norwegian adolescents aged 12 to 16 years own a mobile phone, the use of mobile phone apps in symptom assessment and patient communication is a promising new tool. However, when introducing new technology to patients, their subjective experiences are crucial in identifying risks, further development, and potential integration into clinical care. OBJECTIVE: The objective was to explore the feasibility and acceptability of a newly developed mobile phone app in adolescents with EOP by examining compliance with the app and user experiences. Indication of validity was explored by examining associations between AVH dimensions, which were correlated and analyzed. METHODS: Three adolescents with EOP and active AVH were enrolled. Real-time AVH were logged on an iPod touch using the experience sampling method (ESM), for seven or more consecutive days. The app included five dimensions of AVH characteristics and was programmed with five daily notifications. Feasibility and acceptability were examined using the mean response rate of data sampling and by interviewing the participants. Validity was assessed by examining associations between the AVH dimensions using nonparametric correlation analysis and by visual inspection of temporal fluctuations of the AVH dimensions. RESULTS: One participant was excluded from the statistical analyses but completed the interview and was included in the examination of acceptability. The sampling period of the two participants was mean 12 (SD 6) days with overall completed sampling rate of 74% (SD 30%), indicating adequate to high compliance with the procedure. The user experiences from the interviews clustered into four categories: (1) increased awareness, (2) personal privacy, (3) design and procedure, and (4) usefulness and clinical care. One participant experienced more commenting voices during the sampling period, and all three participants had concerns regarding personal privacy when using electronic devices in symptom assessment. The AVH dimensions of content, control, and influence showed moderate to strong significant correlations with all dimensions (P<.001). Days of data sampling showed weak to moderate correlations with localization (P<.001) and influence (P=.03). Visual inspection indicated that the app was able to capture fluctuations within and across days for all AVH dimensions. CONCLUSIONS: This study demonstrates the value of including patients' experiences in the development and pilot-testing of new technology. Based on the small sample size, the use of mobile phones with ESM seems feasible for patients with EOP, but the acceptability of using apps should be considered. Further investigation with larger samples is warranted before definitive conclusions are made.

An epidemiological study on the prevalence of hallucinations in a general-population sample: Effects of age and sensory modality.

Epidemiological studies have repeatedly shown that a significant minority of the general population have experienced hallucinations, however, a potential effect of age on the prevalence of hallucinations in the general population has never been previously examined in a specific study. The aim of the present study was thus to examine the effects of age and sensory modality on hallucination prevalence in a general population sample. A large, randomly selected and representative sample of the Norwegian population completed measures assessing different hallucination modalities (auditory, visual, olfactory, and tactile) and types (sensed presence and hypnagogic/hypnopompic hallucinations). Three age groups were identified and compared: young (19-30 years), middle (31-60) and old (61-96). There was a significant main-effect of age for all hallucination modalities and types, whereby hallucination prevalence significantly decreased with age. We also found that anxiety partially mediated the effect of age on hallucinations whilst depression was a partial suppressor. Concerning the co-occurrence of hallucination modalities, there was very little co-occurrence of auditory and visual hallucinations in all three age groups. In summary, a main-effect of age for hallucination prevalence was observed. Furthermore, individuals reported a more diverse variety of hallucination modalities compared to what is commonly reported in clinical populations.

Potential Applications of Digital Technology in Assessment, Treatment, and Self-help for Hallucinations.

The field of digital mental health is rapidly expanding with digital tools being used in assessment, intervention, and supporting self-help. The application of digital mental health to hallucinations is, however, at a very early stage. This report from a working group of the International Consortium on Hallucinations Research considers particular synergies between the phenomenon of hallucinations and digital tools that are being developed. Highlighted uses include monitoring and managing intermittently occurring hallucinations in daily life; therapeutic applications of audio and video media including virtual and augmented reality; targeting verbal aspects of hallucinations; and using avatars to represent hallucinatory voices. Although there is a well-established Internet-based peer support network, digital resources for hallucinations have yet to be implemented in routine practice. Implementation may benefit from identifying how to market resources to the broad range of populations who experience hallucinations and identifying sustainable funding models. It is envisaged that digital tools will contribute to improved self-management and service provision for people experiencing hallucinations.

Beyond Trauma: A Multiple Pathways Approach to Auditory Hallucinations in Clinical and Nonclinical Populations.

That trauma can play a significant role in the onset and maintenance of voice-hearing is one of the most striking and important developments in the recent study of psychosis. Yet the finding that trauma increases the risk for hallucination and for psychosis is quite different from the claim that trauma is necessary for either to occur. Trauma is often but not always associated with voice-hearing in populations with psychosis; voice-hearing is sometimes associated with willful training and cultivation in nonclinical populations. This article uses ethnographic data among other data to explore the possibility of multiple pathways to voice-hearing for clinical and nonclinical individuals whose voices are not due to known etiological factors such as drugs, sensory deprivation, epilepsy, and so forth. We suggest that trauma sometimes plays a major role in hallucinations, sometimes a minor role, and sometimes no role at all. Our work also finds seemingly distinct phenomenological patterns for voice-hearing, which may reflect the different salience of trauma for those who hear voices.

Auditive training effects from a dichotic listening app in children with dyslexia.

Dichotic listening (DL) taps information on the brain's language laterality, processing, and attention. Research has shown that DL responses in dyslexia deviate from the typical pattern. Here, effects of DL training and its correspondence to rapid naming (RAN) and digit span (DS) in typical children and children with dyslexia were assessed. Three groups of third graders participated: two training groups, control training (CT) and dyslexia training (DT), and a control group that received no training (control no training, CnT). All took part in testing pretraining and posttraining. DL measures were on laterality, response scores, and attention. The three groups showed different response patterns: minor changes in CnT, change in all measures in CT, and some changes in DT. RAN and DS scores correlated significantly with some of the DL measures, especially with the attention scores. Our findings support arguments that brain architecture for language in dyslexia is lateralised in the same way as in children without dyslexia. However, the ability to modulate attention during DL is weaker in dyslexia than in typically developing children. A training-induced normalisation of lateralisation was observed in free recall in the dyslexia group, which suggests that DL training may be a promising intervention approach.

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.

Training switching focus with a mobile-application by a patient suffering from AVH, a case report.

Auditory verbal hallucinations complicate many psychiatric disorders. Antipsychotic medication is effective in the majority, but a significant minority experiences high burden from resistant hallucinations. Here, we aim to improve executive control, in an attempt to decrease burden from hallucinations. We describe the use of a cognitive trainings app by a young woman with highly resistant hallucinations. With modest training, a significant decrease in the duration of hallucinations was reached. Possibilities of this training technique are discussed.

The Beliefs about Voices Questionnaire - Revised: A factor structure from 450 participants.

Hallucinated voices are common across psychiatric and non-clinical groups. The predominant cognitive theory about the impact of voices posits that beliefs about voice power ('Omnipotence') and voice intent ('Malevolence'/'Benevolence') play a key role in determining emotional and behavioral reactions. The revised Beliefs about Voices Questionnaire (BAVQ-R) was designed to assess these constructs, together with two styles of responding (Engagement and Resistance). The BAVQ-R is widely used in clinical and research settings, yet it has not received validation of its constructs and factor structure. This study examined the factor structure of the BAVQ-R by combining datasets from five study centers, comprising 450 participants (belief constructs) and 269 participants (response styles), and using confirmatory and exploratory factor analysis. Findings failed to support a three factor belief model, instead showing a two-factor structure ('Persecutory beliefs' combining Omnipotence and Malevolence constructs, and a Benevolent construct). Emotional and behavioral items did not separate. Overall, results showed that (i) a two-factor model of beliefs (Persecutory and Benevolent beliefs) provides a better fit to the data than a three-factor model, and (ii) emotional and behavioral modes of responding items should not be separated. Theoretical implications of this finding are discussed in relation to the research and therapy.

Cognitive Control Processes and Functional Cerebral Asymmetries: Association with Variation in the Handedness-Associated Gene LRRTM1.

Cognitive control processes play an essential role not only in controlling actions but also in guiding attentional selection processes. Interestingly, these processes are strongly affected by organizational principles of the cerebral cortex and related functional asymmetries, but the neurobiological foundations are elusive. We ask whether neurobiological mechanisms that affect functional cerebral asymmetries will also modulate effects of top-down control processes on functional cerebral asymmetries. To this end, we examined potential effects of the imprinted gene leucine-rich repeat transmembrane neuronal 1 (LRRTM1) on attentional biasing processes in a forced attention dichotic listening task in 983 healthy adult participants of Caucasian descent using the "iDichotic smartphone app." The results show that functional cerebral asymmetries in the language domain are associated with the rs6733871 LRRTM1 polymorphism when cognitive control and top-down attentional mechanisms modulate processes in bottom-up attentional selection processes that are dependent on functional cerebral asymmetries. There is no evidence for an effect of LRRTM1 on functional cerebral asymmetries in the language domain unrelated to cognitive control processes. The results suggest that cognitive control processes are an important factor to consider when being interested in the molecular genetic basis of functional cerebral architecture.

Investigating heritability of laterality and cognitive control in speech perception.

Several studies analyzing the ontogenetic origin of cerebral lateralization provide evidences for a genetic foundation of handedness in humans that is modulated by environmental influences. Since other forms of behavioral lateralization are less investigated, it is unclear as to how far different functions display similar heritability. But deeper knowledge is necessary to understand if and how developmental coupling of different functions is based on a shared genetic background or on the impact of environmental influences. Here, we investigated the heritability of language lateralization assessed with the dichotic listening task, as well as the heritability of cognitive control processes modulating performance in this task. Overall, 103 families consisting of both parents and offspring were tested with the non-forced, as well as the forced-right and forced-left condition of the forced attention dichotic listening task, implemented in the iDichotic smartphone app, developed at the University of Bergen, Norway. The results indicate that the typical right ear advantage in the dichotic listening task shows weak and non-significant heritability (h2=0.003; p=0.98). In contrast, cognitive factors, like attention focus (forced right condition: h2=0.36; p<0.01; forced left condition: h2=0.28; p<0.05) and cognitive control (Gain forced right: h2=0.39; p<0.01; Gain forced left: h2=0.49; p<0.01) showed stronger and significant heritability. These findings indicate a variable dependence of different aspects of a cognitive function on heritability and implicate a major contribution of non-genetic influences to individual language lateralization.

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.

Cognitive control of speech perception across the lifespan: A large-scale cross-sectional dichotic listening study.

The ability to use cognitive-control functions to regulate speech perception is thought to be crucial in mastering developmental challenges, such as language acquisition during childhood or compensation for sensory decline in older age, enabling interpersonal communication and meaningful social interactions throughout the entire life span. Although previous studies indicate that cognitive control of speech perception is subject to developmental changes, its exact developmental trajectory has not been described. Thus, examining a sample of 2,988 participants (1,119 women) with an age range from 5 to 89 years, the aim of the present cross-sectional study was to examine the development of cognitive control of speech perception across the life span using age as continuous predictor. Based on data collected with the forced-attention consonant-vowel dichotic listening paradigm, the data analysis revealed an inverted U-shaped association of age and performance level: A steep increase in performance level was seen throughout childhood and adolescence, reaching highest performance in the early 20s, and was followed by a monotonous, continuous decline into late adulthood. Thus, cognitive control of speech perceptions shows similar life span developmental trajectories as observed regarding cognitive-control functions in other domains, for example, as assessed in the visual domain.