Altered corollary discharge in the auditory cortex could reflect louder inner voice experience in patients with verbal hallucinations, a pilot fMRI study.

INTRODUCTION: Wide range of evidence associates auditory verbal hallucinations (AVH) with frontotemporal corollary discharge deficit. AVH likely reflect altered experiences of the inner voice and are phenomenologically diverse. The aspects of hallucinations (and related inner voice experiences) that could be explained by this deficit remain unclear. To address this important subject, we examined the temporal cortex activity during two tasks with and without corollary discharge. METHODS: We carried out an event-related BOLD fMRI study to examine temporal cortex activity in seven patients and eight healthy controls during two tasks with and without corollary discharge: reading aloud and hearing, respectively. Data were denoised by removing independent components related to head movement and subsequently processed using finite impulse response basis function to address hemodynamic response variations. To mitigate the small sample size, final analyses were carried out using permutation-based analysis of variance. RESULTS: There was a significant group interaction in the Read relative to Hear condition during the early post-stimulus stage in the left Heschl's Gyrus (p<0.01, corrected for multiple comparisons, at peak voxel [-72,53,41]). This effect was driven by a higher activity in the Read relative to the Hear condition in the same area in the patients (p<0.02, corrected). CONCLUSIONS: Our results are consistent with prior literature indicating abnormal frontotemporal disconnection in participants with hallucinations. The functional repercussions of this deficit were limited to the primary auditory cortex in early post-stimulus stage, which suggests louder experience of the inner voice in patients and could account for the loudness of their hallucinations.

Altered corollary discharge in the auditory cortex could reflect louder inner voice experience in patients with verbal hallucinations, a pilot fMRI study.

INTRODUCTION: Wide range of evidence associates auditory verbal hallucinations (AVH) with frontotemporal corollary discharge deficit. AVH likely reflect altered experiences of the inner voice and are phenomenologically diverse. The aspects of hallucinations (and related inner voice experiences) that could be explained by this deficit remain unclear. To address this important subject, we examined the temporal cortex activity during two tasks with and without corollary discharge. METHODS: We carried out an event-related BOLD fMRI study to examine temporal cortex activity in seven patients and eight healthy controls during two tasks with and without corollary discharge: reading aloud and hearing, respectively. Data were denoised by removing independent components related to head movement and subsequently processed using finite impulse response basis function to address hemodynamic response variations. To mitigate the small sample size, final analyses were carried out using permutation-based analysis of variance. RESULTS: There was a significant group interaction in the Read relative to Hear condition during the early post-stimulus stage in the left Heschl's Gyrus (p < 0.01, corrected for multiple comparisons, at peak voxel [-72,53,41]). This effect was driven by a higher activity in the Read relative to the Hear condition in the same area in the patients (p < 0.02, corrected). CONCLUSIONS: Our results are consistent with prior literature indicating abnormal frontotemporal disconnection in participants with hallucinations. The functional repercussions of this deficit were limited to the primary auditory cortex in early post-stimulus stage, which suggests louder experience of the inner voice in patients and could account for the loudness of their hallucinations.

Keeping the inner voice inside the head, a pilot fMRI study.

INTRODUCTION: The inner voice is experienced during thinking in words (inner speech) and silent reading and evokes brain activity that is highly similar to that associated with external voices. Yet while the inner voice is experienced in internal space (inside the head), external voices (one's own and those of others) are experienced in external space. In this paper, we investigate the neural basis of this differential spatial localization. METHODS: We used fMRI to examine the difference in brain activity between reading silently and reading aloud. As the task involved reading aloud, data were first denoised by removing independent components related to head movement. They were subsequently processed using finite impulse response basis function to address the variations of the hemodynamic response. Final analyses were carried out using permutation-based statistics, which is appropriate for small samples. These analyses produce spatiotemporal maps of brain activity. RESULTS: Reading silently relative to reading aloud was associated with activity of the "where" auditory pathway (Inferior parietal lobule and middle temporal gyrus), and delayed activity of the primary auditory cortex. CONCLUSIONS: These pilot data suggest that internal space localization of the inner voice depends on the same neural resources as that for external space localization of external voices-the "where" auditory pathway. We discuss the implications of these findings on the possible mechanisms of abnormal experiences of the inner voice as is the case in verbal hallucinations.

The Self, Agency and Spatial Externalizations of Inner Verbal Thoughts, and Auditory Verbal Hallucinations.

Aim: Auditory Verbal Hallucinations (AVH) are experienced as the "voices" of others (O-AVH) or self (S-AVH) in internal space/inside the head (IS-AVH) or external space (ES-AVH), and are considered to result from agency and spatial externalizations of inner speech. Both types of externalizations are conflated, and the relationship between these externalizations and AVH experiences is unclear. In this paper, I investigate the relationship between cognitive agency and spatial externalizations and between these externalizations and the types of AVH experience. Method: Twenty-five patients with history of AVH and 24 matched healthy controls performed agency and spatial distinction tasks: distinction between self-generated (read) (S) sentences and other-generated (O) sentences, and between sentences read silently (experienced in internal space, IS) and sentences read aloud (experienced in external space, ES). Regression analyses between misattribution biases (S-O vs. IS-ES, and O-S vs. ES-IS) were obtained. t tests were used to compare misattribution biases between AVH subtypes (S-AVH vs. O-AVH, and IS-AVH vs. ES-AVH). Results: Regressions suggest that agency distinction is independent from spatial distinction in both groups. O-AVH and S-AVH subgroups differed only with respect to S-O bias, and IS-AVH and ES-AVH subgroups differed only with respect to IS-ES bias. Conclusion: These results suggest that agency and spatial externalizations of inner speech are independent at phenomenological and cognitive and levels; and that these externalizations are co-related across levels. I discuss the implications of these findings in the wider context of research on AVH and on the experience of self.

Alcohol withdrawal hallucinations in the general population, an epidemiological study.

Hallucinations are sometimes encountered in the course of alcohol withdrawal; however, both the factors predisposing to alcohol withdrawal hallucinations (AWH) and the implications of AWH with respect to the mechanisms of hallucinations remain unclear. To clarify these issues, we used data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) to investigate the demographic correlates, alcohol-use clinical patterns, and psychiatric comorbidities in two groups: drinkers with and without a history of AWH. We estimated the odds ratios for studied factors and used logistic regression analyses to compare the two groups. We found that over 2% of drinkers reported AWH (758 of a sample of 34,533 subjects). Alcohol tolerance and withdrawal seizures were highly associated with AWH, and exposure to alcohol during brain development was associated with a 10-fold increase in AWH compared to exposure during adulthood. African Americans, Native Americans, and unmarried subjects, as well as subjects with lower levels of education and lower levels of income were more likely to experience AWH. Furthermore, those with a history of AWH had higher odds ratios for most psychiatric illnesses than those without such history-yet of anxiety disorders, only panic was associated with AWH. These associations suggest that higher levels of education and of standard of living could protect against AWH; while social isolation, hypervigilance, exposure to alcohol during brain development, and long and severe exposure to alcohol could predispose to AWH.

Abnormal Neural Oscillations in Schizophrenia Assessed by Spectral Power Ratio of MEG During Word Processing.

This study investigated spectral power of neural oscillations associated with word processing in schizophrenia. Magnetoencephalography (MEG) data were acquired from 12 schizophrenia patients and 10 healthy controls during a visual word processing task. Two spectral power ratio (SPR) feature sets: the band power ratio (BPR) and the window power ratio (WPR) were extracted from MEG data in five frequency bands, four time windows of word processing, and at locations covering whole head. Cluster-based nonparametric permutation tests were employed to identify SPRs that show significant between-group difference. Machine learning based feature selection and classification techniques were then employed to select optimal combinations of the significant SPR features, and distinguish schizophrenia patients from healthy controls. We identified three BPR clusters and three WPR clusters that show significant oscillation power difference between groups. These include the theta/delta, alpha/delta and beta/delta BPRs during base-to-encode and encode time windows, and the beta band WPR from base to encode and from encode to post-encode windows. Based on two WPR and one BPR features combined, over 95% cross-validation classification accuracy was achieved using three different linear classifiers separately. These features may have potential as quantitative markers that discriminate schizophrenia patients and healthy controls; however, this needs further validation on larger samples.

Better than mermaids and stray dogs? Subtyping auditory verbal hallucinations and its implications for research and practice.

The phenomenological diversity of auditory verbal hallucinations (AVH) is not currently accounted for by any model based around a single mechanism. This has led to the proposal that there may be distinct AVH subtypes, which each possess unique (as well as shared) underpinning mechanisms. This could have important implications both for research design and clinical interventions because different subtypes may be responsive to different types of treatment. This article explores how AVH subtypes may be identified at the levels of phenomenology, cognition, neurology, etiology, treatment response, diagnosis, and voice hearer's own interpretations. Five subtypes are proposed; hypervigilance, autobiographical memory (subdivided into dissociative and nondissociative), inner speech (subdivided into obsessional, own thought, and novel), epileptic and deafferentation. We suggest other facets of AVH, including negative content and form (eg, commands), may be best treated as dimensional constructs that vary across subtypes. After considering the limitations and challenges of AVH subtyping, we highlight future research directions, including the need for a subtype assessment tool.

Abnormal dynamics of language in schizophrenia.

Language could be conceptualized as a dynamic system that includes multiple interactive levels (sub-lexical, lexical, sentence, and discourse) and components (phonology, semantics, and syntax). In schizophrenia, abnormalities are observed at all language elements (levels and components) but the dynamic between these elements remains unclear. We hypothesize that the dynamics between language elements in schizophrenia is abnormal and explore how this dynamic is altered. We, first, investigated language elements with comparable procedures in patients and healthy controls. Second, using measures of reaction time, we performed multiple linear regression analyses to evaluate the inter-relationships among language elements and the effect of group on these relationships. Patients significantly differed from controls with respect to sub-lexical/lexical, lexical/sentence, and sentence/discourse regression coefficients. The intercepts of the regression slopes increased in the same order above (from lower to higher levels) in patients but not in controls. Regression coefficients between syntax and both sentence level and discourse level semantics did not differentiate patients from controls. This study indicates that the dynamics between language elements is abnormal in schizophrenia. In patients, top-down flow of linguistic information might be reduced, and the relationship between phonology and semantics but not between syntax and semantics appears to be altered.

Auditory verbal hallucinations result from combinatoric associations of multiple neural events.

While Auditory Verbal Hallucinations (AVH) refer to specific experiences shared by all subjects who have AVH-the perception of auditory speech without corresponding external stimuli, the characteristics of these experiences differ from one subject to another. These characteristics include aspects such as the location of AVH (inside or outside the head), the linguistic complexity of AVH (hearing words, sentences, or conversations), the range of content of AVH (repetitive or systematized content), and many other variables. In another word, AVH are phenomenologically heterogeneous experiences. After decades of research focused on a few explanatory mechanisms for AVH, it is apparent that none of these mechanisms alone explains the wide phenomenological range of AVH experiences. To date, our phenomenological understanding of AVH remains largely disjointed from our understanding of the mechanisms of AVH. For a cohesive understanding of AVH, I review the phenomenology and the cognitive and neural basis of AVH. This review indicates that the phenomenology of AVH is not a pointless curiosity. How a subject describes his AVH experiences could inform about the neural events that resulted in AVH. I suggest that a subject-specific combinatoric associations of different neural events result in AVH experiences phenomenologically diverse across subjects.

Multidimensional analysis of the abnormal neural oscillations associated with lexical processing in schizophrenia.

The neural mechanisms of language abnormalities, the core symptoms in schizophrenia, remain unclear. In this study, a new experimental paradigm, combining magnetoencephalography (MEG) techniques and machine intelligence methodologies, was designed to gain knowledge about the frequency, brain location, and time of occurrence of the neural oscillations that are associated with lexical processing in schizophrenia. The 248-channel MEG recordings were obtained from 12 patients with schizophrenia and 10 healthy controls, during a lexical processing task, where the patients discriminated correct from incorrect lexical stimuli that were visually presented. Event-related desynchronization/synchronization (ERD/ERS) was computed along the frequency, time, and space dimensions combined, that resulted in a large spectral-spatial-temporal ERD/ERS feature set. Machine intelligence techniques were then applied to select a small subset of oscillation patterns that are abnormal in patients with schizophrenia, according to their discriminating power in patient and control classification. Patients with schizophrenia showed abnormal ERD/ERS patterns during both lexical encoding and post-encoding periods. The top-ranked features were located at the occipital and left frontal-temporal areas, and covered a wide frequency range, including δ (1-4 Hz), α (8-12 Hz), ß (12-32 Hz), and γ (32-48 Hz) bands. These top features could discriminate the patient group from the control group with 90.91% high accuracy, which demonstrates significant brain oscillation abnormalities in patients with schizophrenia at the specific frequency, time, and brain location indicated by these top features. As neural oscillation abnormality may be due to the mechanisms of the disease, the spectral, spatial, and temporal content of the discriminating features can offer useful information for helping understand the physiological basis of the language disorder in schizophrenia, as well as the pathology of the disease itself.

The temporal, spatial, and frequency dimensions of neural oscillations associated with verbal working memory.

Cognitive operations engage neural generators oscillating at different frequencies distributed in time and space. Accordingly, oscillatory activity detected by magnetoencephalography (MEG)/electroencephalography (EEG) should be analyzed along frequency, time, and spatial dimensions. MEG data were obtained from 19 healthy individuals while performing a modified Sternberg paradigm. The stimuli were letters, which constituted words or pronounceable nonwords. We applied tridimensional analysis of oscillations and also computed event-related fields (ERFs) in areas where significant changes in oscillatory activity were observed. Verbal working memory for visual verbal stimuli was associated with oscillatory interplay between the bilateral occipital lobes and the left frontoparietotemporal areas. Spatially stable occipital desynchrony was noted during information encoding, while a left hemisphere desynchronization, increasing in amplitude and spatial extent over time, was observed during information encoding and maintenance. No ERF changes were detected during information maintenance. Oscillatory activity associated with verbal working memory is consistent with the above hypothesis. These findings underscore the importance of multidimensional evaluation of oscillations. The findings also indicate that combining electrophysiological methods increase the chance of signal detection.

Maintaining information online in discrete time; rethinking working memory processes.

Linguistic operations occur with verbal information maintained online for a discrete time. It is posited that online maintenance of information is accomplished by verbal working memory (WM), a system that is: (a) independent from the linguistic operations carried out with the information (specialized), and (b) consists of a holding place where information is held in a phonological code (phonological loop) and a rehearsal mechanism that refreshes the phonological loop. This model does not account for the serial position effects associated with information maintenance and additional models are needed to explain the latter effects, which leaves us with a disjointed understanding of online maintenance of information. In this study, 36 middle-aged, healthy subjects (33 males and 3 females) were required to maintain linguistic information (letters) online. The letters called upon different cognitive operations (orthographic; orthographic and phonetic; or orthographic, phonetic and semantic). It was found that online maintenance capacity depends on the cognitive operations associated with the letters and on their serial position. Additionally, the cognitive operation effect on online maintenance was modulated by the serial position. These data favor a model for WM consisting of a simple holding place where verbal information maintenance depends on what the information is used for. We will discuss an integrated model for online information maintenance that accounts for the serial position effects.

The characteristic features of auditory verbal hallucinations in clinical and nonclinical groups: state-of-the-art overview and future directions.

Despite a growing interest in auditory verbal hallucinations (AVHs) in different clinical and nonclinical groups, the phenomenological characteristics of such experiences have not yet been reviewed and contrasted, limiting our understanding of these phenomena on multiple empirical, theoretical, and clinical levels. We look at some of the most prominent descriptive features of AVHs in schizophrenia (SZ). These are then examined in clinical conditions including substance abuse, Parkinson's disease, epilepsy, dementia, late-onset SZ, mood disorders, borderline personality disorder, hearing impairment, and dissociative disorders. The phenomenological changes linked to AVHs in prepsychotic stages are also outlined, together with a review of AVHs in healthy persons. A discussion of key issues and future research directions concludes the review.

Correlation of the vesicular acetylcholine transporter densities in the striata to the clinical abilities of women with Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disability characterized by mutations in the X-linked methyl-CpG-binding protein 2 located at the Xq28 region. The severity is modified in part by X chromosomal inactivation resulting in wide clinical variability. We hypothesized that the ability to perform the activities of daily living (ADL) is correlated with the density of vesicular acetylcholine transporters in the striata of women with RTT. The density of the vesicular acetylcholine transporters in the living human brain can be estimated by single-photon emission-computed tomography (SPECT) after the administration of (-)-5-[¹²³I]iodobenzovesamicol ([¹²³I]IBVM). Twenty-four hours following the intravenous injection of ∼333 MBq (9 mCi) [¹²³ I]IBVM, four women with RTT and nine healthy adult volunteer control participants underwent SPECT brain scans for 60 min. The Vesicular Acetylcholine Transporter Binding Site Index (Kuhl et al., 1994), a measurement of the density of vesicular acetylcholine transporters, was estimated in the striatum and the reference structure, the cerebellum. The women with RTT were assessed for certain ADL. Although the striatal Vesicular Acetylcholine Transporter Binding Site Index was not significantly lower in RTT (5.2 ± 0.9) than in healthy adults (5.7 ± 1.6), RTT striatal Vesicular Acetylcholine Transporter Binding Site Indices and ADL scores were linearly associated (ADL = 0.89*(Vesicular Acetylcholine Transporter Binding Site Index) + 4.5; R² = 0.93; P < 0.01), suggesting a correlation between the ability to perform ADL and the density of vesicular acetylcholine transporters in the striata of women with RTT. [¹²³I]IBVM is a promising tool to characterize the pathophysiological mechanisms of RTT and other neurodevelopmental disabilities.

Selection of abnormal neural oscillation patterns associated with sentence-level language disorder in Schizophrenia.

Language disorder is one of the core symptoms in schizophrenia. We propose a new framework based on machine intelligence techniques to investigate abnormal neural oscillations related to this impairment. Schizophrenia patients and healthy control subjects were instructed to discriminate semantically and syntactically correct sentences from syntactically correct but semantically incorrect sentences presented visually, and 248-channel MEG signals were recorded with a whole head machine during the task performance. Oscillation patterns were extracted from the MEG recordings in 8 frequency sub-bands throughout sentence processing, which form a large feature set. A two-step feature selection algorithm combining F-score filtering and Support Vector Machine recursive feature elimination (SVM-RFE) was designed to pick out a small subset of features which could discriminate patients and controls with high accuracy. We achieved a 90.48% prediction accuracy based on the selected top features, following the leave-one-out cross validation procedure. These top features provide interpretable spectral, spatial, and temporal information about the electrophysiological basis of sentence processing abnormality in schizophrenia which may help understand the underlying mechanism of this disease.