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.

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.

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.

Evaluation of inner-outer space distinction and verbal hallucinations in schizophrenia.

INTRODUCTION: Verbal hallucinations could result from attributing one's own inner speech to another. Inner speech is usually experienced in inner space, whereas hallucinations are often experienced in outer space. To clarify this paradox, we investigated schizophrenia patients' ability to distinguish between speech experienced in inner space, and speech experienced in outer space. METHODS: 32 schizophrenia patients and 26 matched healthy controls underwent a two-stage experiment. First, they read sentences aloud or silently. Afterwards, they were required to distinguish between the sentences read aloud (experienced in outer space), the sentences read silently (experienced in inner space), and new sentences not previously read (no space coding). The sentences were in the first, second, or third person in equal proportions. Linear mixed models were used to investigate the effects of group, sentence location, pronoun, and hallucinations status. RESULTS: Schizophrenia patients were similar to controls in recognition capacity of sentences without space coding. They exhibited both inner-outer and outer-inner space confusion (they confused silently read sentences for sentences read aloud, and vice versa). Patients who experienced hallucinations inside their head were more likely to have outer-inner space bias. CONCLUSIONS: For speech generated by one's own brain, schizophrenia patients have bidirectional failure of inner-outer space distinction (inner-outer and outer-inner space biases); this might explain why hallucinations (abnormal inner speech) could be experienced in outer space. Furthermore, the direction of inner-outer space indistinction could determine the spatial location of the experienced hallucinations (inside or outside the head).

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.

The dynamic architecture of working memory in schizophrenia.

BACKGROUND: The capacity to hold information in working memory is greater for the first and/or last items of a sequence of information (architecture), and varies according to the retention interval (dynamic) and the type of stimuli. Although working memory deficits in schizophrenia have been documented widely, it is not clear how its architecture and dynamics are affected by the disease. METHODS: Using two Sternberg paradigms - the recognition and the context-recall tasks - we investigated the effect of serial position, retention interval, type of stimuli, and task (type of encoding for the serial position) on working memory capacity in 26 schizophrenia patients and 20 healthy control subjects. A mixed model analysis of variance was applied to the proportion of correct responses and reaction time data. RESULTS: All the experimental factors had significant effects. However, the most important effects were those of group, groupxserial position, and groupxdelay interactions. The last two effects were driven by a reduced primacy effect and by a reduced performance with longer delay in schizophrenia compared to control subjects. The serial positionxdelay interaction was significant without triple interaction with group. Groupxtype of stimuli and groupxtask for the serial position interactions were not significant. CONCLUSION: Schizophrenia patients exhibited normal dynamics but abnormal architecture of working memory (reduced primacy effect), and faster decay of information. These impairments affected equally verbal, spatial and object stimuli and operated with implicit and explicit encoding of the serial position. Although these impairments were not correlated with the clinical picture, they are likely to contribute to the pathogenesis of the difficulties with which schizophrenia patients are faced. Consequently, addressing these specific impairments could alleviate these difficulties.

Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders.

We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG). The essence of the test is the measurement of the dynamic synchronous neural interactions, an essential aspect of the brain function. MEG signals were recorded from 248 axial gradiometers while 142 human subjects fixated a spot of light for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) and their z-transforms (z(ij)(0)) between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z(ij)(0) successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimer's disease, schizophrenia, Sjögren's syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.

Computerized binary scale of auditory speech hallucinations (cbSASH).

BACKGROUND: Evidence indicates that the neuropathology of auditory verbal hallucinations (AVH) varies according to their phenomenological characteristics. Therefore, AVH should be subgrouped accordingly in hallucinations research. As evaluation of these characteristics depends entirely on the patient report, obtaining measurement of the reliability of these reports is crucial. METHOD: A computerized binary scale of auditory speech hallucinations (cbSASH) was developed to evaluate the phenomenology of AVH. It includes two subscales (inconsistency and malingering) to assess the reliability of the patient report. The cbSASH was administered along with MMPI-2, a general psychopathology scale, which includes similar validity subscales. Thirty-four psychotic patients with history of AVH were enrolled in this study. RESULTS: The scores on the inconsistency and malingering subscales of the cbSASH were correlated with the scores on the corresponding validity subscales in the MMPI-2. The combination of the malingering and inconsistency subscales provided robust measures of the reliability and ability of the patients' descriptions of their hallucinations. CONCLUSION: The cbSASH provides a reliable and comprehensive evaluation of the phenomenology of AVH. Consequently, it is possible to subgroup patients according to the characteristics of their hallucinations. This refinement of AVH phenotypes could reduce the noise and inconsistency noted in AVH and psychosis research.

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.

Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride.

Aripiprazole (OPC 14597) is an antipsychotic drug that has high affinity for dopamine D2 and D3 receptors and the dopamine autoreceptor. It is being developed for treatment of patients with schizophrenia. The purpose of this study was to determine whether a dose response following graduated doses of aripiprazole could be quantified and correlated with its occupancy of the D2 and D3 dopamine receptors in the brain of living humans. Dopamine D2 and D3 receptor occupancy in fifteen normal male human brains was measured using positron emission tomography (PET) with [11C]raclopride. PET studies were performed before and after two weeks of administration of aripiprazole. The dopamine D2 receptor occupancy was quantified with two kinetic modeling methods without using a blood input function. Administration of aripiprazole for 14 days resulted in a dose-dependent receptor occupancy between 40 - 95% after the administration of 0.5mg, 1 mg, 2 mg, 10 mg, and 30 mg per day. These results suggest that an adequate occupancy can be obtained, and this may be useful to predict an appropriate therapeutic dose for an individual patient. Interestingly, even at striatal D2 receptor occupancy values above 90%, which occurred with the higher doses, extrapyramidal side effects (EPS) were not observed. This underlines aripiprazole's unique mechanism of action as a partial dopamine receptor agonist, which might become a novel principle in the treatment of schizophrenia.

The internal structure of the phenomenology of auditory verbal hallucinations.

BACKGROUND: Auditory verbal hallucinations (AVH) do not have uniform pathological significance. They affect patients with different brain disorders, and vary along multiple phenomenological dimensions. Evidence indicates that some of the phenomenological variables have specific neural substrates. Therefore, a comprehensive characterization of the phenomenological variations of AVH and the interrelationship between these variables was undertaken. METHOD: Twenty phenomenological variables were identified; on each AVH had a binary value (present or absent). Information about 11 of these variables were obtained from 30 patients. Hierarchical cluster (HC) and multidimensional scaling (MDS) analyses were performed to investigate the hidden structure and dimensions of these variables. RESULTS: HC yielded two main clusters with further sub-clusters in each. The first cluster included hallucinations with low linguistic complexity, repetitive content, attributed to self, located in outer space, and associated with different kinds of control strategies. The second cluster included hallucinations with high linguistic complexity, systematized content, multiple voices, attributed to others, and located in inner space. In MDS, three dimensions were identified: linguistic complexity, self-other attribution, and inner-outer space location. CONCLUSION: The patterns of clustering and dimensional configuration of AVH characteristics were in accord with intuitive expectation and validated the patients' descriptions of their experiences. These findings could reflect aspects of the neural mechanisms of AVH. For example, the presence of neural specificity for each phenomenological variable, intermediate neural commonality for groups of variables, and a final common pathway for all subtypes of AVH. Another example is a differential level of language dysfunction according to the linguistic complexity of AVH.

New phenomenon of abnormal auditory perception associated with emotional and head trauma: pathological confirmation by SPECT scan.

We report the case of an immigrant who suffered from death threats and head trauma while a prisoner of war in Kuwait. Two months later, he began to hear conversations that had taken place previously. These perceptions occurred spontaneously or were induced by the patient's effortful concentration. The single photon emission computerized tomography (SPECT) scan performed during this abnormal perceptual experience indicated an increase in regional cerebral blood flow in the left temporal lobe and in the brainstem.

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.

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.

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.