Hearing voices inside and outside the head: Spatial source monitoring in participants prone to auditory hallucinations

Introduction. Previous studies of source monitoring and auditory hallucinations (AH) have often conflated spatial source (internal-external) with source agency (self–other). Other studies have used suboptimal manipulations of auditory space (e.g., imagine saying vs. saying aloud). We avoided these problems by presenting experimenter-generated stimuli over headphones in the voice of another person so that the location of the voice sounded either internal or external to the participant's head.

Methods. Participants (N=121) studied 96 words and indicated for each whether it was presented internally or externally (online spatial source monitoring). At test, studied words were presented visually, intermixed randomly with 96 unstudied words. Participants indicated whether each item was old or new (item memory) and whether it was presented internally or externally during study (spatial source memory). Independent measures of memory accuracy and response bias were derived for online source monitoring, item memory and source memory using signal detection theory. Performance on these measures was compared between two groups of 30 participants who scored low or high on a measure of AH proneness.

Results. ANOVAs revealed no differences between the high- and low-AH groups in online spatial source monitoring, item memory, or spatial source memory.

Conclusions. We found no evidence that proneness to AH in a sample of healthy volunteers was related to any of the measures of spatial source monitoring performance. We recommend that the methods introduced be applied to future investigations of spatial source monitoring with patient groups and with individuals at-risk for psychosis.     

Sequential processing in the classic oddball task: ERP components,probability, and behavior

This study compared the ERP components and behavior associated with the auditory equiprobable and classic oddball tasks, to relate the cognitive processing stages in those paradigms and continue the development of the sequential processing schema. Target and nontarget ERP data were acquired from 66 healthy young adults (M_age = 20.1, SD = 2.4 years, 14 male) who completed both equiprobable (target p = 0.5) and oddball tasks (target p = 0.3). Separate temporal PCAs were used to decompose the ERP data in each task and condition, and the similarity of the components identified in each condition was examined between tasks. Probability effects on component amplitudes and behavior were also analyzed to identify task differences in cognitive demands. A highly similar series of components was identified in each task, closely matching the schema: targets elicited N1‐3, N1‐1, PN, N2c, P3b, SW1, SW2; whereas nontargets elicited N1‐3, N1‐1, PN, N2b, P3a, SW1, SW2. N1‐1 and PN amplitudes increased as stimulus probability decreased, irrespective of the condition. N2b, P3b, SW1, and SW2 amplitudes also varied between tasks, illustrating task‐specific demands on those processing stages. These findings complemented the behavioral outcomes, which demonstrated greater accuracy and control in the classic oddball task. Overall, this study demonstrated comparable processing in the auditory equiprobable and classic oddball tasks, extending the generalizability of the schema and enabling further integration of the ERP theory associated with these tasks. This study also clarifies stimulus probability effects on the schema, providing important insight into the functionality of common ERP components.     

Triage of cervical cytological diagnoses of atypical squamous cells by DNA methylation of paired boxed gene 1 (PAX1)

Detection of cervical high‐grade squamous intraepithelial lesions (HSIL) in patients with equivocal cytological abnormalities, such as atypical squamous cells (ASC) of undetermined significance (ASCUS) or inability to exclude high‐grade squamous intraepithelial lesions (ASC‐H) is still a challenge. This study tested the efficacy of PAX1 methylation analysis in the triage of cervical ASCUS and ASC‐H and compared its performance with Hybrid Capture 2 (HC2) HPV test. A hospital‐based case–control study was conducted. Cervical scrapings from patients with ASCUS or ASC‐H were used for the quantitative methylation analysis of PAX1 methylation by MethyLight and HPV testing by HC2. Patients with ASC‐H or ASCUS with repeated abnormal smears underwent colposcopic biopsy and subsequent therapies. Diagnoses were made by histopathology at a follow‐up of 2 years. The efficacies of detecting high‐grade lesions were compared. Fifty‐eight cervical scrapings with cytological diagnosis of ASCUS (n = 41) and ASC‐H (n = 17) were analyzed. One of the 41 (2.4%) ASCUS patients and seven of 17 (41.2%) ASC‐H patients were confirmed to have HSIL. After dichotomy of the PMR, PAX1 methylation rates were significantly higher in ASC developing HSIL compared with those developing reactive atypia (87.5% vs. 12.5%, P < 0.001). Testing PAX1 methylation in cervical swabs of patients with ASC confers better sensitivity (87.5% vs. 62.5%) and specificity (98.0% vs. 86.0%) than HC2 HPV testing. We show for the first time that PAX1 hypermethylation analysis may be a better choice than HC2 in the triage of ASCUS and ASC‐H. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

A reply to Dolan's and Cordess' reviews of The Psychopathology of Crime

Introduction. Both clinical and non-clinical auditory hallucinations (AH) have been associated with source memory deficits, supporting a continuum of underlying cognitive mechanisms, though few studies have employed the same task in patient and nonpatient samples. Recent commentators have called for more debate on the continuum model of psychosis. Consequently, the current study investigated the continuity model of AH with reference to memory binding.

Methods. We used an identical voice and word recognition memory task to assess binding in two separate studies of: (1) healthy hallucination-prone individuals and controls (30 high and 30 low scorers on the Launay-Slade Hallucination Scale–Revised) and (2) schizophrenia patient samples (32 with AH, 32 without AH) and 32 healthy controls.

Results. There was no evidence of impaired binding in high hallucination-prone, compared to low hallucination-prone individuals. In contrast, individuals with schizophrenia (both with and without AH) had difficulties binding (remembering “who said what”), alongside difficulties remembering individual words and voices. Binding ability and memory for voices were also negatively linked to the loudness of hallucinated voices reported by patients with AH.

Conclusions. These findings suggest that different mechanisms may exist in clinical and non-clinical hallucinators, adding to the growing debate on the continuum model of psychotic symptoms.     

Working memory capacity affects the interference control of distractors at auditory gating

It is important to understand the role of individual differences in working memory capacity (WMC). We investigated the relation between differences in WMC and N1 in event-related brain potentials as a measure of early selective attention for an auditory distractor in three-stimulus oddball tasks that required minimum memory. A high-WMC group (n = 13) showed a smaller N1 in response to a distractor and target than did a low-WMC group (n = 13) in the novel condition with high distraction. However, in the simple condition with low distraction, there was no difference in N1 between the groups. For all participants (n = 52), the correlation between the scores for WMC and N1 peak amplitude was strong for distractors in the novel condition, whereas there was no relation in the simple condition. These results suggest that WMC can predict the interference control for a salient distractor at auditory gating even during a selective attention task.     

A pragmatic comparison of noise burst and electric shock unconditioned stimuli for fear conditioning research with many trials

Several methods that are promising for studying the neurophysiology of fear conditioning (e.g., EEG, MEG) require a high number of trials to achieve an adequate signal‐to‐noise ratio. While electric shock and white noise burst are among the most commonly used unconditioned stimuli (US) in conventional fear conditioning studies with few trials, it is unknown whether these stimuli are equally well suited for paradigms with many trials. Here, N = 32 participants underwent a 260‐trial differential fear conditioning and extinction paradigm with a 240‐trial recall test 24 h later and neutral faces as conditioned stimuli. In a between‐subjects design, either white noise bursts (n = 16) or electric shocks (n = 16) served as US, and intensities were determined using the most common procedure for each US (i.e., a fixed 95 dB noise burst and a work‐up procedure for electric shocks, respectively). In addition to differing US types, groups also differed in closely linked US‐associated characteristics (e.g., calibration methods, stimulus intensities, timing). Subjective ratings (arousal/valence), skin conductance, and evoked heart period changes (i.e., fear bradycardia) indicated more reliable, extinction‐resistant, and stable conditioning in the white noise burst versus electric shock group. In fear conditioning experiments where many trials are presented, white noise burst should serve as US.     

Visual contrast sensitivity in Alzheimer’s disease,mild cognitive impairment,and older adults with cognitive complaints

Deficits in contrast sensitivity (CS) have been reported in Alzheimer’s disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker.     

The effects of stimulus novelty and familiarity on neuronal activity in the amygdala of monkeys performing recognition memory tasks

The function of the amygdala in behavioural responses to novel stimuli and its possible function in recognition memory were investigated by recording the responses of 659 amygdaloid neurons in monkeys performing recognition memory and visual discrimination tasks. The aim was to determine the contribution of the amygdala in the encoding of familiarity and therefore its role in supporting memory-related neuronal mechanisms in the basal forebrain. The responses of three groups of neurons reflected different forms of memory. One group (n= 10) responded maximally to novel stimuli and significantly less so to the same stimuli when they were familiar. The calculated memory spans of these neurons were in the range of 2–10 intervening trials, and this shortterm retention of information may reflect the operation of a neural mechanism encoding memory for the recency of stimulus presentation. Two other groups responded to the sight of particular categories of familiar stimuli: to foods (n = 6) or to faces (n = 10). The responses of some of these stimulus-selective neurons declined with repeated presentations of foods (3/4 tests) and faces (2/6 tests). The activity of these latter two groups of neurons may be involved in behavioural responses to familiar visual stimuli, particularly when such stimuli have affective or motivational significance. We conclude that the neurophysiological data provide evidence of amygdaloid mechanisms for the recognition of recently seen visual stimuli. However, these amygdaloid mechanisms do not appear to be sufficient to support the performance of long-term recognition memory tasks without additional and complementary functions carried out by other ventromedial temporal, prefrontal and diencephalic structures which also project to the basal forebrain.     

Inhibition of neutrophil-mediated production of reactive oxygen species (ROS) by endothelial cells is not impaired in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis patients

Leucocyte transendothelial migration is strictly regulated to prevent undesired inflammation and collateral damage of endothelial cells by activated neutrophils/monocytes. We hypothesized that in anti‐neutrophil cytoplasmic autoantibodies (ANCA)‐associated vasculitis (AAV) patients' dysregulation of this process might underlie vascular inflammation. Peripheral blood mononuclear cells (PBMC) and neutrophils from AAV patients (n = 12) and healthy controls (HC, n = 12) were isolated. The influence of human umbilical vein endothelial cells (HUVEC) on neutrophil/monocytes function was tested by N‐formyl‐methionyl‐leucyl‐phenyl‐alanine (fMLP)‐ and phorbol 12‐myristate 13‐acetate (PMA)‐mediated ROS production, degranulation and interleukin (IL)‐8 production. In addition, the ability of lipopolysaccharide (LPS)‐stimulated PBMC to produce tumour necrosis factor (TNF)‐α in the presence or absence of HUVEC was tested. HUVEC inhibited ROS production dose‐dependently by fMLP‐stimulated neutrophils but did not influence degranulation. No differences between neutrophils from HC and AAV were found. However, in only one active patient was degranulation inhibited significantly by HUVEC only before cyclophosphamide treatment, but not 6 weeks later. Co‐cultures of HUVEC with LPS‐stimulated neutrophils/monocytes increased IL‐8 production while TNF‐α production was inhibited significantly. There was no apparent difference between AAV patients and HC in this respect. Our findings demonstrate that HUVEC are able to inhibit ROS and modulate cytokine production upon stimulation of neutrophils or monocytes. Our data do not support the hypothesis that endothelial cells inhibit ROS production of neutrophils from AAV patients inadequately. Impaired neutrophil degranulation may exist in active patients, but this finding needs to be confirmed.     

Systematic transcriptome analysis reveals elevated expression of alcohol‐metabolizing genes in NAFLD livers

Obese animals and non‐alcoholic fatty liver disease (NAFLD) patients exhibit elevated blood alcohol, suggesting potential contributions of alcohol metabolism to the development of NAFLD. Liver gene expression in patients with biopsy‐proven mild (N = 40) and severe (N = 32) NAFLD were compared to that in healthy liver donors (N = 7) and alcoholic hepatitis (AH; N = 15) using microarrays. Principal components analyses (PCA) revealed similar gene expression patterns between mild and severe NAFLD which clustered with those of AH but were distinct from those of healthy livers. Differential gene expression between NAFLD and healthy livers was consistent with established NAFLD‐associated genes and NAFLD pathophysiology. Alcohol‐metabolizing enzymes including ADH, ALDH, CYP2E1, and CAT were up‐regulated in NAFLD livers. The expression level of alcohol‐metabolizing genes in severe NAFLD was similar to that in AH. The NAFLD gene expression profiles provide new directions for future investigations to identify disease markers and targets for prevention and treatment, as well as to foster our understanding of NAFLD pathogenesis and pathophysiology. Particularly, increased expression of alcohol‐metabolizing genes in NAFLD livers supports a role for endogenous alcohol metabolism in NAFLD pathology and provides further support for gut microbiome therapy in NAFLD management. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley © Sons, Ltd.     

Interhemispheric transfer time in patients with auditory hallucinations: an auditory event-related potential study

Central auditory processing in schizophrenia patients with a history of auditory hallucinations has been reported to be impaired, and abnormalities of interhemispheric transfer have been implicated in these patients. This study examined interhemispheric functional connectivity between auditory cortical regions, using temporal information obtained from latency measures of the auditory N1 evoked potential. Interhemispheric Transfer Times (IHTTs) were compared across 3 subject groups: schizophrenia patients who had experienced auditory hallucinations, schizophrenia patients without a history of auditory hallucinations, and normal controls. Pure tones and single-syllable words were presented monaurally to each ear, while EEG was recorded continuously. IHTT was calculated for each stimulus type by comparing the latencies of the auditory N1 evoked potential recorded contralaterally and ipsilaterally to the ear of stimulation. The IHTTs for pure tones did not differ between groups. For word stimuli, the IHTT was significantly different across the 3 groups: the IHTT was close to zero in normal controls, was highest in the AH group, and was negative (shorter latencies ipsilaterally) in the nonAH group. Differences in IHTTs may be attributed to transcallosal dysfunction in the AH group, but altered or reversed cerebral lateralization in nonAH participants is also possible.     

Neurophysiological Mechanisms of Auditory Information Processing in Adolescence: A Study on Sex Differences

To date, little is known about sex differences in the neurophysiological correlates underlying auditory information processing. In the present study, auditory evoked potentials were evoked in typically developing male (n = 15) and female (n = 14) adolescents (13–18 years) during an auditory oddball task. Girls compared to boys displayed lower N100 and P300 amplitudes to targets. Larger N100 amplitudes in adolescent boys might indicate higher neural sensitivity to changes of incoming auditory information. The P300 findings point toward sex differences in auditory working memory and might suggest that adolescent boys might allocate more attentional resources when processing relevant auditory stimuli than adolescent girls.     

Genome‐wide mutation analysis in precancerous lesions of endometrial carcinoma

Clinicopathological evidence supports endometrial atypical hyperplasia (AH) or endometrial intraepithelial neoplasia as the precursor of uterine endometrioid carcinoma (EC), the most common gynecologic malignancy. However, the pathogenic progression from AH to EC remains unclear. Here, we employed whole‐exome sequencing to identify somatic mutations and copy number changes in micro‐dissected lesions from 30 pairs of newly diagnosed AH and EC. We found that all but one pair of AHs shared the same DNA mismatch repair status as their corresponding ECs. The percentage of common mutations between AH lesions and corresponding ECs varied significantly, ranging from 0.1% to 82%. Microsatellite stable AHs had fewer cancer driver mutations than ECs (5 versus 7, p = 0.017), but among microsatellite unstable AHs and ECs there was no difference in mutational numbers (36 versus 38, p = 0.65). As compared to AH specimens, 19 (79%) of 24 microsatellite stable EC tumors gained new cancer driver mutations, most of which involved PTEN, ARID1A, PIK3CA, CTNNB1, or CHD4. Our results suggest that some AH lesions are the immediate precursor of ECs, and progression depends on acquisition of additional cancer driver mutations. However, a complex clonal relationship between AH and EC can also be appreciated, as in some cases both lesions diverge very early or arise independently, thus co‐developing with distinct genetic trajectories. Our genome‐wide profile of mutations in AH and EC shines new light on the molecular landscape of tumor progression. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Synthesis and Liquid Crystalline Properties of Poly(ethylene oxide) Brushes with Amphiphilic Side Groups

Summary: Poly(ethylene oxide)s containing decylthiomethyl (DTP), decylsulfonylmethyl (DSP), methyl‐oligo(ethylene oxide) thiomethyl (MnOTP), methyl‐oligo(ethylene oxide) sulfonylmethyl (MnOSP), decyl‐oligo(ethylene oxide) thiomethyl (DnOTP), and decyl‐oligo(ethylene oxide) sulfonylmethyl (DnOSP) groups in the side‐chains, where n (the number of ethylene oxide units) = 1, 2, 3, or 4 for DnOTP and DnOSP, and n = 2, 3, or 7 for MnOTP and MnOSP, were synthesized to study the effect of the structure of the side‐chains on the ordered phases of the polymers. All of the MnOSPs, as well as M2OTP and M3OTP, were found to be amorphous polymers. DTP, M7OTP, D1OTP, D2OTP, and D3OTP showed crystalline phases below their isotropic temperatures. DSP, D1OSP, D2OSP, D3OSP, D4OSP, and D4OTP were found to be liquid crystalline. Therefore, the phase separation facilitated by the introduction of the sulfone group and/or by the addition of the longer ethylene oxide units between the ethylene oxide backbones and the hydrophobic decyl tails was found to be a key factor in the formation of the liquid crystalline phases. These ordered phases were characterized using differential scanning calorimetry, polarized optical microscopy, and X‐ray diffraction.

Schematic illustration of the structures of poly(ethylene oxide) brushes showing liquid crystalline phases.     

Immunohistochemical characterization of renal tumors in patients with Birt‐Hogg‐Dubé Syndrome

Birt‐Hogg‐Dubé syndrome (BHD) is an autosomal dominant disorder associated with a germline mutation of folliculin (FLCN). The affected families are at a high risk for developing multiple renal cell carcinomas (RCC). Little is known about the immunostaining patterns of mutant FLCN‐associated RCCs. We investigated 32 RCCs obtained from 17 BHD patients. The studied tumors included chromophobe RCCs (n = 15), hybrid oncocytic/chromophobe tumors (HOCT) (n = 14) and clear cell RCCs (n = 3). Almost all chromophobe RCCs and HOCTs revealed positive staining for S100A1, Ksp‐cadherin and CD82. They stained either focally or diffusely for CK7, and were negative for CA‐IX. All clear cell RCCs were positively stained for CA‐IX and negative for CK7. These data confirmed that mutant FLCN‐associated oncocytic and clear cell RCCs exhibited generally similar immunostaining patterns compared to their sporadic counterparts. Frequent positive staining for S100A1, Ksp‐cadherin and CD82 in chromophobe RCCs and HOCTs indicated that these two types were relatively similar rather than distinctively different in their patterns of immunoreactivity. Characteristic peri‐nuclear halos and polygonal cells with clear cytoplasm, which often misleads pathologists into the diagnosis of clear cell RCC, should be carefully examined using an immunohistochemical panel including CA‐IX, Ksp‐cadherin, CD82 and CK7.     

Auditory hallucinations: Failure to inhibit irrelevant memories

Introduction. The frequency of auditory hallucinations (AH) is associated with efficiency in inhibiting irrelevant memories, suggesting that the presence of AH may be related to the intrusion of strongly activated representations in memory. Therefore, we hypothesised that the inability to suppress irrelevant memories would be found only in patients currently experiencing AH.

Method. Performance on a repeated, continuous recognition task was examined in 23 schizophrenia patients with AH present, 20 schizophrenia patients with AH absent, and 24 healthy controls.

Results. Patients with current AH made significantly more inappropriate responses (false alarms) to distractors seen on previous runs of the task than nonhallucinating patients. The ability to detect targets (hits) was significantly better in healthy controls than schizophrenia patients, however, there was no significant difference between the two patient subgroups.

Conclusions. The findings confirm that the presence of AH involves a failure to suppress memories that are not relevant to ongoing reality. We propose that a combination of deficits in inhibition and (episodic) memory provides a useful model of AH, which can accommodate many of the characteristic features of the symptom and fits well with the neuroanatomical circuitry that is believed to underlie the occurrence of AH.     

Metabolic,pathologic, and genetic analysis of prostate tissues: quantitative evaluation of histopathologic and mRNA integrity after HR‐MAS spectroscopy

The impact of high‐resolution magic angle spinning (HR‐MAS) spectroscopy on the histopathologic and mRNA integrity of human prostate tissues was evaluated. Forty prostate tissues were harvested at transrectal ultrasound (TRUS) guided biopsy (n = 20) or radical prostatectomy surgery (n = 20), snap‐frozen on dry ice, and stored at ?80°C until use. Twenty‐one samples (n = 11 biopsy, n = 10 surgical) underwent HR‐MAS spectroscopy prior to histopathologic and cDNA microarray analysis, while 19 control samples (n = 9 biopsy, n = 10 surgical) underwent only histopathologic and microarray analysis. Frozen tissues were sectioned at 14‐µm intervals and placed on individual histopathology slides. Every 8th slide was stained with hematoxylin and eosin (H&E) and used to target areas of predominantly epithelial tissue on the remaining slides for mRNA integrity and cDNA microarray analysis. Histopathologic integrity was graded from 1 (best) to 5 (worst) by two ‘blinded’ pathologists. Histopathologic integrity scores were not significantly different for post‐surgical tissues (HR‐MAS vs controls); however, one pathologist's scores were significantly lower for biopsy tissues following HR‐MAS while the other pathologist's scores were not. mRNA integrity assays were performed using an Agilent 2100 Bioanalyzer and the electrophoretic traces were scored with an RNA integrity number (RIN) from 1 (degraded) to 10 (intact). RIN scores were not significantly different for surgical tissues, but were significantly lower for biopsy tissues following HR‐MAS spectroscopy. The isolated mRNA then underwent two rounds of amplification, conversion to cDNA, coupling to Cy3 and Cy5 dyes, microarray hybridization, imaging, and analysis. Significance analysis of microarrays (SAM) identified no significantly over‐ or under‐expressed genes, including 14 housekeeping genes, between HR‐MAS and control samples of surgical and biopsy tissues (5% false discovery rate). This study demonstrates that histopathologic and genetic microarray analysis can be successfully performed on prostate surgical and biopsy tissues following HR‐MAS analysis; however, biopsy tissues are more fragile than surgical tissues. Copyright © 2009 John Wiley & Sons, Ltd.     

Safety and efficacy of icatibant self-administration for acute hereditary angioedema

We evaluated the efficacy and safety of icatibant self‐administration in 15 patients with hereditary angioedema (HAE) types I or III, for 55 acute attacks (mostly severe or very severe). Icatibant self‐administration was generally effective: first symptom improvement occurred in 5 min–2 h (HAE type I; n = 17) and 8 min–1 h (HAE type III; n = 9) for abdominal attacks and 5–30 min (HAE type I; n = 4) and 10 min–12 h (HAE type III; n = 6) for laryngeal attacks. Complete symptom resolution occurred in 15 min–19 h (HAE type I; n = 8) and 15 min–48 h (HAE type III; n = 9) for abdominal attacks and 5–48 h (HAE type I; n = 3) and 8–48 h (HAE type III; n = 5) for laryngeal attacks. No patient required emergency hospitalization. The only adverse events were mild, spontaneously resolving injection site reactions. Patients reported that carrying icatibant with them gave them greater confidence in managing their condition.