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We explore how hallucinations might be studied within the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) framework, which asks investigators to step back from diagnoses based on symptoms and focus on basic dimensions of function

BackgroundIn electroencephalogram (EEG) studies of auditory steady-state responses (ASSRs), patients with schizophrenia show a deficit in power and/or phase-locking, particularly at the 40 Hz frequency where these responses resonate. In addition, studies of the transient gamma-band response (GBR) elicited by single tones have revealed deficits in gamma power and phase-locking in schizophrenia. We examined the degree to which the 40 Hz ASSR and the transient GBR to single tones are correlated and whether they assess overlapping or distinct gamma-band abnormalities in schizophrenia.MethodsEEG was recorded during 40 Hz ASSR and auditory oddball paradigms from 28 patients with schizophrenia or schizoaffective disorder (SZ) and 25 age- and gender-matched healthy controls (HC). The ASSR was elicited by 500 ms click trains, and the transient GBR was elicited by the standard tones from the oddball paradigm. Gamma phase and magnitude values, calculated using Morlet wavelet transformations, were used to derive total power and phase-locking measures.ResultsRelative to HC, SZ patients had significant deficits in total gamma power and phase-locking for both ASSR- and GBR-based measures. Within both groups, the 40 Hz ASSR and GBR phase-locking measures were significantly correlated, with a similar trend evident for the total power measures. Moreover, co-varying for GBR substantially reduced 40 Hz ASSR power and phase-locking differences between the groups.Conclusions40 Hz ASSR and transient GBR measures provide very similar information about auditory gamma abnormalities in schizophrenia, despite the overall enhancement of 40 Hz ASSR total power and phase-locking values relative to the corresponding GBR values.

BACKGROUND: Determining how patients distinguish auditory verbal hallucinations (AVHs) from their everyday thoughts may shed light on neurocognitive processes leading to these symptoms.MethodFifty patients reporting active AVHs ('voices') with a diagnosis of schizophrenia or schizo-affective disorder were surveyed using a structured questionnaire. Data were collected to determine: (a) the degree to which patients distinguished voices from their own thoughts; (b) the degree to which their thoughts had verbal form; and (c) the experiential basis for identifying experiences as voices versus their own verbal thoughts. Six characteristics of acoustic/verbal images were considered: (1) non-self speaking voice, (2) loudness, (3) clarity, (4) verbal content, (5) repetition of verbal content, and (6) sense of control. RESULTS: Four subjects were eliminated from the analysis because they reported absent verbal thought or a total inability to differentiate their own verbal thoughts from voices. For the remaining 46 patients, verbal content and sense of control were rated as most salient in distinguishing voices from everyday thoughts. With regard to sensory/perceptual features, identification of speaking voice as non-self was more important in differentiating voices from thought than either loudness or clarity of sound images. CONCLUSIONS: Most patients with schizophrenia and persistent AVHs clearly distinguish these experiences from their everyday thoughts. An adequate mechanistic model of AVHs should account for distinctive content, recognizable non-self speaking voices, and diminished sense of control relative to ordinary thought. Loudness and clarity of sound images appear to be of secondary importance in demarcating these hallucination experiences. [ABSTRACT FROM AUTHOR]

Context: The risk of vaccine-preventable diseases among children who have philosophical and religious exemptions from immunization has been understudied.Objectives: To evaluate whether personal exemption from immunization is associated with risk of measles and pertussis at individual and community levels.Design, Setting, and Participants: Population-based, retrospective cohort study using data collected on standardized forms regarding all reported measles and pertussis cases among children aged 3 to 18 years in Colorado during 1987-1998.Main Outcome Measures: Relative risk of measles and pertussis among exemptors and vaccinated children; association between incidence rates among vaccinated children and frequency of exemptors in Colorado counties; association between school outbreaks and frequency of exemptors in schools; and risk associated with exposure to an exemptor in measles outbreaks.Results: Exemptors were 22.2 times (95% confidence interval [CI], 15.9-31.1) more likely to acquire measles and 5.9 times (95% CI, 4.2-8.2) more likely to acquire pertussis than vaccinated children. After adjusting for confounders, the frequency of exemptors in a county was associated with the incidence rate of measles (relative risk [RR], 1.6; 95% CI, 1.0-2.4) and pertussis (RR, 1.9; 95% CI, 1.7-2.1) in vaccinated children. Schools with pertussis outbreaks had more exemptors (mean, 4.3% of students) than schools without outbreaks (1. 5% of students; P =.001). At least 11% of vaccinated children in measles outbreaks acquired infection through contact with an exemptor.Conclusions: The risk of measles and pertussis is elevated in personal exemptors. Public health personnel should recognize the potential effect of exemptors in outbreaks in their communities, and parents should be made aware of the risks involved in not vaccinating their children. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Two sequential outbreaks of respiratory disease among lifeguards at an indoor swimming pool with water spray features were investigated. METHODS: Questionnaires were administered to recreation center employees following each outbreak. Respondents reporting 2 or more pool-related symptoms were offered clinical evaluation, including bronchoscopy with bronchoalveolar lavage and transbronchial biopsy. Pool air and water were sampled for fungi, bacteria, amoebae, endotoxin, and respirable particulates. RESULTS: Thirty-three lifeguards had noncaseating granulomas on biopsy and/or bronchoalveolar lavage lymphocytosis. Attack rates for the outbreaks were 27% and 65%. Case patients had higher cumulative hours of work and tended to work more hours per week. Analyses indicated increased levels of endotoxin in pool air and water (relative to control pools) and gram-negative bacterial colonization of water sprays. Use of water spray features generated a 5.2-fold increase in the number of respirable particles and up to an 8-fold increase in air endotoxin levels. CONCLUSIONS: Lifeguards in this indoor swimming pool developed granulomatous lung disease associated with endotoxin-containing respirable bioaerosols from water spray features, which ventilation system improvements did not prevent. [ABSTRACT FROM AUTHOR]

Describes the first reported cases of blastomycosis acquired occupationally in Colorado in 1998. Medical conditions of the patients; Complaints from the patients; Factors that contributed to blastomycosis; Risk factors of blastomycosis.

We present a comprehensive study on the conformational behavior of diversely substituted 4-fluorotetrahydrothiopyran derivatives. Through quantum chemical simulations including DFT as well as NBO and NPA analysis, we elucidate the pivotal role of electrostatic interactions, occasionally complemented by hyperconjugative interactions, in stabilizing axial fluorine conformers. Less polar conformers were occasionally obtained, attributed to the interplay of electrostatic and hyperconjugative interactions. Experimental validation through NMR spectroscopy aligns with the computational analysis, thus providing a coherent understanding of the structural dynamics of these compounds., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

Titanium(IV) complexes of diaminobis(phenolato)-bis(alkoxo) ligands are promising anticancer drugs, showing marked in-vivo efficacy with no toxic side-effects in mice, hence, it is of interest to elucidate their mechanism of action. Herein, we employed a fluoro-substituted derivative, FenolaTi, for mechanistic analysis of the active species and its cellular target by quantitative 19 F NMR detection to reveal its biodistribution and reactivity in extracellular and intracellular matrices. Upon administration to the serum-containing medium, FenolaTi interacted with bovine serum albumin. 20 h post administration, the cellular accumulation of FenolaTi derivatives was estimated as 37% of the administered compound, in a concentration three orders-of-magnitude higher than the administered dose, implying that active membrane transportation facilitates cellular penetration. An additional 19% of the administered dose that was detected in the extracellular environment had originated from post-apoptotic cells. In the cell, interaction with cellular proteins was detected. Although some intact Ti(IV) complex localized in the nucleus, no signals for isolated DNA fractions were detected and no reactivity with nuclear proteins was observed. Interestingly, higher accumulation of FenolaTi-derived compounds in the endoplasmic reticulum (ER) and interaction with proteins therein were detected, supporting the role of the ER as a possible target for cytotoxic bis(phenolato)-bis(alkoxo) Ti(IV) complexes., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Thallium chemical shifts are very sensitive to chemical and physical conditions. This makes accurate chemical shift referencing difficult. Therefore, chemical shifts are usually referenced to the 1 H reference multiplied by a standard factor. However, past papers are referenced to TlNO 3 solution in water at infinite dilution. The chemical shift of TlNO 3 at infinite dilution is measured accurately and found to be -22.16 and 0.75 ppm for 203 Tl and 205 Tl, respectively relative to the standard frequency ratios to proton. The behavior of thallium chemical-shift with concentration and temperature are determined and discussed in relation to the degree of ionic association., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Usually a dedicated susceptometer is needed to measure diamagnetism accurately. An NMR spectrometer is more readily available in most chemistry departments but till now has been inaccurate for measuring diamagnetism. An improved NMR method is introduced to measure the magnetic susceptibility, or diamagnetism with similar absolute accuracy as other methods. This is achieved by accurate modelling of the NMR sample shape and response profile of the probe. The new method is validated by comparing the measured diamagnetism of water against the literature standard to within 0.05%. As a first example of its application, the diamagnetism of CDCl 3 was measured over a range of temperatures and used to reanalyze earlier measurements of the variation of the chemical shift of tetramethylsilane in CDCl 3 against 3 He gas. This improved on the accuracy and reliability of the result and will allow, for the first time, accurate studies of the absolute effect of temperature on chemical shift., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The accurate dissection of binding energies into their microscopic components is challenging, especially in solution. Here we study the binding of noble gases (He-Xe) with the macrocyclic receptor cucurbit[5]uril in water by displacement of methane and ethane as 1 H NMR probes. We dissect the hydration free energies of the noble gases into an attractive dispersive component and a repulsive one for formation of a cavity in water. This allows us to identify the contributions to host-guest binding and to conclude that the binding process is driven by differential cavitation energies rather than dispersion interactions. The free energy required to create a cavity to accept the noble gas inside the cucurbit[5]uril is much lower than that to create a similarly sized cavity in bulk water. The recovery of the latter cavitation energy drives the overall process, which has implications for the refinement of gas-storage materials and the understanding of biological receptors.

Omega fatty acids, mainly the triglyceride of docosahexaenoic acid (TG-DHA), are considered important nutraceuticals. These compounds are water-insoluble and their transport across membranes depends on their carriers. Dendrimers are known as drug carriers across cell membranes and also as permeation enhancers. The solubilization of TG-DHA and dendrimer into a microemulsion (ME) system serving as a carrier could be used for a targeted delivery in the future. The interactions between TG-DHA and second generation poly(propyleneimine) dendrimers (PPI-G2) and their effect on structural transitions of ME were explored along the water dilution line using electron paramagnetic resonance and pulsed-gradient spin-echo NMR along with other analytical techniques. The microviscosity, order parameter, and micropolarity of all studied systems decrease upon water dilution. Incorporation of TG-DHA reduces the microviscosity, order, and micropolarity, whereas PPI-G2 leads to an increase in these parameters. The effect of PPI-G2 is more pronounced at relative high contents (1 and 5wt%) where PPI-G2 interacts with the hydrophilic headgroups of the surfactants. In the macroscale, the effects of TG-DHA and PPI-G2 differ mostly in the bicontinuous region, where macroviscosity increases upon TG-DHA incorporation and decreases upon solubilization of 5wt% PPI-G2. From DSC measurements it was concluded that in the presence of TG-DHA the PPI-G2 is intercalated easily at the interface., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In microemulsions, changes in droplet size and shape and possible transformations occur under various conditions. They are difficult to characterize by most analytical tools because of their nano-sized structure and dynamic nature. Several methods are usually combined to obtain reliable information, guiding the scientist in understanding their physical behavior. We felt that there is a need for a technique that complements those in use today in order to provide more information on the microemulsion behavior, mainly as a function of dilution with water. The improvement of NMR chemical shift measurements independent of bulk magnetization effects makes it possible to study the very weak intermolecular chemical shift effects. In the present study, we used NMR high resolution magic angle spinning to measure the chemical shift very accurately, free of bulk magnetization effects. The chemical shift of microemulsion components is measured as a function of the water content in order to validate the method in an interesting and promising, U-type dilutable microemulsion, which had been previously studied by a variety of techniques. Phase transition points of the microemulsion (O/W, bicontinuous, W/O) and changes in droplet shape were successfully detected using high-accuracy chemical shift measurements. We analyzed the results and found them to be compatible with the previous studies, paving the way for high-accuracy chemical shifts to be used for the study of other microemulsion systems. We detected two transition points along the water dilution line of the concentrate (reverse micelles) corresponding to the transition from swollen W/O nano-droplets to bicontinuous to the O/W droplets along with the changes in the droplets' sizes and shapes. The method seems to be in excellent agreement with other previously studied techniques and shows the advantage of this easy and valid technique., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In our previous report we suggested a new analytical tool, high accuracy NMR chemical shift corrected for bulk magnetization as a supplementary tool to study structural transitions and droplet size and shape of dilutable microemulsions. The aim of this study was to show the generality of this technique and to demonstrate that in almost any type of microemulsion this technique provides additional valuable structural information. The analysis made by the technique adds to the elucidation of some structural aspects that could not be clearly determined by other classical techniques. Therefore, in this part we are extending the study to three additional systems differing in the type of oil phase (toluene and cyclohexane), the nature of the surfactants (anionic and nonionic), and other microemulsion characteristics. We studied sodium dodecyl sulfate (SDS)-based anionic microemulsions with different oils and a nonionic microemulsion based on Tween 20 as the surfactant and toluene as the oil phase. All the microemulsions were fully dilutable with water. We found that the change in the slope of chemical shift against dilution reflects phase transition points of the microemulsion (O/W, bicontinuous, W/O). Chemical shift changes were clearly observed with the transition between spherical and non-spherical (wormlike, etc.) droplet shapes. We compared the interaction of cyclohexane and toluene and used the anisotropic effect of toluene's ring current to determine its preferred orientation relative to SDS. Chemical shifts of the microemulsion components are therefore a useful addition to the arsenal of techniques for characterizing microemulsions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We explore how hallucinations might be studied within the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) framework, which asks investigators to step back from diagnoses based on symptoms and focus on basic dimensions of functioning. We start with a description of the objectives of the RDoC project and its domains and constructs. Because the RDoC initiative asks investigators to study phenomena across the wellness spectrum and different diagnoses, we address whether hallucinations experienced in nonclinical populations are the same as those experienced by people with psychotic diagnoses, and whether hallucinations studied in one clinical group can inform our understanding of the same phenomenon in another. We then discuss the phenomenology of hallucinations and how different RDoC domains might be relevant to their study. We end with a discussion of various challenges and potential next steps to advance the application of the RDoC approach to this area of research., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Auditory/verbal hallucinations (AVHs) are accompanied by activation in Wernicke's and right homologous regions. Efficacy in curtailing AVHs via 1-Hz repetitive magnetic stimulation (rTMS) targeting a site in each region ("W" and "rW") was therefore studied., Methods: Patients with schizophrenia and AVHs (N = 83) were randomly allocated to double-masked rTMS versus sham stimulation, with blocks of five sessions given to W and rW in random order, followed by five sessions to the site yielding greater improvement. The primary outcome measure was the Hallucination Change Score (HCS). Hallucination frequency, total auditory hallucination rating scale score, and clinical global improvement were secondary outcome measures. Attentional salience of AVHs and neuropsychological measures of laterality were studied as predictors of site-specific response., Results: After 15 sessions, rTMS produced significant improvements relative to sham stimulation for hallucination frequency and clinical global improvement but not for HCS. After limiting analyses to patients whose motor threshold was detected consistently: 1) endpoint HCS demonstrated significantly greater improvement for rTMS compared with sham stimulation; 2) for high-salience AVHs, rTMS to rW after the first five sessions yielded significantly improved HCS scores relative to sham stimulation, whereas for low salience AVHs, rTMS to W produced this finding. Nondominant motor impairment correlated positively with hallucination improvement following rW rTMS., Conclusions: One-hertz rTMS per our site-optimization protocol produced some clinical benefit in patients with persistent AVHs as a group, especially when motor threshold was consistently detected. Level of hallucination salience may usefully guide selection of W versus rW as intervention sites., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: In electroencephalogram (EEG) studies of auditory steady-state responses (ASSRs), patients with schizophrenia show a deficit in power and/or phase-locking, particularly at the 40 Hz frequency where these responses resonate. In addition, studies of the transient gamma-band response (GBR) elicited by single tones have revealed deficits in gamma power and phase-locking in schizophrenia. We examined the degree to which the 40 Hz ASSR and the transient GBR to single tones are correlated and whether they assess overlapping or distinct gamma-band abnormalities in schizophrenia., Methods: EEG was recorded during 40 Hz ASSR and auditory oddball paradigms from 28 patients with schizophrenia or schizoaffective disorder (SZ) and 25 age- and gender-matched healthy controls (HC). The ASSR was elicited by 500 ms click trains, and the transient GBR was elicited by the standard tones from the oddball paradigm. Gamma phase and magnitude values, calculated using Morlet wavelet transformations, were used to derive total power and phase-locking measures., Results: Relative to HC, SZ patients had significant deficits in total gamma power and phase-locking for both ASSR- and GBR-based measures. Within both groups, the 40 Hz ASSR and GBR phase-locking measures were significantly correlated, with a similar trend evident for the total power measures. Moreover, co-varying for GBR substantially reduced 40 Hz ASSR power and phase-locking differences between the groups., Conclusions: 40 Hz ASSR and transient GBR measures provide very similar information about auditory gamma abnormalities in schizophrenia, despite the overall enhancement of 40 Hz ASSR total power and phase-locking values relative to the corresponding GBR values.

The NMR chromatography method is applied to a class of molecules with similar physical properties. We correlate the separation ability of microemulsions to the physical properties of the analyzed molecules. Flavor and aroma compounds are very widespread. Compositional analysis is in many cases tedious. Any new method of analysis is always useful and challenging. Here we show a new application to a class of fragrance molecules, with only a moderate variation in their chemical and physical characteristics. Up to 11 selected compounds in one mixture are resolved in one spectrum by NMR chromatography, despite the similarity of the compounds. The differences between O/W and W/O microemulsions and their resolution mechanism as applied to fragrance molecules are explained in terms of hydrophilicity and lipophilicity and effective critical packing parameters of the microemulsions. The observed diffusion rates are shown to correlate with solvation parameters. These results can be used to estimate the diffusion rates of molecules to be separated, allowing selection of the microemulsion or NMR chromatography solvent appropriate for each specific application., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Functional connectivity (FC) studies of brain mechanisms leading to auditory verbal hallucinations (AVHs) utilizing functional magnetic resonance imaging (fMRI) data are reviewed. Initial FC studies utilized fMRI data collected during performance of various tasks, which suggested frontotemporal disconnection and/or source-monitoring disturbances. Later FC studies have utilized resting (no-task) fMRI data. These studies have produced a mixed picture of disconnection and hyperconnectivity involving different pathways associated with AVHs. Results of our most recent FC study of AVHs are reviewed in detail. This study suggests that the core mechanism producing AVHs involves not a single pathway, but a more complex functional loop. Components of this loop include Wernicke's area and its right homologue, the left inferior frontal cortex, and the putamen. It is noteworthy that the putamen appears to play a critical role in the generation of spontaneous language, and in determining whether auditory stimuli are registered consciously as percepts. Excessive functional coordination linking this region with the Wernicke's seed region in patients with schizophrenia could, therefore, generate an overabundance of potentially conscious language representations. In our model, intact FC in the other two legs of corticostriatal loop (Wernicke's with left IFG, and left IFG with putamen) appeared to allow hyperconnectivity linking the putamen and Wernicke's area (common to schizophrenia overall) to be expressed as conscious hallucinations of speech. Recommendations for future studies are discussed, including inclusion of multiple methodologies applied to the same subjects in order to compare and contrast different mechanistic hypotheses, utilizing EEG to better parse time-course of neural synchronization leading to AVHs, and ascertaining experiential subtypes of AVHs that may reflect distinct mechanisms.

Background: Various malfunctions involving working memory, semantics, prediction error, and dopamine neuromodulation have been hypothesized to cause disorganized speech and delusions in schizophrenia. Computational models may provide insights into why some mechanisms are unlikely, suggest alternative mechanisms, and tie together explanations of seemingly disparate symptoms and experimental findings., Methods: Eight corresponding illness mechanisms were simulated in DISCERN, an artificial neural network model of narrative understanding and recall. For this study, DISCERN learned sets of autobiographical and impersonal crime stories with associated emotion coding. In addition, 20 healthy control subjects and 37 patients with schizophrenia or schizoaffective disorder matched for age, gender, and parental education were studied using a delayed story recall task. A goodness-of-fit analysis was performed to determine the mechanism best reproducing narrative breakdown profiles generated by healthy control subjects and patients with schizophrenia. Evidence of delusion-like narratives was sought in simulations best matching the narrative breakdown profile of patients., Results: All mechanisms were equivalent in matching the narrative breakdown profile of healthy control subjects. However, exaggerated prediction-error signaling during consolidation of episodic memories, termed hyperlearning, was statistically superior to other mechanisms in matching the narrative breakdown profile of patients. These simulations also systematically confused autobiographical agents with impersonal crime story agents to model fixed, self-referential delusions., Conclusions: Findings suggest that exaggerated prediction-error signaling in schizophrenia intermingles and corrupts narrative memories when incorporated into long-term storage, thereby disrupting narrative language and producing fixed delusional narratives. If further validated by clinical studies, these computational patients could provide a platform for developing and testing novel treatments., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

NMR spectroscopy is an excellent tool for structural analysis of pure compounds. However, for mixtures, it performs poorly because of overlapping signals. Diffusion ordered NMR spectroscopy (DOSY) can be used to separate the spectra of compounds with widely differing molecular weights, but the separation is usually insufficient. NMR "chromatographic" methods have been developed to increase the diffusion separation but these usually introduced solids into the NMR sample that reduce resolution. Using nanostructured dispersed media, such as microemulsions, eliminates the need for suspensions of solids and brings NMR chromatography into the mainstream of NMR analytical techniques. DOSY was used in this study to resolve spectra of mixtures with no increase in line-width as compared to regular solutions. Components of a mixture are differentially dissolved into the separate phases of the microemulsions. Several examples of previously reported microemulsions and those specifically developed for this purpose were used here. These include a fully dilutable microemulsion, a fluorinated microemulsion, and a fully deuterated microemulsion. Log(diffusion) difference enhancements of up to 1.7 orders of magnitude were observed for compounds that have similar diffusion rates in conventional solvents. Examples of commercial pharmaceutical drugs were also analyzed via this new technique, and the spectra of up to six components were resolved from one sample., (© 2011 American Chemical Society)

Background: The pathophysiology of auditory verbal hallucinations remains poorly understood., Aims: To characterise the time course of regional brain activity leading to auditory verbal hallucinations., Method: During functional magnetic resonance imaging, 11 patients with schizophrenia or schizoaffective disorder signalled auditory verbal hallucination events by pressing a button. To control for effects of motor behaviour, regional activity associated with hallucination events was scaled against corresponding activity arising from random button-presses produced by 10 patients who did not experience hallucinations., Results: Immediately prior to the hallucinations, motor-adjusted activity in the left inferior frontal gyrus was significantly greater than corresponding activity in the right inferior frontal gyrus. In contrast, motor-adjusted activity in a right posterior temporal region overshadowed corresponding activity in the left homologous temporal region. Robustly elevated motor-adjusted activity in the left temporal region associated with auditory verbal hallucinations was also detected, but only subsequent to hallucination events. At the earliest time shift studied, the correlation between left inferior frontal gyrus and right temporal activity was significantly higher for the hallucination group compared with non-hallucinating patients., Conclusions: Findings suggest that heightened functional coupling between the left inferior frontal gyrus and right temporal regions leads to coactivation in these speech processing regions that is hallucinogenic. Delayed left temporal activation may reflect impaired corollary discharge contributing to source misattribution of resulting verbal images.

Background: Higher levels of inter-region functional coordination can facilitate emergence of neural activity as conscious percepts. We consequently tested the hypothesis that auditory/verbal hallucinations (AVHs) arise from elevated functional coordination within a speech processing network., Methods: Functional coordination was indexed with functional connectivity (FC) computed from functional magnetic resonance imaging data. Thirty-two patients with schizophrenia reporting AVHs, 24 similarly diagnosed patients without hallucinations, and 23 healthy control subjects were studied. FC was seeded from a bilateral Wernicke's region delineated according to activation detected during AVHs in a prior study., Results: Wernicke's-seeded FC with Brodmann area 45/46 of the left inferior frontal gyrus (IFG) was significantly greater for hallucinating patients compared with nonhallucinating patients but not compared with healthy control subjects. In contrast, Wernicke's-seeded FC with a large subcortical region that included the thalamus, midbrain, and putamen was significantly greater for the combined patient group compared with healthy control subjects after false discovery rate correction, but not when comparing the two patient groups. Within that subcortical domain, the putamen demonstrated significantly greater FC relative to a secondary left IFG seed region when hallucinators were compared with nonhallucinating patients. A follow-up analysis found that FC summed along a loop linking the Wernicke's and IFG seed regions and the putamen was robustly greater for hallucinating patients compared with nonhallucinating patients and healthy control subjects., Conclusions: These findings suggest that higher levels of functional coordination intrinsic to a corticostriatal loop comprise a causal factor leading to AVHs in schizophrenia., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

It is widely accepted that indigo dyes derived from Murex trunculus were used to produce the biblical dyes tekhelet and argaman. We describe a method of following the debromination of natural leucoindigos and their binding to wool using NMR spectroscopy. Debromination is observed prior to reaction with the wool and prior to oxidation. Binding to the wool is shown to occur prior to oxidation. NMR allows the dyeing process to be followed. This, in principle, could be used to correct problems during dyeing that would increase the reliability of the process., (2010 John Wiley & Sons, Ltd.)

Introduction: Reduction of P300 event-related potential amplitude in schizophrenia is perhaps the most replicated biological reflection of the illness. P300 is typically elicited by infrequent deviant events that are imbedded in a series of identical frequent standard events. Deviants have features that explicitly distinguish them from standards, whereas standards can be distinguished from each other based on their local sequential probabilities within the stimulus series. The improbable occurrence of a standard should generate a P300, but only if the implicit local context generated by the recent stimulus history is processed., Method: To assess the ability of schizophrenia patients to process this implicit contextual information, ERPs were elicited from 22 controls and 16 schizophrenia patients during an auditory oddball task containing infrequent target tones (15%) and novel distracter sounds (15%) imbedded pseudo-randomly in a series of standard tones (70%). Consecutively presented standards following deviant stimuli varied in sequential probability from p=1.0 for the 1st standard to p=0.16 for the 4th consecutive standard., Results: Patients compared to controls demonstrated smaller P300 (P3a) to the fourth consecutive standard. However, in controls but not patients a contingent negative variation (CNV) was observed prior to the fourth standard, and an N2b/mismatch negativity (MMN) was observed following it., Conclusions: These outcomes suggest that patients are deficient in using the implicit context established by recent stimulus history to anticipate that an otherwise standard stimulus was unlikely and its occurrence unexpected., (2010. Published by Elsevier B.V.)

There has been an increasing emphasis on characterizing pathophysiology underlying psychiatric and neurological disorders in terms of altered neural connectivity and network dynamics. Transcranial magnetic stimulation (TMS) provides a unique opportunity for investigating connectivity in the human brain. TMS allows researchers and clinicians to directly stimulate cortical regions accessible to electromagnetic coils positioned on the scalp. The induced activation can then propagate through long-range connections to other brain areas. Thus, by identifying distal regions activated during TMS, researchers can infer connectivity patterns in the healthy human brain and can examine how those patterns may be disrupted in patients with different brain disorders. Conversely, connectivity maps derived using neuroimaging methods can identify components of a dysfunctional network. Nodes in this dysfunctional network accessible as targets for TMS by virtue of their proximity to the scalp may then permit TMS-induced alterations of components of the network not directly accessible to TMS via propagated effects. Thus TMS can provide a portal for accessing and altering neural dynamics in networks that are widely distributed anatomically. Finally, when long-term modulation of network dynamics is induced by trains of repetitive TMS, changes in functional connectivity patterns can be studied in parallel with changes in patient symptoms. These correlational data can elucidate neural mechanisms underlying illness and recovery. In this review, we focus on the application of these approaches to the study of psychiatric and neurological illnesses.

Silvano Arieti proposed that auditory/verbal hallucinations (AVHs) are triggered by momentary states of heightened auditory attention that he identified as a "listening attitude." Studies and clinical observations by our group support this view. Patients enrolled in our repetitive transcranial magnetic stimulation trials, if experiencing a significant curtailment of these hallucinations, often report an episodic sense that their voices are still occurring even if they no longer can be heard, suggesting episodic states of heightened auditory expectancy. Moreover, a functional magnetic resonance study reported by our group detected activation in the left insula prior to hallucination events. This finding is suggestive of activation in the same region detected in healthy subjects during "auditory search" in response to ambiguous sounds when anticipating meaningful speech. AVHs often are experienced with a deep emotional salience and may occur in the context of dramatic social isolation that together could reinforce heightened auditory expectancy. These findings and clinical observations suggest that Arieti's original formulation deserves further study.

Schizoaffective disorder (SA) is distinguished from schizophrenia (SZ) based on the presence of prominent mood symptoms over the illness course. Despite this clinical distinction, SA and SZ patients are often combined in research studies, in part because data supporting a distinct pathophysiological boundary between the disorders are lacking. Indeed, few studies have addressed whether neurobiological abnormalities associated with SZ, such as the widely replicated reduction and delay of the P300 event-related potential (ERP), are also present in SA. Scalp EEG was acquired from patients with DSM-IV SA (n = 15) or SZ (n = 22), as well as healthy controls (HC; n = 22) to assess the P300 elicited by infrequent target (15%) and task-irrelevant distractor (15%) stimuli in separate auditory and visual "oddball" tasks. P300 amplitude was reduced and delayed in SZ, relative to HC, consistent with prior studies. These SZ abnormalities did not interact with stimulus type (target vs. task-irrelevant distractor) or modality (auditory vs. visual). Across sensory modality and stimulus type, SA patients exhibited normal P300 amplitudes (significantly larger than SZ patients and indistinguishable from HC). However, P300 latency and reaction time were both equivalently delayed in SZ and SA patients, relative to HC. P300 differences between SA and SZ patients could not be accounted for by variation in symptom severity, socio-economic status, education, or illness duration. Although both groups show similar deficits in processing speed, SA patients do not exhibit the P300 amplitude deficits evident in SZ, consistent with an underlying pathophysiological boundary between these disorders.

Current treatments for psychiatric disorders were developed with the aim of providing symptomatic relief rather than reversing underlying abnormalities in neuroplasticity or neurodevelopment that might contribute to psychiatric disorders. This review considers the possibility that psychiatric treatments might be developed that target neuroplasticity deficits or that manipulate neuroplasticity in novel ways. These treatments might not provide direct symptomatic relief. However, they might complement or enhance current pharmacotherapies and psychotherapies aimed at the prevention and treatment of psychiatric disorders. In considering neuroplasticity as a target for the treatment of psychiatric disorders, we build on exciting new findings in the areas of anxiety disorders, mood disorders, and schizophrenia.

The time course of brain activation prior to onset of auditory/verbal hallucinations was characterised using functional magnetic resonance imaging in six dextral patients with schizophrenia. Composite maps of pre-hallucination periods revealed activation in the left anterior insula and in the right middle temporal gyrus, partially replicating two previous case reports, as well as deactivation in the anterior cingulate and parahippocampal gyri. These findings may reflect brain events that trigger or increase vulnerability to auditory/verbal hallucinations.

NMR spectroscopy is an excellent tool for the structural analysis of pure compounds. However, for mixtures it performs poorly because of overlapping signals. Diffusion can be used to separate compounds of widely differing molecular weight but the amount of separation is usually insufficient. Addition of a solid medium, analogous to the stationary phase in chromatography, can preferentially slow the diffusion of some components of a mixture permitting separation in the diffusion dimension. However, this would usually require a solid-state NMR spectrometer otherwise the signals would be too broad. Susceptibility matching the solvent to the solid medium yields a spectrum with narrow signals allowing the measurement of a DOSY spectrum with enhanced separation in the diffusion dimension.

We studied the effect of a model electrolytic drug on intermolecular interactions, conformational changes, and phase transitions in structured discontinuous cubic QL lyotropic liquid crystals. These changes were due to competition with hydration of the lipid headgroups. Structural changes of the phase induced by solubilization loads of sodium diclofenac (Na-DFC) were investigated by directly observing the water, ethanol, and Na-DFC components of the resulting phases using 2H and 23Na NMR. Na-DFC interacted with the surfactant glycerol monoolein (GMO) at the interface while interfering with the mesophase curvature and also competed with hydration of the surfactant headgroups. Increasing quantities of solubilized Na-DFC promoted phase transitions from cubic phase (discontinuous (QL) and bicontinuous (Q)) into lamellar structures and subsequently into a disordered lamellar phase. Quadrupolar coupling of deuterated ethanol by 2H NMR showed that it is located near the headgroups of the lipid and apparently is hydrogen bonded to the GMO headgroups. A phase transition between two lamellar phases (L alpha to L alpha*) was seen by 23Na NMR of Na-DFC at a concentration where the characteristics of the drug change from kosmotropic to chaotropic. These findings show that loads of solubilized drug may affect the structure of its vehicle and, as a result, its transport across skin-blood barriers. The structural changes of the mesophase may also aid controlled drug delivery.

IUPAC has published a number of recommendations regarding the reporting of nuclear magnetic resonance (NMR) data, especially chemical shifts. The most recent publication [Pure Appl. Chem. 73, 1795 (2001)] recommended that tetramethylsilane (TMS) serve as a universal reference for reporting the shifts of all nuclides, but it deferred recommendations for several aspects of this subject. This document first examines the extent to which the (1)H shielding in TMS itself is subject to change by variation in temperature, concentration, and solvent. On the basis of recently published results, it has been established that the shielding of TMS in solution [along with that of sodium-3-(trimethylsilyl)propanesulfonate, DSS, often used as a reference for aqueous solutions] varies only slightly with temperature but is subject to solvent perturbations of a few tenths of a part per million (ppm). Recommendations are given for reporting chemical shifts under most routine experimental conditions and for quantifying effects of temperature and solvent variation, including the use of magnetic susceptibility corrections and of magic-angle spinning (MAS). This document provides the first IUPAC recommendations for referencing and reporting chemical shifts in solids, based on high-resolution MAS studies. Procedures are given for relating (13)C NMR chemical shifts in solids to the scales used for high-resolution studies in the liquid phase. The notation and terminology used for describing chemical shift and shielding tensors in solids are reviewed in some detail, and recommendations are given for best practice., (Copyright (c) 2008 John Wiley & Sons, Ltd)

Auditory/verbal hallucinations (AVHs) are comprised of spoken conversational speech seeming to arise from specific, nonself speakers. One hertz repetitive transcranial magnetic stimulation (rTMS) reduces excitability in the brain region stimulated. Studies utilizing 1-Hz rTMS delivered to the left temporoparietal cortex, a brain area critical to speech perception, have demonstrated statistically significant improvements in AVHs relative to sham simulation. A novel mechanism of AVHs is proposed whereby dramatic pre-psychotic social withdrawal prompts neuroplastic reorganization by the "social brain" to produce spurious social meaning via hallucinations of conversational speech. Preliminary evidence supporting this hypothesis includes a very high rate of social withdrawal emerging prior to the onset of frank psychosis in patients who develop schizophrenia and AVHs. Moreover, reduced AVHs elicited by temporoparietal 1-Hz rTMS are likely to reflect enhanced long-term depression. Some evidence suggests a loss of long-term depression following experimentally-induced deafferentation. Finally, abnormal cortico-cortical coupling is associated with AVHs and also is a common outcome of deafferentation. Auditory/verbal hallucinations (AVHs) of spoken speech or "voices" are reported by 60-80% of persons with schizophrenia at various times during the course of illness. AVHs are associated with high levels of distress, functional disability, and can lead to violent acts. Among patients with AVHs, these symptoms remain poorly or incompletely responsive to currently available treatments in approximately 25% of cases. For patients with AVHs who do respond to antipsychotic drugs, there is a very high likelihood that these experiences will recur in subsequent episodes. A more precise characterization of underlying pathophysiology may lead to more efficacious treatments.

Functional magnetic resonance imaging and repetitive transcranial magnetic stimulation (rTMS) were used to explore the pathophysiology of auditory/verbal hallucinations (AVHs). Sixteen patients with schizophrenia-spectrum disorder were studied with continuous or near continuous AVHs. For patients with intermittent hallucinations (N = 8), blood oxygenation level-dependent (BOLD) activation maps comparing hallucination and nonhallucination periods were generated. For patients with continuous hallucinations (N = 8) correlations between BOLD signal time course in Wernicke's area, and other regions were used to map functional coupling to the former. These maps were used to identify 3-6 cortical sites per patient that were probed with 1-Hz rTMS and sham stimulation. Delivering rTMS to left temporoparietal sites in Wernicke's area and the adjacent supramarginal gyrus was accompanied by a greater rate of AVH improvement compared with sham stimulation and rTMS delivered to anterior temporal sites. For intermittent hallucinators, lower levels of hallucination-related activation in Broca's area strongly predicted greater rate of response to left temporoparietal rTMS. For continuous hallucinators, reduced coupling between Wernicke's and a right homologue of Broca's area strongly predicted greater left temporoparietal rTMS rate of response. These findings suggest that dominant hemisphere temporoparietal areas are involved in expressing AVHs, with higher levels of coactivation and/or coupling involving inferior frontal regions reinforcing underlying pathophysiology.

Atendency to extract spurious, message-like meaning from meaningless noise was assessed as a risk factor leading to schizophrenia-spectrum disorders by assessing word length of speech illusions elicited by multispeaker babble in 43 people with prodromal symptoms. These individuals were randomised to olanzapine v. placebo groups during year 1 followed by no pharmacological treatment for those with no disorder conversion during year 2. A time-dependent Cox regression analysis of conversion to schizophrenia-spectrum disorder revealed a significant interaction between condition (olanzapine v. no drug) and length of speech illusion, with the latter strongly predicting subsequent conversion during medication-free intervals but not during olanzapine treatment.

The "social brain" of humans reflects widespread neural resources dedicated to understanding the conversational language, emotionality, states of mind, and intentions of other persons. A social deafferentation (SDA) hypothesis for induction of active schizophrenia is proposed. Analogous to hallucinations produced by sensory deafferentation, such as phantom limb, the SDA hypothesis assumes that high levels of social withdrawal/isolation in vulnerable individuals prompt social cognition programs to produce spurious social meaning in the form of complex, emotionally compelling hallucinations and delusions representing other persons or agents. Arguments against the SDA hypothesis are discussed, and predictions deriving from the hypothesis are offered.

Objective: The neurocognitive basis of verbal/auditory hallucinations remains uncertain. A leading hypothesis is that these hallucinations correspond to ordinary inner speech mislabeled as non-self. However, some studies suggest pathogenic activation of receptive language neurocircuitry as the cause. A form of visualized verbal hallucinations not previously reported in the literature is described that may shed light on this controversy., Method: Review of three cases., Results: Two patients described visual hallucinations of speech-like lip and mouth movements fused with simultaneous auditory verbal hallucinations superimposed on perceptions of faces of actual persons in their immediate environment. A third patient described similar experiences incorporated into visual hallucinations of human figures who also exhibited finger and hand movements corresponding to American Sign Language., Conclusion: These fused, multimodal verbal hallucinations seem unlikely to be due to inner speech mislabeled as non-self, and instead suggest top-down re-shaping of activation in visual processing brain centers by pathogenically active receptive language neurocircuitry.

The standard for chemical shift is dilute tetramethylsilane (TMS) in CDCl3, but many measurements are made relative to TMS in other solvents, the proton resonance of the solvent peak or relative to the lock frequency. Here, the chemical shifts of TMS and the proton and deuterium chemical shifts of the solvent signals of several solvents are measured over a wide temperature range. This allows for the use of TMS or the solvent and lock signal as a secondary reference for other NMR signals, as compared with dilute TMS in CDCl3 at a chosen temperature; 25 degrees C is chosen here. An accuracy of 0.02 ppm is achievable for dilute solutions, provided that the interaction with the solvent is not very strong. The proton chemical shift of residual water is also reported where appropriate., (2006 John Wiley & Sons, Ltd.)