Test-retest reliability of time-frequency measures of auditory steady-state responses in patients with schizophrenia and healthy controls.

BackgroundAuditory steady-state response (ASSR) paradigms have consistently demonstrated gamma band abnormalities in schizophrenia at a 40-Hz driving frequency with both electroencephalography (EEG) and magnetoencephalography (MEG). Various time-frequency measures have been used to assess the 40-Hz ASSR, including evoked power, single trial total power, phase-locking factor (PLF), and phase-locking angle (PLA). While both EEG and MEG studies have shown power and PLF ASSR measures to exhibit excellent test-retest reliability in healthy adults, the reliability of these measures in patients with schizophrenia has not been determined.MethodsASSRs were obtained by recording EEG data during presentation of repeated 20-Hz, 30-Hz and 40-Hz auditory click trains from nine schizophrenia patients (SZ) and nine healthy controls (HC) tested on two occasions. Similar ASSR data were collected from a separate group of 30 HC on two to three test occasions. A subset of these HC subjects had EEG recordings during two tasks, passively listening and actively attending to click train stimuli. Evoked power, total power, PLF, and PLA were calculated following Morlet wavelet time-frequency decomposition of EEG data and test-retest generalizability (G) coefficients were calculated for each ASSR condition, time-frequency measure, and subject group.ResultsG-coefficients ranged from good to excellent (> 0.6) for most 40-Hz time-frequency measures and participant groups, whereas 20-Hz G-coefficients were much more variable. Importantly, test-retest reliability was excellent for the various 40-Hz ASSR measures in SZ, similar to reliabilities in HC. Active attention to click train stimuli modestly reduced G-coefficients in HC relative to the passive listening condition.DiscussionThe excellent test-retest reliability of 40-Hz ASSR measures replicates previous EEG and MEG studies. PLA, a relatively new time-frequency measure, was shown for the first time to have excellent reliability, comparable to power and PLF measures. Excellent reliability of 40 Hz ASSR measures in SZ supports their use in clinical trials and longitudinal observational studies

What Brown saw and you can too

A discussion is given of Robert Brown's original observations of particles ejected by pollen of the plant \textit{Clarkia pulchella} undergoing what is now called Brownian motion. We consider the nature of those particles, and how he misinterpreted the Airy disc of the smallest particles to be universal organic building blocks. Relevant qualitative and quantitative investigations with a modern microscope and with a "homemade" single lens microscope similar to Brown's, are presented.Comment: 14.1 pages, 11 figures, to be published in the American Journal of Physics. This differs from the previous version only in the web site referred to in reference 3. Today, this Brownian motion web site was launched, and http://physerver.hamilton.edu/Research/Brownian/index.html, is now correc

Aberrant activity in conceptual networks underlies N400 deficits and unusual thoughts in schizophrenia.

BackgroundThe N400 event-related potential (ERP) is triggered by meaningful stimuli that are incongruous, or unmatched, with their semantic context. Functional magnetic resonance imaging (fMRI) studies have identified brain regions activated by semantic incongruity, but their precise links to the N400 ERP are unclear. In schizophrenia (SZ), N400 amplitude reduction is thought to reflect overly broad associations in semantic networks, but the abnormalities in brain networks underlying deficient N400 remain unknown. We utilized joint independent component analysis (JICA) to link temporal patterns in ERPs to neuroanatomical patterns from fMRI and investigate relationships between N400 amplitude and neuroanatomical activation in SZ patients and healthy controls (HC).MethodsSZ patients (n = 24) and HC participants (n = 25) performed a picture-word matching task, in which words were either matched (APPLE→apple) by preceding pictures, or were unmatched by semantically related (in-category; IC, APPLE→lemon) or unrelated (out of category; OC, APPLE→cow) pictures, in separate ERP and fMRI sessions. A JICA "data fusion" analysis was conducted to identify the fMRI brain regions specifically associated with the ERP N400 component. SZ and HC loading weights were compared and correlations with clinical symptoms were assessed.ResultsJICA identified an ERP-fMRI "fused" component that captured the N400, with loading weights that were reduced in SZ. The JICA map for the IC condition showed peaks of activation in the cingulate, precuneus, bilateral temporal poles and cerebellum, whereas the JICA map from the OC condition was linked primarily to visual cortical activation and the left temporal pole. Among SZ patients, fMRI activity from the IC condition was inversely correlated with unusual thought content.ConclusionsThe neural networks associated with the N400 ERP response to semantic violations depends on conceptual relatedness. These findings are consistent with a distributed network underlying neural responses to semantic incongruity including unimodal visual areas as well as integrative, transmodal areas. Unusual thoughts in SZ may reflect impaired processing in transmodal hub regions such as the precuneus, leading to overly broad semantic associations

Role of N-methyl-D-aspartate receptors in action-based predictive coding deficits in schizophrenia

Published in final edited form as:Biol Psychiatry. 2017 March 15; 81(6): 514–524. doi:10.1016/j.biopsych.2016.06.019.BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia. METHODS: In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared. RESULTS: N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen’s d = 1.14) and schizophrenia (Cohen’s d = .85). CONCLUSIONS: Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.This work was supported by AstraZeneca for an investigator-initiated study (DHM) and the National Institute of Mental Health Grant Nos. R01 MH-58262 (to JMF) and T32 MH089920 (to NSK). JHK was supported by the Yale Center for Clinical Investigation Grant No. UL1RR024139 and the US National Institute on Alcohol Abuse and Alcoholism Grant No. P50AA012879. (AstraZeneca for an investigator-initiated study (DHM); R01 MH-58262 - National Institute of Mental Health; T32 MH089920 - National Institute of Mental Health; UL1RR024139 - Yale Center for Clinical Investigation; P50AA012879 - US National Institute on Alcohol Abuse and Alcoholism)Accepted manuscrip

Did I Do That? Abnormal Predictive Processes in Schizophrenia When Button Pressing to Deliver a Tone

Motor actions are preceded by an efference copy of the motor command, resulting in a corollary discharge of the expected sensation in sensory cortex. These mechanisms allow animals to predict sensations, suppress responses to self-generated sensations, and thereby process sensations efficiently and economically. During talking, patients with schizophrenia show less evidence of pretalking activity and less suppression of the speech sound, consistent with dysfunction of efference copy and corollary discharge, respectively. We asked if patterns seen in talking would generalize to pressing a button to hear a tone, a paradigm translatable to less vocal animals. In 26 patients [23 schizophrenia, 3 schizoaffective (SZ)] and 22 healthy controls (HC), suppression of the N1 component of the auditory event-related potential was estimated by comparing N1 to tones delivered by button presses and N1 to those tones played back. The lateralized readiness potential (LRP) associated with the motor plan preceding presses to deliver tones was estimated by comparing right and left hemispheres' neural activity. The relationship between N1 suppression and LRP amplitude was assessed. LRP preceding button presses to deliver tones was larger in HC than SZ, as was N1 suppression. LRP amplitude and N1 suppression were correlated in both groups, suggesting stronger efference copies are associated with stronger corollary discharges. SZ have reduced N1 suppression, reflecting corollary discharge action, and smaller LRPs preceding button presses to deliver tones, reflecting the efference copy of the motor plan. Effects seen during vocalization largely extend to other motor acts more translatable to lab animals

Pharmaceutical induction of ApoE secretion by multipotent mesenchymal stromal cells (MSCs)

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein E (ApoE) is a molecular scavenger in the blood and brain. Aberrant function of the molecule causes formation of protein and lipid deposits or "plaques" that characterize Alzheimer's disease (AD) and atherosclerosis. There are three human isoforms of ApoE designated ε2, ε3, and ε4. Each isoform differentially affects the structure and function of the protein and thus the development of disease. Homozygosity for ApoE ε4 is associated with atherosclerosis and Alzheimer's disease whereas ApoE ε2 and ε3 tend to be protective. Furthermore, the ε2 form may cause forms of hyperlipoproteinemia. Therefore, introduction of ApoE ε3 may be beneficial to patients that are susceptible to or suffering from these diseases. Mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) are adult progenitor cells found in numerous tissues. They are easily expanded in culture and engraft into host tissues when administered appropriately. Furthermore, MSCs are immunosuppressive and have been reported to engraft as allogeneic transplants. In our previous study, mouse MSCs (mMSCs) were implanted into the brains of ApoE null mice, resulting in production of small amounts of ApoE in the brain and attenuation of cognitive deficits. Therefore human MSCs (hMSCs) are a promising vector for the administration of ApoE ε3 in humans.</p> <p>Results</p> <p>Unlike mMSCs, hMSCs were found not to express ApoE in culture; therefore a molecular screen was performed for compounds that induce expression. PPARγ agonists, neural stem cell conditioned medium, osteo-inductive media, dexamethasone, and adipo-inductive media (AIM) were tested. Of the conditions tested, only AIM or dexamethasone induced sustained secretion of ApoE in MSCs and the duration of secretion was only limited by the length of time MSCs could be sustained in culture. Upon withdrawal of the inductive stimuli, the ApoE secretion persisted for a further 14 days.</p> <p>Conclusion</p> <p>The data demonstrated that pre-treatment and perhaps co-administration of MSCs homozygous for ApoE ε3 and dexamethasone may represent a novel therapy for severe instances of AD, atherosclerosis and other ApoE-related diseases.</p

A Search for Exozodiacal Clouds with Kepler

Planets embedded within dust disks may drive the formation of large scale clumpy dust structures by trapping dust into resonant orbits. Detection and subsequent modeling of the dust structures would help constrain the mass and orbit of the planet and the disk architecture, give clues to the history of the planetary system, and provide a statistical estimate of disk asymmetry for future exoEarth-imaging missions. Here we present the first search for these resonant structures in the inner regions of planetary systems by analyzing the light curves of hot Jupiter planetary candidates identified by the Kepler mission. We detect only one candidate disk structure associated with KOI 838.01 at the 3-sigma confidence level, but subsequent radial velocity measurements reveal that KOI 838.01 is a grazing eclipsing binary and the candidate disk structure is a false positive. Using our null result, we place an upper limit on the frequency of dense exozodi structures created by hot Jupiters. We find that at the 90% confidence level, less than 21% of Kepler hot Jupiters create resonant dust clumps that lead and trail the planet by ~90 degrees with optical depths >~5*10^-6, which corresponds to the resonant structure expected for a lone hot Jupiter perturbing a dynamically cold dust disk 50 times as dense as the zodiacal cloud.Comment: 22 pages, 6 figures, Accepted for publication in Ap