Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Broad-Band Activatable White-Opsin

The authors would like to thank C. Cote and K. Dhakal (UTA) for help during initiation of the project. SM would like to thank K. Deisseroth (Stanford University) for ChR2 and C1V1 plasmids, and J. Lin (UCSD) for the ReaChR construct.Currently, the use of optogenetic sensitization of retinal cells combined with activation/inhibition has the potential to be an alternative to retinal implants that would require electrodes inside every single neuron for high visual resolution. However, clinical translation of optogenetic activation for restoration of vision suffers from the drawback that the narrow spectral sensitivity of an opsin requires active stimulation by a blue laser or a light emitting diode with much higher intensities than ambient light. In order to allow an ambient light-based stimulation paradigm, we report the development of a ‘white-opsin’ that has broad spectral excitability in the visible spectrum. The cells sensitized with white-opsin showed excitability at an order of magnitude higher with white light compared to using only narrow-band light components. Further, cells sensitized with white-opsin produced a photocurrent that was five times higher than Channelrhodopsin-2 under similar photo-excitation conditions. The use of fast white-opsin may allow opsin-sensitized neurons in a degenerated retina to exhibit a higher sensitivity to ambient white light. This property, therefore, significantly lowers the activation threshold in contrast to conventional approaches that use intense narrow-band opsins and light to activate cellular stimulation.Yeshttp://www.plosone.org/static/editorial#pee

Expression of white-opsin in mammalian cells.

<p>(a) Representative confocal image of a white-opsin-transfected HEK293 cell without nuclear staining. Scale bar: 5 μm. (b) Confocal fluorescence image of white-opsin transfected live HEK293 cells stained with nuclear staining dye Hoechst 33242. (c) Confocal image of multiple HEK293 cells showing white-opsin expression. Scale bar: 10 μm. (d) Reporter fluorescence intensity along lines across representative cells (shown in c, dotted blue lines) showing localized expression of white-opsin at the plasma membrane. a.u. = arbitrary units.</p

Spectral-dependent activation of narrow-band ChR2-sensitized cells.

<p>Representative inward current responses of ChR2-sensitized HEK293 cell stimulated by (a) white light, as well as spectrally-filtered blue (b), green (c) and red (d) components, respectively. The white light power is fixed and then spectrally-filtered (lower powers for the narrow band measurements). (e) Measured inward peak-currents for varying spectral excitation of ChR2-sensitized cells. N = 3 biological replicates (total of 4 cells, 18 sweeps). Average ± S.D. An asterisk (*) represents p<0.05 between blue and other experiments (i.e. green and red). No statistical difference was found between green and red experiments. There is a significant statistical difference between white and other experiments (red, blue and green) (^#p<0.01). (f) Comparison of representative white light-induced inward currents in a ChR2-expressing HEK293 cell (blue) with a cell expressing white-opsin (gray) at same light intensity. WO: white-opsin.</p

Quantitative comparison between broad-band and spectrally-filtered narrow-band optogenetic activation of white-opsin.

<p>(a) Spectra of white-light and spectrally-filtered (not intensity-calibrated) narrow-band lights used for optogenetic activation of white-opsin-expressing cells. Representative inward current responses of white-opsin-sensitized HEK293 cells stimulated by (b) white, (c) blue, (d) green and (e) red light. The white light power is fixed and then spectrally-filtered (lower powers for the narrow band measurements). (f) Measured inward peak-currents for varying spectral excitation of white-opsin-sensitized cells. N = 3 biological replicates (total of five cells, 20 sweeps). Average ± S.D. a.u. = arbitrary units.</p

Activation spectrum of white-opsin.

<p>(a) Spectra of narrow-band (spectrally-filtered from white light) components measured using Ocean Optics spectrometer. (b) Normalized activation spectrum of white-opsin. Average ± S.D (N = 3 biological replicates, total 25 sweeps per wavelength). This activation spectrum is based on the inward current response of patch-clamped HEK293 cells stimulated with different wavelengths of light. a.u. = arbitrary units.</p

White-opsin construct and broad-band activation.

<p>(a) Schematic of normalized activation spectra of narrow-band opsins (ChR2, C1V1 and ReaChR), redrawn from published literature [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136958#pone.0136958.ref022" target="_blank">22</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136958#pone.0136958.ref023" target="_blank">23</a>]. (b) Schematic vector map of the broad-band activatable white-opsin coding region made by fusing three opsin genes of interest encoding ChR2, C1V1 and ReaChR for blue, green and red sensitivity, respectively. The expression of the fusion protein is driven by a CMV promoter. The fusion protein also contains domains that correspond to two different reporter proteins, enhanced yellow fluorescent protein (EYFP) and Citrine. (c) Bands showing control (extracted from HEK293 cells not transfected with white-opsin) and white-opsin (extracted from HEK293 cells transfected with white-opsin).</p

Alcohol use history increases the likelihood of suicide behavior among male chronic patients with schizophrenia in a Chinese population

Aims This study was designed to detect the association between the history of alcohol drinking and suicidality in schizophrenia (SCZ) inpatients in a Chinese population. Methods We recruited 616 male SCZ inpatients and collected demographic and clinical data. Five-factor model of the Positive and Negative Syndrome Scale (PANSS) was used to assess their psychopathological symptoms. Results Our results showed that 31.33% of SCZ patients had a history of alcohol drinking. They had higher rates of lifetime suicide attempt and suicidal ideation than those without a history of alcohol drinking. Moreover, patients with a history of drinking were more likely to attempt suicide (14.51% vs. 7.09%; chi(2) = 7.70, df = 1, p = 0.006), with an odds ratio (OR) of 2.22 and have suicidal ideation (29.02% vs. 17.49%; chi(2) = 9.89, df = 1, p = 0.002), with an OR of 1.93. In addition, patients who used to drink alcohol were more likely to be smokers and had more severe positive and depressive symptoms (all p < 0.05). Conclusions Our study indicates that history of alcohol drinking may increase the prevalence of lifetime suicide attempt and suicidal ideation in male patients with chronic SCZ. Moreover, the history of alcohol drinking may be associated with some demographic data and clinical symptoms

Epilepsy care in the southern Caribbean

Very little has been reported about the health resources available for patients with epilepsy in the five English-speaking southern Caribbean countries of Trinidad and Tobago, Barbados, Grenada, Saint Vincent and the Grenadines, and Saint Lucia. There is no comprehensive resource describing their health systems, access to specialty care, antiepileptic drug (AED) use, and availability of brain imaging and EEG. The purpose of this study was to profile epilepsy care in these countries as an initial step toward improving the standard of care and identifying gaps in care to guide future policy changes. In each southern Caribbean country, we conducted study visits and interviewed health-care providers, government health ministers, pharmacy directors, hospital medical directors, pharmacists, clinic staff, radiologists, and radiology and EEG technicians. Health-care providers completed extensive epilepsy care surveys. The five countries all have integrated government health systems with clinics and hospitals that provide free or heavily subsidized care and AEDs for patients with epilepsy. Only Trinidad and Tobago and Barbados, however, have neurology specialists. The three smaller countries lack government imaging and EEG facilities. Trinidad had up to one-year waits for public MRI/EEG. Government formularies in Grenada, Saint Vincent and the Grenadines, and Saint Lucia are limited to first-generation AEDs. One or more second-line agents are formulary in Trinidad and Barbados. Nonformulary drugs may be obtained for individual patients in Barbados. Grenada, Saint Lucia, and Saint Vincent and the Grenadines participate in an Organization of Eastern Caribbean States formulary purchasing system, which added levetiracetam following the survey. Newer generic AED formulations with the lowest risks for pregnancy malformation were not in use. In conclusion, patients with epilepsy in the southern Caribbean have excellent access to government clinics and hospitals, but AED choices are limited. Local medical providers reported that the major limitations in care were lack of specialty care, lack of imaging and EEG services, financial barriers to care, long wait times for care, and limited access to additional AEDs