Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations.

Genome-wide association studies have confirmed the polygenic nature of schizophrenia and suggest that there are hundreds or thousands of alleles associated with increased liability for the disorder. However, the generalizability of any one allelic marker of liability is remarkably low and has bred the notion that schizophrenia may be better conceptualized as a pathway(s) disorder. Here, we empirically tested this notion by conducting a pathway-wide association study (PWAS) encompassing 255 experimentally validated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways among 5033 individuals diagnosed with schizophrenia and 5332 unrelated healthy controls across three distinct ethnic populations; European-American (EA), African-American (AA) and Han Chinese (CH). We identified 103, 74 and 87 pathways associated with schizophrenia liability in the EA, CH and AA populations, respectively. About half of these pathways were uniquely associated with schizophrenia liability in each of the three populations. Five pathways (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling and renin secretion) were shared across all three populations and the single-nucleotide polymorphism sets representing these five pathways were enriched for single-nucleotide polymorphisms with regulatory function. Our findings provide empirical support for schizophrenia as a pathway disorder and suggest schizophrenia is not only a polygenic but likely also a poly-pathway disorder characterized by both genetic and pathway heterogeneity.

Environmentally friendly power generator based on moving liquid dielectric and double layer effect.

An electrostatic power generator converts mechanical energy to electrical energy by utilising the principle of variable capacitance. This change in capacitance is usually achieved by varying the gap or overlap between two parallel metallic plates. This paper proposes a novel electrostatic micro power generator where the change in capacitance is achieved by the movement of an aqueous solution of NaCl. A significant change in capacitance is achieved due to the higher than air dielectric constant of water and the Helmholtz double layer capacitor formed by ion separation at the electrode interfaces. The proposed device has significant advantages over traditional electrostatic devices which include low bias voltage and low mechanical frequency of operation. This is critical if the proposed device is to have utility in harvesting power from the environment. A figure of merit exceeding 10000(10(8)µW)/(mm(2)HzV(2)) which is two orders of magnitude greater than previous devices, is demonstrated for a prototype operating at a bias voltage of 1.2 V and a droplet frequency of 6 Hz. Concepts are presented for large scale power harvesting.

Microglial activation and progressive brain changes in schizophrenia.

Schizophrenia is a debilitating disorder that typically begins in adolescence and is characterized by perceptual abnormalities, delusions, cognitive and behavioural disturbances and functional impairments. While current treatments can be effective, they are often insufficient to alleviate the full range of symptoms. Schizophrenia is associated with structural brain abnormalities including grey and white matter volume loss and impaired connectivity. Recent findings suggest these abnormalities follow a neuroprogressive course in the earliest stages of the illness, which may be associated with episodes of acute relapse. Neuroinflammation has been proposed as a potential mechanism underlying these brain changes, with evidence of increased density and activation of microglia, immune cells resident in the brain, at various stages of the illness. We review evidence for microglial dysfunction in schizophrenia from both neuroimaging and neuropathological data, with a specific focus on studies examining microglial activation in relation to the pathology of grey and white matter. The studies available indicate that the link between microglial dysfunction and brain change in schizophrenia remains an intriguing hypothesis worthy of further examination. Future studies in schizophrenia should: (i) use multimodal imaging to clarify this association by mapping brain changes longitudinally across illness stages in relation to microglial activation; (ii) clarify the nature of microglial dysfunction with markers specific to activation states and phenotypes; (iii) examine the role of microglia and neurons with reference to their overlapping roles in neuroinflammatory pathways; and (iv) examine the impact of novel immunomodulatory treatments on brain structure in schizophrenia.

Predicting the diagnosis of autism spectrum disorder using gene pathway analysis.

Autism spectrum disorder (ASD) depends on a clinical interview with no biomarkers to aid diagnosis. The current investigation interrogated single-nucleotide polymorphisms (SNPs) of individuals with ASD from the Autism Genetic Resource Exchange (AGRE) database. SNPs were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived pathways to identify affected cellular processes and develop a diagnostic test. This test was then applied to two independent samples from the Simons Foundation Autism Research Initiative (SFARI) and Wellcome Trust 1958 normal birth cohort (WTBC) for validation. Using AGRE SNP data from a Central European (CEU) cohort, we created a genetic diagnostic classifier consisting of 237 SNPs in 146 genes that correctly predicted ASD diagnosis in 85.6% of CEU cases. This classifier also predicted 84.3% of cases in an ethnically related Tuscan cohort; however, prediction was less accurate (56.4%) in a genetically dissimilar Han Chinese cohort (HAN). Eight SNPs in three genes (KCNMB4, GNAO1, GRM5) had the largest effect in the classifier with some acting as vulnerability SNPs, whereas others were protective. Prediction accuracy diminished as the number of SNPs analyzed in the model was decreased. Our diagnostic classifier correctly predicted ASD diagnosis with an accuracy of 71.7% in CEU individuals from the SFARI (ASD) and WTBC (controls) validation data sets. In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD. While SNPs differ across ethnic groups, our pathway approach identified cellular processes common to ASD across ethnicities. Our results have wide implications for detection, intervention and prevention of ASD.

A fully integrated 200 µW, 40 pJ/b wireless transmitter for implanted medical devices and neural prostheses.

In this paper we introduce a wireless transmitter suitable for implanted medical devices (IMDs) and neural prostheses. The transmitter achieves 500 kbps data rate while consuming a peak power of 200 µW from a 1.2 V supply in a 130 nm technology and has an active area of 35 µm by 45 µm. The transmitter works in the Medical Implant Communication Service (MICS) frequency band (401-406 MHz) and transmits the signal at a power of -20 dBm while achieves energy efficiency of 40 pJ/b. The transmitter achieves this performance through a modified pulse position modulation called saturated analog signal (SAS) which has been tailored to reduce not only the peak and average power consumption but also helps reduces the number of elements required for signal generation and dispenses the need for a crystal which in turn minimizes the overall footprint of the transmitter. The transmitter can also dynamically trade off duty cycling and energy consumption with data rate and range requirements for better operability on a constantly changing environment due to the inherent flexibility of the modulation scheme.

Crosstalk current measurements using multi-electrode arrays in saline.

This paper investigates how the configuration of return electrodes in an electrode array affects the amount of current crosstalk when electrodes are driven simultaneously in saline. Two pairs of electrodes in different return configurations were stimulated with different-amplitude biphasic currents. Stimulating electrodes were controlled by current sinks and current sources while return electrodes were connected to supply voltage or ground. Measurement results show that no matter what return configuration was used, the return current was almost equally distributed amongst the return electrodes, which is problematic in bipolar concurrent stimulation, at least in saline. This result is due to the fact that the spreading impedance of saline solution is small compared to the electrode-electrolyte impedance, which makes the saline solution have almost the same potential. This result suggests that monopolar stimulation using a common remote return electrode be used in simultaneous stimulation to avoid crosstalk.

A prototype 64-electrode stimulator in 65 nm CMOS process towards a high density epi-retinal prosthesis.

This paper presents a highly flexible 64-electrode stimulator using 65 nm CMOS process fabricated as a stage towards a 1024-electrode epi-retinal prosthesis, which aims to restore partial vision in patients suffering from eye diseases such as retinitis pigmentosa (RP) and age-related macular degradation (AMD). The stimulator drives 64 electrodes with many flexible features, which are necessary before making a complete 1024-electrode implant chip. Each electrode driver can provide a bi-phasic stimulus current with fully programmable parameters such as amplitude, pulse duration, inter-phase gap, and stimulation rate. The electrode driver operates in an alternately pull-push manner with only one current source working at a time, which helps reduce headroom voltage while controlling charge balance at the active electrode. The stimulator varies both stimulus current amplitude and stimulation rate to represent phosphene brightness. The stimulus current amplitude starts from the tissue depolarization threshold with 64 different levels. The selection of active and return electrodes is arbitrary, any electrodes and any number of them can be selected at any time. The power consumption of the stimulator is 400 µW excluding the stimulus power. Measurement results verify correct operation. The stimulator is easily scaled up to drive 1024 electrodes.

A fully flexible stimulator using 65 nm CMOS process for 1024-electrode epi-retinal prosthesis.

This paper presents a fully flexible stimulator using 65 nm CMOS process for a 1024-electrode epi-retinal prosthesis. The stimulator can select any number of electrodes at any time and also supports both mono-polar and multi-polar stimulation. Furthermore, the stimulator supports a wide range of stimulus parameters. A novel feature is that the electrode driver operates in an alternately pull-push manner, which helps reduce headroom voltage while guaranteeing charge balance at the active electrode. The use of positive supplies instead of both positive and negative supplies simplifies CMOS circuit design. The current distribution between two nearby simultaneously active electrode groups was investigated and measurement result showed a maximum current crosstalk of 8%.