Modeling, Design and Test of an Integrated Optical Neural Recording Device

It has long been a goal of neuroscientists to understand how electrophysiological activity in the nervous system corresponds to, and causes, specific physiological actions. Such knowledge could be used to develop cures for disabilities related to nervous system dysfunction, and to control artificial limbs or restore motion to a paralyzed patient. This has motivated research into technologies, broadly termed brain-machine interfaces, for interfacing with the nervous system. One category of such neural interfaces is implantable neural recording devices, which monitor and record neural signals through a microelectronic device implanted in the body. Typical implantable neural recording devices use a micro-electrode array to record electrical signals simultaneously from a multitude of neurons. Unfortunately, devices employing micro-electrode arrays have several issues from both the biological and circuit design points of view. These issues include tissue damage due to implantation of a micro-electrode array, degradation of recording fidelity over time, limited spatial resolution, the requirement to maintain charge balance in tissue, and the difficulty in implementing low-frequency (large time constant) filter cutoffs with limited chip area. These issues provided the motivation to investigate alternative methods for neural recording - namely optical methods based on fluorescence detection with voltage-sensitive fluorescent proteins. Optical recording methods can alleviate many of the issues with electrical recording, as well as provide other advantages, such as recording targeted to specific neurons/neuron types and higher spatial resolution due to reduced recording site pitch. The major limitations of fully implantable optical recording devices stem from size constraints, the attenuation of light in tissue, which limits imaging depth, and the need for genetically programmed voltage-sensitive fluorescent proteins, which must be introduced to the tissue in the case of chronic recording. This research began with investigating the feasibility of replacing an electrical neural record- ing front end with an optical front end - the conclusion being that producing an initial design was worthwhile. Thus, this thesis presents a prototype optical neural recording device for detecting individual spikes in Layer I of the brain. The device is designed for the fully implantable scenario, where space for typical fluorescence imaging optical components is limited, and a high level of integration is required. The thesis describes: 1) Modeling: a general framework for modeling near-field fluorescence detection systems is presented; the model is then extended and applied to the design of the optical neural recording device for detecting individual spikes in Layer I of the brain, taking into account light attenuation in tissue; 2) Design: the design of a high-sensitivity CMOS imaging chip used in the device; 3) Packaging: the packaging of the CMOS imager with LED dies and an excitation filter; and 4) Testing: the experimental results from testing the packaged device with a fluorescent tissue phantom designed to emulate layer I of the brain. Ideas for future work on such devices are discussed

Genetic Variation in Clinical Varicella-Zoster Virus Isolates Collected in Ireland Between 2002 and 2003

Analysis of genetic variation in 16 varicella-zoster virus (VZV) isolates selected at random and circulating in the Irish population between March 2002 and February 2003 was carried out. A 919 bp fragment of the glycoprotein E gene (open reading frame 68) encompassing codon 150, at which a non-synonymous mutation defines the escape mutant VZV-MSP, and including two other epitope regions e1 and c1, was sequenced. No new single nucleotide polymorphisms (SNPs) were detected, indicating stability of these epitopes in clinical isolates of VZV. However, when four informative polymorphic markers consisting of defined regions from genes 1, 21, 50, and 54 were sequenced 14 variable nucleotide positions were identified. Phylogenetic analysis showed the presence of three highly supported clades A, B, and C circulating in the Irish population. Approximately one third (6/16; 37.5%) of the Irish VZV isolates in this study belonged to genotype C, 4/16 (25%) to genotype A, and 4/16 (25%) to genotype B. A smaller number 2/16 (12.5%) belonged to genotype J1. This indicates remarkable heterogeneity in the Irish population given the small sample size. No evidence was found to suggest any of the 16 isolates was a recombinant. These findings have implications for the model of geographic isolation of VZV clades to certain regions as the circulating Irish VZV population appears to comprise approximately equal numbers of each of the main genotypes. This data is inconsistent with a model of strict geographical separation of VZV genotypes and suggests that VZVdiversity ismorepronounced in certain areas than had been thought previously

Genetic Variation in Clinical Varicella-Zoster Virus Isolates Collected in Ireland Between 2002 and 2003

Analysis of genetic variation in 16 varicella-zoster virus (VZV) isolates selected at random and circulating in the Irish population between March 2002 and February 2003 was carried out. A 919 bp fragment of the glycoprotein E gene (open reading frame 68) encompassing codon 150, at which a non-synonymous mutation defines the escape mutant VZV-MSP, and including two other epitope regions e1 and c1, was sequenced. No new single nucleotide polymorphisms (SNPs) were detected, indicating stability of these epitopes in clinical isolates of VZV. However, when four informative polymorphic markers consisting of defined regions from genes 1, 21, 50, and 54 were sequenced 14 variable nucleotide positions were identified. Phylogenetic analysis showed the presence of three highly supported clades A, B, and C circulating in the Irish population. Approximately one third (6/16; 37.5%) of the Irish VZV isolates in this study belonged to genotype C, 4/16 (25%) to genotype A, and 4/16 (25%) to genotype B. A smaller number 2/16 (12.5%) belonged to genotype J1. This indicates remarkable heterogeneity in the Irish population given the small sample size. No evidence was found to suggest any of the 16 isolates was a recombinant. These findings have implications for the model of geographic isolation of VZV clades to certain regions as the circulating Irish VZV population appears to comprise approximately equal numbers of each of the main genotypes. This data is inconsistent with a model of strict geographical separation of VZV genotypes and suggests that VZVdiversity ismorepronounced in certain areas than had been thought previously

Pneumonia failing to respond to treatment

SummaryHerpes simplex virus type 1 (HSV-1) is frequently isolated from the respiratory tract of critically ill patients. However, diagnosis of clinically significant HSV-1 pneumonia is difficult as the presentation is non-specific and there is no diagnostic reference standard to differentiate from non-infectious contamination.We present a case of HSV-1 pneumonia in a young asthmatic patient who was potentially immunocompromised through long-term corticosteroid usage. The quantitative PCR titre from bronchoalveolar lavage fluid was high (9×103copies/ml) and the patient made a dramatic clinical and radiographic recovery upon treatment with acyclovir. We suggest that similar PCR levels in the appropriate clinical setting should prompt consideration of anti-viral therapy

Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia

Schizophrenia is a heritable disorder with substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases, 6,243 controls) followed by meta-analysis with prior schizophrenia GWAS (8,832 cases, 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls, and 581 trios). In total, 22 regions met genome-wide significance (14 novel and one previously implicated in bipolar disorder). The results strongly implicate calcium signaling in the etiology of schizophrenia, and include genome-wide significant results for CACNA1C and CACNB2 whose protein products interact. We estimate that ∼8,300 independent and predominantly common SNPs contribute to risk for schizophrenia and that these collectively account for most of its heritability. Common genetic variation plays an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this devastating disorder

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders