Optical and Spin Properties of NV Center Ensembles in Diamond Nano-Pillars.

Nitrogen-vacancy (NV) color centers in diamond are excellent quantum sensors possessing high sensitivity and nano-scale spatial resolution. Their integration in photonic structures is often desired, since it leads to an increased photon emission and also allows the realization of solid-state quantum technology architectures. Here, we report the fabrication of diamond nano-pillars with diameters up to 1000 nm by electron beam lithography and inductively coupled plasma reactive ion etching in nitrogen-rich diamonds (type Ib) with [100] and [111] crystal orientations. The NV centers were created by keV-He ion bombardment and subsequent annealing, and we estimate an average number of NVs per pillar to be 4300 ± 300 and 520 ± 120 for the [100] and [111] samples, respectively. Lifetime measurements of the NVs' excited state showed two time constants with average values of τ1 ≈ 2 ns and τ2 ≈ 8 ns, which are shorter as compared to a single color center in a bulk crystal (τ ≈ 10 ns). This is probably due to a coupling between the NVs as well as due to interaction with bombardment-induced defects and substitutional nitrogen (P1 centers). Optically detected magnetic resonance measurements revealed a contrast of about 5% and average coherence and relaxation times of T2 [100] = 420 ± 40 ns, T2 [111] = 560 ± 50 ns, and T1 [100] = 162 ± 11 µs, T1 [111] = 174 ± 24 µs. These pillars could find an application for scanning probe magnetic field imaging.

Fabrication and Characterization of Single-Crystal Diamond Membranes for Quantum Photonics with Tunable Microcavities.

The development of quantum technologies is one of the big challenges in modern research. A crucial component for many applications is an efficient, coherent spin-photon interface, and coupling single-color centers in thin diamond membranes to a microcavity is a promising approach. To structure such micrometer thin single-crystal diamond (SCD) membranes with a good quality, it is important to minimize defects originating from polishing or etching procedures. Here, we report on the fabrication of SCD membranes, with various diameters, exhibiting a low surface roughness down to 0.4 nm on a small area scale, by etching through a diamond bulk mask with angled holes. A significant reduction in pits induced by micromasking and polishing damages was accomplished by the application of alternating Ar/Cl2 + O2 dry etching steps. By a variation of etching parameters regarding the Ar/Cl2 step, an enhanced planarization of the surface was obtained, in particular, for surfaces with a higher initial surface roughness of several nanometers. Furthermore, we present the successful bonding of an SCD membrane via van der Waals forces on a cavity mirror and perform finesse measurements which yielded values between 500 and 5000, depending on the position and hence on the membrane thickness. Our results are promising for, e.g., an efficient spin-photon interface.

Is brain arousal regulation a predictor of response to psychostimulant therapy in adult ADHD patients?

We investigated whether baseline brain arousal instability during resting state EEG, using the Vigilance Algorithm Leipzig (VIGALL 2.1), can predict response to methylphenidate therapy in adult ADHD patients. An arousal stability score of the EEGs of 28 adult ADHD patients was calculated quantifying the extent of arousal decline. In logistic regression analysis, arousal stability score predicted response to MPH [odds ratio 1.28 (95% CI 1.0-1.65); p = 0.027]. In this pilot study, we demonstrated that arousal stability at baseline predicted methylphenidate treatment response, indicating that less stable arousal regulation during a 15-min EEG at rest increases the chance of treatment response.

P2X7R: independent modulation of aquaporin 5 expression in CdCl2-injured alveolar epithelial cells.

The expression of aquaporin 5 in alveolar epithelial type I cells under conditions of cadmium-induced injury has not yet been discovered. We investigated the effect of the P2X7R agonist BzATP under this condition, since P2X7R is involved in altered regulation of aquaporin 5 in pulmonary fibrosis. CdCl2/TGF-ß1 treatment of lung epithelial MLE-12 cells was leading to increasing P2X7R, and aquaporin 5 protein levels. The aquaporin 5 expression was P2X7R-independent in MLE-12 cells under cadmium, as was shown in blocking experiments with oxATP. Further, the expression of both proteins increased after 24 h CdCl2/TGF-ß1 treatment of precision-cut lung slices, but decreased after 72 h. Using immunohistochemistry, the activation of the P2X7R with the agonist BzATP modulated the aquaporin 5 immunoreactivity in the alveolar epithelium of precision-cut lung slices from wild-type but not from P2X7R knockout mice. Similarly, aquaporin 5 protein was reduced in BzATP-treated immortal lung epithelial E10 cells. Surprisingly, untreated alveolar epithelial type II cells of P2X7R knockouts exhibited a pronounced apical immunoreactivity in addition to the remaining alveolar epithelial type I cells. BzATP exposure did not alter this distribution pattern, but increased the number of apoptotic alveolar epithelial type II cells in wild-type lung slices.

Increase or Decrease of fMRI Activity in Adult Attention Deficit/ Hyperactivity Disorder: Does It Depend on Task Difficulty?

BACKGROUND: Attention deficit/hyperactivity disorder has been shown to affect working memory, and fMRI studies in children and adolescents with attention deficit/hyperactivity disorder report hypoactivation in task-related attentional networks. However, studies with adult attention deficit/hyperactivity disorder patients addressing this issue as well as the effects of clinically valid methylphenidate treatment are scarce. This study contributes to closing this gap. METHODS: Thirty-five adult patients were randomized to 6 weeks of double-blind placebo or methylphenidate treatment. Patients completed an fMRI n-back working memory task both before and after the assigned treatment, and matched healthy controls were tested and compared to the untreated patients. RESULTS: There were no whole-brain differences between any of the groups. However, when specified regions of interest were investigated, the patient group showed enhanced BOLD responses in dorsal and ventral areas before treatment. This increase was correlated with performance across all participants and with attention deficit/hyperactivity disorder symptoms in the patient group. Furthermore, we found an effect of treatment in the right superior frontal gyrus, with methylphenidate-treated patients exhibiting increased activation, which was absent in the placebo-treated patients. CONCLUSIONS: Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes.

On the role of NOS1 ex1f-VNTR in ADHD-allelic, subgroup, and meta-analysis.

Attention deficit/ hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1f-VNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the 21-repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the 21-repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association. © 2015 Wiley Periodicals, Inc.

A preliminary study on methylphenidate-regulated gene expression in lymphoblastoid cells of ADHD patients.

OBJECTIVES: Methylphenidate (MPH) is a commonly used stimulant medication for treating attention-deficit/hyperactivity disorder (ADHD). Besides inhibiting monoamine reuptake there is evidence that MPH also influences gene expression directly. METHODS: We investigated the impact of MPH treatment on gene expression levels of lymphoblastoid cells derived from adult ADHD patients and healthy controls by hypothesis-free, genome-wide microarray analysis. Significant findings were subsequently confirmed by quantitative Real-Time PCR (qRT PCR) analysis. RESULTS: The microarray analysis from pooled samples after correction for multiple testing revealed 138 genes to be marginally significantly regulated due to MPH treatment, and one gene due to diagnosis. By qRT PCR we could confirm that GUCY1B3 expression was differential due to diagnosis. We verified chronic MPH treatment effects on the expression of ATXN1, HEY1, MAP3K8 and GLUT3 in controls as well as acute treatment effects on the expression of NAV2 and ATXN1 specifically in ADHD patients. CONCLUSIONS: Our preliminary results demonstrate MPH treatment differences in ADHD patients and healthy controls in a peripheral primary cell model. Our results need to be replicated in larger samples and also using patient-derived neuronal cell models to validate the contribution of those genes to the pathophysiology of ADHD and mode of action of MPH.

Does adult ADHD interact with COMT val (158) met genotype to influence working memory performance?

Both attention-deficit/hyperactivity disorder (ADHD) and catechol-O-methyltransferase (COMT) genotype have been linked to altered dopaminergic transmission and possible impairment in frontal lobe functioning. This study offers an investigation of a possible interaction between ADHD diagnosis and COMT genotype on measures of working memory and executive function. Thirty-five adults with ADHD, who were recruited from the ADHD outpatient clinic at the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, and thirty-five matched healthy controls completed the Digit Span test and the Stroop Color Word Test. While there were no main effects of ADHD or COMT, the two factors interacted on both Digit Span subtests with the two groups' met/met carriers showing significantly different performance on the Digit Span Forward subtest and the val/val carriers showing significantly different performance on the Digit Span Backward subtest. Findings provide preliminary support for a differential impact of COMT genotype on working memory measures in adult patients with ADHD compared to healthy controls.

SPOCK3, a risk gene for adult ADHD and personality disorders.

Attention-deficit/hyperactivity disorder (ADHD) is the most frequent psychiatric disorder in children, where it displays a global prevalence of 5 %. In up to 50 % of the cases, ADHD may persist into adulthood (aADHD), where it is often comorbid with personality disorders. Due to a potentially heritable nature of this comorbidity, we hypothesized that their genetic framework may contain common risk-modifying genes. SPOCK3, a poorly characterized, putatively Ca(2+)-binding extracellular heparan/chondroitin sulfate proteoglycan gene encoded by the human chromosomal region 4q32.3, was found to be associated with polymorphisms among the top ranks in a genome-wide association study (GWAS) on ADHD and a pooled GWAS on personality disorder (PD). We therefore genotyped 48 single nucleotide polymorphisms (SNPs) representative of the SPOCK3 gene region in 1,790 individuals (n aADHD = 624, n PD = 630, n controls = 536). In this analysis, we found two SNPs to be nominally associated with aADHD (rs7689440, rs897511) and four PD-associated SNPs (rs7689440, rs897511, rs17052671 and rs1485318); the latter even reached marginal significance after rigorous Bonferroni correction. Bioinformatics tools predicted a possible influence of rs1485318 on transcription factor binding, whereas the other candidate SNPs may have effects on alternative splicing. Our results suggest that SPOCK3 may modify the genetic risk for ADHD and PD; further studies are, however, needed to identify the underlying mechanisms.

Acetylcholine-metabolizing butyrylcholinesterase (BCHE) copy number and single nucleotide polymorphisms and their role in attention-deficit/hyperactivity syndrome.

A previous genome-wide screen for copy number variations (CNVs) in attention deficit/hyperactivity disorder (ADHD) revealed a de novo chromosome 3q26.1 deletion in one of the patients. Candidate genes at this locus include the acetylcholine-metabolizing butyrylcholinesterase (BCHE) expressing gene (OMIM #177400), which is of particular interest. The present study investigates the hypothesis that the heterozygous deletion of the BCHE gene is associated with adult ADHD (aADHD). Ina first step, we screened 348 aADHD patients and 352 controls for stretches of loss of heterozygosity (LOH) across the entire BCHE gene to screen for the deletion. Our second aim was to clarify whether BCHE single nucleotide polymorphisms (SNPs) themselves influence the risk towards ADHD. Putative functional consequences of associated SNPs as well as their un-typed proxies were predicted by several bioinformatic tools. 96 individuals displayed entirely homozygous genotype reads in all 12 examined SNPs, making them possible candidates to harbor a heterozygous BCHE deletion. DNA from these 96 probands was further analyzed by real-time PCR using a BCHE-specific CNV assay. However, no deletion was found. Of the 12 tag SNPs that passed inclusion criteria, rs4680612 and rs829508 were significantly associated with aADHD, as their minor alleles occurred more often in cases than in controls (p = 0.018 and p = 0.039, respectively). The risk variant rs4680612 is located in the transcriptional control region of the gene and predicted to disrupt a binding site for MYT-1, which has previously been associated with mental disorders. However, when examining a second independent adult ADHD sample of 353 cases, the association did not replicate. When looking up the deletion in three genome-wide screens for CNV in ADHD and combining it with the present study, it became apparent that 3 from a total of 1030 ADHD patients, but none of 5787 controls, featured a deletion of the BCHE promoter region including rs4680612 (p = 0.00004). Taken together, there are several lines of evidence suggesting a potential involvement of BCHE in the etiopathology of ADHD, as a rare hemizygous deletion as well as a common SNP in the same region are associated with disease, although with different penetrance. Both variations result in the disruption of the binding site of the transcription factor MYT-1 suggesting epistatic effects of BCHE and MYT-1 in the pathogenesis of ADHD. As we were not able to replicate the SNP association, our findings should be considered preliminary and call for larger studies in extended phenotypes.