Genetic risk for schizophrenia is associated with increased proportion of indirect connections in brain networks revealed by a semi-metric analysis: evidence from population sample stratified for polygenic risk.

Research studies based on tractography have revealed a prominent reduction of asymmetry in some key white-matter tracts in schizophrenia (SCZ). However, we know little about the influence of common genetic risk factors for SCZ on the efficiency of routing on structural brain networks (SBNs). Here, we use a novel recall-by-genotype approach, where we sample young adults from a population-based cohort (ALSPAC:N genotyped = 8,365) based on their burden of common SCZ risk alleles as defined by polygenic risk score (PRS). We compared 181 individuals at extremes of low (N = 91) or high (N = 90) SCZ-PRS under a robust diffusion MRI-based graph theoretical SBN framework. We applied a semi-metric analysis revealing higher SMR values for the high SCZ-PRS group compared with the low SCZ-PRS group in the left hemisphere. Furthermore, a hemispheric asymmetry index showed a higher leftward preponderance of indirect connections for the high SCZ-PRS group compared with the low SCZ-PRS group (PFDR < 0.05). These findings might indicate less efficient structural connectivity in the higher genetic risk group. This is the first study in a population-based sample that reveals differences in the efficiency of SBNs associated with common genetic risk variants for SCZ.

Field-Tunable Berezinskii-Kosterlitz-Thouless Correlations in a Heisenberg Magnet.

We report the manifestation of field-induced Berezinskii-Kosterlitz-Thouless (BKT) correlations in the weakly coupled spin-1/2 Heisenberg layers of the molecular-based bulk material [Cu(pz)_{2}(2-HOpy)_{2}](PF_{6})_{2}. At zero field, a transition to long-range order occurs at 1.38 K, caused by a weak intrinsic easy-plane anisotropy and an interlayer exchange of J^{'}/k_{B}≈1 mK. Because of the moderate intralayer exchange coupling of J/k_{B}=6.8 K, the application of laboratory magnetic fields induces a substantial XY anisotropy of the spin correlations. Crucially, this provides a significant BKT regime, as the tiny interlayer exchange J^{'} only induces 3D correlations upon close approach to the BKT transition with its exponential growth in the spin-correlation length. We employ nuclear magnetic resonance measurements to probe the spin correlations that determine the critical temperatures of the BKT transition as well as that of the onset of long-range order. Further, we perform stochastic series expansion quantum Monte Carlo simulations based on the experimentally determined model parameters. Finite-size scaling of the in-plane spin stiffness yields excellent agreement of critical temperatures between theory and experiment, providing clear evidence that the nonmonotonic magnetic phase diagram of [Cu(pz)_{2}(2-HOpy)_{2}](PF_{6})_{2} is determined by the field-tuned XY anisotropy and the concomitant BKT physics.

Intrinsic Nature of Spontaneous Magnetic Fields in Superconductors with Time-Reversal Symmetry Breaking.

We present a systematic investigation of muon-stopping states in superconductors that reportedly exhibit spontaneous magnetic fields below their transition temperatures due to time-reversal symmetry breaking. These materials include elemental rhenium, several intermetallic systems, and Sr_{2}RuO_{4}. We demonstrate that the presence of the muon leads to only a limited and relatively localized perturbation to the local crystal structure, while any small changes to the electronic structure occur several electron volts below the Fermi energy, leading to only minimal changes in the charge density on ions close to the muon. Our results imply that the muon-induced perturbation alone is unlikely to lead to the observed spontaneous fields in these materials, whose origin is more likely intrinsic to the time-reversal symmetry-broken superconducting state.

Origin of Magnetic Ordering in a Structurally Perfect Quantum Kagome Antiferromagnet.

The ground state of the simple Heisenberg nearest-neighbor quantum kagome antiferromagnetic model is a magnetically disordered spin liquid, yet various perturbations may lead to fundamentally different states. Here we disclose the origin of magnetic ordering in the structurally perfect kagome material YCu_{3}(OH)_{6}Cl_{3}, which is free of the widespread impurity problem. Ab initio calculations and modeling of its magnetic susceptibility reveal that, similar to the archetypal case of herbertsmithite, the nearest-neighbor exchange is by far the dominant isotropic interaction. Dzyaloshinskii-Moriya (DM) anisotropy deduced from electron spin resonance, susceptibility, and specific-heat data is, however, significantly larger than in herbertsmithite. By enhancing spin correlations within kagome planes, this anisotropy is essential for magnetic ordering. Our study isolates the effect of DM anisotropy from other perturbations and unambiguously confirms the predicted phase diagram.

Unconventional Field-Induced Spin Gap in an S=1/2 Chiral Staggered Chain.

We investigate the low-temperature magnetic properties of the molecule-based chiral spin chain [Cu(pym)(H_{2}O)_{4}]SiF_{6}·H_{2}O (pym=pyrimidine). Electron-spin resonance, magnetometry and heat capacity measurements reveal the presence of staggered g tensors, a rich low-temperature excitation spectrum, a staggered susceptibility, and a spin gap that opens on the application of a magnetic field. These phenomena are reminiscent of those previously observed in nonchiral staggered chains, which are explicable within the sine-Gordon quantum-field theory. In the present case, however, although the sine-Gordon model accounts well for the form of the temperature dependence of the heat capacity, the size of the gap and its measured linear field dependence do not fit with the sine-Gordon theory as it stands. We propose that the differences arise due to additional terms in the Hamiltonian resulting from the chiral structure of [Cu(pym)(H_{2}O)_{4}]SiF_{6}·H_{2}O, particularly a uniform Dzyaloshinskii-Moriya coupling and a fourfold periodic staggered field.

Microglia - mediated immunity partly contributes to the genetic association between Alzheimer's disease and hippocampal volume.

Genome-wide association studies (GWAS) suggest that Alzheimer's disease (AD) is partly explained by a burden of risk alleles (single nucleotide polymorphisms; SNPs) with relatively small effects. However, the mechanisms by which these loci cumulatively confer susceptibility remain largely unknown. Accumulating evidence suggests an association between increased AD risk allele burden (measured via a polygenic risk profile score; AD-RPS) with reduced hippocampal volume (HV) across a number of independent cohorts. These lines of research suggest that the reduced HV may be a causal mechanism of risk in the development of late-onset Alzheimer's disease (AD). However, as RPS assesses broad, cumulative genetic risk, little is known about the biological processes which may explain this observation. Here, we leverage GWAS data from i) 17,008 late onset AD cases & 37,154 controls and ii) hippocampal volume (N = 12,147; N = 9707) to explore putative pathways that may explain this association. We first demonstrate an association between whole genome AD-RPS and HV (PT < 0.5, Z = -2.07, P = 0.038), confirming previous associations. Second, we restrict our analysis to SNPs within AD genes within a microglia mediated immunity network (NGENES = 56). A microglia AD-RPS was further associated with HV (PT < 0.01; Z = -2.152, P = 0.031). Last, using a competitive, permutation based approach, we show that the common variation within this candidate gene-set is associated with HV, controlling for SNP set-size (P = 0.024). Together, the observations suggest that the relationship between AD and HV is partially explained by genes within an AD-linked microglia mediated immunity network.

The impact of the COMT genotype and cognitive demands on facets of intra-subject variability.

Intra-Subject Variability (ISV), a potential index of catecholaminergic regulation, is elevated in several disorders linked with altered dopamine function. ISV has typically been defined as reaction time standard deviation. However, the ex-Gaussian and spectral measures capture different aspects and may delineate different underlying sources of ISV; thus reflecting different facets of the construct. We examined the impact of factors associated with dopamine metabolism, namely, Catechol-O-Methyltransferase Val158Met (COMT) genotype and Working Memory (WM) and response-switching on ISV facets in young healthy adults. The Met allele was associated with overall increased variability. The rather exclusive sensitivity of ex-Gaussian tau to frequencies below 0.025 Hz and the quasi-periodic structure of particularly slow responses support the interpretation of tau as low frequency fluctuations of neuronal networks. Sigma, by contrast, may reflect neural noise. Regarding cognitive demands, a WM load-related increase in variability was present for all genotypes and all ISV facets. Contrastingly, ISV facets reacted differently to variations in response-switching as, across genotypes, sigma was elevated for rare target trials whereas tau was elevated for frequent standard trials, particularly for Met homozygotes. Our findings support the significant role of COMT in regulating behavioural ISV with its facetted structure and presumed underlying neural processes.

Quantum mechanical tunneling in the automerization of cyclobutadiene.

Cyclobutadiene has a four-membered carbon ring with two double bonds, but this highly strained molecular configuration is almost square and, via a coordinated motion, the nuclei quantum mechanically tunnels through the high-energy square state to a configuration equivalent to the initial configuration under a 90° rotation. This results in a square ground state, comprising a superposition of two molecular configurations, that is driven by quantum tunneling. Using a quantum mechanical model, and an effective nuclear potential from density functional theory, we calculate the vibrational energy spectrum and the accompanying wavefunctions. We use the wavefunctions to identify the motions of the molecule and detail how different motions can enhance or suppress the tunneling rate. This is relevant for kinematics of tunneling-driven reactions, and we discuss these implications. We are also able to provide a qualitative account of how the molecule will respond to an external perturbation and how this may enhance or suppress infra-red-active vibrational transitions.

Magnetic and non-magnetic phases of a quantum spin liquid.

A quantum spin-liquid phase is an intriguing possibility for a system of strongly interacting magnetic units in which the usual magnetically ordered ground state is avoided owing to strong quantum fluctuations. It was first predicted theoretically for a triangular-lattice model with antiferromagnetically coupled S = 1/2 spins. Recently, materials have become available showing persuasive experimental evidence for such a state. Although many studies show that the ideal triangular lattice of S = 1/2 Heisenberg spins actually orders magnetically into a three-sublattice, non-collinear 120° arrangement, quantum fluctuations significantly reduce the size of the ordered moment. This residual ordering can be completely suppressed when higher-order ring-exchange magnetic interactions are significant, as found in nearly metallic Mott insulators. The layered molecular system κ-(BEDT-TTF)(2)Cu(2)(CN)(3) is a Mott insulator with an almost isotropic, triangular magnetic lattice of spin-1/2 BEDT-TTF dimers that provides a prime example of a spin liquid formed in this way. Despite a high-temperature exchange coupling, J, of 250 K (ref. 6), no obvious signature of conventional magnetic ordering is seen down to 20 mK (refs 7, 8). Here we show, using muon spin rotation, that applying a small magnetic field to this system produces a quantum phase transition between the spin-liquid phase and an antiferromagnetic phase with a strongly suppressed moment. This can be described as Bose-Einstein condensation of spin excitations with an extremely small spin gap. At higher fields, a second transition is found that suggests a threshold for deconfinement of the spin excitations. Our studies reveal the low-temperature magnetic phase diagram and enable us to measure characteristic critical properties. We compare our results closely with current theoretical models, and this gives some further insight into the nature of the spin-liquid phase.

A Hedonism Hub in the Human Brain.

Human values are abstract ideals that motivate behavior. The motivational nature of human values raises the possibility that they might be underpinned by brain structures that are particularly involved in motivated behavior and reward processing. We hypothesized that variation in subcortical hubs of the reward system and their main connecting pathway, the superolateral medial forebrain bundle (slMFB) is associated with individual value orientation. We conducted Pearson's correlation between the scores of 10 human values and the volumes of 14 subcortical structures and microstructural properties of the medial forebrain bundle in a sample of 87 participants, correcting for multiple comparisons (i.e.,190). We found a positive association between the value that people attach to hedonism and the volume of the left globus pallidus (GP).We then tested whether microstructural parameters (i.e., fractional anisotropy and myelin volume fraction) of the slMFB, which connects with the GP, are also associated to hedonism and found a significant, albeit in an uncorrected level, positive association between the myelin volume fraction within the left slMFB and hedonism scores. This is the first study to elucidate the relationship between the importance people attach to the human value of hedonism and structural variation in reward-related subcortical brain regions.

CACNA1C risk variant is associated with increased amygdala volume.

Genome-wide association studies suggest that genetic variation within L-type calcium channel subunits confer risk to psychosis. The single nucleotide polymorphism at rs1006737 in CACNA1C has been associated with both schizophrenia and bipolar disorder and with several intermediate phenotypes that may serve as neurobiological antecedents, linking psychosis to genetic aetiology. Amongst others, it has been implicated in alterations in amygdala structure and function. In the present study, we show that the risk allele (A) is associated with increased amygdala volume in healthy individuals (n = 258). This observation reinforces a hypothesis that genetic variation may confer risk to psychosis via alterations in limbic structures. Further study of CACNA1C using intermediate phenotypes for psychosis will determine the mechanisms by which variation in this gene confers risk.

Anisotropic local modification of crystal field levels in Pr-based pyrochlores: a muon-induced effect modeled using density functional theory.

Although muon spin relaxation is commonly used to probe local magnetic order, spin freezing, and spin dynamics, we identify an experimental situation in which the measured response is dominated by an effect resulting from the muon-induced local distortion rather than the intrinsic behavior of the host compound. We demonstrate this effect in some quantum spin ice candidate materials Pr(2)B(2)O(7) (B=Sn, Zr, Hf), where we detect a static distribution of magnetic moments that appears to grow on cooling. Using density functional theory we show how this effect can be explained via a hyperfine enhancement arising from a splitting of the non-Kramers doublet ground states on Pr ions close to the muon, which itself causes a highly anisotropic distortion field. We provide a quantitative relationship between this effect and the measured temperature dependence of the muon relaxation and discuss the relevance of these observations to muon experiments in other magnetic materials.

COMT Val158Met genotype is associated with fluctuations in working memory performance: converging evidence from behavioural and single-trial P3b measures.

Intra-subject variability in reaction times (ISV) is a promising endophenotype for several psychiatric conditions, but its neural underpinnings are not yet established. Converging evidence from neuroimaging, molecular genetics, and psychopharmacology suggests that ISV could index catecholaminergically-mediated neural noise. The fine-grained temporal resolution of electroencephalography is ideal for investigating ISV, but only if potential neural correlates of ISV can be assessed in single trials. Based on evidence that ISV is associated with dopaminergic functioning, we apply a recently developed method of single-trial P3b analysis to investigate the association of COMT Val(158)Met genotype with measures of ISV on the behavioural and neural levels at different working memory loads. Greater number of Met alleles was associated with poorer and more intra-individually variable performance on the tasks, and greater latency jitter in single-trial P3bs. These converging results at the behavioural and neurophysiological levels confirm previous observations that prefrontal dopamine availability is associated with stability and accuracy of cognitive performance. Together with previous studies, these data imply pleiotropic cognitive effects of COMT genotype.

Low-field superconducting phase of (TMTSF)2ClO4.

The low-field phase of the organic superconductor (TMTSF)(2)ClO(4) is studied by muon-spin rotation. The zero temperature limit of the magnetic penetration depth within the TMTSF layers is obtained to be λ(ab)(0) = 0.86(2) µm. Temperature dependence of the muon-spin relaxation shows no indication of gap nodes on the Fermi surface nor of any spontaneous fields due to time-reversal-symmetry breaking. The weight of evidence suggests that the symmetry of this low-field phase is odd-frequency p-wave singlet, a novel example of odd-frequency pairing in a bulk superconductor.

Pre-frontal stimulation does not reliably increase reward responsiveness.

Depression is the leading cause of disability worldwide and its effects can be fatal, with over 800,000 people dying by suicide each year. Neuromodulatory treatments such as transcranial magnetic stimulation (TMS) are being used to treat depression. Despite its endorsement by two regulatory bodies: NICE (2016) and the FDA (2008), there are major questions about the treatment efficacy and biological mechanisms of TMS. Ahn et al.'s (2013) justified the use of TMS in a clinical context in an important study indicating that excitatory TMS increases reward responsiveness. A pseudo-replication of this study by Duprat et al., (2016) also found a similar effect of active TMS, but only with the addition of an exploratory covariate to the analyses-trait reward responsiveness. Here we replicate Ahn et al.'s (2013) key study, and to test the reliability of the effects, and their dependency on trait reward responsiveness as described by Duprat et al., (2016). Using excitatory and sham TMS, we tested volunteers using the probabilistic learning task to measure their reward responsiveness both before and after stimulation. We also examined affect (positive, negative) following stimulation. Irrespective of TMS, the task was shown to be sensitive to reward responsiveness. However, we did not show TMS to be effective in increasing reward responsiveness and we did not replicate Ahn et al., (2013) or Duprat et al., (2016)'s key findings for TMS efficacy, where we provide evidence favouring the null. Moreover, exploratory analyses suggested following active stimulation, positive affect was reduced. Given our findings, we question the basic effects, which support the use of TMS for depression, particularly considering potential deleterious effects of reduced positive affect in patients with depression.

Quantitative proteomic analysis reveals novel mitochondrial targets of estrogen deficiency in the aged female rat heart.

The incidence of myocardial infarction rises sharply at menopause, implicating a potential role for estrogen (E(2)) loss in age-related increases in ischemic injury. We aimed to identify quantitative changes to the cardiac mitochondrial proteome of aging females, based on the hypothesis that E(2) deficiency exacerbates age-dependent disruptions in mitochondrial proteins. Mitochondria isolated from left ventricles of adult (6 mo) and aged (24 mo) F344 ovary-intact or ovariectomized (OVX) rats were labeled with 8plex isobaric tags for relative and absolute quantification (iTRAQ; n = 5-6/group). Groups studied were adult, adult OVX, aged, and aged OVX. In vivo coronary artery ligation and in vitro mitochondrial respiration studies were also performed in a subset of rats. We identified 965 proteins across groups and significant directional changes in 67 proteins of aged and/or aged OVX; 32 proteins were unique to aged OVX. Notably, only six proteins were similarly altered in adult OVX (voltage-dependent ion channel 1, adenine nucleotide translocator 1, cytochrome c oxidase subunits VIIc and VIc, catalase, and myosin binding protein C). Proteins affected by aging were primarily related to cellular metabolism, oxidative stress, and cell death. The largest change occurred in monoamine oxidase-A (MAO-A), a source of oxidative stress. While acute MAO-A inhibition induced mild uncoupling in aged mitochondria, reductions in infarct size were not observed. Age-dependent alterations in mitochondrial signaling indicate a highly selective myocardial response to E(2) deficiency. The combined proteomic and functional approaches described here offer possibility of new protein targets for experimentation and therapeutic intervention in the aged female population.

Spin waves and revised crystal structure of honeycomb iridate Na2IrO3.

We report inelastic neutron scattering measurements on Na2IrO3, a candidate for the Kitaev spin model on the honeycomb lattice. We observe spin-wave excitations below 5 meV with a dispersion that can be accounted for by including substantial further-neighbor exchanges that stabilize zigzag magnetic order. The onset of long-range magnetic order below T(N)=15.3 K is confirmed via the observation of oscillations in zero-field muon-spin rotation experiments. Combining single-crystal diffraction and density functional calculations we propose a revised crystal structure model with significant departures from the ideal 90° Ir-O-Ir bonds required for dominant Kitaev exchange.

Local delivery of a PKCε-activating peptide limits ischemia reperfusion injury in the aged female rat heart.

Reduced efficacy of cardioprotective interventions in the aged female heart, including estrogen replacement, highlights the need for alternative therapeutics to reduce myocardial ischemia-reperfusion (I/R) injury in postmenopausal women. Here, we sought to determine the efficacy of protein kinase-Cε (PKCε)-mediated cardioprotection in the aged, estradiol-deficient rat heart. Infarct size and functional recovery were assessed in Langendorff-perfused hearts from adult (5 mo) or aged (23 mo) female Fisher 344 ovary-intact or ovariectomized (OVX) rats administered a PKCε-activator, receptor for activated C kinase (ψεRACK) prior to 47-min ischemia and 60-min reperfusion. Proteomic analysis was conducted on left ventricular mitochondrial fractions treated with ψεRACK prior to I/R, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) 8plex labeling and tandem mass spectrometry. Real-time PCR was utilized to assess connexin 43 (Cx43) and RACK2 mRNA post-I/R. Greater infarct size in aged OVX (78%) vs. adult (37%) was reduced by ψεRACK (35%, P < 0.0001) and associated with greater mitochondrial PKCε localization (P < 0.0003). Proteomic analysis revealed three novel mitochondrial targets of PKCε-mediated cardioprotection with aging (P < 0.05): the antioxidant enzymes glutathione peroxidase (GPX) and MnSOD2, and heat shock protein 10. Finally, decreased levels of Cx43 and RACK2 mRNA seen with age were partially abrogated by administration of ψεRACK (P < 0.05). The mechanisms described here may represent important therapeutic candidates for the treatment of acute myocardial infarction in postmenopausal women and age-associated estradiol deficiency.

Coexistence of static magnetism and superconductivity in SmFeAsO(1-x)F(x) as revealed by muon spin rotation.

The recent observation of superconductivity with critical temperatures (Tc) up to 55 K in the pnictide RFeAsO(1-x)F(x), where R is a lanthanide, marks the first discovery of a non-copper-oxide-based layered high-Tc superconductor. It has raised the suspicion that these new materials share a similar pairing mechanism to the cuprate superconductors, as both families exhibit superconductivity following charge doping of a magnetic parent material. In this context, it is important to follow the evolution of the microscopic magnetic properties of the pnictides with doping and hence to determine whether magnetic correlations coexist with superconductivity. Here, we present a muon spin rotation study on SmFeAsO(1-x)F(x), with x=0-0.30 that shows that, as in the cuprates, static magnetism persists well into the superconducting regime. This analogy is quite surprising as the parent compounds of the two families have rather different magnetic ground states: itinerant spin density wave for the pnictides contrasted with the Mott-Hubbard insulator in the cuprates. Our findings therefore suggest that the proximity to magnetic order and associated soft magnetic fluctuations, rather than strong electronic correlations in the vicinity of a Mott-Hubbard transition, may be the key ingredients of high-Tc superconductors.

Local magnetism, magnetic order and spin freezing in the 'nonmetallic metal' FeCrAs.

We present the results of x-ray scattering and muon-spin relaxation ([Formula: see text]SR) measurements on the iron-pnictide compound FeCrAs. Polarized non-resonant magnetic x-ray scattering results reveal the 120° periodicity expected from the suggested three-fold symmetric, non-collinear antiferromagnetic structure. [Formula: see text]SR measurements indicate a magnetically ordered phase throughout the bulk of the material below [Formula: see text] K. There are signs of fluctuating magnetism in a narrow range of temperatures above [Formula: see text] involving low-energy excitations, while at temperatures well below [Formula: see text] behaviour characteristic of freezing of dynamics is observed, likely reflecting the effect of disorder in our polycrystalline sample. Using density functional theory we propose a distinct muon stopping site in this compound and assess the degree of distortion induced by the implanted muon.