Fractal Resonance: Can Fractal Geometry Be Used to Optimize the Connectivity of Neurons to Artificial Implants?

In parallel to medical applications, exploring how neurons interact with the artificial interface of implants in the human body can be used to learn about their fundamental behavior. For both fundamental and applied research, it is important to determine the conditions that encourage neurons to maintain their natural behavior during these interactions. Whereas previous biocompatibility studies have focused on the material properties of the neuron-implant interface, here we discuss the concept of fractal resonance - the possibility that favorable connectivity properties might emerge by matching the fractal geometry of the implant surface to that of the neurons.To investigate fractal resonance, we first determine the degree to which neurons are fractal and the impact of this fractality on their functionality. By analyzing three-dimensional images of rat hippocampal neurons, we find that the way their dendrites fork and weave through space is important for generating their fractal-like behavior. By modeling variations in neuron connectivity along with the associated energetic and material costs, we highlight how the neurons' fractal dimension optimizes these constraints. To simulate neuron interactions with implant interfaces, we distort the neuron models away from their natural form by modifying the dendrites' fork and weaving patterns. We find that small deviations can induce large changes in fractal dimension, causing the balance between connectivity and cost to deteriorate rapidly. We propose that implant surfaces should be patterned to match the fractal dimension of the neurons, allowing them to maintain their natural functionality as they interact with the implant.

How neurons exploit fractal geometry to optimize their network connectivity.

We investigate the degree to which neurons are fractal, the origin of this fractality, and its impact on functionality. By analyzing three-dimensional images of rat neurons, we show the way their dendrites fork and weave through space is unexpectedly important for generating fractal-like behavior well-described by an 'effective' fractal dimension D. This discovery motivated us to create distorted neuron models by modifying the dendritic patterns, so generating neurons across wide ranges of D extending beyond their natural values. By charting the D-dependent variations in inter-neuron connectivity along with the associated costs, we propose that their D values reflect a network cooperation that optimizes these constraints. We discuss the implications for healthy and pathological neurons, and for connecting neurons to medical implants. Our automated approach also facilitates insights relating form and function, applicable to individual neurons and their networks, providing a crucial tool for addressing massive data collection projects (e.g. connectomes).

Anterior thalamic nuclei neurons sustain memory.

A hippocampal-diencephalic-cortical network supports memory function. The anterior thalamic nuclei (ATN) form a key anatomical hub within this system. Consistent with this, injury to the mammillary body-ATN axis is associated with examples of clinical amnesia. However, there is only limited and indirect support that the output of ATN neurons actively enhances memory. Here, in rats, we first showed that mammillothalamic tract (MTT) lesions caused a persistent impairment in spatial working memory. MTT lesions also reduced rhythmic electrical activity across the memory system. Next, we introduced 8.5 Hz optogenetic theta-burst stimulation of the ATN glutamatergic neurons. The exogenously-triggered, regular pattern of stimulation produced an acute and substantial improvement of spatial working memory in rats with MTT lesions and enhanced rhythmic electrical activity. Neither behaviour nor rhythmic activity was affected by endogenous stimulation derived from the dorsal hippocampus. Analysis of immediate early gene activity, after the rats foraged for food in an open field, showed that exogenously-triggered ATN stimulation also increased Zif268 expression across memory-related structures. These findings provide clear evidence that increased ATN neuronal activity supports memory. They suggest that ATN-focused gene therapy may be feasible to counter clinical amnesia associated with dysfunction in the mammillary body-ATN axis.

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson's disease cohort.

INTRODUCTION: Bi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson's disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD. METHOD: We examined amplicons encompassing the coding region of GBA (8.9 kb) from 229 PD cases and 50 healthy controls using the GridION nanopore sequencing platform, and Sanger validation. RESULTS: We detected 23 variants in 21 PD cases (9.2% of patients). We detected modest PD risk variant p.N409S (rs76763715) in one case, p.E365K (rs2230288) in 12 cases, and p.T408 M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally detected the possible risk variants p.R78C (rs146774384) in one case, p.D179H (rs147138516) in one case which occurred on the same haplotype as p.E365K, and one novel variant c.335C > T or p.(L335 = ), that potentially impacts splicing of GBA transcripts. Additionally, we found a higher prevalence of dementia among patients with GBA variants. CONCLUSION: This work confirmed the utility of nanopore sequencing as a high-throughput method to identify known and novel GBA variants, and to assign precise haplotypes. Our observations may contribute to improved understanding of the effects of variants on disease pathogenesis, and to the development of more targeted treatments.

Erratum: Observation of D

This corrects the article DOI: 10.1103/PhysRevLett.113.142301.

Optogenetic stimulation: Understanding memory and treating deficits.

Technology allowing genetically targeted cells to be modulated by light has revolutionized neuroscience in the past decade, and given rise to the field of optogenetic stimulation. For this, non-native, light activated proteins (e.g., channelrhodopsin) are expressed in a specific cell phenotype (e.g., glutamatergic neurons) in a subset of central nervous system nuclei, and short pulses of light of a narrow wavelength (e.g., blue, 473 nm) are used to modulate cell activity. Cell activity can be increased or decreased depending on which light activated protein is used. We review how the greater precision provided by optogenetics has transformed the study of neural circuits, in terms of cognition and behavior, with a focus on learning and memory. We also explain how optogenetic modulation is facilitating a better understanding of the mechanistic underpinnings of some neurological and psychiatric conditions. Based on this research, we suggest that optogenetics may provide tools to improve memory in neurological conditions, particularly diencephalic amnesia and Alzheimer's disease.

Parkinson's in the oldest old: Impact on estimates of future disease burden.

BACKGROUND: Traditionally the risk of Parkinson's has been considered to increase monotonically with age, although there is evidence that prevalence and incidence may decrease in the oldest old. To examine this further we estimated the national prevalence and incidence of Parkinson's in New Zealand, using drug-tracing methods, to examine the relationship of Parkinson's with sex and age up to 100+. METHODS: Information on Parkinson's-related medications was extracted from the national pharmaceutical database of community-dispensed medications from 2005 to 2014. Diagnoses for a large subset of individuals were independently determined through national mortality and hospital admissions datasets. We used a Bayesian model, accommodating diagnostic uncertainty and bias, to estimate the number of people with Parkinson's. RESULTS: The 2013 prevalence of Parkinson's in New Zealand was 210 per 100 000 population (95% uncertainty interval 208-212) with age-standardized prevalence rates higher for males (ratio 1.6:1). Incidence was 31 per 100 000 person-years (95% uncertainty interval 30-32), also higher in males (ratio 1.8:1). Incidence and prevalence by age increased exponentially until 75 years, peaked at 85 years, and then dropped sharply. CONCLUSIONS: The prevalence of Parkinson's in New Zealand is expected to double over a 25-year period but then increase at a slower rate due to the drop-off in prevalence and incidence in the oldest old. The findings suggest that Parkinson's disease is not an aging-dependent but an age-dependent disorder.

Azimuthal Anisotropy in U+U and Au+Au Collisions at RHIC.

Collisions between prolate uranium nuclei are used to study how particle production and azimuthal anisotropies depend on initial geometry in heavy-ion collisions. We report the two- and four-particle cumulants, v_{2}{2} and v_{2}{4}, for charged hadrons from U+U collisions at sqrt[s_{NN}]=193 GeV and Au+Au collisions at sqrt[s_{NN}]=200 GeV. Nearly fully overlapping collisions are selected based on the energy deposited by spectators in zero degree calorimeters (ZDCs). Within this sample, the observed dependence of v_{2}{2} on multiplicity demonstrates that ZDC information combined with multiplicity can preferentially select different overlap configurations in U+U collisions. We also show that v_{2} vs multiplicity can be better described by models, such as gluon saturation or quark participant models, that eliminate the dependence of the multiplicity on the number of binary nucleon-nucleon collisions.

Observation of Transverse Spin-Dependent Azimuthal Correlations of Charged Pion Pairs in p

We report the observation of transverse polarization-dependent azimuthal correlations in charged pion pair production with the STAR experiment in p^{↑}+p collisions at RHIC. These correlations directly probe quark transversity distributions. We measure signals in excess of 5 standard deviations at high transverse momenta, at high pseudorapidities η>0.5, and for pair masses around the mass of the ρ meson. This is the first direct transversity measurement in p+p collisions.

Precision Measurement of the Longitudinal Double-Spin Asymmetry for Inclusive Jet Production in Polarized Proton Collisions at sqrt[s]=200 GeV.

We report a new measurement of the midrapidity inclusive jet longitudinal double-spin asymmetry, A_{LL}, in polarized pp collisions at center-of-mass energy sqrt[s]=200 GeV. The STAR data place stringent constraints on polarized parton distribution functions extracted at next-to-leading order from global analyses of inclusive deep-inelastic scattering (DIS), semi-inclusive DIS, and RHIC pp data. The measured asymmetries provide evidence at the 3σ level for positive gluon polarization in the Bjorken-x region x>0.05.

Observation of Charge Asymmetry Dependence of Pion Elliptic Flow and the Possible Chiral Magnetic Wave in Heavy-Ion Collisions.

We present measurements of π(-) and π(+) elliptic flow, v(2), at midrapidity in Au+Au collisions at √[s(NN)]=200, 62.4, 39, 27, 19.6, 11.5, and 7.7 GeV, as a function of event-by-event charge asymmetry, A(ch), based on data from the STAR experiment at RHIC. We find that π(-) (π(+)) elliptic flow linearly increases (decreases) with charge asymmetry for most centrality bins at √[s(NN)]=27 GeV and higher. At √[s(NN)]=200 GeV, the slope of the difference of v(2) between π(-) and π(+) as a function of A(ch) exhibits a centrality dependence, which is qualitatively similar to calculations that incorporate a chiral magnetic wave effect. Similar centrality dependence is also observed at lower energies.

Effect of time at temperature on wild poliovirus titers in stool specimens.

BACKGROUND: The effect of transport temperature on the viability of poliovirus in stool specimens from paralyzed cases has not been tested. Quality assurance of programmatic indicators will be necessary in the final phase of polio eradication. OBJECTIVE: To estimate the effect of time at elevated temperatures on wild poliovirus titers in stool specimens. METHODS: We exposed aliquots of pooled wild poliovirus type 1 specimens to elevated temperatures (27 °C, 31 °C, and 35 °C) for varying time periods up to 14 days. We determined the virus titer of these aliquots and created decay curves at each temperature to estimate the relationship between time at temperature and virus titer. RESULTS: We found significantly different slopes of decay at each temperature. The negative slopes increased as the temperature increased. CONCLUSIONS: While poliovirus in stool remains relatively stable at moderately elevated temperature, transport at higher temperatures could impact sample integrity and virus isolation results.

ΛΛ Correlation function in Au+Au collisions at √[S(NN)]=200 GeV.

We present ΛΛ correlation measurements in heavy-ion collisions for Au+Au collisions at sqrt[s_{NN}]=200 GeV using the STAR experiment at the Relativistic Heavy-Ion Collider. The Lednický-Lyuboshitz analytical model has been used to fit the data to obtain a source size, a scattering length and an effective range. Implications of the measurement of the ΛΛ correlation function and interaction parameters for dihyperon searches are discussed.

Observation of D0 meson nuclear modifications in Au+Au collisions at sqrt[s(NN)] = 200 GeV.

We report the first measurement of charmed-hadron (D(0)) production via the hadronic decay channel (D(0) → K(-) + π(+)) in Au+Au collisions at sqrt[s(NN)] = 200 GeV with the STAR experiment. The charm production cross section per nucleon-nucleon collision at midrapidity scales with the number of binary collisions, N(bin), from p+p to central Au+Au collisions. The D(0) meson yields in central Au + Au collisions are strongly suppressed compared to those in p+p scaled by N(bin), for transverse momenta p(T) > 3 GeV/c, demonstrating significant energy loss of charm quarks in the hot and dense medium. An enhancement at intermediate p(T) is also observed. Model calculations including strong charm-medium interactions and coalescence hadronization describe our measurements.

Beam energy dependence of moments of the net-charge multiplicity distributions in Au+Au collisions at RHIC.

We report the first measurements of the moments--mean (M), variance (σ(2)), skewness (S), and kurtosis (κ)--of the net-charge multiplicity distributions at midrapidity in Au+Au collisions at seven energies, ranging from sqrt[sNN]=7.7 to 200 GeV, as a part of the Beam Energy Scan program at RHIC. The moments are related to the thermodynamic susceptibilities of net charge, and are sensitive to the location of the QCD critical point. We compare the products of the moments, σ(2)/M, Sσ, and κσ(2), with the expectations from Poisson and negative binomial distributions (NBDs). The Sσ values deviate from the Poisson baseline and are close to the NBD baseline, while the κσ(2) values tend to lie between the two. Within the present uncertainties, our data do not show nonmonotonic behavior as a function of collision energy. These measurements provide a valuable tool to extract the freeze-out parameters in heavy-ion collisions by comparing with theoretical models.

Beam-energy dependence of charge separation along the magnetic field in Au+Au collisions at RHIC.

Local parity-odd domains are theorized to form inside a quark-gluon plasma which has been produced in high-energy heavy-ion collisions. The local parity-odd domains manifest themselves as charge separation along the magnetic field axis via the chiral magnetic effect. The experimental observation of charge separation has previously been reported for heavy-ion collisions at the top RHIC energies. In this Letter, we present the results of the beam-energy dependence of the charge correlations in Au+Au collisions at midrapidity for center-of-mass energies of 7.7, 11.5, 19.6, 27, 39, and 62.4 GeV from the STAR experiment. After background subtraction, the signal gradually reduces with decreased beam energy and tends to vanish by 7.7 GeV. This implies the dominance of hadronic interactions over partonic ones at lower collision energies.

Measurement of longitudinal spin asymmetries for weak boson production in polarized proton-proton collisions at RHIC.

We report measurements of single- and double-spin asymmetries for W^{±} and Z/γ^{*} boson production in longitudinally polarized p+p collisions at sqrt[s]=510 GeV by the STAR experiment at RHIC. The asymmetries for W^{±} were measured as a function of the decay lepton pseudorapidity, which provides a theoretically clean probe of the proton's polarized quark distributions at the scale of the W mass. The results are compared to theoretical predictions, constrained by polarized deep inelastic scattering measurements, and show a preference for a sizable, positive up antiquark polarization in the range 0.05

Dielectron mass spectra from Au+Au collisions at √[s(NN)]=200 GeV.

We report the STAR measurements of dielectron (e(+)e(-)) production at midrapidity (|y(ee)|<1) in Au+Au collisions at √[s(NN)]=200 GeV. The measurements are evaluated in different invariant mass regions with a focus on 0.30-0.76 (ρ-like), 0.76-0.80 (ω-like), and 0.98-1.05 (ϕ-like) GeV/c(2). The spectrum in the ω-like and ϕ-like regions can be well described by the hadronic cocktail simulation. In the ρ-like region, however, the vacuum ρ spectral function cannot describe the shape of the dielectron excess. In this range, an enhancement of 1.77±0.11(stat)±0.24(syst)±0.33(cocktail) is determined with respect to the hadronic cocktail simulation that excludes the ρ meson. The excess yield in the ρ-like region increases with the number of collision participants faster than the ω and ϕ yields. Theoretical models with broadened ρ contributions through interactions with constituents in the hot QCD medium provide a consistent description of the dilepton mass spectra for the measurement presented here and the earlier data at the Super Proton Synchrotron energies.

Beam-energy dependence of the directed flow of protons, antiprotons, and pions in Au+Au collisions.

Rapidity-odd directed flow (v1) measurements for charged pions, protons, and antiprotons near midrapidity (y=0) are reported in sNN=7.7, 11.5, 19.6, 27, 39, 62.4, and 200 GeV Au+Au collisions as recorded by the STAR detector at the Relativistic Heavy Ion Collider. At intermediate impact parameters, the proton and net-proton slope parameter dv1/dy|y=0 shows a minimum between 11.5 and 19.6 GeV. In addition, the net-proton dv1/dy|y=0 changes sign twice between 7.7 and 39 GeV. The proton and net-proton results qualitatively resemble predictions of a hydrodynamic model with a first-order phase transition from hadronic matter to deconfined matter, and differ from hadronic transport calculations.

Jet-hadron correlations in √[s(NN)]=200 GeV p+p and central Au+Au collisions.

Azimuthal angular correlations of charged hadrons with respect to the axis of a reconstructed (trigger) jet in Au+Au and p+p collisions at √[s(NN)]=200 GeV in STAR are presented. The trigger jet population in Au+Au collisions is biased toward jets that have not interacted with the medium, allowing easier matching of jet energies between Au+Au and p+p collisions while enhancing medium effects on the recoil jet. The associated hadron yield of the recoil jet is significantly suppressed at high transverse momentum (pTassoc) and enhanced at low pTassoc in 0%-20% central Au+Au collisions compared to p+p collisions, which is indicative of medium-induced parton energy loss in ultrarelativistic heavy-ion collisions.