Ultrasonic spectroscopy of sessile droplets coupled to optomechanical sensors.

We describe a system for interrogating the acoustic properties of sub-nanoliter liquid samples within an open microfluidics platform. Sessile droplets were deposited onto integrated optomechanical sensors, which possess ambient-medium-noise-limited sensitivity and can thus passively sense the thermally driven acoustic spectrum of the droplets. The droplet acoustic breathing modes manifest as resonant features in the thermomechanical noise spectrum of the sensor, in some cases hybridized with the sensor's own vibrational modes. Excellent agreement is found between experimental observations and theoretical predictions, over the entire ∼0-40 MHz operating range of our sensors. As an application example, we used the technique to monitor the temporal evolution of evaporating droplets. With suitable control over droplet size and morphology, this technique has the potential for precision acoustic sensing of small-volume biological and chemical samples.

Enhanced emission from hBN in sputtered microcavities.

In this observational study, we embed few-layer hexagonal boron nitride (hBN) inside a planar Fabry-Perot cavity fabricated using a pulsed DC magnetron sputtering system and show that the hBN retains its inherent visible range, defect-based luminescent properties following relatively energetic deposition processing. The observed surface-normal emission enhancement factor of ∼40 is in good agreement with theoretical predictions. We also found that embedded hBN subjected to a rapid thermal annealing treatment exhibits a cracking effect where the edges of the material glow distinctly brighter than adjacent regions. Our results might inform future efforts involving monolithic integration of hBN active layers.

Ultrasound sensing at thermomechanical limits with optomechanical buckled-dome microcavities.

We describe the use of monolithic, buckled-dome cavities as ultrasound sensors. Patterned delamination within a compressively stressed thin film stack produces high-finesse plano-concave optical resonators with sealed and empty cavity regions. The buckled mirror also functions as a flexible membrane, highly responsive to changes in external pressure. Owing to their efficient opto-acousto-mechanical coupling, thermal-displacement-noise limited sensitivity is achieved at low optical interrogation powers and for modest optical (Q ∼ 103) and mechanical (Q ∼ 102) quality factors. We predict and verify broadband (up to ∼ 5 MHz), air-coupled ultrasound detection with noise-equivalent pressure (NEP) as low as ∼ 30-100 µPa/Hz1/2. This corresponds to an ultrasonic force sensitivity ∼ 2 × 10-13 N/Hz1/2 and enables the detection of MHz-range signals propagated over distances as large as ∼ 20 cm in air. In water, thermal-noise-limited sensitivity is demonstrated over a wide frequency range (up to ∼ 30 MHz), with NEP as low as ∼ 100-800 µPa/Hz1/2. These cavities exhibit a nearly omnidirectional response, while being ∼ 3-4 orders of magnitude more sensitive than piezoelectric devices of similar size. Easily realized as large arrays and naturally suited to direct coupling by free-space beams or optical fibers, they offer significant practical advantages over competing optical devices, and thus could be of interest for several emerging applications in medical and industrial ultrasound imaging.

Polymer transfer technique for strain-activated emission in hexagonal boron nitride.

We present a hexagonal boron nitride (hBN) polymer-assisted transfer technique and discuss subtleties about the process. We then demonstrate localized emission from strained regions of the film draped over features on a prepatterned substrate. Notably, we provide insight into the brightness distribution of these emitters and show that the brightest emission is clearly localized to the underlyin-g substrate features rather than unintentional wrinkles present in the hBN film. Our results aide in the current discussion surrounding scalability of single photon emitter arrays.

Tunable bandpass imaging filter based on resonant tunneling through a ball lens assembly.

We describe a ball lens assembly, which functions as a broadly tunable bandpass filter and polarizer with imaging capabilities. The physical basis is resonant tunneling of light through an air gap between two half-ball lenses symmetrically coated by few-layer (Si/SiO2 or Ta2O5/SiO2) admittance matching stacks. Tuning is achieved by simultaneous adjustments of the incident angle and the air gap thickness. Individual filters with operational ranges spanning visible (∼400-700nm) and near-infrared (∼1000-1800nm) wavelengths were assembled using 10 mm diameter lenses. We show that these filters, configured as a stand-alone scanning spectrometer, can provide a resolving power ∼100 and f-number ∼2.5 for a fiber-compatible input aperture <15µm in diameter. We also demonstrate that, with supplementary optics, the tunable ball filter might be used to implement a compact hyperspectral imaging system.

Widely tunable bandpass filter based on resonant optical tunneling.

We describe a tunable bandpass filter and polarizer based on resonant tunneling through an air gap between two hemi-cylindrical prisms coated with 4-layer a-Si/SiO2 matching stacks. Tuning is achieved by simultaneous variations in the incident angle and the air gap thickness, enabling the pass-band center wavelength to be continuously adjusted over a very wide range (potentially ~1000 - 1800 nm) with an approximately fixed fractional bandwidth (Δλ/λ ~1%). An analytical derivation of the conditions required to produce a flat-top TE pass-band at a desired wavelength is given. The filter provides excellent out-of-band rejection and strong suppression of the orthogonal TM polarization over the entire tuning range. For applications involving collimated light, it could be a useful alternative to existing widely tunable filters based on gratings or liquid crystals.

Double-blind crossover trial of gabapentin in SPG4-linked hereditary spastic paraplegia.

Patients with hereditary spastic paraplegia (HSP) are often treated with antispastic drugs to relieve symptoms but documentation is lacking. In this study, gabapentin was tested in a double-blind crossover trial on a group of patients with HSP and linkage to the SPG4 locus. There was no difference between periods with gabapentin and placebo treatment in clinical assessment, self-reported parameters or paired transcranial magnetic stimulation evaluation of motor cortical excitability.

Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation.

Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.

Piracetam improves cognitive performance by restoring neurochemical deficits of the aged rat brain.

In order to test the hypothesis that piracetam improves cognitive functions by restoring biochemical deficits of the aging brain, we investigated the effects of piracetam treatment (300 mg/kg daily for 6 weeks) on the active avoidance performance of young and aged rats. After testing, the rats were killed and membrane fluidity and NMDA as well muscarinic cholinergic receptor densities were determined in the frontal cortex, the hippocampus, the striatum, as well as the cerebellum. Piracetam treatment improved active avoidance learning in the aged rats only and elevated membrane fluidity in all brain regions except the cerebellum in the aged animals. Moreover, we observed a positive effect of piracetam treatment on NMDA receptor density in the hippocampus and on muscarinic cholinergic receptor densities in the frontal cortex and the striatum and to a lesser extent in the hippocampus. Again, these effects were only observed in aged animals. Discrimination analysis indicated that piracetam effects on membrane fluidity in the frontal cortex, the hippocampus, and the striatum and its effects on NMDA densities in the hippocampus might be involved in its positive effects on cognitive performance.

Effects of beta-amyloid peptides on the fluidity of membranes from frontal and parietal lobes of human brain. High potencies of A beta 1-42 and A beta 1-43.

beta-amyloid peptide (A beta) and several A beta-fragments decrease the fluidity of human cortex membranes in a concentration dependent fashion. The effect of A beta on membrane fluidity increases with peptide length, is most pronounced for A beta 1-43 and can be seen at concentrations as low as 100 nmol/l. While the fragment A beta 25-35 is active, scrambled peptide (A beta 35-25) when investigated under similar conditions shows no effects on membrane fluidity. The effect of A beta peptides on fluidity of the phospholipid bilayer is more pronounced in the hydrocarbon core (labeled with the fluorescence probe 1,6-diphenylhexa-1,3,5-triene) than in the region of the hydrophilic heads (labeled with the fluorescence probe 1-[4'-(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene). It is suggested that the effect of A beta on neuronal membranes is probably a major initial mechanism in a cascade of events finally leading to neurotoxicity and cell death in Alzheimer's disease.

Effects of piracetam on membrane fluidity in the aged mouse, rat, and human brain.

In vitro preincubation of brain membranes of aged mice with piracetam (0.1-1.0 mmol/L) enhanced membrane fluidity, as indicated by decreased anisotropy of the membrane-bound fluorescence probe 1,6-diphenyl-1,3,5-hexatriene (DPH). Piracetam had similar in vitro effects on brain membranes of aged rats and humans, but it did not alter brain membrane fluidity in young mice. Chronic treatment of young and aged rats with piracetam (300 mg/kg once daily) significantly increased membrane fluidity in some brain regions of the aged animals, but had no measurable effect on membrane fluidity in the young rats. The same treatment significantly improved active avoidance learning in the aged rats only. It is suggested that some of the pharmacological properties of piracetam can be explained by its effects on membrane fluidity.

Cortical NMDA receptor properties and membrane fluidity are altered in Alzheimer's disease.

NMDA receptor density as measured by the specific binding of [3H]MK 801 was significantly decreased (about 20%) in the frontal but not in the parietal cortex of postmortem brain samples of Alzheimer's disease (AD) patients (n = 21), when compared with control brains (n = 20). Membrane fluidity was not altered in the frontal cortex samples, but was slightly reduced in the parietal cortex samples of the AD patients. Since AD-specific histopathological changes (densities of senile plaques and neurofibrillary tangles) were about similar in both areas, it is concluded that the reductions of NMDA receptor densities in the frontal cortex is independent of AD-specific histopathological changes and of changes of membrane fluidity.

Ginkgo biloba extract (EGb 761) independently improves changes in passive avoidance learning and brain membrane fluidity in the aging mouse.

Decreases in cell membrane fluidity may be a major mechanism of age-related functional decline. A prime cause for the decline of membrane fluidity may be the presence of free radicals. Gingko biloba extract EGb 761 protects neuronal cell membranes from free radical damage in vitro. Further, EGb 761 has repeatedly been shown to improve cognitive functions in man and in laboratory animals. To test if there is a link between these two actions we assessed the effects of EGb 761 on passive avoidance learning and on neuronal membrane fluidity in vivo in young (three-month-old), middle-aged (12-month-old) and aged (22 to 24-month-old) female NMRI mice. The animals were treated daily with 100 mg/kg EGb 761 for three weeks. There was a significant improvement in short-term memory, measured by the avoidance latency 60 seconds after the aversive stimulus (p < 0.0311), and of membrane fluidity (p < 0.01) in the aged animals, but no improvement in long-term memory as measured by the avoidance latency 24 hours after shock. However, no significant correlation between membrane fluidity and short-term memory performance was found. Taken together, these results indicate that EGb 761 independently improves changes in passive avoidance learning and brain membrane fluidity.

beta-Amyloid peptide decreases membrane fluidity.

The beta-amyloid peptide-25-35 (beta A25-35) decreases the fluidity of mouse brain membranes in a concentration-depending fashion. First effects were already seen at a beta A25-35 concentration of 100 nmol/1. beta-Amyloid peptide(1-40) was similarly active. beta A25-35 also decreases the fluidity of human lymphocyte membranes and of membranes from the cortex, hippocampus, striatum, and cerebellum of the rat, although the effects in the rat cerebellum are only weak. Scrambled beta A25-35 when investigated under similar conditions showed no effects on membrane fluidity. It is suggest that the effect on cellular calcium-signalling but also the neurotoxic properties of beta-amyloid might be the result of its concentration depending effects on membrane properties.

N-methyl-D-aspartate receptor density and membrane fluidity as possible determinants of the decline of passive avoidance performance in aging.

The effect of aging on three different parameters possibly relevant for cognition was investigated in female Naval Medical Research Institute mice: a) N-methyl-D-aspartate (NMDA) receptor density, as determined by the specific binding of [3H]MK-801 to forebrain membranes, decreased by 22% in aged (23 mo) and by 19% in middle-aged (12 mo) animals compared with young (3 mo) animals. b) In a passive avoidance acquisition task, the 24-h latency decreased significantly with age; the middle-aged mice also tended to show impairment in this task. c) The fluidity of the forebrain membranes also decreased significantly with age. Again, there was a significant reduction in the middle-aged group. A comparison of these parameters revealed significant correlations between NMDA receptor density and 24-h latency (r = 0.52, p < 0.003) over all three age groups, as well as significant correlations between membrane fluidity and either NMDA receptor density or 24-h latency. These findings do not prove a causal relationship, but are compatible with the hypothesis that changes of membrane fluidity, by decreasing the number of NMDA receptors, affect passive avoidance performance.

Glutamatergic treatment strategies for age-related memory disorders.

Age-related changes of N-methyl-D-aspartate (NMDA) receptors have been found in cortical areas and in the hippocampus of many species. On the basis of a variety of experimental observations it has been suggested that the decrease of NMDA receptor density might be one of the causative factors of the cognitive decline with aging. Based on these findings several strategies have been developed to improve cognition by compensating the NMDA receptor deficits in aging. The most promising approaches are the indirect activation of glutamatergic neurotransmission by agonists of the glycine site or the restoration of the age-related deficit of receptor density by several nootropics.

The function of the NMDA-receptor during normal brain aging.

Age-related changes of N-methyl-D-aspartate (NMDA) receptors have been found in cortical areas and in the hippocampus of many species. On the basis of a variety of experimental observations it has been suggested that the decrease of NMDA-receptor density might be one of the causative factors of the cognitive decline with aging. Based on these findings several strategies have been developed to improve cognition by compensating the NMDA-receptor deficits in aging. The most promising approaches are the indirect activation of glutamatergic neurotransmission by agonists of the glycine site or the restoration of the age-related deficit of receptor density by several nootropics.