The Efficacy and Optimization of Somatosensory Intracortical Microstimulation in Rats

Demand exists for brain-machine interfaces that offer a wide range of sensory feedback along with volitional motor control to individuals with limited control of natural sensory or motor function. As these sensorimotor devices are developed, it is necessary to improve the interaction between the prostheses and higher-level cortical structures. Optimizing these somatosensory stimulation parameters will require the use of a high-throughput experimental design. To address this, one Sprague-Dawley rat was trained to respond to auditory stimuli during a conditioned-avoidance behavior task and then implanted with a penetrating microelectrode array in the part of the somatosensory cortex corresponding to the left forelimb. After implantation, the task was repeated using electrical stimuli instead of auditory signals. Detection threshold data was collected from each electrode site to prove stimulation efficacy. The pulse rate of electrical stimulation was varied to optimize power usage by the neuroprosthesis while still achieving the lowest possible thresholds. Electrical impedance spectroscopy and cyclic voltammetry data were collected to monitor the performance of the electrode. Testing shows that auditory learning can be translated to somatosensory stimulation. As an aggregate, somatosensory detection thresholds are significantly different from those in the auditory cortex (Student’s t-test, p \u3c 0.0003). With these results in mind, future research can further optimize somatosensory intracortical microstimulation to provide more sensory feedback in motor prostheses

Overexpression of antibiotic resistance genes in hospital effluents over time

$\textbf{Objectives}$: Effluents contain a diverse abundance of antibiotic resistance genes that augment the resistome of receiving aquatic environments. However, uncertainty remains regarding their temporal persistence, transcription and response to anthropogenic factors, such as antibiotic usage. We present a spatiotemporal study within a river catchment (River Cam, UK) that aims to determine the contribution of antibiotic resistance gene-containing effluents originating from sites of varying antibiotic usage to the receiving environment. $\textbf{Methods}$: Gene abundance in effluents (municipal hospital and dairy farm) was compared against background samples of the receiving aquatic environment (i.e. the catchment source) to determine the resistome contribution of effluents. We used metagenomics and metatranscriptomics to correlate DNA and RNA abundance and identified differentially regulated gene transcripts. $\textbf{Results}$: We found that mean antibiotic resistance gene and transcript abundances were correlated for both hospital (ρ=0.9, two-tailed $\textit{P}$<0.0001) and farm (ρ=0.5, two-tailed $\textit{P}$<0.0001) effluents and that two β-lactam resistance genes ($\textit{bla}$GES and $\textit{bla}$OXA) were overexpressed in all hospital effluent samples. High β-lactam resistance gene transcript abundance was related to hospital antibiotic usage over time and hospital effluents contained antibiotic residues. $\textbf{Conclusions}$: We conclude that effluents contribute high levels of antibiotic resistance genes to the aquatic environment; these genes are expressed at significant levels and are possibly related to the level of antibiotic usage at the effluent source.This research was funded by the Biotechnology and Biological Sciences Research Council, GlaxoSmithKline and the Centre for Environment, Fisheries and Aquaculture Science

Metal abundances and ionization conditions in a possibly dust-free damped Ly-alpha system at z=2.3

We have obtained a high resolution, high S/N UVES spectrum of the bright QSO HE2243-6031 to analyze the damped Ly-alpha system (DLA) observed at z=2.33. The metallicity of this system is 1/12 solar at a neutral hydrogen column density of log N(HI)=20.7. From the observed ratios [Zn/Cr]=-0.01+/-0.05 and [S/Si]=-0.06+/-0.03$ we conclude that dust is very likely absent from the ISM of this protogalaxy. We observe an enhancement of the alpha/Fe-peak ratios of +0.2 dex for various elements, a marked odd-even effect in Mn, and a strong underabundance of N relative to Si and S, [N/Si,S]=-1 at [Si/H]=-0.86. All of these ratios support an environment that is in an early evolutionary stage, where the onset of star formation has begun only shortly before the DLA was observed. We also perform a cloud-by-cloud analysis -- without precedent at high redshift -- and find a tight correlation of all low-ionization species with respect to FeII extending over 2.5 orders of magnitude in N(FeII). We interpret this trend as being due to homogeneous physical conditions (very mild ionization effects, common dust-destruction histories, same chemical composition) and propose that this line of sight encounters absorbing clouds that share a common environment. In addition, photoionization models show that these single clouds are shielded from the external ionizing radiation, so the fraction of ionized gas is small and, except for argon, does not influence the measured metal abundances. The observed AlIII/low-ion ratios suggest the mildly ionized gas occurs in shells surrounding neutral cores of AlII.Comment: To be published in A&

Cancellous bone and theropod dinosaur locomotion. Part I—an examination of cancellous bone architecture in the hindlimb bones of theropods

This paper is the first of a three-part series that investigates the architecture of cancellous (‘spongy’) bone in the main hindlimb bones of theropod dinosaurs, and uses cancellous bone architectural patterns to infer locomotor biomechanics in extinct non-avian species. Cancellous bone is widely known to be highly sensitive to its mechanical environment, and has previously been used to infer locomotor biomechanics in extinct tetrapod vertebrates, especially primates. Despite great promise, cancellous bone architecture has remained little utilized for investigating locomotion in many other extinct vertebrate groups, such as dinosaurs. Documentation and quantification of architectural patterns across a whole bone, and across multiple bones, can provide much information on cancellous bone architectural patterns and variation across species. Additionally, this also lends itself to analysis of the musculoskeletal biomechanical factors involved in a direct, mechanistic fashion. On this premise, computed tomographic and image analysis techniques were used to describe and analyse the three-dimensional architecture of cancellous bone in the main hindlimb bones of theropod dinosaurs for the first time. A comprehensive survey across many extant and extinct species is produced, identifying several patterns of similarity and contrast between groups. For instance, more stemward non-avian theropods (e.g. ceratosaurs and tyrannosaurids) exhibit cancellous bone architectures more comparable to that present in humans, whereas species more closely related to birds (e.g. paravians) exhibit architectural patterns bearing greater similarity to those of extant birds. Many of the observed patterns may be linked to particular aspects of locomotor biomechanics, such as the degree of hip or knee flexion during stance and gait. A further important observation is the abundance of markedly oblique trabeculae in the diaphyses of the femur and tibia of birds, which in large species produces spiralling patterns along the endosteal surface. Not only do these observations provide new insight into theropod anatomy and behaviour, they also provide the foundation for mechanistic testing of locomotor hypotheses via musculoskeletal biomechanical modelling

Cancellous bone and theropod dinosaur locomotion. Part II—a new approach to inferring posture and locomotor biomechanics in extinct tetrapod vertebrates

This paper is the second of a three-part series that investigates the architecture of cancellous bone in the main hindlimb bones of theropod dinosaurs, and uses cancellous bone architectural patterns to infer locomotor biomechanics in extinct non-avian species. Cancellous bone is widely known to be highly sensitive to its mechanical environment, and therefore has the potential to provide insight into locomotor biomechanics in extinct tetrapod vertebrates such as dinosaurs. Here in Part II, a new biomechanical modelling approach is outlined, one which mechanistically links cancellous bone architectural patterns with three-dimensional musculoskeletal and finite element modelling of the hindlimb. In particular, the architecture of cancellous bone is used to derive a single ‘characteristic posture’ for a given species—one in which bone continuum-level principal stresses best align with cancellous bone fabric—and thereby clarify hindlimb locomotor biomechanics. The quasi-static approach was validated for an extant theropod, the chicken, and is shown to provide a good estimate of limb posture at around mid-stance. It also provides reasonable predictions of bone loading mechanics, especially for the proximal hindlimb, and also provides a broadly accurate assessment of muscle recruitment insofar as limb stabilization is concerned. In addition to being useful for better understanding locomotor biomechanics in extant species, the approach hence provides a new avenue by which to analyse, test and refine palaeobiomechanical hypotheses, not just for extinct theropods, but potentially many other extinct tetrapod groups as well

Modulation of the thalamus by microburst vagus nerve stimulation: a feasibility study protocol

Vagus nerve stimulation (VNS) was the first device-based therapy for epilepsy, having launched in 1994 in Europe and 1997 in the United States. Since then, significant advances in the understanding of the mechanism of action of VNS and the central neurocircuitry that VNS modulates have impacted how the therapy is practically implemented. However, there has been little change to VNS stimulation parameters since the late 1990s. Short bursts of high frequency stimulation have been of increasing interest to other neuromodulation targets e.g., the spine, and these high frequency bursts elicit unique effects in the central nervous system, especially when applied to the vagus nerve. In the current study, we describe a protocol design that is aimed to assess the impact of high frequency bursts of stimulation, called “Microburst VNS”, in subjects with refractory focal and generalized epilepsies treated with this novel stimulation pattern in addition to standard anti-seizure medications. This protocol also employed an investigational, fMRI-guided titration protocol that permits personalized dosing of Microburst VNS among the treated population depending on the thalamic blood-oxygen-level-dependent signal. The study was registered on clinicaltrials.gov (NCT03446664). The first subject was enrolled in 2018 and the final results are expected in 2023

The psychology of passion: A meta-analytical review of a decade of research on intrapersonal outcomes

It is just over a decade since Vallerand et al. (J Personal Soc Psychol 85:756–767, 2003) introduced the dualistic model of passion. In this study, we conduct a meta-analytical review of relationships between Vallerand et al’s two passions (viz. harmonious and obsessive), and intrapersonal outcomes, and test the moderating role of age, gender, domain, and culture. A systematic literature search yielded 94 studies, within which 27 criterion variables were reported. These criterion variables derived from four research areas within the intrapersonal sphere: (a) well-/ill-being, (b) motivation factors, (c) cognitive outcomes and, (d) behaviour and performance. From these areas we retrieved 1308 independent effect sizes and analysed them using random-effects models. Results showed harmonious passion positively corresponded with positive intrapersonal outcomes (e.g., positive affect, flow, performance). Obsessive passion, conversely, showed positive associations with positive and negative

Electrophysiological, Behavioral, and Histological Assessment of the Thalamocortical Network as a Stimulation Target for Central Auditory Neuroprostheses

Brain-machine interfaces aim to restore natural sensation or locomotion to individuals who have lost such ability. While the field of neuroprostheses has developed some flagship technologies which have enjoyed great clinical success, such as the cochlear implant, it is generally understood that no single device will be ideal for all patients. For example, the cochlear implant is unable to help patients suffering from neurofibromatosis type 2, which is commonly characterized by bilateral vestibular schwannomas for which surgical removal requires transection of the auditory nerve. In an effort to develop stimulatory neuroprostheses which can help the maximum number of patients, research groups have developed central sensory neuroprostheses. However, moving through ascending sensory processing centers introduces more uniqueness of neuronal feature selectivity and greater coding complexity, and chronic implantation of devices becomes less efficacious as the brain’s glial cells respond to implanted devices. In this work, we propose a neuroprosthetic targeting auditory thalamus, specifically the ventral division of the medial geniculate body (MGV). Thalamus represents an information bottleneck through which many sensory systems send information. Primary (MGV) and non-primary (MGD, MGM) subdivisions provide parallel auditory inputs to cortex and receive feedback excitation and inhibition from cortex and thalamic reticular nucleus (TRN), respectively. We characterize the potential of the thalamocortical circuit as a neuroprosthetic target through electrophysiological, behavioral, and histological methods

Vagus nerve stimulation parameters evoke differential neuronal responses in the locus coeruleus

Abstract Vagus nerve stimulation (VNS) is used to treat drug‐resistant epilepsy and depression, with additional applications under investigation. The noradrenergic center locus coeruleus (LC) is vital for VNS effects; however, the impact of varying stimulation parameters on LC activation is poorly understood. This study characterized LC activation across VNS parameters. Extracellular activity was recorded in rats' left LC while 11 VNS paradigms, utilizing variable frequencies and bursting characteristics, were pseudorandomly delivered to the left cervical vagus for five cycles. Neurons' change from baseline firing rate and timing response profiles were assessed. The proportion of neurons categorized as responders over 5 VNS cycles doubled in comparison to the first VNS cycle (p < 0.001) for all VNS paradigms, demonstrating an amplification effect. The percentage of positively consistent/positive responders increased for standard VNS paradigms with frequencies ≥10 Hz and for bursting paradigms with shorter interburst intervals and more pulses per burst. The synchrony between pairs of LC neurons increased during bursting VNS but not standard paradigms. Also, the probability of evoking a direct response during bursting VNS was higher with longer interburst intervals and a higher number of pulses per burst. Standard paradigms between 10–30 Hz best positively activates LC with consistency to VNS while the best bursting paradigm to increase activity was 300 Hz, seven pulses per burst separated by 1 s. Bursting VNS was effective in increasing synchrony between pairs of neurons, suggesting a common network recruitment originating from vagal afferents. These results indicate differential activation of LC neurons depending on the VNS parameters delivered