Biology subjects

Little, S.

Publications and source records attributed to Little, S..

27 records · Page 2Linked to original sources

bioRxiv2020

Chronic wireless streaming of invasive neural recordings at home for circuit discovery and adaptive stimulation

Invasive neural recording in humans shows promise for understanding the circuit basis of brain disorders. Most recordings have been done for short durations from externalized brain leads in hospital settings, or from first-generation implantable sensing devices that offer only intermittent brief streaming of time series data. Here we report the first human use of an implantable neural interface for wireless multichannel streaming of field potentials over long periods, with and without simultaneous therapeutic neurostimulation, untethered to receiving devices. Four Parkinsons disease patients streamed bilateral 4-channel motor cortical and basal ganglia field potentials at home for over 500 hours, paired with wearable monitors that behaviorally categorize states of inadequate or excessive movement. Motor state during normal home activities was efficiently decoded using either supervised learning or unsupervised clustering algorithms. This platform supports adaptive deep brain stimulation, and may be widely applicable to brain disorders treatable by invasive neuromodulation.

neuroscience↗

bioRxiv2019

Social reprogramming in ants induces longevity-associated glia remodeling

Healthy brain aging is of crucial societal importance; however, the mechanisms that regulate it are largely unknown. Social insects are an outstanding model to study the impact of environment and epigenetics on brain function and aging because workers and queens arise from the same genome but display profound differences in behavior and longevity. In Harpegnathos saltator ants, adult workers can transition to a queen-like phenotypic state called gamergate. This caste transition results in reprogramming of social behavior and lifespan extension. Whether these changes in brain function and physiology cause brain remodeling at the cellular level is not known. Using single-cell RNA-sequencing of Harpegnathos brains undergoing caste transition, we uncovered shifts in neuronal and glial populations. In particular, the conversion of workers into long-lived gamergates caused the expansion of ensheathing glia, which maintain brain health by phagocytosing damaged neuronal structures. These glia cells were lost during aging in normal workers but not in longer-lived gamergates. We observed similar caste- and age-associated differences in ensheathing glia in other Hymenoptera as well as Drosophila melanogaster. We propose that enhanced glia-based neuroprotection promotes healthy brain aging and contributes to the extended lifespan of the reproductive caste in social insects.

neuroscience↗

bioRxiv2019

Adaptive Deep Brain Stimulation as an Advanced Parkinson’s disease Treatment (ADAPT): a pseudorandomised clinical trial

BackgroundBeta-based adaptive Deep Brain Stimulation (aDBS) is effective in Parkinsons disease (PD), when assessed in the immediate post-implantation phase. However, the potential benefits of aDBS in patients with electrodes chronically implanted, in whom the benefits of the microlesion effect have disappeared, are yet to be assessed. MethodsTo determine the acute effectiveness and side-effect profile of aDBS in PD compared to conventional continuous DBS (cDBS) and no stimulation (NoStim), years after DBS implantation. 13 PD patients undergoing battery replacement were pseudo-randomised in a crossover fashion, in- to three conditions (NoStim, aDBS or cDBS). Patient videos were blindly evaluated using a short version of the Unified Parkinsons Disease Rating Scale (subUPDRS) and the Speech Intelligibility Test (SIT). ResultsPatients had a mean disease duration of 16 years, and the mean time since DBS implantation was 6.9 years. subUPDRS scores (11 patients tested) were significantly lower both in aDBS (p=<.001), and cDBS (p=.001), when compared to NoStim. Bradykinesia subscores were significantly lower in aDBS (p=.002), but not in cDBS (p=.08), when compared to NoStim. Two patients presented re-emerging tremor during NoStim. SIT scores of patients with stimulation-induced dysarthria (11 patients tested) significantly worsened in cDBS (p=.009), but not in aDBS (p=.407), when compared to NoStim. Overall, stimulation was applied 48.8% of the time during aDBS. ConclusionBeta oscillations is effective in PD patients with bradykinetic phenotypes, delivers less stimulation than cDBS, and potentially has a more favourable speech side-effect profile. Patients with prominent tremor may require a modified adaptive control strategy.

neuroscience↗

bioRxiv2019

Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques

Chromatin loops enable transcription factor-bound distal enhancers to interact with their target promoters to regulate transcriptional programs. Although developmental transcription factors, such as active forms of Notch, can directly stimulate transcription by activating enhancers, the effect of their oncogenic subversion on the 3-dimensional (3D) organization of the cancer genome is largely undetermined. By mapping chromatin looping genome-wide in Notch-dependent triple-negative breast cancer and B-cell lymphoma, we show that far beyond the well-characterized role of Notch as an activator of distal enhancers, Notch regulates its direct target genes through establishing new long-range regulatory interactions. Moreover, a large fraction of Notch-promoted regulatory loops forms highly interacting enhancer and promoter spatial clusters, termed "3D cliques". Loss-and gain-of-function experiments show that Notch preferentially targets hyperconnected 3D cliques that regulate the expression of crucial proto-oncogenes. Our observations suggest that oncogenic hijacking of developmental transcription factors can dysregulate transcription through widespread effects on the spatial organization of cancer genomes.

cancer biology↗

bioRxiv2018

Phylogenomics of the major tropical plant family Annonaceae using targeted enrichment of nuclear genes

Targeted enrichment and sequencing of hundreds of nuclear loci for phylogenetic reconstruction is becoming an important tool for plant systematics and evolution. Annonaceae is a major pantropical plant family with 109 genera and ca. 2450 species, occurring across all major and minor tropical forests of the world. Baits were designed by sequencing the transcriptomes of five species from two of the largest Annonaceae subfamilies. Orthologous loci were identified. The resulting baiting kit was used to reconstruct phylogenetic relationships at two different levels using concatenated and gene tree approaches: a family wide Annonaceae analysis sampling 65 genera and a species level analysis of tribe Piptostigmateae sampling 29 species with multiple individuals per species. DNA extraction was undertaken mainly on silicagel dried leaves, with two samples from herbarium dried leaves. Our kit targets 469 exons (364 653 bp of sequence data), successfully capturing sequences from across Annonaceae. Silicagel dried and herbarium DNA worked eaually well. We present for the first time a nuclear gene-based phylogenetic tree at the generic level based on 317 supercontigs. Results mainly confirm previous chloroplast based studies. However, several new relationships are found and discussed. We show significant differences in branch lengths between the two large subfamilies Annonoideae and Malmeoideae. A new tribe, Annickieae, is erected containing a single African genus Annickia. We also reconstructed a well resolved species-level phylogenetic tree of the Piptostigmteae tribe. Our baiting kit is useful for reconstructing well supported phylogenetic relationships within Annonaceae at different taxonomic levels. The nuclear genome is mainly concordant with plastome information with a few exceptions. Moreover, we find that substitution rate heterogeneity between the two subfamilies is also found within the nuclear compartment, and not just plastomes and ribosomal DNA as previously shown. Our results have implications for understanding the biogeography, molecular dating and evolution of Annonaceae.

evolutionary biology↗

bioRxiv2018

Motor cortical beta transients delay movement initiation and track errors

Motor cortical activity in the beta range (13-30 Hz) is a hallmark signature of healthy and pathological movement, but its behavioural relevance remains unclear. Recent work in primates and human sensory cortex suggests that sustained oscillatory beta activity observed on average, may arise from the summation of underlying short-lasting, high-amplitude bursts of activity. Classical human movement-related event-related beta desynchronisation (ERD) and synchronization (ERS) may thus provide insufficient, non-dynamic, summaries of underlying focal spatio-temporal burst activity, limiting insight into their functional role during healthy and pathological movement.\n\nHere we directly investigate this transient beta burst activity and its putative behavioural relevance for movement control, using high-precision magnetoencephalography (MEG). We quantified the subject-specific (n=8), trial-wise (n>12,000) dynamics of beta bursts, before and after movement. We show that beta activity on individual trials is dominated by high amplitude, short lasting bursts. While average beta changes generally manifest as bilaterally distributed activity (FWHM = 25mm), individual bursts are spatially more focal (FWHM = 6 mm), sporadic (1.3 -1.5/s), and transient (mean: 96 ms).\n\nPrior to movement (the period of the classical ERD), the timing of the last pre-movement burst predicts movement onset, suggesting a role in the specification of the goal of movement. After movement (the period of the classical ERS), the first beta burst is delayed by ~100ms after a response error occurs, intimating a role in error monitoring and evaluation.\n\nMovement-related beta activity is therefore dominated by a spatially dispersed summation of short lasting, sporadic and focal bursts. Movement-related beta bursts coordinate the retrieval and updating of movement goals in the pre- and post-movement periods, respectively.

neuroscience↗

bioRxiv2018

Phase-dependent suppression of beta oscillations in Parkinson’s disease patients

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (~20Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's Disease patients. Computational modelling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here we demonstrate in awake, parkinsonian patients undergoing functional neurosurgery, that electrical stimulation arriving on consecutive cycles of a specific phase of the subthalamic oscillation can suppress its amplitude and coupling to cortex. Stimulus-evoked changes in spiking did not have a consistent time course, suggesting that the oscillation was modulated independently of net output. Phase-dependent stimulation could thus be a valuable strategy for treating brain diseases and probing the function of oscillations in the healthy brain.

neuroscience↗

bioRxiv2017

Laminar-specific cortical dynamics in human visual and sensorimotor cortices

Lower frequency, feedback, activity in the alpha and beta range is thought to predominantly originate from infragranular cortical layers, whereas feedforward signals in the gamma range stem largely from supragranular layers. Distinct anatomical and spectral channels may therefore play specialized roles in communication within hierarchical cortical networks; however, empirical evidence for this organization in humans is limited. We leverage high precision MEG to test this proposal, directly and non-invasively, in human participants during visually guided actions. Visual alpha activity mapped onto deep cortical laminae, whereas visual gamma activity predominantly arose from superficial laminae. This laminar-specificity was echoed in sensorimotor beta and gamma activity. Visual gamma activity scaled with task demands in a way compatible with feedforward signaling. For sensorimotor activity, we observed a more complex relationship with feedback and feedforward processes. Distinct frequency channels thus operate in a laminar-specific manner, but with dissociable functional roles across sensory and motor cortices.

neuroscience↗

bioRxiv2017

Non-invasive laminar inference with MEG: Comparison of methods and source inversion algorithms

Magnetoencephalography (MEG) is a direct measure of neuronal current flow; its anatomical resolution is therefore not constrained by physiology but rather by data quality and the models used to explain these data. Recent simulation work has shown that it is possible to distinguish between signals arising in the deep and superficial cortical laminae given accurate knowledge of these surfaces with respect to the MEG sensors. This previous work has focused around a single inversion scheme (multiple sparse priors) and a single global parametric fit metric (free energy). In this paper we use several different source inversion algorithms and both local and global, as well as parametric and non-parametric fit metrics in order to demonstrate the robustness of the discrimination between layers. We find that only algorithms with some sparsity constraint can successfully be used to make laminar discrimination. Importantly, local t-statistics, global cross-validation and free energy all provide robust and mutually corroborating metrics of fit. We show that discrimination accuracy is affected by patch size estimates, cortical surface features, and lead field strength, which suggests several possible future improvements to this technique. This study demonstrates the possibility of determining the laminar origin of MEG sensor activity, and thus directly testing theories of human cognition that involve laminar- and frequency- specific mechanisms. This possibility can now be achieved using recent developments in high precision MEG, most notably the use of subject-specific head-casts, which allow for significant increases in data quality and therefore anatomically precise MEG recordings.

neuroscience↗