Biology subjects

Ward, M. J.

Publications and source records attributed to Ward, M. J..

11 recordsLinked to original sources

bioRxiv2026

Depressive status modulates hippocampal-cortical dynamics during acute nicotine use

Nicotine use disorder shows heterogeneity in treatment response, potentially reflecting differences in underlying neural circuitry, particularly in the presence of depression. We examined real-time neural dynamics during nicotine inhalation in two chronic users - one with depression and one without - using simultaneous hippocampal recordings from responsive neurostimulation (RNS) electrodes and scalp EEG. Oscillatory activity and hippocampal-cortical connectivity were analyzed in relation to mood and craving. Oscillatory activity tracked mood in the non-depressed individual but was attenuated or reversed in the depressed individual, suggesting reduced reward-related neural responsiveness. In contrast, both participants showed reduced alpha hippocampal-cortical connectivity following nicotine use, suggesting a shift from reward-seeking to reward and relief processing. These findings support a network-based framework of nicotine-driven neural dynamics and provide preliminary evidence that depressive status may modulate these processes. Although limited to two cases, this work highlights the potential for identifying neurophysiological subtypes of nicotine users and informs future efforts toward personalized treatment approaches.

neuroscience↗

bioRxiv2021

A Multimodal Approach to Investigate the Neural Mechanisms of Real World Social Vision

Eye tracking and other behavioral measurements collected from patient-participants in their hospital rooms afford a unique opportunity to study immersive natural behavior for basic and clinical translational research. We describe an immersive social and behavioral paradigm implemented in patients undergoing evaluation for surgical treatment of epilepsy, with electrodes implanted in the brain to determine the source of their seizures. Our studies entail collecting eye tracking with other behavioral and psychophysiological measurements from patient-participants during unscripted behavior, including social interactions with clinical staff, friends and family, in the hospital room. This approach affords a unique opportunity to study the neurobiology of natural social behavior, though it requires carefully addressing distinct logistical, technical, and ethical challenges. Collecting neurophysiological data synchronized to behavioral and psychophysiological measures helps us to study the relationship between behavior and physiology. Combining across these rich data sources while participants eat, read, converse with friends and family, etc., enables clinical-translational research aimed at understanding the participants disorders and clinician-patient interactions, as well as basic research into natural, real-world behavior. We discuss data acquisition, quality control, annotation, and analysis pipelines that are required for our studies. We also discuss the clinical, logistical, and ethical and privacy considerations critical to working in the hospital setting.

neuroscience↗

bioRxiv2021

Identification and characterization of novel proteins from Arizona bark scorpion venom that inhibit Nav1.8, a voltage-gated sodium channel regulator of pain signaling

The voltage-gated sodium channel Nav1.8 is linked to neuropathic and inflammatory pain, highlighting the potential to serve as a drug target. However, the biophysical mechanisms that regulate Nav1.8 activation and inactivation gating are not completely understood. Progress has been hindered by a lack of biochemical tools for examining Nav1.8 gating mechanisms. Arizona bark scorpion (Centruroides sculpturatus) venom proteins inhibit Nav1.8 and block pain in grasshopper mice (Onychomys torridus). These proteins provide tools for examining Nav1.8 structure-activity relationships. To identify proteins that inhibit Nav1.8 activity, venom samples were fractioned using liquid chromatography (reversed phase and ion exchange). A recombinant Nav1.8 clone expressed in ND7/23 cells was used to identify subfractions that inhibited Nav1.8 Na+ current. Mass spectrometry-based bottom-up proteomic analyses identified unique peptides from inhibitory subfractions. A search of the peptides against the AZ bark scorpion venom gland transcriptome revealed four novel proteins between 40 and 60% conserved with venom proteins from scorpions in four genera (Centruroides, Parabuthus, Androctonus, and Tityus). Ranging from 63 to 82 amino acids, each primary structure includes 8 cysteines and a "CXCE" motif where X = an aromatic residue (tryptophan, tyrosine or phenylalanine). Electrophysiology data demonstrated that the inhibitory effects of bioactive subfractions can be removed by hyperpolarizing the channels, suggesting that proteins may function as gating modifiers as opposed to pore blockers.

pharmacology and toxicology↗

bioRxiv2021

Deep Brain Stimulation for Parkinson's Disease Induces Spontaneous Cortical Hypersynchrony In Extended Motor and Cognitive Networks

The mechanism of action of deep brain stimulation (DBS) for Parkinsons disease remains unclear. Studies have shown that DBS decreases pathological beta hypersynchrony between the basal ganglia and motor cortex. However, little is known about DBSs effects on long range corticocortical synchronization. Here, we use machine learning combined with spectral graph theory to compare resting-state cortical connectivity between the off and on-stimulation states and compare these differences to healthy controls. We found that turning DBS on increased high beta and gamma band coherence in a cortical circuit spanning the motor, occipitoparietal, middle temporal, and prefrontal cortices. We found no significant difference between DBS-off and controls in this network with multivariate pattern classification showing that the brain connectivity pattern in control subjects is more like those during DBS-off than DBS-on. These results show that therapeutic DBS increases spontaneous high beta-gamma synchrony in a network that couples motor areas to broader cognitive systems.

neuroscience↗

bioRxiv2020

Multiple adjoining word and face selective regions in ventral temporal cortex exhibit distinct dynamics

The map of category-selectivity in human ventral temporal cortex (VTC) provides organizational constraints to models of object recognition. One important principle is lateral-medial response biases to stimuli that are typically viewed in the center or periphery of the visual field. However, little is known about the relative temporal dynamics and location of regions that respond preferentially to stimulus classes that are centrally viewed, like the face- and word-processing networks. Here, word- and face-selective regions within VTC were mapped using intracranial recordings from 36 patients. Partially overlapping, but also anatomically dissociable patches of face- and word-selectivity were found in VTC. In addition to canonical word-selective regions along the left posterior occipitotemporal sulcus, selectivity was also located medial and anterior to face-selective regions on the fusiform gyrus at the group level and within individual subjects. These regions were replicated using 7 Tesla fMRI in healthy subjects. Left hemisphere word-selective regions preceded right hemisphere responses by 125 ms, potentially reflecting the left hemisphere bias for language; with no hemispheric difference in face-selective response latency. Word-selective regions along the posterior fusiform responded first, then spread medially and laterally, then anteriorally. Face-selective responses were first seen in posterior fusiform regions bilaterally, then proceeded anteriorally from there. For both words and faces, the relative delay between regions was longer than would be predicted by purely feedforward models of visual processing. The distinct time-courses of responses across these regions, and between hemispheres, suggest a complex and dynamic functional circuit supports face and word perception. Significance StatementRepresentations of visual objects in the human brain have been shown to be organized by several principles, including whether those objects tend to be viewed centrally or peripherally in the visual field. However, it remains unclear how regions that process objects that are viewed centrally, like words and faces, are organized relative to one another. Here, invasive and non-invasive neuroimaging suggests there is a mosaic of regions in ventral temporal cortex that respond selectively to either words or faces. These regions display differences in the strength and timing of their responses, both within and between brain hemispheres, suggesting they play different roles in perception. These results illuminate extended, bilateral, and dynamic brain pathways that support face perception and reading.

neuroscience↗

bioRxiv2019

Transcranial Near-Infrared Light: Dose-Dependent Effects on EEG Oscillations but not Cerebral Blood Flow

ObjectiveOur objective was to assess whether transcranial photobiomodulation (tPBM) with near-infrared light (NIR) shows modulatory effects on cerebral electrical activity through electroencephalogram (EEG) and cerebral blood flow (CBF). BackgroundtPBM has emerged as a novel intervention for several neuropsychiatric conditions due to its neuroprotective and neuroenhancement effects. MethodsWe conducted a single-blind, sham-controlled pilot study to test the effect of continuous (c-tPBM), pulse (p-tPBM) and sham (s-tPBM) transcranial photobiomodulation on EEG oscillations and CBT using diffuse correlation spectroscopy (DCS) in a sample of ten healthy subjects [6 F/ 4 M; mean age 28.6 {+/-} 12.9 (SD) years]. c-tPBM NIR (830 nm; 54.8 mW/cm{superscript 2}; 65.8 J/cm{superscript 2}; 2.3 kJ) and p-tPBM (830 nm; 10Hz; 54.8 mW/cm{superscript 2}; 33%; 21.7 J/cm{superscript 2}; 0.8 kJ) were delivered concurrently to the frontal areas (F4, Fp2, Fp1, F3 - total surface 35.8 cm{superscript 2}) by four LED clusters (TPBM-1000 Litecure). EEG and DCS recordings were performed weekly before, during, and after each tPBM session (in sequence: c-tPBM, s-tPBM and p-tPBM). ResultsOnly c-tPBM significantly boosted gamma (t = 3.02, df = 7, p < .02) and beta (t = 2.91, df = 7, p < .03) EEG spectral powers in eyes-open recordings and gamma power (t = 3.61, df = 6, p < .015) in eyes-closed recordings, with the largest effects in the posterior regions. There was no significant effect of NIR-tPBM on CBF compared to sham. ConclusionsOur data suggest a dose-dependent effect of tPBM with NIR (c-tPBM) on cerebral gamma and beta neuronal activity. Altogether, our findings support the neuromodulatory effect of transcranial NIR.

neuroscience↗

bioRxiv2019

Endogenous activity modulates stimulus and circuit-specific neural tuning and perception

Perception reflects not only input from the sensory periphery, but also the endogenous neural state when sensory inputs enter the brain. Whether endogenous neural states influence perception only through global mechanisms, such as arousal, or can also perception in a neural circuit and stimulus specific manner remains largely unknown. Intracranial recordings from 30 pre-surgical epilepsy patients showed that endogenous activity independently modulated the strength of trial-by-trial neural tuning of different visual category-selective neural circuits. Furthermore, the same aspect of the endogenous activity that influenced tuning in a particular neural circuit also correlated with reaction time only for trials with the category of image that circuit was selective for. These results suggest that endogenous activity may influence neural tuning and perception through circuit-specific predictive coding processes.

neuroscience↗

bioRxiv2018

CD8+ lymphocytes modulate acute ZIKV viremia, innate antiviral immunity and tissue dissemination in nonhuman primates

CD8+ lymphocytes are critically important in the control of viral infections, but their roles in acute Zika virus (ZIKV) infection remain incompletely explored in a model sufficiently similar to humans immunologically. Here, we use CD8+ lymphocyte depletion to dissect acute immune responses in adult male rhesus and cynomolgus macaques infected with ZIKV. CD8 depletion delayed serum viremia and dysregulated patterns of innate immune cell homing and monocyte-driven transcriptional responses in the blood. CD8-depleted macaques also showed evidence of compensatory adaptive immune responses, with elevated Th1 activity and persistence of neutralizing antibodies beyond the clearance of serum viremia. The absence of CD8+ lymphocytes increased viral burdens in lymphatic tissues, semen, and cerebrospinal fluid, and neural lesions were also evident in both CD8-depleted rhesus macaques. Together, these data support a role for CD8+ lymphocytes in the control of ZIKV dissemination and in maintaining immune regulation during acute infection of nonhuman primates.

immunology↗

bioRxiv2018

The left midfusiform gyrus interacts with early visual cortex and the anterior temporal lobe to support word individuation.

The left mid-ventral temporal cortex (lmVTC) plays a dynamic role in reading. In this study we investigated the neural interactions that influence lmVTC dynamics and the lexical information these interactions are dependent on. We monitored activity with either intracranial electroencephalography or magnetoencephalography while participants viewed real words, pseudowords, consonant strings, and false fonts. A coarse level representation in early lmVTC activity allowed for decoding of visually dissimilar real words, pseudowords, and false fonts. Functional interactions between anterior ventral temporal regions, possibly containing stored knowledge about words, and low-order visual regions occurred after this initial stage of processing and was followed by the individuation of orthographically similar real words in lmVTC, but not similar pseudowords, letter strings, or false fonts. These results suggest that the individuation of real word representations in lmVTC is catalyzed by stored knowledge about word forms that emerges from network-level interactions with anterior regions of the temporal lobe.

neuroscience↗

bioRxiv2018

Pan-cancer deconvolution of cellular composition identifies molecular correlates of antitumour immunity and checkpoint blockade response

The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a novel DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: immune hot and immune cold, which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity, and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to hot tumours, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations and define a catalogue of novel and known mediators of active antitumour immunity, deriving biomarkers and potential targets for precision immunotherapy.

cancer biology↗

bioRxiv2017

Spot dynamics in a reaction-diffusion model of plant root hair initiation

We study pattern formation in a 2-D reaction-diffusion (RD) sub-cellular model characterizing the effect of a spatial gradient of a plant hormone distribution on a family of G-proteins associated with root-hair (RH) initiation in the plant cell Arabidopsis thaliana. The activation of these G-proteins, known as the Rho of Plants (ROPs), by the plant hormone auxin, is known to promote certain protuberances on root hair cells, which are crucial for both anchorage and the uptake of nutrients from the soil. Our mathematical model for the activation of ROPs by the auxin gradient is an extension of the model of Payne and Grierson [PLoS ONE, 12(4), (2009)], and consists of a two-component Schnakenberg-type RD system with spatially heterogeneous coefficients on a 2-D domain. The nonlinear kinetics in this RD system model the nonlinear interactions between the active and inactive forms of ROPs. By using a singular perturbation analysis to study 2-D localized spatial patterns of active ROPs, it is shown that the spatial variations in the nonlinear reaction kinetics, due to the auxin gradient, lead to a slow spatial alignment of the localized regions of active ROPs along the longitudinal midline of the plant cell. Numerical bifurcation analysis, together with time-dependent numerical simulations of the RD system are used to illustrate both 2-D localized patterns in the model, and the spatial alignment of localized structures.

plant biology↗