Biology subjects

McNamara, C. G.

Publications and source records attributed to McNamara, C. G..

7 recordsLinked to original sources

bioRxiv2026

Gut Microbial Signals Influence Motivational Responses in the Male Mouse

Mammalian motivation to obtain natural rewards is regulated by internal biological and external environmental factors. Increasing evidence suggests the gut microbiota may represent one such factor. Here, we observed that antibiotic (ABX)-induced disruption of the gut microbiota increased the motivation to obtain palatable rewards, elevated inflammatory cytokine levels and elicited significant alterations in synaptic plasticity-related gene pathways in the mouse nucleus accumbens (NAc). We also observed that the dynamic state of the gut microbiota partially impacts motivational responses and identified several gut microbial metabolites that could be driving this phenotype. Finally, surgical ablation of vagal signalling via subdiaphragmatic vagotomy partially rescued transcriptomic signatures in the NAc and elevations in inflammatory markers but was not enough to prevent the increase in motivational responses. Overall, our results highlight an important new role for the gut microbiota in regulating the cascade of metabolic, neurochemical and immunological events necessary for reward processing and motivation.

neuroscience↗

bioRxiv2025

Modulation of motor cortical theta and gamma oscillations using phase-targeted, closed-loop optogenetic stimulation of local excitatory and inhibitory neurons

Theta and gamma oscillations are prominent features of cortical local field potentials (LFPs) and stimulation of the motor cortex at these frequencies can enhance motor learning. Phase-targeted closed-loop stimulation could provide a more precise and effective method to modulate these oscillations, particularly if stimulation parameters could harness the dynamics of the specific circuit mechanisms underpinning the generation of these activities. To address this question, we defined the response of theta-and gamma-frequency oscillations in the motor cortex to closed-loop optogenetic stimulation of excitatory pyramidal neurons and inhibitory interneurons transfected with Channelrhodopsin-2 in awake, head-fixed RBP4-Cre (retinol-binding-protein-4) and PV-Cre (parvalbumin) mice, respectively. Phase-targeted blue-light pulses were delivered using the OscillTrack algorithm to track theta phase in the cortical LFP in real time and trigger stimulation at one of four target theta phases. Stimulation was delivered over a quarter of the target theta cycle, either as a single continuous pulse ("continuous" protocol) or three short pulses at gamma (75Hz) frequency ("gamma" protocol). Stimulation of both neuron types, using either stimulation protocol, modulated theta power in a phase-dependent manner, with continuous stimulation of excitatory cells leading to stronger modulation. Phase-dependent amplification during stimulation of excitatory vs inhibitory neurons was offset by 90{degrees}, in line with predictions from computational models. Open-loop replay of previously recorded closed-loop stimulation patterns did not elicit the same phase-specific effects, demonstrating the necessity of the closed-loop interaction to produce these effects. Stimulation of pyramidal neurons using the gamma protocol amplified gamma power, independently of target theta phase. These findings reveal phase-dependent amplification of cortical theta power can be induced by stimulation of local excitatory or inhibitory neurons, with a phase-offset likely resulting from circuit interactions. This approach can be used to inform the development of brain stimulation methods to modulate these activities more effectively in humans.

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bioRxiv2024

Response of neuronal populations to phase-locked stimulation: model-based predictions and validation

BackgroundModulation of neuronal oscillations holds promise for the treatment of neurological disorders. Nonetheless, stimulating neuronal populations in a continuous open-loop manner can lead to side effects and suboptimal efficiency. Closed-loop strategies such as phase-locked stimulation aim to address these shortcomings by offering a more targeted modulation. While theories have been developed to understand the neural response to stimulation, their predictions have not been thoroughly tested using experimental data. ObjectiveWe aimed to test the predictions of a mathematical model regarding the response of neuronal populations to phase-locked stimulation. MethodsUsing a coupled oscillator model, we expanded on two key predictions describing the response to stimulation as a function of the phase and amplitude of ongoing neural activity. To investigate these predictions, we analyzed electrocorticogram (ECoG) recordings from a previously conducted study in Parkinsonian rats, and extracted the corresponding phase and response curves. ResultsWe demonstrated that the amplitude response to stimulation is strongly correlated to the derivative of the phase response ({rho} > 0.8) in all animals except one, thereby validating a key model prediction. The second prediction postulated that the stimulation becomes ineffective when the network synchrony is high, a trend that appeared missing in the data. Our analysis explained this discrepancy by showing that the neural populations in Parkinsonian rats did not reach the level of synchrony for which the theory would predict ineffective stimulation. ConclusionsOur results highlight the potential of fine-tuning stimulation paradigms informed by mathematical models that consider both the ongoing phase and amplitude of the targeted neural oscillation.

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bioRxiv2021

Stable modulation of neuronal oscillations produced through brain-machine equilibrium

Brain stimulation is predominantly delivered independent of ongoing activity, whereas closed-loop systems can modify activity through interaction. They have the unrealised potential to continuously bind external stimulation to specific dynamics of a neural circuit. Such manipulations are particularly suited to rhythmic activities, where neuronal activity is organised in oscillatory cycles. Here, we developed a fast algorithm that responds on a cycle-by-cycle basis to stimulate basal ganglia nuclei at predetermined phases of successive cortical beta cycles in parkinsonian rats. Using this approach, we demonstrate a stable brain-machine interaction. An equilibrium emerged between the modified brain signal and feedback-dependent stimulation pattern, which led to sustained amplification or suppression of the oscillation. Sustained beta amplification slowed movement speed by altering the mode of locomotion. Integrating an external stimulus with network activity in this way could be used to correct maladaptive activities and to define the role of oscillations in fundamental brain functions.

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bioRxiv2020

Phase-dependent closed-loop modulation of neural oscillations in vivo

Normal brain function is associated with an assortment of oscillations of various frequencies, each reflecting the timing of separate computational processes and levels of synchronization within and between brain areas. Stimulation accurately delivered on a specified phase of a given oscillation provides the opportunity to target individual aspects of brain function. To achieve this, we have developed a highly responsive system to produce a continuous online phase-estimate. In addition to stable oscillations, the system accurately tracks the early cycles of short, transient oscillations and can operate across the frequency range of most established neuronal oscillations (4 to 250 Hz). Here we demonstrate bidirectional modulation of the pathologically elevated parkinsonian beta-band oscillation (around 35 Hz) in 6-OHDA hemi-lesioned rats. Beta phase, monitored using a single channel electrocorticogram above secondary motor cortex, was used to drive electrical stimulation of the globus pallidus on one of eight phases spanning the oscillation cycle. Stimulation of the early ascending phase suppressed the oscillation whereas stimulation of the early descending phase was amplifying. By implementing a rule that prevented stimulation when the phase estimate was unstable, we achieved a system that could adapt stimulation rate and pattern to respond to the changes produced in the target oscillation. This allowed the electronic system to create and maintain a state of equilibrium with the biological system resulting in continuous stable modulation of the target oscillation over time. These results demonstrate the feasibility of phase locked stimulation as a more refined strategy for remediation of pathological beta oscillations in the treatment of the motor symptoms of Parkinsons disease. Furthermore, they establish the utility of our algorithm and allow for the potential to assess the contribution of rhythmic activity in neuronal computation across a number of brain systems.

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bioRxiv2019

Parkinsons disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinsons disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In PD patients, we demonstrate that a subset of STN neurons are strongly and selectively sensitive to fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to full range of instantaneous amplitude. In rats, we probed the frequency response of STN neurons more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40Hz) and constant amplitude. In both healthy and dopamine-depleted animals, only beta-frequency stimulation selectively led to a progressive reduction in the variability of spike timing through the stimulation train. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.

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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↗