Biology subjects

Levenstein, J. M.

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

7 recordsLinked to original sources

bioRxiv2025

Baclofen, a GABAB receptor agonist, impairs motor learning in healthy people and changes inhibitory dynamics in motor areas

Inhibition mediated by {gamma}-aminobutyric acid (GABA) is implicated in motor plasticity and learning, with [GABA] in the motor cortex decreasing during motor learning. However, the causal relationship between [GABA] and learning has yet to be determined. Here, we conducted a within-subject, double-blind, placebo-controlled, crossover study to investigate the effect of increased GABAergic inhibition via GABAB-receptor agonist baclofen on motor learning and Magnetic Resonance Spectroscopic Imaging (MRSI) metrics. Increasing GABA-mediated inhibition with baclofen did not change response times, but significantly impaired motor sequence learning. In parallel, we demonstrated a blunting of the expected decrease in [GABA] during motor learning. These results highlight a causal role for GABAergic inhibition in motor learning and may have clinical implications: baclofen is commonly used to treat post brain-injury spasticity, but may impair motor learning during rehabilitation.

neuroscience↗

bioRxiv2025

Resting-State EEG Aperiodic Exponent Moderates the Association Between Age and Memory Performance in Older Adults

Memory functions are susceptible to age-related cognitive decline, making it essential to explore the underlying neurophysiological mechanisms that contribute to memory function during healthy ageing. Resting-state EEG (rsEEG) parameters, particularly the aperiodic exponent, a marker of cortical excitation-inhibition balance, and individual alpha peak frequency, a correlate of neural processing efficiency, have demonstrated associations with ageing and cognitive functions. This study investigated associations between these rsEEG markers and performance across multiple memory systems in healthy older adults (n = 99) aged 50-84 years, specifically the direct associations of these markers on memory across episodic, working, and visual short-term memory systems, assessed via computerised tasks, as well as their moderating effects on age-memory relationships. While no direct associations were seen between rsEEG markers and memory performance across tasks beyond the contribution of age, gender and education, results revealed significant moderating effects of the aperiodic exponent on age-related performance in episodic and visual short-term memory. Notably, for individuals with a higher exponent, age was not significantly associated with episodic or visual short-term memory performance, whereas those with average and lower exponent values showed poorer performance with older age. These findings suggest that average and lower aperiodic exponents may reflect a marker of decrement in age-related memory performance and higher exponents may index an underlying protective mechanism against age-related memory decline. This investigation extends the current understanding of cognitive ageing mechanisms by identifying the aperiodic exponent as a potential biomarker explaining individual differences in cognitive ageing trajectories in older adult populations, particularly in episodic and visual short-term memory systems, and establishes a framework for studying neuroprotective mechanisms and developing interventions to preserve cognitive function in older adults.

neuroscience↗

bioRxiv2025

Relationships between GABA+ and Glx concentrations with age and inhibition in healthy older adults

Inhibition represents a core executive function which underlies the ability to suppress interfering and/or distracting stimuli, thereby building resistance against task-irrelevant information. However, the impact of ageing on inhibitory functioning and the potential role of neuroplasticity - largely driven by predominant excitatory (glutamatergic) and inhibitory (GABAergic) neurochemicals - remains poorly understood. In this study, we investigated age relationships with neurochemical concentrations (GABA+ and Glx) and examined the associations between these neurochemicals and inhibitory sub-components in the context of healthy ageing. To this end, participants completed three inhibition tasks (i.e., flanker, Stroop and go/no-go), each measuring a different sub-component process, via the PsyToolkit platform. MRS data was acquired in the sensorimotor (SM1; n=71, mean age (SD) = 68.3 ({+/-}9.7) years, 39 females) and prefrontal (PFC; n=58, mean age (SD) = 67.6 ({+/-}9.6) years, 30 females) regions using a HERMES sequence and analysed using OSPREYs pipeline. After correcting for gender and education, semi-partial correlations (rho) revealed no significant relationships between age and GABA+ or Glx concentrations in either the SM1 or PFC regions. Furthermore, through partial correlations (rho), after correcting for age, gender and education, we identified a significant negative relationship between SM1 Glx concentrations and go/no-go error rates, such that greater concentrations of Glx in the SM1 region were associated with greater accuracy on the go/no-go task. The null age-neurochemical results suggest that GABA+ and Glx may not uniformly decline during healthy ageing. This finding suggests that the relationship between older age and neurochemistry may be more nuanced than previously reported. In addition, our neurochemical-behavioural findings provide neurochemically-and-spatially specific evidence that SM1 Glx concentrations may be important for response inhibition. This result indicates a role for the glutamatergic system in supporting inhibition over the normal course of ageing.

neuroscience↗

bioRxiv2025

Neurophysiological Correlates of Modifiable Dementia Risk Factors in Cognitively Unimpaired Older Adults

The 2024 Lancet Commission on Dementia estimates that up to 45% of dementia cases could be prevented by addressing modifiable risk factors, emphasising both prevention opportunities and the need to understand the biological mechanisms. This study investigated neurophysiological mechanisms underlying modifiable dementia risk factors in cognitively unimpaired older adults. Seventy-nine cognitively unimpaired older adults underwent MRI brain scans, with spectroscopy measurements taken from the sensorimotor cortex (SMC) and prefrontal cortex (PFC), using a Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) sequence, optimised for measuring GABA+. Modifiable dementia risk scores were calculated using the Assessment for Cognitive Health and Dementia Risk (CogDrisk). Hierarchical linear regression analyses revealed a significant negative relationship within the SMC, with lower GABA+ ({beta} = -0.249, p = 0.009) associated with higher risk scores. In the PFC, lower tNAA and tCho concentrations significantly predicted higher risk scores ({beta} = -0.168 and -0.170, respectively). These findings suggest that GABAergic system alterations may underlie the pathophysiology of modifiable dementia risk in healthy ageing, whilst changes in tNAA and tCho may reflect early alterations in neuronal integrity. These region-specific neurochemical findings may help identify potential early biomarkers for dementia risk, and suggest new therapeutic pathways for preventive interventions.

neuroscience↗

bioRxiv2025

Age-related Inhibitory Decline: Examining Inhibition Sub-Components and their Impact on Sustained Attention in Healthy Ageing

ObjectiveThe inhibition deficit hypothesis postulates that inhibitory functioning declines with age, which negatively impacts other cognitive abilities. Yet still, the impact of healthy ageing on inhibitory functioning remains unclear, with the multifaceted nature of inhibition often an overlooked factor. Moreover, no prior study has empirically tested whether inhibitory sub-components explain differential age-effects in sustained attention - an open question that this work aims to address. MethodIn this cross-sectional study, we investigated the inhibition deficit hypothesis in a sample of eighty healthy older adults (mean age = 67.78 years, 44f). We utilised the PsyToolkit platform to administer three inhibition tasks (i.e., flanker, Stroop, and go/no-go), each targeting a distinct sub-component process, along with the Sustained Attention to Response Task (SART). ResultsSemi-partial correlations (rho) of the three inhibition sub-component measures (correcting for gender and education) with age resulted in significant positive relationships with task performance on the Stroop and go/no-go, such that older individuals had more pronounced Stroop effects and worse go/no-go accuracy, respectively. Lastly, go/no-go performance completely mediated the relationship between ageing and sustained attention performance, whilst Stroop effects partially mediated this association. ConclusionAge-related declines were observed in specific inhibition tasks, which speaks against a general inhibition deficit in healthy ageing and cautions against conflating these sub-components into a generalised concept of inhibition. The mediation findings demonstrate that inhibitory sub-components account for age-related declines in sustained attention, over and beyond ageing itself via an indirect path, representing an important cognitive domain to maintain throughout ageing. Key pointsO_ST_ABSQuestionC_ST_ABSAre different inhibitory sub-components associated with age, and do they mediate age-related changes in sustained attention? FindingsDifferent inhibition tasks were uncorrelated, demonstrating specific relationships with age and providing evidence that select inhibition tasks can explain differential age-effects in sustained attention. ImportanceThis study lends support for the inhibition deficit hypothesis and underlines the importance of considering inhibitions multifaceted nature. Next stepsFuture research should adopt longitudinal designs to examine causal relationships

animal behavior and cognition↗

bioRxiv2023

Sustained activation in basal ganglia and cerebellum after repetitive movement in a non-task-specific dystonia

We previously observed sustained fMRI BOLD signal in the basal ganglia in focal hand dystonia patients after a repetitive finger tapping task. Since this was observed in a task-specific dystonia, for which excessive task repetition may play a role in pathogenesis, in the current study we asked if this effect would be observed in a focal dystonia (cervical dystonia [CD]) that is not considered task-specific or thought to result from overuse. We evaluated fMRI BOLD signal time courses before, during, and after the finger tapping task in CD patients. We observed patient/control differences in post-tapping BOLD signal in left putamen and left cerebellum during the non-dominant (left) hand tapping condition, reflecting abnormally sustained BOLD signal in CD. BOLD signals in left putamen and cerebellum were also abnormally elevated in CD during tapping itself and escalated as tapping was repeated. There were no cerebellar differences in the previously studied FHD cohort, either during or after tapping. We conclude that some elements of pathogenesis and/or pathophysiology associated with motor task execution/repetition may not be limited to task-specific dystonias, but there may be regional differences in these effects across dystonias, associated with different types of motor control programs.

neuroscience↗

bioRxiv2021

Fatigue induces behavioural improvements in the unfatigued hand via altered functional connectivity and neurochemicals in cortical motor areas

In humans, motor learning is underpinned by changes in sensorimotor network functional connectivity (FC). Unilateral contractions increase FC in the ipsilateral primary motor cortex (M1) and supplementary motor area (SMA); areas involved in motor planning and execution of the contralateral hand. Therefore, unilateral contractions are a promising approach to augment motor performance in the contralateral hand. In a within-participant, randomized, cross-over design, 15 right-handed adults had two magnetic resonance imaging (MRI) sessions, where functional-MRI and MR-Spectroscopic Imaging were acquired before and after repeated right-hand contractions at either 5% or 50% maximum voluntary contraction (MVC). Before and after scanning, response times (RTs) were determined in both hands. Nine minutes of 50% MVC contractions resulted in decreased handgrip force in the contracting hand, and decreased RTs in the contralateral hand. This improved motor performance in the contralateral hand was supported by significant neural changes: increased FC between SMA-SMA and increased FC between right M1 and right Orbitofrontal Cortex. At a neurochemical level, the degree of GABA decline in left M1, left and right SMA correlated with subsequent behavioural improvements in the left-hand. These results support the use of repeated handgrip contractions as a potential modality for improving motor performance in the contralateral hand. Significance StatementEnhanced functional connectivity and decreased inhibition in sensorimotor areas of the brain underpin enhancements in motor performance and learning. In this study we investigated the impact of repeated right handgrip contractions at 50% MVC to improve behaviour, enhance functional connectivity and alter sensorimotor inhibition. We found that after nine minutes of repeated 50% MVC handgrip contractions with the right-hand, left-hand response times were significantly improved. This behavioural improvement was accompanied by altered interhemispheric functional connectivity and neurochemical changes across sensorimotor areas. Repeated unilateral handgrip contractions may be an effective method for enhancing contralateral limb motor performance in rehabilitation settings.

neuroscience↗