bioRxiv Science⌕ Search

Biology subjects

Pouget, P.

Publications and source records attributed to Pouget, P..

At least 19 recordsLinked to original sources

Saccadic network dysfunction underlies eye-movement variability in early Parkinson's disease

Parkinsons disease is a neurodegenerative disorder characterized by altered subcortical-cortical connectivity, leading to motor and cognitive deficits. Saccadic eye movement abnormalities are among the earliest and most persistent markers of the disease, serving as sensitive indicators of disrupted oculomotor and cognitive control. While changes in average saccadic behavioral measures are widely reported in Parkinson's disease, intra-individual variability in saccadic performance and the underlying network dysfunction remain poorly understood. Here, we quantified intra-individual saccadic variability in early-stage Parkinsons disease and identified its functional correlates within the resting-state saccadic network. We analyzed data from 91 patients with early-stage Parkinsons disease and 46 healthy controls who underwent oculomotor testing and resting-state functional magnetic resonance imaging. First, at the behavioral level, we assessed intra-individual variability in saccadic performance within each group using the coefficient of variation of reaction time and normalized peak velocity across trials. Second, at the brain level, we assessed group differences in static and dynamic functional connectivity across 39 regions comprising the saccadic network. We examined the relationship between network connectivity and saccadic variability using partial least squares analysis. We also quantified network organization using graph-theory measures of global efficiency and clustering coefficient. Finally, we tested the relevance of intra-individual saccadic variability and network features in distinguishing patients from healthy controls using a multivariate Mahalanobis classifier. Our results showed that, compared to HC, patients had higher intra-individual variability in saccadic behavioral measures of reaction time (pHolm = 0.012) and normalized peak velocity (pHolm = 0.012). Interestingly, patients had (i) reduced static and dynamic connectivity within the saccadic network and (ii) weaker associations between network connectivity and intra-individual saccadic variability of specifically normalized peak velocity. These results were particularly driven by regions within the cognitive saccade network. The classifier that integrated intra-individual saccadic variability and network connectivity achieved 95.62% accuracy in distinguishing patients from healthy controls, with dynamic connectivity contributing more strongly to classification performance than static connectivity. We demonstrate that elevated intra-individual variability of saccades, underpinned by altered functional connectivity within cognitive-oculomotor networks, is a prominent feature of early-stage Parkinsons disease. Emerging as a promising physiological marker of disease pathophysiology, intra-individual variability offers a powerful new framework to refine early diagnosis and improve the tracking of neurodegeneration before severe clinical milestones are reached.

neuroscience↗

From Functional Organization to Vascular Structure in the Primate Visual Cortex Using Ultrasound Imaging

The primary visual cortex (V1) provides an exceptional structure to assess information encoding in the cortex thanks to its highly controlled visual input. However, optical measures and electrophysiology are limited to very superficial layers while fMRI provides low spatial resolution. Taking advantages of functional ultrasound imaging (fUSi), we examined large volumes of V1 in two awake non-human primates. We showed the conservation of retinotopic maps within deep sulcal regions and across cortical layers. We then assessed the cortical point image and compared it to its vasculature distribution through ultrasound localization microscopy (ULM). We further identified the smallest vascular compartment underlying the signal. Together, these results establish fUSi, complemented by ULM, as a minimally invasive mesoscale approach for resolving functional organization of the cortex in deep sulci.

neuroscience↗

Within-Trial Noise Accounts for Inhibition of Return

Inhibition of return (IOR) refers to the slowing of response times (RTs) for stimuli presented at previously inspected locations relative to novel locations. However, the exact processing stage(s) at which IOR occurs, and its nature across different response modalities, remain debated. By reanalyzing RT data from a target-target IOR paradigm with a single noisy accumulator model, we tested whether IOR could occur at sensory or attentional stages of processing, or at later stages of decision and action selection. We considered IOR under two conditions: manual and saccadic responses. The within-trial Gaussian noise parameter best explained both manual and saccadic IOR, suggesting that in both modalities, IOR may result from a more fluctuating accumulation of evidence for repeated locations. These results support the hypothesis that target-target IOR may primarily involve attentional-level mechanisms. Significance statementWe respond more slowly to a stimulus that is presented within a short interval in the same location ("inhibition of return"), a bias thought to promote efficient visual exploration. Using evidence-accumulation modeling of manual and eye-movement reaction times from two previous studies, we found that the key change linked to inhibition of return is greater within-trial variability (noise) in evidence accumulation, not a higher decision threshold. Understanding which processing stage is affected can help connect behavioral effects to the brain networks that support attention and orienting.

neuroscience↗

Cardiac-neurovascular crosstalk: Cardiac rhythms reveal maladaptive cerebral autoregulation and constrained ventilatory status

In brain-heart interactions, several pathways have been proposed to mediate feedback loops between systems. Among these, cerebrovascular dynamics operate at their interface. However, how cardiovascular control, ventilation mechanisms, and cerebral autoregulation interact is not well characterized, especially in ageing and post-stroke conditions, where perfusion can be compromised. In a cohort of 57 elderly participants, including 30 stroke survivors, we investigated the relationship between cardiac sympathetic activity and both, cerebral blood flow regulation and ventilatory status. Sympathetic reflexes, assessed via cardiac sympathetic index (CSI) during sit-to-stand transitions, were preserved across all participants, with marginal group differences between stroke and non-stroke populations. However, among individuals with constrained ventilation, indexed by reduced end-tidal CO2 at baseline, we identified a more elevated CSI following postural change, scaling with the degree of CO2 dysregulation. Furthermore, transcranial Doppler measurements revealed exaggerated changes in mean flow velocity (MFV) within the right middle cerebral artery in most participants. These MFV shifts significantly correlated with the magnitude of cardiac sympathetic change under orthostatic stress, suggesting that CSI can capture maladaptive cerebrovascular responses. Together, these findings highlight a distinct cardiac-cerebrovascular crosstalk in elderly individuals, revealing patterns consistent with compensatory or maladaptive sympathetic overactivation under conditions of impaired cerebrovascular control.

neuroscience↗

Transcranial in-depth ultrafast ultrasound brain imaging in non-human primates

Ultrasound Localization Microscopy (ULM) offers sub-diffraction resolution vascular imaging by tracking individual contrast microbubbles. However, transcranial implementation in non-human primates remains challenging due to the skulls acoustic attenuation and distortion. This study presents a method for non-invasive transcranial ULM imaging of the anesthetized squirrel monkey through intact skull and skin. We systematically evaluated key ultrasound acquisition parameters and identified an optimal configuration balancing resolution, depth, and vascular representation. Using these refined parameters, we achieved a system resolution of 9.5 {micro}m, measured by Fourier Ring Correlation (FRC), and consistently visualized vessels as small as 23 {micro}m. Full-brain coronal and sagittal acquisitions revealed major vascular landmarks that were reproducible across animals and slices. Importantly, this resolution enables reliable detection of penetrating arterioles and venules, key elements in neurovascular coupling and implicated in various cerebrovascular pathologies. Finally, by tracking microbubbles, we quantified flow velocities from 8.8 to 55 mm/s, corresponding to flow rates ranging from 0.1 to 279 {micro}L/min, demonstrating the techniques ability to access micro- and macrovascular dynamics. This work establishes a framework for high-resolution, non-invasive brain imaging in non-human primates, and opens promising perspectives for studying cerebral structure, function, and dysfunction in translational neuroscience.

neuroscience↗

Revisiting Free Will: Distributed Activity in the Medial Frontal Cortex Predicts Self-Initiated Action

Research indicates that significant damage to primates medial frontal cortex (MFC) can impede action initiation when anticipating rewards. However, the specific roles within the MFC related to self-generated action preparation remain debated. Here, while two macaques were engaged in an oculomotor task, they occasionally paused and self-resumed the task after varying amounts of time. We utilized the high signal-to-noise ratio from spatial changes in cerebrovascular blood volume (CBV) recorded with ultrafast ultrasound imaging (fUSi) to determine whether the intervals of breaks or the resumption of task-related CBV signals could predict the execution of an ongoing single action. We show that self-initiated eye movements activate the Supplementary eye field (SEF) and the midcingulate cortex (MCC) up to 5.5 seconds before movement execution. Importantly, our results show that a concurrent activity in the SEF and MCC predicts how these two regions might simultaneously exert opposing influences on the voluntary pause and resume of tasks on a single trial basis. The quantification of this dynamic interaction is a novel step for understanding voluntary action in primates and its ability to initiate ones movement based on internal motivations rather than driven, instructed behavior.

neuroscience↗

Assessing perceptual chromatic equiluminance using a reflexive pupillary response

Equiluminant stimuli help assess the integrity of colour perception and the relationship of colour to other visual features. As a result of individual variation, it is necessary to calibrate experimental visual stimuli to suit each individuals unique equiluminant ratio. Most traditional methods rely on training observers to report their subjective equiluminance point. Such paradigms cannot easily be implemented on pre-verbal or non-verbal observers. Here, we present a novel Pupil Frequency-Tagging Method (PFTM) for detecting a participants unique equiluminance point without verbal instruction and with minimal training. PFTM analyses reflexive pupil oscillations induced by slow (< 2 Hz) temporal alternations between coloured stimuli. Two equiluminant stimuli will induce a similar pupil dilation response regardless of colour; therefore, an observers equiluminant point can be identified as the luminance ratio between two colours for which the oscillatory amplitude of the pupil at the tagged frequency is minimal. We compared pupillometry-based equiluminance ratios to those obtained with two established techniques in humans: minimum flicker and minimum motion. In addition, we estimated the equiluminance point in non-human primates, demonstrating that this new technique can be successfully employed in non-verbal subjects. Key PointsO_LIMeasuring equiluminance is challenging in non-verbal subjects. C_LIO_LIThe pupil diameter varies as perceived brightness changes. C_LIO_LIUtilising oscillatory pupillometry, PFTM provides a way to measure equiluminance points without training or the need for a subjective report. C_LI

neuroscience↗

Covariations of cerebral blood volume and single neurons discharge during resting state and behavioral visual cognitive tasks in non-human primates

To better understand how the brain allows primates to perform various set of tasks, the ability to simultaneously record the activity of the brain at multiple temporal and spatial scales is challenging but necessary. In non-human primates, combined fMRI and electrophysiological recordings have not disentangle the contributions of spiking activity to the neurovascular response. Here, we combined functional ultrasound imaging (fUS) of cerebral blood volume (CBV) and recording of single-unit activities (SUA) in visual and fronto-medial cortices of behaving macaques. We computed task-induced and SUA-induced CBV activation maps. We demonstrate that SUA provides a significant estimate of the neurovascular response below the typical fMRI voxel spatial resolution of 2mm3. Furthermore, our results also show that single unit and CBV activities are statistically uncorrelated during the resting states but correlate during behaving tasks. Conversely, during the resting states, CBV activities across known connected brain areas are correlated but decorrelate at the onset of the tasks as expected if participating in the default mode network (DMN). These results have important implications for interpreting functional imaging findings collected with fMRI or fUS while one constructs inferences of spiking activities during resting-state or while primates perform tasks.

neuroscience↗

Behavioral and brain responses to verbal stimuli reveal transient periods of cognitive integration of external world in all sleep stages

Sleep has long been considered as a state of disconnection from the environment, with absent reactivity to external stimuli. Here, we questioned this sleep disconnection dogma by directly investigating behavioral responsiveness in 49 napping subjects (27 with narcolepsy and 22 healthy volunteers) engaged in a lexical decision task. Participants were instructed to frown or smile depending on the stimulus type (words vs pseudo-words). We found accurate behavioral responses, visible via contractions of the corrugator or zygomatic muscles, in all sleep stages in both groups (except slow-wave sleep for healthy volunteers). Stimuli presented during states with high (vs. low) values of neural markers indexing rich cognitive states more often yielded responses. Our findings suggest that transient windows of reactivity to external stimuli exist in all sleep stages, even in healthy individuals. Such windows of reactivity could be used to probe sleep-related mental and cognitive processes in real-time across all sleep stages.

neuroscience↗

Failed remyelination of the non-human primate optic nerve leads to axon degeneration, retinal damages and visual dysfunction.

White matter disorders of the CNS such as MS, lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue, to prevent neuronal degeneration and promote recovery. Most of these strategies are developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined non-human primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculo-motor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This non-human primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair pro-myelinating/neuroprotective therapies to the clinic for myelin disorders such as MS. Significance StatementPromotion of remyelination has become a new therapeutic avenue, to prevent neuronal degeneration and promote recovery in white matter diseases such as MS. To date most of these strategies are developed in short-lived rodent models of demyelination, which spontaneously repair. Well-defined non-human primate models closer to man would allow to efficiently advance therapeutic approaches. Here we present a non-human primate model of optic nerve demyelination that recapitulates several features of MS lesions. The model leads to failed remyelination, associated with progressive axonal degeneration and visual dysfunction, thus providing the missing link to translate emerging pre-clinical therapies to the clinic for myelin disorders such as MS.

neuroscience↗

Action inhibition revisited: a new method identifiescompromised reactive but intact proactive control inTourette disorder

Tourette disorder (TD) is characterized by tics, which are sudden repetitive involuntary movements or vocalizations. Deficits in inhibitory control in TD patients remain inconclusive from the traditional method of estimating the ability to stop an impending action, which requires careful interpretation of a parameter derived from race model. One possible explanation for these inconsistencies is that race models assumptions are often violated. Here, we used a pair of metrics derived from a recent alternative model to address why stopping performance in TD patients is unaffected by impairments in neural circuitry. These new metrics distinguish between proactive and reactive inhibitory control and estimate them separately. When these metrics were contrasted with healthy controls (HC), we identified robust deficits in reactive control in TD patients, but not in proactive control. The patient population exhibited difficulty in slowing down the speed of movement planning, which they compensated by their intact ability of procrastination. TEASERTourette disorder patients inhibit action by means of strategic postponement to compensate impaired slowness in preparation.

neuroscience↗

In vivo optogenetic stimulation of the primate retina activates the visual cortex after long-term transfection

Over the last 15 years, optogenetics has changed fundamental research in neuroscience, and is now reaching toward therapeutic applications. Vision restoration strategies using optogenetics are now at the forefront of these new clinical opportunities. But applications to human patients suffering from retinal diseases leading to blindness rise important concerns on the long-term functional expression of optogenes and the efficient signal transmission to higher visual centers. Here we demonstrate in non-human primates, continued expression and functionality at the retina level [~]20 months after delivery of our construct. We also performed in-vivo recordings of visually evoked potentials in the primary visual cortex of anaesthetized animals. Using synaptic blockers, we isolated the in-vivo cortical activation resulting from the direct optogenetic stimulation of primate retina. In conclusion, our work indicates long-term transgene expression and transmission of the signal generated in the macaque retina to the visual cortex, two important features for future clinical applications.

neuroscience↗

The Supplementary Eye Field Tracks Cognitive Efforts

Pupil dilation is known to be an index of cognitive effort. Nevertheless, our lack of knowledge of the precise dynamics through which pupil size and activity of the medial prefrontal cortex are conjugated during cognitive tasks highlights the need for its further investigation before, during, and after changes in pupil size. Here, we tested whether pupil dynamics are related to the activity of the supplementary eye field (SEF) during a mixed pro/anti-saccade oculomotor task in two macaque monkeys. We used functional ultrasound imaging (fUS) to examine temporal changes in brain activity at the 0.1-s time scale and 0.1-mm spatial resolution in relation to behavioral performance and pupil dynamics. By combining the pupil signals and real-time imaging of NHP during cognitive tasks, we were able to infer localized CBV responses within a restricted part of the dorsomedial prefrontal cortex, referred to as the SEF, an area in which anti-saccade preparation activity is also recorded. Inversely, SEF neurovascular activity measured by fUS imaging was found to be a robust predictor of specific variations in pupil diameter over short and long time scales. Furthermore, we directly manipulated pupil diameter and CBV in the SEF using reward and cognitive effort. These results demonstrate that the SEF is an underestimated but pivotal cortical area for the monitoring and implementation of cognitive effort signals.

neuroscience↗

LATER but FORTIOR: diffusion modelling of inhibition of return

Inhibition of return (IOR) refers to the slowing of response times (RTs) for stimuli repeated at previously inspected locations, as compared with novel ones. However, the exact processing stage(s) at which IOR occurs, and its nature across different response modalities, remain debated. We tested predictions on these issues originating from the FORTIOR model (fronto-parietal organization of response times in IOR; Seidel Malkinson & Bartolomeo, 2018), and from evidence accumulation models. We reanalysed RT data from a target-target IOR paradigm (Bourgeois et al.,2013a, 2013b) by using a LATER-like evidence accumulation model (Carpenter & Williams, 1995), to test the predictions of FORTIOR, and specifically whether IOR could occur at sensory/attentional stages of processing, or at stages of decision and action selection. We considered the following conditions: manual or saccadic response modality, before or after TMS perturbation over four cortical regions. Results showed that the Gaussian noise parameter best explained both manual and saccadic IOR, suggesting that in both response modalities IOR may result from slower accumulation of evidence for repeated locations. Additionally, across stimulated regions, TMS affected only manual RTs, lowering them equally in the conditions with repeated targets (Return) and non-repeated targets (Non-return). Accordingly, the modelling results show that TMS stimulation did not significantly alter the pattern between model parameters, with the Gaussian noise parameter remaining the parameter best explaining the Return - Non-return RT difference. Moreover, TMS over the right intra-parietal sulcus (IPS) perturbed IOR by shortening the Return RT. When directly testing this effect by modelling the TMS impact in the Return condition, the Bayesian information criterion of the Gaussian noise parameter was the smallest, but this effect did not reach significance. These results support the hypothesis that target-target IOR is a predominantly sensory/attentional phenomenon, and may be modulated by activity in fronto-parietal networks.

neuroscience↗

Optogenetic therapy: High spatiotemporal resolution and pattern recognition compatible with vision restoration in non-human primates

Restoring vision using optogenetics is an ideal medical application because the eye offers a direct window to access and stimulate the pathological area: the retina. Optogenetic therapy could be applied to diseases with photoreceptor degeneration such as retinitis pigmentosa. Here, we select the specific optogenetic construct that is now used in the clinical trial and assess the opsin functional efficacy on non-human primates retinal ganglion cells (RGCs). We chose the microbial opsin ChrimsonR and showed that the vector AAV2.7m8 produced greater transfection in RGCs compared to AAV2, and that ChrimsonR attached to tdTomato (ChR-tdT) is more efficiently expressed than ChrimsonR. The 600 nm light activates the RGCs transfected with the vector AAV2.7m8-ChR-tdT from an irradiance of 1015 photons.cm-2.s-1. Vector doses of 5.1010 and 5.1011 vg/eye transfect up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. Furthermore, using a multielectrode array we recorded RGCs responses starting from 1ms stimulus duration. Using the recorded activity we were able to decode stimulus information and estimate a theoretical visual acuity of 20/249, above legal blindness. Altogether, our results pave the way for the ongoing clinical trial with the AAV2.7m8-ChrimsonR-tdT vector for vision restoration in patients affected by retinitis pigmentosa. One Sentence SummaryWe select here the vector and genetic construct best suited to provide vision restoration in patients suffering from retinopathies, we demonstrate temporal resolution compatible with high dynamic visual scenes and a visual acuity above legal blindness.

neuroscience↗

Faster is better: Visual responses to motion are stronger for higher refresh rates

Although neural responses with a millisecond precision were reported in the retina, lateral geniculate nucleus and visual cortex of multiple species, the presence and role of such a fine temporal structure is still debated at the cortical level and the general belief remains that early visual system encodes information at slower timescales. In this study, we used a new stimulation platform to generate visual stimuli that were very precisely encoded in time and we characterized in human subjects the EEG responses to moving patterns that shared the same global motion but differed in their fine scale spatio-temporal properties. In two experiments, we manipulated the information within temporal windows that corresponded to the frame duration in conventional (1/60 = 16.7ms, experience 1) and more recent (1/120 = 8.3ms, experience 2) visual displays. Our results demonstrate that EEG responses to temporally dense and coherent trajectories are significantly stronger than those to control conditions without these properties. They extend previous results from our group that showed that accurate temporal information (<10ms) significantly improve perceptual judgments on spatial discrimination, digit recognition and sensitivity for speed [Kime et al., 2016]. Altogether, our results suggest that instead of low-pass filtering the temporal information it receives from its thalamic afferents, the visual cortex may actually exploit its richness to improve visual perception.\n\nSignificance statementMost visual experiments use frame-based stimulation screens which are synchronous and slow. This might not engage the full encoding capacity of the visual system, as in natural condition, visual information is asynchronously acquired by the retina with a very high temporal resolution. In the present study, we used an unconventional and highly configurable stimulation platform to determine the EEG responses to moving patterns that shared the same global motion but differed in their fine scale (<10ms) spatio-temporal properties. Our results demonstrate that brain responses in human are significantly stronger for motion patterns that are refreshed at very high frame rate (360Hz) and thereby provide a strong support for the use of very precise temporal stimulations in vision studies.

neuroscience↗

Ultrasound functional neuroimaging reveals propagation of task-related brain activity in behaving primates

In recent decades, neuroimaging has played an invaluable role in improving the fundamental understanding of the brain. At the macro scale, neuroimaging modalities such as MRI, EEG, and MEG, exploit a wide field of view to explore the brain as a global network of interacting regions. However, this comes at the price of either limited spatiotemporal resolution or limited sensitivity. At the micro scale, electrophysiology is used to explore the dynamic aspects of neuronal activity with a very high temporal resolution. However, this modality requires a statistical averaging of several tens of single task responses. A large-scale neuroimaging modality of sufficient spatial and temporal resolution and sensitivity to study brain region activation dynamically would open new territories of possibility in neuroscience\n\nWe show that neurofunctional ultrasound imaging (fUS) is both able to assess brain activation during single cognitive tasks within superficial and deeper areas of the frontal cortex areas, and image the directional propagation of information within and between these regions. Equipped with an fUS device, two macaque rhesus monkeys were instructed before a stimulus appeared to rest (fixation) or to look towards (saccade) or away (antisaccade) from a stimulus. Our results identified an abrupt transient change in activity for all acquisitions in the supplementary eye field (SEF) when the animals were required to change a rule regarding the task cued by a stimulus. Simultaneous imaging in the anterior cingulate cortex and SEF revealed a time delay in the directional functional connectivity of 0.27 {+/-} 0.07 s and 0.9 {+/-} 0.2 s for animals S and Y, respectively. These results provide initial evidence that recording cerebral hemodynamics over large brain areas at a high spatiotemporal resolution and sensitivity with neurofunctional ultrasound can reveal instantaneous monitoring of endogenous brain signals and behavior.

animal behavior and cognition↗

Non-invasive ultrasonic modulation of visual evoked response by GABA delivery through the blood brain barrier

We demonstrate the feasibility of non-invasively modulating the visual cortex activity of non-human primates by local ultrasound-induced delivery of an inhibitory neurotransmitter (GABA). GABA was injected intravenously after the blood brain barrier (BBB) was transiently disrupted with focused ultrasound (FUS) coupled with ultrasound contrast agents (UCA). Visual evoked potentials exhibited a significant and progressive decrease of the activity. Combined effects of neuromodulation and BBB opening were shown to be 8.7 times less important than GABA-induced inhibition. During the sonication, the UCA harmonic response was monitored to estimate the level of stable cavitation (signature of BBB opening efficiency) and to avoid damages due to inertial cavitation (automatic shutdown of the sonication when detected). As recent developments in beam forming have shown that ultrasound beams can be focused non-invasively in deep-seated human brain locations, our results hold promise to explore and treat the brain with a non-invasive, controllable, repeatable and reversible method.

neuroscience↗