Biology subjects

Kozak, R. A.

Publications and source records attributed to Kozak, R. A..

8 recordsLinked to original sources

bioRxiv2024

Parkinson's Disease affects the contextual control, but not the expression, of a rapid visuomotor response that initiates visually-guided reaching: Evidence for multiple, interacting motor pathways and implications for motor symptoms in Parkinson's Disease

Despite significant deficits in voluntary motor control, patients with Parkinsons disease (PD) can generate reflexive or stimulus-driven movements. How are such spared capabilities realized? Here, we recorded upper limb muscle activity in patients with PD and age-matched healthy controls (HCs) as they reached either toward or away from a visual stimulus. The task promoted express visuomotor responses (EVRs), which are brief bursts of muscle recruitment time-locked (<100 ms) to stimulus presentation that are thought to originate from the midbrain superior colliculus. Across two experiments, we observed a remarkable sparing of the latency and magnitude of EVRs in patients with PD, but a decreased ability for patients with PD to contextually modulate the EVR depending on trial instruction. EVR Magnitudes were strikingly strongly correlated with PD Reaction times and Error rates, despite compromised levels of electromyographic (EMG) recruitment in subsequent phases of muscle activity, which predicted lower Peak velocities. Our results are consistent with a differential influence of PD on parallel-but-interacting subcortical and cortical pathways that converge onto brainstem and spinal circuits during reaching. This differential influence is discriminable even within a single trial in the selective sparing of stimulus-aligned but not movement-aligned muscle recruitment, and has implications for our understanding of the motor and cognitive deficits seen in PD.

neuroscience↗

bioRxiv2023

Done in 65 ms: Express visuomotor responses in upper limb muscles in Rhesus Macaques

How rapidly can the brain transform vision into action? Work in humans has established that the transformation for visually-guided reaching can be remarkably rapid, with the first phase of upper limb muscle recruitment, the express visuomotor response, beginning within less than 100 ms of visual target presentation. Such short-latency responses limit the opportunities for extensive cortical processing, leading to the hypothesis that they are generated via the subcortical tectoreticulospinal pathway. Here, we examine if non-human primates (NHPs) exhibit express visuomotor responses. Two male macaques made visually-guided reaches in a behavioral paradigm known to elicit express visuomotor responses in humans, while we acquired intramuscular recordings from the deltoid muscle. Across several variants of this paradigm, express visuomotor responses began within 65 ms (range 48-91 ms) of target presentation. Although the timing of the express visuomotor response did not co-vary with reaction time, larger express visuomotor responses tended to precede shorter latency reaches. Finally, the magnitude of the express visuomotor response was muted on trials where NHPs withheld a reach to one stimulus in order to move to a stimulus appearing 34 ms later in the opposite direction. Overall, the response properties and contextual control of express visuomotor responses in NHPs resemble those in humans. Our results establish a new benchmark for visuomotor transformations underlying visually-guided reaches, setting the stage for experiments that can directly compare the role of cortical and subcortical areas in reaching when time is of the essence. Significance statementExpress visuomotor responses in upper limb muscles are brief periods of recruitment preceding visually-guided reaches. Such responses begin [~]90 ms after visual target presentation in humans, and potentially arise from signaling along the tecto-reticulo-spinal pathway. Here, we show that express visuomotor responses in macaques upper limb muscles resemble those in humans, excepting that they evolve [~]65 ms after target onset, consistent with shorter responses latencies in macaques versus humans. Our results clock the completion of the visuomotor transformation for rapid reaching, and set the stage for experiments to directly test the underlying substrates.

neuroscience↗

bioRxiv2021

Express arm Responses Appear Bilaterally on Upper-limb Muscles in Arm Choice Reaching Task

When required, humans can generate very short latency reaches towards visual targets, like catching a falling cellphone. During such rapid reaches, express arm responses are the first wave of upper limb muscle recruitment, occurring ~80-100 ms after target appearance. There is accumulating evidence that express arm responses arise from signaling along the tecto-reticulo-spinal tract, but the involvement of the reticulo-spinal tract has not been well-studied. Since the reticulospinal tract projects bilaterally, we studied whether express arm responses would be generated bilaterally. Human participants (n = 14; 7 female) performed visually guided reaches in a modified emerging target paradigm where either arm could intercept the target. We recorded electromyographic activity bilaterally from the pectoralis major muscle. Our analysis focused on target locations where participants reached with the right arm on some trials, and the left arm on others. In support of the involvement of the reticulospinal tract, express arm responses persisted bilaterally regardless of which arm reached to the target. The latency and magnitude of the express arm response did not depend on whether the arm was chosen to reach or not. However, on the reaching arm, the magnitude of the express arm response was correlated to the level of anticipatory activity. The bilateral generation of express arm responses supports the involvement of the reticulo-spinal tract. We surmise that the correlation between anticipatory activity and the magnitude of express arm responses on the reaching arm arises from convergence of cortically-derived signals with a parallel subcortical pathway mediating the express arm response. New and NoteworthyExpress arm responses have been proposed to arise from the tecto-reticulo-spinal tract originating within the superior colliculus, but the involvement of the reticulo-spinal tract has not been well studied. Here, we show these responses appear bilaterally in a task where either arm can reach to a newly appearing stimulus. Our results suggest that the most rapid visuomotor transformations for reaching are performed by a subcortical pathway.

neuroscience↗

bioRxiv2021

Preclinical evaluation of a SARS-CoV-2 mRNA vaccine PTX-COVID19-B

Safe and effective vaccines are needed to end the COVID-19 pandemic caused by SARS-CoV-2. Here we report the preclinical development of a lipid nanoparticle (LNP) formulated SARS-CoV-2 mRNA vaccine, PTX-COVID19-B. PTX-COVID19-B was chosen among three candidates after the initial mouse vaccination results showed that it elicited the strongest neutralizing antibody response against SARS-CoV-2. Further tests in mice and hamsters indicated that PTX-COVID19-B induced robust humoral and cellular immune responses and completely protected the vaccinated animals from SARS-CoV-2 infection in the lung. Studies in hamsters also showed that PTX-COVID19-B protected the upper respiratory tract from SARS-CoV-2 infection. Mouse immune sera elicited by PTX-COVID19-B vaccination were able to neutralize SARS-CoV-2 variants of concern (VOCs), including the B.1.1.7, B.1.351 and P.1 lineages. No adverse effects were induced by PTX-COVID19-B in both mice and hamsters. These preclinical results indicate that PTX-COVID19-B is safe and effective. Based on these results, PTX-COVID19-B was authorized by Health Canada to enter clinical trials in December 2020 with a phase 1 clinical trial ongoing (ClinicalTrials.gov number: NCT04765436). One Sentence SummaryPTX-COVID19-B is a SARS-CoV-2 mRNA vaccine that is highly immunogenic, safe, and effective in preventing SARS-CoV-2 infection in mice and hamsters and is currently being evaluated in human clinical trials.

immunology↗

bioRxiv2021

High contrast, moving targets in an emerging target paradigm promote fast visuomotor responses during visually guided reaching

Humans have a remarkable capacity to rapidly interact with the surrounding environment, often by transforming visual input into motor output on a moment-to-moment basis. But what visual features promote rapid reaching? High contrast, fast-moving targets elicit strong responses in the superior colliculus (SC), a structure associated with express saccades and implicated in rapid electromyographic (EMG) responses on upper limb muscles. To test the influence of stimulus properties on rapid reaches, we had human subjects perform visually guided reaches to moving targets varied by speed (experiment 1) or speed and contrast (experiment 2), in an emerging target paradigm which has recently been shown to robustly elicit fast visuomotor responses. Our analysis focused on stimulus-locked responses (SLRs) on upper limb muscles. SLRs appear within <100 ms of target presentation, and as the first wave of muscle recruitment, they have been hypothesized to arise from the SC. Across 32 subjects studied in both experiments, 97% expressed SLRs in the emerging target paradigm, whereas only 69% expressed SLRs in an immediate response paradigm towards static targets. Faster moving targets (experiment 1) evoked large magnitude SLRs, while high contrast fast moving targets (experiment 2) evoked short latency, large magnitude SLRs. In some instances, SLR magnitude exceeded the magnitude of movement aligned activity. Both large magnitude and short latency SLRs were correlated with short latency reach reaction times. Our results support the hypothesis that, in scenarios requiring expedited responses, a subcortical pathway originating in the SC elicits the earliest wave of muscle recruitment, expediting reaction times. New & NoteworthyHow does the brain rapidly transform vision into action? Here, by recording upper limb muscle activity, we find that high contrast and fast moving targets are highly effective at evoking rapid visually guided reaches. We surmise that a brainstem circuit originating in the superior colliculus contributes to the most rapid reaching responses. When time is of the essence, cortical areas may serve to prime this circuit, and elaborate subsequent phases of recruitment.

neuroscience↗

bioRxiv2020

Sequence, infectivity and replication kinetics of SARS-CoV-2 isolated from COVID-19 patients in Canada

SARS-CoV-2 emerged in December 2019 in Wuhan, China and has since infected over 1.5 million people, of which over 107,000 have died. As SARS-CoV-2 spreads across the planet, speculations remain about the range of human cells that can be infected by SARS-CoV-2. In this study, we report the isolation of SARS-CoV-2 from two COVID-19 patients in Toronto, Canada. We determined the genomic sequences of the two isolates and identified single nucleotide changes in representative populations of our virus stocks. More importantly, we tested a wide range of human immune cells for productive infection with SARS-CoV-2. Here we confirm that human primary peripheral blood mononuclear cells (PBMCs) are not permissive to SARS-CoV-2. As SARS-CoV-2 continues to spread globally, it is essential to monitor small nucleotide polymorphisms in the virus and to continue to isolate circulating viruses to determine cell susceptibility and pathogenicity using in vitro and in vivo infection models.

microbiology↗

bioRxiv2020

An emerging target paradigm evokes fast visuomotor responses on human upper limb muscles

To reach towards a seen object, visual information has to be transformed into motor commands. Visual information such as the objects colour, shape, and size is processed and integrated within numerous brain areas, then ultimately relayed to the motor periphery. In some instances we must react as fast as possible. These fast visuomotor transformations, and their underlying neurological substrates, are poorly understood in humans as they have lacked a reliable biomarker. Stimulus-locked responses (SLRs) are short latency (<100 ms) bursts of electromyographic (EMG) activity representing the first wave of muscle recruitment influenced by visual stimulus presentation. SLRs provide a quantifiable output of rapid visuomotor transformations, but SLRs have not been consistently observed in all subjects in past studies. Here we describe a new, behavioural paradigm featuring the sudden emergence of a moving target below an obstacle that consistently evokes robust SLRs. Human participants generated visually-guided reaches toward or away from the emerging target using a robotic manipulandum while surface electrodes recorded EMG activity from the pectoralis major muscle. In comparison to previous studies that investigated SLRs using static stimuli, the SLRs evoked with this emerging target paradigm were larger, evolved earlier, and were present in all participants. Reach reaction times (RTs) were also expedited in the emerging target paradigm. This paradigm affords numerous opportunities for modification that could permit systematic study of the impact of various sensory, cognitive, and motor manipulations on fast visuomotor responses. Overall, our results demonstrate that an emerging target paradigm is capable of consistently and robustly evoking activity within a fast visuomotor system. SUMMARYWe present a new behavioual paradigm that elicits robust fast visuomotor responses on human upper limb muscles during visually guided reaches.

neuroscience↗

bioRxiv2019

Stimulus-Locked Responses on Human Upper Limb Muscles and Corrective Reaches are Preferentially Evoked by Low Spatial Frequencies

In situations requiring immediate action, humans can generate visually-guided responses at remarkably short latencies. Here, to better understand the visual attributes that best evoke such rapid responses, we recorded upper limb muscle activity while participants performed visually-guided reaches towards Gabor patches composed of differing spatial frequencies. We studied reaches initiated from a stable posture (experiment 1, a static condition), or during on-line reach corrections to an abruptly displaced target (experiment 2, a dynamic condition). In both experiments, we detail the latency and prevalence of stimulus-locked responses (SLRs), which are brief bursts of EMG activity that are time-locked to target presentation rather than movement onset. SLRs represent the first wave of EMG recruitment influenced by target presentation, and enable quantification of rapid visuomotor transformations. In both experiments, reach targets composed of low spatial frequencies elicited the shortest latency and most prevalent SLRs, with SLR latency increasing and SLR prevalence decreasing for reach targets composed of progressively higher spatial frequencies. SLRs could be evoked in either the static or dynamic condition, and when present in experiment 2, were associated with shorter latency and larger magnitude corrections. Furthermore, SLRs evolved at shorter latencies (~20 ms) when the arm was already in motion. These results demonstrate that stimuli composed of low spatial frequencies preferentially evoke the most rapid visuomotor responses which, in the context of rapidly correcting an on-going reaching movement, are associated with earlier and larger on-line reach corrections.\n\nSignificance StatementHumans have a remarkable capacity to respond quickly to changes in our visual environment. Although our visual world is composed of a range of spatial frequencies, surprisingly little is known about which frequencies preferentially evoke rapid reaching responses. Here, we systematically varied the spatial frequency of peripheral reach targets while measuring EMG activity on an upper limb muscle. We found that visual stimuli composed of low-spatial frequencies elicit the most rapid and robust EMG responses and corrective reaches. Thus, when time is of the essence, low spatial frequencies preferentially drive fast visuomotor responses.

neuroscience↗