Selective autophagy of the adaptor TRIF regulates innate inflammatory signaling.

Defective autophagy is linked to diseases such as rheumatoid arthritis, lupus and inflammatory bowel disease (IBD). However, the mechanisms by which autophagy limits inflammation remain poorly understood. Here we found that loss of the autophagy-related gene Atg16l1 promoted accumulation of the adaptor TRIF and downstream signaling in macrophages. Multiplex proteomic profiling identified SQSTM1 and Tax1BP1 as selective autophagy-related receptors that mediated the turnover of TRIF. Knockdown of Tax1bp1 increased production of the cytokines IFN-ß and IL-1ß. Mice lacking Atg16l1 in myeloid cells succumbed to lipopolysaccharide-mediated sepsis but enhanced their clearance of intestinal Salmonella typhimurium in an interferon receptor-dependent manner. Human macrophages with the Crohn's disease-associated Atg16l1 variant T300A exhibited more production of IFN-ß and IL-1ß. An elevated interferon-response gene signature was observed in patients with IBD who were resistant to treatment with an antibody to the cytokine TNF. These findings identify selective autophagy as a key regulator of signaling via the innate immune system.

OTULIN limits cell death and inflammation by deubiquitinating LUBAC.

OTULIN (OTU deubiquitinase with linear linkage specificity) removes linear polyubiquitin from proteins that have been modified by LUBAC (linear ubiquitin chain assembly complex) and is critical for preventing auto-inflammatory disease1,2 and embryonic lethality during mouse development3. Here we show that OTULIN promotes rather than counteracts LUBAC activity by preventing its auto-ubiquitination with linear polyubiquitin. Thus, knock-in mice that express catalytically inactive OTULIN, either constitutively or selectively in endothelial cells, resembled LUBAC-deficient mice4 and died midgestation as a result of cell death mediated by TNFR1 (tumour necrosis factor receptor 1) and the kinase activity of RIPK1 (receptor-interacting protein kinase 1). Inactivation of OTULIN in adult mice also caused pro-inflammatory cell death. Accordingly, embryonic lethality and adult auto-inflammation were prevented by the combined loss of cell death mediators: caspase 8 for apoptosis and RIPK3 for necroptosis. Unexpectedly, OTULIN mutant mice that lacked caspase 8 and RIPK3 died in the perinatal period, exhibiting enhanced production of type I interferon that was dependent on RIPK1. Collectively, our results indicate that OTULIN and LUBAC function in a linear pathway, and highlight a previously unrecognized interaction between linear ubiquitination, regulators of cell death, and induction of type I interferon.

Neural mechanisms underlying the temporal control of sequential saccade planning in the frontal eye field.

Sequences of saccadic eye movements are instrumental in navigating our visual environment. While neural activity has been shown to ramp up to a threshold before single saccades, the neural underpinnings of multiple saccades is unknown. To understand the neural control of saccade sequences, we recorded from the frontal eye field (FEF) of macaque monkeys while they performed a sequential saccade task. We show that the concurrent planning of two saccade plans brings forth processing bottlenecks, specifically by decreasing the growth rate and increasing the threshold of saccade-related ramping activity. The rate disruption affected both saccade plans, and a computational model, wherein activity related to the two saccade plans mutually and asymmetrically inhibited each other, predicted the behavioral and neural results observed experimentally. Borrowing from models in psychology, our results demonstrate a capacity-sharing mechanism of processing bottlenecks, wherein multiple saccade plans in a sequence compete for the processing capacity by the perturbation of the saccade-related ramping activity. Finally, we show that, in contrast to movement-related neurons, visual activity in FEF neurons is not affected by the presence of multiple saccade targets, indicating that, for perceptually simple tasks, inhibition within movement-related neurons mainly instantiates capacity sharing. Taken together, we show how psychology-inspired models of capacity sharing can be mapped onto neural responses to understand the control of rapid saccade sequences.

Neural correlates of goal-directed and non-goal-directed movements.

What are the cortical neural correlates that distinguish goal-directed and non-goal-directed movements? We investigated this question in the monkey frontal eye field (FEF), which is implicated in voluntary control of saccades. Here, we compared FEF activity associated with goal-directed (G) saccades and non-goal-directed (nG) saccades made by the monkey. Although the FEF neurons discharged before these nG saccades, there were three major differences in the neural activity: First, the variability in spike rate across trials decreased only for G saccades. Second, the local field potential beta-band power decreased during G saccades but did not change during nG saccades. Third, the time from saccade direction selection to the saccade onset was significantly longer for G saccades compared with nG saccades. Overall, our results reveal unexpected differences in neural signatures for G versus nG saccades in a brain area that has been implicated selectively in voluntary control. Taken together, these data add critical constraints to the way we think about saccade generation in the brain.

Evaluating gender effect in the generic bioequivalence studies by physiologically based pharmacokinetic modeling - A case study of dextromethorphan modified release tablets.

The United States Food and Drug Administration guidelines for the bioequivalence (BE) testing of the generic drug products suggests that there should be an equal proportion of male and female population in the BE study. Despite this requirement, many generic drug companies do not maintain the suggested proportion of female population in their studies. Several socio-economic and cultural factors lead to lower participation of the females in the BE studies. More recently, the regulatory agencies across the globe are requesting the generic drug companies to demonstrate the performance of their drug products in the under-represented sex via additional studies. In this work, we describe the case of Dextromethorphan modified release tablets where the gender effect on the product performance was evaluated by physiologically based pharmacokinetic (PBPK) modeling approach. We have compared the drug product's performance by population simulations considering four different scenarios. The data from all-male population (from in house Pharmacokinetic [PK] BE studies) was considered as a reference and other scenarios were compared against the all-male population data. In the first scenario, we made a comparison between all-male (100% male) vs all-female (100% female) population. Second scenario was as per agency's requirements-equal proportion of male and female in the BE study. As an extreme scenario, 100% male vs 30:70 male:female was considered (higher females than males in the BE studies). Finally, as a more realistic scenario, 100% male versus 70:30 male:female was considered (lower females than males in the BE studies). Population PK followed by virtual BE was employed to demonstrate the similarity/differences in the drug product performance between the sexes. This approach can be potentially utilized to seek BE study waivers thus saving cost and accelerating the entry of the generic products to the market.

Context-specific early recruitment of small motor units in the shoulder muscle reflects a reach movement plan.

Understanding how motor plans are transformed into appropriate patterns of muscle activity is a central question in motor control. Although muscle activity during the delay period has not been reported using conventional electromyographic (EMG) approaches, we isolated motor unit activity using a high-density surface EMG signal from the anterior deltoid muscle to test whether heterogeneity in motor units could reveal early preparatory activity. Consistent with our previous work (Rungta SP, Basu D, Sendhilnathan N, Murthy A. J Neurophysiol 126: 451-463, 2021), we observed early selective recruitment of small amplitude size motor units during the delay period for hand movements similar to the observed early recruitment of small-amplitude motor units in neck muscles of nonhuman primates performing delayed saccade tasks. This early activity was spatially specific and increased with time and resembled an accumulation to threshold model that correlated with movement onset time. Such early recruitment of ramping motor units was observed at the single trial level as well. In contrast, no such recruitment of large amplitude size motor units, called nonrampers, was observed during the delay period. Instead, nonrampers became spatially specific and predicted movement onset time after the delay period. Interestingly, spatially specific delay period activity was only observed for hand movements but was absent for isometric force-driven cursor movements. Nonetheless, muscle activity was correlated with the time it took to initiate movements in both task conditions for nonrampers. Overall, our results reveal a novel heterogeneity in the EMG activity that allows the expression of early motor preparation via small amplitude size motor units that are differentially activated during movement initiation.NEW & NOTEWORTHY We studied the spatial and temporal aspects of response preparation in the anterior deltoid muscle using high-density surface EMG. Our results show that early spatially specific ramping activity that predicted reaction times could be accessed from muscle activity but was absent during isometric force-driven cursor movements. Such ramping activity could be quantified using an accumulator framework across trials, as well as within single trials, but was not observed in isometric reach tasks involving cursor movements.

Velocity tracking control best explains the modulation of saccade kinematics during eye-hand coordination.

Fast movements like saccadic eye movements that occur in the absence of sensory feedback are thought to be controlled by internal feedback. Such internal feedback provides an instantaneous estimate of the output, which serves as a proxy for sensory feedback, that can be used by the controller to correct deviations from the desired plan. In the predominant view, the desired plan/input is encoded in the form of a static displacement signal (endpoint model), believed to be encoded in the spatial map of the superior colliculus (SC). However, recent evidence has shown that SC neurons have a dynamic signal that correlates with saccade velocity, suggesting that information for velocity-based control is available for generating saccades. Motivated by this observation, we used a novel optimal control framework to test whether saccadic execution could be achieved by tracking a dynamic velocity signal at the input. We validated this velocity tracking model in a task where the peak saccade velocity was modulated by the speed of a concurrent hand movement independent of the saccade endpoint. A comparison showed that in this task, the velocity tracking model performed significantly better than the endpoint model. These results suggest that the saccadic system may have additional flexibility to incorporate a velocity-based internal feedback control when imposed by task goals or context.

Neck muscle activity reflects neural patterns of sequential saccade planning in head-restrained primates.

Goal-directed behavior involves the transformation of neural movement plans into appropriate muscle activity patterns. Studies involving single saccades have shown that a rapid pathway links saccade planning in frontal eye fields (FEFs) to neck muscle activity. However, it is unknown if the rapid connection between FEF and neck muscle is also maintained during sequential saccade planning. Using neural recordings from FEF, and electromyographic (EMG) recordings from the dorsal neck muscles of head-restrained monkeys, we show that neural sequence planning signals are largely preserved in the neck EMG response. Like FEF movement neurons, we found that neck motor unit activity displayed an accumulation-to-threshold response before saccade onset. Responses of both neck motor units and FEF neurons displayed similar trends during saccade sequencing; multiple saccadic eye movements could be programmed in parallel, while processing bottlenecks, indexed by reduced accumulation rates, limited the extent of parallel programming. These results suggest that even without the need for overt head movements, neck muscle activity shows signatures of central gaze planning. We propose that multiple upcoming gaze plans are rapidly passed down from the FEF to the neck muscles to initiate recruitment for anticipated gaze movements. Similarities in neural and neck motor activity may enable synchronous yet controlled eye-head responses to sequential gaze shifts.NEW & NOTEWORTHY Gaze shifts, brought about by coordinated eye-head movements through the eye and neck muscle system, are a part of everyday behavior, yet the neuromuscular underpinnings of gaze sequences are unclear. Using a combination of behavioral analyses, neural recordings, and electromyographic recordings, we show that sequential saccade plans developing in neural oculomotor centers can be extracted from the neck muscle activity of head-restrained macaques. Neck motor units, thus provide a readout of central sequence planning signals.

Preparatory activity links the frontal eye field response with small amplitude motor unit recruitment of neck muscles during gaze planning.

A hallmark of intelligent behavior is that we can separate intention from action. To understand the mechanism that gates the flow of information between motor planning and execution, we compared the activity of frontal eye field neurons with motor unit activity from neck muscles in the presence of an intervening delay period in which spatial information regarding the target was available to plan a response. Although spatially specific delay period activity was present in the activity of frontal eye field neurons, it was absent in motor unit activity. Nonetheless, motor unit activity was correlated with the time it took to initiate saccades. Interestingly, we observed a heterogeneity of responses among motor units, such that only units with smaller amplitudes showed a clear modulation during the delay period. These small amplitude motor units also had higher spontaneous activity compared with the units which showed modulation only during the movement epoch. Taken together, our results suggest the activity of smaller motor units convey temporal information and explains how the delay period primes muscle activity leading to faster reaction times.NEW & NOTEWORTHY This study shows that the temporal aspects of a motor plan in the oculomotor circuitry can be accessed by peripheral neck muscles hundreds of milliseconds before the instruction to initiate a saccadic eye movement. The coupling between central and peripheral processes during the delay time is mediated by the recruitment pattern of motor units with smaller amplitude. These findings suggest that information processed in cortical areas could be read from periphery before execution.

Notch activation by the metalloproteinase ADAM17 regulates myeloproliferation and atopic barrier immunity by suppressing epithelial cytokine synthesis.

Epithelial cells of mucosal tissues provide a barrier against environmental stress, and keratinocytes are key decision makers for immune cell function in the skin. Currently, epithelial signaling networks that instruct barrier immunity remain uncharacterized. Here we have shown that keratinocyte-specific deletion of a disintegrin and metalloproteinase 17 (Adam17) triggers T helper 2 and/or T helper 17 (Th2 and/or Th17) cell-driven atopic dermatitis and myeloproliferative disease. In vivo and in vitro deficiency of ADAM17 dampened Notch signaling, increasing production of the Th2 cell-polarizing cytokine TSLP and myeloid growth factor G-CSF. Ligand-independent Notch activation was identified as a regulator of AP-1 transcriptional activity, with Notch antagonizing c-Fos recruitment to the promoters of Tslp and Csf3 (G-CSF). Further, skin inflammation was rescued and myeloproliferation ameliorated by delivery of active Notch to Adam17(-)(/-) epidermis. Our findings uncover an essential role of ADAM17 in the adult epidermis, demonstrating a gatekeeper function of the ADAM17-Notch-c-Fos triad in barrier immunity.

Parallel programming of saccades in the macaque frontal eye field: are sequential motor plans coactivated?

We use sequences of saccadic eye movements to continually explore our visual environments. Previous behavioral studies have established that saccades in a sequence may be programmed in parallel by the oculomotor system. In this study, we tested the neural correlates of parallel programming of saccade sequences in the frontal eye field (FEF), using single-unit electrophysiological recordings from macaques performing a sequential saccade task. It is known that FEF visual neurons instantiate target selection whereas FEF movement neurons undertake saccade preparation, where the activity corresponding to a saccade vector gradually ramps up. The question of whether FEF movement neurons are involved in concurrent processing of saccade plans is as yet unresolved. In the present study, we show that, when a peripheral target is foveated after a sequence of two saccades, presaccadic activity of FEF movement neurons for the second saccade can be activated while the first is still underway. Moreover, the onset of movement activity varied parametrically with the behaviorally measured time available for parallel programming. Although at central fixation coactivated FEF movement activity may vectorially encode the retinotopic location of the second target with respect to the fixation point or the remapped location of the second target, with respect to the first our evidence suggests the possibility of early encoding of the remapped second saccade vector. Taken together, the results indicate that movement neurons, although located terminally in the FEF visual-motor spectrum, can accomplish concurrent processing of multiple saccade plans, leading to rapid execution of saccade sequences.NEW & NOTEWORTHY The execution of purposeful sequences underlies much of goal-directed behavior. How different brain areas accomplish sequencing is poorly understood. Using a modified double-step task to generate a rapid sequence of two saccades, we demonstrate that downstream movement neurons in the frontal eye field (FEF), a prefrontal oculomotor area, allow for coactivation of the first and second movement plans that constitute the sequence. These results provide fundamental insights into the neural control of action sequencing.

Assessing within-trial and across-trial neural variability in macaque frontal eye fields and their relation to behaviour.

The conventional approach to understanding neural responses underlying complex computations is to study across-trial averages of repeatedly performed computations from single neurons. When neurons perform complex computations, such as processing stimulus-related information or movement planning, it has been repeatedly shown, through measures such as the Fano factor (FF), that neural variability across trials decreases. However, multiple neurons contribute to a common computation on a single trial, rather than a single neuron contributing to a computation across multiple trials. Therefore, at the level of a single trial, the concept of FF loses significance. Here, using a combination of simulations and empirical data, we show that changes in the spiking regularity on single trials produce changes in FF. Further, at the behavioural level, the reaction time of the animal was faster when the neural spiking regularity both within and across trials was lower. Taken together, our results provide further constraints on how changes in spiking statistics help neurons optimally encode visual and saccade-related information across multiple timescales and its implication on behaviour.

A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3.

Crohn's disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn's disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296-299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3, or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn's disease.

Simultaneous analysis of the LFP and spiking activity reveals essential components of a visuomotor transformation in the frontal eye field.

The frontal eye field (FEF) is a key brain region to study visuomotor transformations because the primary input to FEF is visual in nature, whereas its output reflects the planning of behaviorally relevant saccadic eye movements. In this study, we used a memory-guided saccade task to temporally dissociate the visual epoch from the saccadic epoch through a delay epoch, and used the local field potential (LFP) along with simultaneously recorded spike data to study the visuomotor transformation process. We showed that visual latency of the LFP preceded spiking activity in the visual epoch, whereas spiking activity preceded LFP activity in the saccade epoch. We also found a spatially tuned elevation in gamma band activity (30-70 Hz), but not in the corresponding spiking activity, only during the delay epoch, whose activity predicted saccade reaction times and the cells' saccade tuning. In contrast, beta band activity (13-30 Hz) showed a nonspatially selective suppression during the saccade epoch. Taken together, these results suggest that motor plans leading to saccades may be generated internally within the FEF from local activity represented by gamma activity.

Basal ganglia contributions during the learning of a visuomotor rotation: Effect of dopamine, deep brain stimulation and reinforcement.

It is commonly thought that visuomotor adaptation is mediated by the cerebellum while reinforcement learning is mediated by the basal ganglia. In contrast to this strict dichotomy, we demonstrate a role for the basal ganglia in visuomotor adaptation (error-based motor learning) in patients with Parkinson's disease (PD) by comparing the degree of motor learning in the presence and absence of dopamine medication. We further show similar modulation of learning rates in the presence and absence of subthalamic deep brain stimulation. We also report that reinforcement is an essential component of visuomotor adaptation by demonstrating the lack of motor learning in patients with PD during the ON-dopamine state relative to the OFF-dopamine state in the absence of a reinforcement signal. Taken together, these results raise the possibility that the basal ganglia modulate the gain of visuomotor adaptation based on the reinforcement received at the end of the trial.

Exploration of joint redundancy but not task space variability facilitates supervised motor learning.

The number of joints and muscles in a human arm is more than what is required for reaching to a desired point in 3D space. Although previous studies have emphasized how such redundancy and the associated flexibility may play an important role in path planning, control of noise, and optimization of motion, whether and how redundancy might promote motor learning has not been investigated. In this work, we quantify redundancy space and investigate its significance and effect on motor learning. We propose that a larger redundancy space leads to faster learning across subjects. We observed this pattern in subjects learning novel kinematics (visuomotor adaptation) and dynamics (force-field adaptation). Interestingly, we also observed differences in the redundancy space between the dominant hand and nondominant hand that explained differences in the learning of dynamics. Taken together, these results provide support for the hypothesis that redundancy aids in motor learning and that the redundant component of motor variability is not noise.

Distinct mechanisms explain the control of reach speed planning: evidence from a race model framework.

Previous studies have investigated the computational architecture underlying the voluntary control of reach movements that demands a change in position or direction of movement planning. Here we used a novel task in which subjects had to either increase or decrease the movement speed according to a change in target color that occurred randomly during a trial. The applicability of different race models to such a speed redirect task was assessed. We found that the predictions of an independent race model that instantiated an abort-and-replan strategy was consistent with all aspects of performance in the fast-to-slow speed condition. The results from modeling indicated a peculiar asymmetry, in that although the fast-to-slow speed change required inhibition, none of the standard race models was able to explain how movements changed from slow to fast speeds. Interestingly, a weighted averaging model that simulated the gradual merging of two kinematic plans explained behavior in the slow-to-fast speed task. In summary, our work shows how a race model framework can provide an understanding of how the brain controls different aspects of reach movement planning and help distinguish between an abort-and-replan strategy and merging of plans. NEW & NOTEWORTHY For the first time, a race model framework was used to understand how reach speeds are modified. We provide evidence that a fast-to-slow speed change required aborting the current plan and a complete respecification of a new plan, while none of the race models was able to explain an instructed increase of hand movement speed, which was instead accomplished by a merging of a new kinematic plan with the existing kinematic plan.

Task context determines whether common or separate inhibitory signals underlie the control of eye-hand movements.

Whereas inhibitory control of single effector movements has been widely studied, the control of coordinated eye-hand movements has received less attention. Nevertheless, previous studies have contradictorily suggested that either a common or separate signal/s is/are responsible for inhibition of coordinated eye-hand movements. In continuation of our previous study, we varied behavioral contexts and used a stochastic accumulation-to-threshold model, which predicts a scaling of the mean reaction time distribution with its variance, to study the inhibitory control of eye-hand movements. Participants performed eye-hand movements in different task conditions, and in each condition they had to redirect movements in a fraction of trials. Task contexts where the behavior could be best explained by a common initiation signal had similar error responses for eye and hand, despite having different mean reaction times, indicating a common inhibitory signal. In contrast, behavior that could be best explained by separate initiation signals had dissimilar error responses for eye and hand indicating separate inhibitory signals. These behavioral responses were further validated using electromyography and computational models having either a common or separate inhibitory control signal/s. Interestingly, in a particular context, whereas in majority trials a common initiation and inhibitory signal could explain the behavior, in a subset of trials separate initiation and inhibitory signals predicted the behavior better. This highlights the flexibility that exists in the brain and in effect reconciles the heterogeneous results reported by previous studies. NEW & NOTEWORTHY Prior studies have contradictorily suggested either a single or separate inhibitory signal/s underlying inhibition of coordinated eye-hand movements. With the use of different tasks, we observed that when eye-hand movements were initiated by a common signal, they were controlled by a common inhibitory signal. However, when the two effectors were initiated by separate signals, they were controlled by separate inhibitory signals. This highlights the flexible control of eye-hand movements and reconciles the heterogeneous results previously reported in the literature.

An independent race model involving an abort and re-plan strategy explains reach redirecting movements during planning and execution.

Although race models have been extensively used to study inhibitory control, the mechanisms that enable change of reach plans in the context of race models remain unexplored. We used a redirect task in which targets occasionally changed their locations to study the control of reaching movements during movement planning and execution phases. We tested nine different race model architectures that could explain the redirect behavior of reaching movements. We show that an independent GO-STOP-GO model that reflects a plan-abort-re-plan strategy involving non-interacting elements successfully explained the various behavioral measures such as the compensation function and the pattern of error response reaction times. By extending the same race model to the execution phase, we could explain the extent and the pattern of hypometric trials. Interestingly, the race model also provided evidence that redirecting a movement during planning and execution shared the same inhibitory mechanism. Taken together, this study demonstrates the applicability of an independent race model to understand the computational mechanisms underlying the control of reach movements.

Evidence of common and separate eye and hand accumulators underlying flexible eye-hand coordination.

Eye and hand movements are initiated by anatomically separate regions in the brain, and yet these movements can be flexibly coupled and decoupled, depending on the need. The computational architecture that enables this flexible coupling of independent effectors is not understood. Here, we studied the computational architecture that enables flexible eye-hand coordination using a drift diffusion framework, which predicts that the variability of the reaction time (RT) distribution scales with its mean. We show that a common stochastic accumulator to threshold, followed by a noisy effector-dependent delay, explains eye-hand RT distributions and their correlation in a visual search task that required decision-making, while an interactive eye and hand accumulator model did not. In contrast, in an eye-hand dual task, an interactive model better predicted the observed correlations and RT distributions than a common accumulator model. Notably, these two models could only be distinguished on the basis of the variability and not the means of the predicted RT distributions. Additionally, signatures of separate initiation signals were also observed in a small fraction of trials in the visual search task, implying that these distinct computational architectures were not a manifestation of the task design per se. Taken together, our results suggest two unique computational architectures for eye-hand coordination, with task context biasing the brain toward instantiating one of the two architectures. NEW & NOTEWORTHY: Previous studies on eye-hand coordination have considered mainly the means of eye and hand reaction time (RT) distributions. Here, we leverage the approximately linear relationship between the mean and standard deviation of RT distributions, as predicted by the drift-diffusion model, to propose the existence of two distinct computational architectures underlying coordinated eye-hand movements. These architectures, for the first time, provide a computational basis for the flexible coupling between eye and hand movements.