Biology subjects

Sajad, A.

Publications and source records attributed to Sajad, A..

9 recordsLinked to original sources

bioRxiv2024

Conflict neurons in cingulate cortex of macaques

Conflict--the magnitude of co-activation of mutually incompatible response processes--was proposed to explain how cognitive control is invoked (Botvinick et al. 2001) and continues to engage debate (Becker et al. 2024). Original observations consistent with this construct emphasized the primary contribution of cingulate cortex (CC) based on human functional imaging (Botvinick et al., 1999; Carter et al., 2000) and electroencephalogram (Yeung, Botvinick, & Cohen, 2004). In countermanding tasks conflict arises through co-activation of competing GO and STOP processes (Boucher et al. 2007; Schall & Boucher 2007; Sajad et al. 2022). Single neuron activity representing conflict has been described in the supplementary motor cortex of human epilepsy patients (Fu et al., 2019; Sheth et al., 2012) and of macaque monkeys (Sajad, Errington, & Schall, 2022; Stuphorn, Taylor, & Schall, 2000) and in human cingulate cortex (Fu et al., 2019; Sheth et al., 2012) but not in monkey cingulate cortex (Ebitz & Platt, 2015; Ito, Stuphorn, Brown, & Schall, 2003; Nakamura, Roesch, & Olson, 2005). This lack of homology generated debate about the utility of macaques for investigation of cognitive control (Cole et al. 2009; Schall & Emeric 2010). With higher-resolution, less-biased samples, we re-examined the presence of a conflict signal in cingulate cortex of monkeys. Neurons modulating specifically when response conflict was maximal were found in cingulate cortex-- more commonly in the dorsal than the ventral bank. However, such neurons were much more common in supplementary motor cortex. These data confirm the presence of a conflict signal in medial frontal cortex and demonstrate that it can be found in a small fraction of neurons in cingulate cortex. Further research is needed to determine if the weak response conflict signal in cingulate cortex is sufficient or negligible.

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bioRxiv2023

Laminar architecture of visual responses in supplementary eye field of macaques

Previously, we have described the laminar organization of neurons in the supplementary eye field (SEF) that signal error, reward gain and loss, conflict, event timing, and goal maintenance. Here we describe the laminar organization of visually responsive neurons that were active during performance of a saccade stop-signal task. Nearly 40% of isolated neurons exhibited enhanced or suppressed responses to a visual target for a potential saccade, with the majority exhibiting enhanced activity and three-quarters with broad spikes. Visually responsive neurons were observed in all layers but were less common in layers 5 and 6. Response latencies were comparable to those reported previously, which are significantly later than those measured in occipital and temporal visual areas but overlapping those measured in cingulate cortex. Task-related visual response latency varied across cortical layers. Response latency was significantly earlier for neurons with narrow spikes. Neurons with task-related visual responses discharged until after saccade production. Around three-fifths of visually responsive neurons were most sensitive to the visual target appearing in one hemifield. Many neurons in layer 2 had ipsilateral receptive fields. Laminar current-source density aligned on visual target presentation revealed the earliest sink in layers 3 followed by a prolonged strong sink more superficially coupled with a weaker prolonged sink in layer 5 and a transient sink in layer 6. The current sink in layers 2 and 3 was stronger for ipsilateral stimuli. These findings reveal new details about visual processing in medial frontal cortex and complete the first catalogue of laminar organization of functional signals in a frontal lobe area.

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bioRxiv2023

Cortical Origin of Theta Error Signals

A multi-scale approach elucidated the origin of the error-related-negativity (ERN), with its associated theta-rhythm, and the post-error-positivity (Pe) in macaque supplementary eye field (SEF). Using biophysical modeling, synaptic inputs to layer-3 (L3) and layer-5 (L5) pyramidal cells (PCs) were optimized to account for error-related modulation and inter-spike intervals. The intrinsic dynamics of dendrites in L5 but not L3 PCs generate theta rhythmicity with random phase. Saccades synchronized the phase of this theta-rhythm, which was magnified on errors. Contributions from L5 PCs to the laminar current source density (CSD) observed in SEF were negligible. The CSD derived from L3 PCs could not explain the observed association between their error-related spiking modulation and scalp-EEG. Laminar CSD comprises multipolar components, with dipoles explaining ERN features, and quadrupoles reproducing those for Pe. The presence of monopoles indicates diffuse activation. These results provide the most advanced explanation of the cellular mechanisms generating the ERN.

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bioRxiv2021

Cortical Microcircuitry of Executive Control and Source of Associated Event-Related Potentials

Medial frontal cortex enables executive control by monitoring relevant information and using it to adapt behavior. In macaques performing a saccade countermanding (stop-signal) task, we recorded EEG over and neural spiking across all layers of the supplementary eye field (SEF). We report the laminar organization of concurrently activated neurons monitoring the conflict between incompatible responses and the timing of events serving goal maintenance and executive control. We also show their relation to coincident event-related potentials (ERP). Neurons signaling response conflict were largely broad-spiking found across all layers. Neurons signaling the interval until specific task events were largely broad-spiking neurons concentrated in L3 and L5. Neurons predicting the duration of control and sustaining the task goal until the release of operant control were a mix of narrow- and broad-spiking neurons confined to L2/3. We complement these results with the first report of a monkey homologue of the N2/P3 ERP complex associated with response inhibition. N2 polarization varied with error likelihood and P3 polarization varied with the duration of expected control. The amplitude of the N2 and P3 were predicted by the spike rate of different classes of neurons located in L2/3 but not L5/6. These findings reveal important, new features of the cortical microcircuitry supporting executive control and producing associated ERP.

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bioRxiv2020

Spatiotemporal coding in the macaque supplementary eye fields: landmark influence in the target-to-gaze transformation

Eye-centered (egocentric) and landmark-centered (allocentric) visual signals influence spatial cognition, navigation and goal-directed action, but the neural mechanisms that integrate these signals for motor control are poorly understood. A likely candidate for ego / allocentric integration in the gaze control system is the supplementary eye fields (SEF), a mediofrontal structure with high-level executive functions, spatially tuned visual / motor response fields, and reciprocal projections with the frontal eye fields (FEF). To test this hypothesis, we trained two head-unrestrained animals to saccade toward a remembered visual target in the presence of a visual landmark that shifted during the delay, causing gaze end points to shift partially in the same direction. 256 SEF neurons were recorded, including 68 with spatially tuned response fields. Model fits to the latter established that, like the FEF and superior colliculus, spatially tuned SEF responses primarily showed an egocentric (eye-centered) target-to-gaze position transformation. However, the landmark shift influenced this default egocentric transformation: during the delay, motor neurons (with no visual response) showed a transient but unintegrated shift (i.e., not correlated with the target-to-gaze transformation), whereas during the saccade-related burst visuomotor neurons showed an integrated shift (i.e., correlated with the target-to-gaze transformation). This differed from our simultaneous FEF recordings (Bharmauria et al., 2020), which showed a transient shift in visuomotor neurons, followed by an integrated response in all motor responses. Based on these findings and past literature, we propose that prefrontal cortex incorporates landmark-centered information into a distributed, eye-centered target-to-gaze transformation through a reciprocal prefrontal circuit.

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bioRxiv2020

A Minimal Biophysical Model of Neocortical Pyramidal Cells: Implications for Frontal Cortex Microcircuitry and Field Potential Generation

Ca2+ spikes initiated in the apical dendrites of layer-5 pyramidal cells (PC) underlie nonlinear dynamic changes in the gain of cellular response, which is critical for top-down cognitive control. Detailed models with several compartments and dozens of ionic channels have been proposed to account for this Ca2+ spike-dependent gain with its associated critical frequency. However, current models do not account for all known Ca2+-dependent features. Previous attempts to include more features have required increasing complexity, limiting their interpretability and utility for studying large population dynamics. We present a minimal 2-compartment biophysical model, overcoming these limitations. In our model, a basal-dendritic/somatic compartment included typical Na+ and K+ conductances, while an apical-dendritic/trunk compartment included persistent Na+, hyperpolarization-activated cation (Ih), slow inactivation K+, muscarinic K+, and Ca2+ L-type. The model replicated the Ca2+ spike morphology and its critical frequency plus three other defining features of layer-5 PC synaptic integration: linear frequency-current relationships, backpropagation-activated Ca2+ spike firing, and a shift in the critical frequency by blocking Ih. Simulating 1,000 synchronized layer-5 PCs, we reproduced the current source density patterns evoked by Ca2+-spikes both with and without Ih current. Thus, a 2-compartment model with five non-classic ionic currents in the apical-dendrites reproduces all features of these neurons. We discuss the utility of this minimal model to study the microcircuitry of agranular areas of the frontal lobe involved in cognitive control and responsible for event-related potentials such as the error-related negativity. Significance StatementA tractable model of layer-5 pyramidal cells replicates all known features crucial for distal synaptic integration in these neurons. This minimal model enables new multi-scale investigations of microcircuit functions with associated current flows measured by intracranial local field potentials. It thus establishes a foundation for the future computational evaluation of scalp electroencephalogram signatures imprinted by Ca2+ spikes in pyramidal cells, a phenomenon underlying many brain cognitive processes.

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bioRxiv2019

Integration of eye-centered and landmark-centered codes in frontal eye field gaze responses

The visual system is thought to separate egocentric and allocentric representations, but behavioral experiments show that these codes are optimally integrated to influence goal-directed movements. To test if frontal cortex participates in this integration process, we recorded primate frontal eye field (FEF) activity during a cue-conflict memory delay saccade task. To dissociate egocentric and allocentric coordinates, we surreptitiously shifted a visual landmark during the delay period, causing saccades to deviate by 37% in the same direction. To assess the cellular mechanisms, we fit neural response fields against an egocentric (eye centered target-to-gaze) continuum, and an allocentric shift (eye-to-landmark centered) continuum. Initial visual responses best fit target position. Motor responses (after the landmark shift) predicted future gaze position but embedded within the motor code was a 29% shift toward allocentric coordinates. This shift appeared transiently in memory-related visuomotor activity, and then reappeared in motor activity before saccades. Notably, fits along the egocentric and allocentric shift continua were initially independent, but became correlated just before the motor burst. Overall, these results implicate frontal cortex in the integration of egocentric and allocentric visual information for goal-directed action, and demonstrate the cell-specific, temporal progression of signal multiplexing for this process in the gaze system.

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bioRxiv2018

Timing Determines Tuning: a Rapid Spatiotemporal Transformation in Superior Colliculus Neurons During Reactive Gaze Shifts.

Gaze saccades -rapid shifts of the eyes and head toward a goal-- have provided fundamental insights into the neural control of movement. For example, it has been shown that the superior colliculus (SC) transforms a visual target (T) code to future gaze (G) location commands after a memory delay. However, this transformation has not been observed in reactive saccades made directly to a stimulus, so its contribution to normal gaze behavior is unclear. Here, we tested this using a quantitative measure of the spatial continuum between T and G coding based on variable gaze errors. We demonstrate that a rapid T-G transformation occurs between SC visual and motor responses during reactive saccades, even within visuomotor cells, with a continuous spatiotemporal shift in coding occurring in cell types (visual, visuomotor, motor). We further show that the primary determinant of this spatial code was not the intrinsic visual-motor index of different cells or populations, but rather the timing of the response in all cells. These results suggest that the SC provides a rapid spatiotemporal transformation for normal gaze saccades, that its motor responses contribute to variable gaze errors, and that those errors arise from a noisy spatiotemporal transformation involving all SC neurons.\n\nSignificance StatementOculomotor studies have demonstrated visuomotor transformations in structures like the superior colliculus with the use of trained behavioral manipulations, like the memory delay and antisaccades tasks, but it is not known how this happens during normal saccades. Here, using a spatiotemporal model fitting method based on endogenous gaze errors in reactive gaze saccades, we show that the superior colliculus provides a rapid spatiotemporal transformation from target to gaze coding that involves visual, visuomotor, and motor neurons. This technique demonstrates that SC spatial codes are not fixed, and may provide a quantitative biomarker for assessing the health of sensorimotor transformations.

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bioRxiv2017

Microcircuitry of Performance Monitoring

AcknowledgmentsThis work was supported by R01-MH55806, P30-EY08126, and by Robin and Richard Patton through the E. Bronson Ingram Chair in Neuroscience. We thank J. Easley M. Feurtado, M. Maddox, P. Middlebrooks, S. Motorny, J. Parker, M. Schall, C.R. Subraveti, A. Tomarken, and L. Toy for animal care and other technical assistance. We thank J. Brown, M. Cox, K. Dougherty, S. Errington, A. Maier, V. Stuphorn, A. Tomarken, and J. Westerberg for helpful discussions and comments on the manuscript.\n\nConflicts of interestNone\n\nCortical circuit mechanisms in medial frontal cortex enabling executive control are unknown. Hence, in monkeys performing a saccade countermanding task to earn larger or smaller fluid rewards, we sampled spiking and synaptic activity simultaneously across all layers of the supplementary eye field (SEF), an agranular cortical area contributing to performance monitoring in nonhuman primate and human studies. Laminar-specific synaptic currents with associated spike rate facilitation and suppression represented error production, reward gain or loss feedback, and reward delivery. The latency, polarity and magnitude of current and spike rate modulation were not predicted by the canonical cortical microcircuit. Pronounced synaptic currents in layer 2/3, which are modulated by loss magnitude, will contribute to the error-related negativity (ERN) and feedback-related negativity (FRN). These unprecedented findings reveal critical features of the cortical microcircuitry supporting performance monitoring and demonstrate that SEF can contribute to the error- and feedback-related negativity.\n\nSubject termscountermanding, stop signal task, goal selection, response inhibition, executive control, canonical cortical microcircuit, error-related negativity, reinforcement learning, reward prediction error

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