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Reactive inhibitory control is crucial for survival. Traditionally, this control in mammals was attributed solely to the hyperdirect pathway, with cortical control signals flowing unidirectionally from the subthalamic nucleus (STN) to basal ganglia output regions. Yet recent findings have put this model into question, suggesting that the STN is assisted in stopping actions through ascending control signals to the striatum mediated by the external globus pallidus (GPe). Here, we investigate this suggestion by harnessing a biologically constrained spiking model of the cortico-basal ganglia-thalamic (CBGT) circuit that includes pallidostriatal pathways originating from arkypallidal neurons. Through a series of experiments probing the interaction between three critical inhibitory nodes (the STN, arkypallidal cells, and indirect pathway spiny projection neurons), we find that the GPe acts as a critical mediator of both ascending and descending inhibitory signals in the CBGT circuit. In particular, pallidostriatal pathways regulate this process by weakening the direct pathway dominance of the evidence accumulation process driving decisions, which increases the relative suppressive influence of the indirect pathway on basal ganglia output. These findings delineate how pallidostriatal pathways can facilitate action cancellation by managing the bidirectional flow of information within CBGT circuits., Competing Interests: Competing interests statement:The authors declare no competing interest.

Adolescent-onset schizophrenia (AOS) is rare, under-studied, and associated with more severe cognitive impairments and poorer outcomes than adult-onset schizophrenia. Neuroimaging has shown altered regional activations (first-order effects) and functional connectivity (second-order effects) in AOS compared to controls. The pairwise maximum entropy model (MEM) integrates first- and second-order factors into a single quantity called energy, which is inversely related to probability of occurrence of brain activity patterns. We take a combinatorial approach to study multiple brain-wide MEMs of task-associated components; hundreds of independent MEMs for various sub-systems are fit to 7 Tesla functional MRI scans. Acquisitions were collected from 23 AOS individuals and 53 healthy controls while performing the Penn Conditional Exclusion Test (PCET) for executive function, which is known to be impaired in AOS. Accuracy of PCET performance was significantly reduced among AOS compared to controls. A majority of the models showed significant negative correlation between PCET scores and the total energy attained over the fMRI. Across all instantiations, the AOS group was associated with significantly more frequent occurrence of states of higher energy, assessed with a mixed effects model. An example MEM instance was investigated further using energy landscapes, which visualize high and low energy states on a low-dimensional plane, and trajectory analysis, which quantify the evolution of brain states throughout this landscape. Both supported patient-control differences in the energy profiles. Severity of psychopathology was correlated positively with energy. The MEM's integrated representation of energy in task-associated systems can help characterize pathophysiology of AOS, cognitive impairments, and psychopathology., Competing Interests: Conflicts of Interest All authors declare no conflicts of interest associated with this work.

Here we introduce CBGTPy, a virtual environment for designing and testing goal-directed agents with internal dynamics that are modeled on the cortico-basal-ganglia-thalamic (CBGT) pathways in the mammalian brain. CBGTPy enables researchers to investigate the internal dynamics of the CBGT system during a variety of tasks, allowing for the formation of testable predictions about animal behavior and neural activity. The framework has been designed around the principle of flexibility, such that many experimental parameters in a decision making paradigm can be easily defined and modified. Here we demonstrate the capabilities of CBGTPy across a range of single and multi-choice tasks, highlighting the ease of set up and the biologically realistic behavior that it produces. We show that CBGTPy is extensible enough to apply to a range of experimental protocols and to allow for the implementation of model extensions with minimal developmental effort., Competing Interests: Conflict of interest The authors declare no conflict of interest.

Objective: Existing neuroimaging studies of psychotic and mood disorders have reported brain activation differences (first-order properties) and altered pairwise correlation-based functional connectivity (second-order properties). However, both approaches have certain limitations that can be overcome by integrating them in a pairwise maximum entropy model (MEM) that better represents a comprehensive picture of fMRI signal patterns and provides a system-wide summary measure called energy. This study examines the applicability of individual-level MEM for psychiatry and identifies image-derived model coefficients related to model parameters., Method: MEMs are fit to resting state fMRI data from each individual with schizophrenia/schizoaffective disorder, bipolar disorder, and major depression (n=132) and demographically matched healthy controls (n=132) from the UK Biobank to different subsets of the default mode network (DMN) regions., Results: The model satisfactorily explained observed brain energy state occurrence probabilities across all participants, and model parameters were significantly correlated with image-derived coefficients for all groups. Within clinical groups, averaged energy level distributions were higher in schizophrenia/schizoaffective disorder but lower in bipolar disorder compared to controls for both bilateral and unilateral DMN. Major depression energy distributions were higher compared to controls only in the right hemisphere DMN., Conclusions: Diagnostically distinct energy states suggest that probability distributions of temporal changes in synchronously active nodes may underlie each diagnostic entity. Subject-specific MEMs allow for factoring in the individual variations compared to traditional group-level inferences, offering an improved measure of biologically meaningful correlates of brain activity that may have potential clinical utility., Competing Interests: Conflicts of Interest: All authors declare no conflicts of interest associated with this work.

All mammals exhibit flexible decision policies that depend, at least in part, on the cortico-basal ganglia-thalamic (CBGT) pathways. Yet understanding how the complex connectivity, dynamics, and plasticity of CBGT circuits translates into experience-dependent shifts of decision policies represents a longstanding challenge in neuroscience. Here we used a computational approach to address this problem. Specifically, we simulated decisions driven by CBGT circuits under baseline, unrewarded conditions using a spiking neural network, and fit the resulting behavior to an evidence accumulation model. Using canonical correlation analysis, we then replicated the existence of three recently identified control ensembles ( responsiveness , pliancy and choice ) within CBGT circuits, with each ensemble mapping to a specific configuration of the evidence accumulation process. We subsequently simulated learning in a simple two-choice task with one optimal (i.e., rewarded) target. We find that value-based learning, via dopaminergic signals acting on cortico-striatal synapses, effectively manages the speed-accuracy tradeoff so as to increase reward rate over time. Within this process, learning-related changes in decision policy can be decomposed in terms of the contributions of each control ensemble, and these changes are driven by sequential reward prediction errors on individual trials. Our results provide a clear and simple mechanism for how dopaminergic plasticity shifts specific subnetworks within CBGT circuits so as to strategically modulate decision policies in order to maximize effective reward rate.

Beta-band (13-35 Hz) modulations following reward, task outcome feedback, and error have been described in cognitive and/or motor adaptation tasks. Observations from different studies are, however, difficult to conciliate. Among the studies that used cognitive response selection tasks, several reported an increase in beta-band activity following reward, whereas others observed increased beta power after negative feedback. Moreover, in motor adaptation tasks, an attenuation of the postmovement beta rebound follows a movement execution error induced by visual or mechanical perturbations. Given that kinematic error typically leads to negative task-outcome feedback (e.g., target missed), one may wonder how contradictory modulations, beta power decrease with movement error versus beta power increase with negative feedback, may coexist. We designed a motor adaptation task in which female and male participants experience varied feedbacks-binary success/failure feedback, kinematic error, and sensory-prediction error-and demonstrate that beta-band modulations in opposite directions coexist at different spatial locations, time windows, and frequency ranges. First, high beta power in the medial frontal cortex showed opposite modulations well separated in time when compared in success and failure trials; that is, power was higher in success trials just after the binary success feedback, whereas it was lower in the postmovement period compared with failure trials. Second, although medial frontal high-beta activity was sensitive to task outcome, low-beta power in the medial parietal cortex was strongly attenuated following movement execution error but was not affected by either the outcome of the task or sensory-prediction error. These findings suggest that medial beta activity in different spatio-temporal-spectral configurations play a multifaceted role in encoding qualitatively distinct feedback signals. SIGNIFICANCE STATEMENT Beta-band activity reflects neural processes well beyond sensorimotor functions, including cognition and motivation. By disentangling alternative spatio-temporal-spectral patterns of possible beta-oscillatory activity, we reconcile a seemingly discrepant literature. First, high-beta power in the medial frontal cortex showed opposite modulations separated in time in success and failure trials; power was higher in success trials just after success feedback and lower in the postmovement period compared with failure trials. Second, although medial frontal high-beta activity was sensitive to task outcome, low-beta power in the medial parietal cortex was strongly attenuated following movement execution error but was not affected by the task outcome or the sensory-prediction error. We propose that medial beta activity reflects distinct feedback signals depending on its anatomic location, time window, and frequency range., (Copyright © 2023 the authors.)

The sensitive and accurate detection of glucose and lactate is essential for early diagnosis and effective management of diabetes complications. Herein, a 3D Printed ECL imaging system integrated with a Smartphone has been demonstrated to advance the traditional ECL to make a portable, affordable, and turnkey point-of-care solution to detect various human metabolites. A universal cross-platform application was introduced for analyzing ECL emitted signals to automate the whole detection process for real-time monitoring and rapid diagnostics. The developed ECL system was successfully applied and validated for detecting glucose and lactate using a single-electrode ECL biosensing platform. For glucose and lactate detection, the device showed a linear range from 0.1 mM to 1 mM and 0.1 mM-4 mM with a detection limit (LoD) of 0.04 mM and 0.1 mM, and a quantification limit (LoQ) of 0.142 mM and 0.342 mM, respectively. The developed method was evaluated for device stability, accuracy, interference, and real sample analysis. Furthermore, to assist in selecting the accurate and economic ECL sensing platform, SE-ECL devices fabricated via different fabrication approaches such as Laser-Induced Graphene, Screen Printing, and 3D Printing are studied for the conductivity of electrode and its significance on ECL signal. It was observed that emitted ECL signal is independent of the electrical conductivity for the same concentration of analytes. The findings suggested that the developed miniaturized point-of-care ECL platform would be a comprehensive and integrated solution for detecting other human metabolites and have the potential to be used in clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Making adaptive choices in dynamic environments requires flexible decision policies. Previously, we showed how shifts in outcome contingency change the evidence accumulation process that determines decision policies. Using in silico experiments to generate predictions, here we show how the cortico-basal ganglia-thalamic (CBGT) circuits can feasibly implement shifts in decision policies. When action contingencies change, dopaminergic plasticity redirects the balance of power, both within and between action representations, to divert the flow of evidence from one option to another. When competition between action representations is highest, the rate of evidence accumulation is the lowest. This prediction was validated in in vivo experiments on human participants, using fMRI, which showed that (1) evoked hemodynamic responses can reliably predict trial-wise choices and (2) competition between action representations, measured using a classifier model, tracked with changes in the rate of evidence accumulation. These results paint a holistic picture of how CBGT circuits manage and adapt the evidence accumulation process in mammals., Competing Interests: KB, JR, RM, JB, JR, TV No competing interests declared, (© 2023, Bond et al.)

The cerebellar cortex encodes sensorimotor adaptation during skilled locomotor behaviors, however the precise relationship between synaptic connectivity and behavior is unclear. We studied synaptic connectivity between granule cells (GCs) and Purkinje cells (PCs) in murine acute cerebellar slices using photostimulation of caged glutamate combined with patch-clamp in developing or after mice adapted to different locomotor contexts. By translating individual maps into graph network entities, we found that synaptic maps in juvenile animals undergo critical period characterized by dissolution of their structure followed by the re-establishment of a patchy functional organization in adults. Although, in adapted mice, subdivisions in anatomical microzones do not fully account for the observed spatial map organization in relation to behavior, we can discriminate locomotor contexts with high accuracy. We also demonstrate that the variability observed in connectivity maps directly accounts for motor behavior traits at the individual level. Our findings suggest that, beyond general motor contexts, GC-PC networks also encode internal models underlying individual-specific motor adaptation., (© 2022. The Author(s).)