Cerebellar Neurodynamics Predict Decision Timing and Outcome on the Single-Trial Level.

Goal-directed behavior requires the interaction of multiple brain regions. How these regions and their interactions with brain-wide activity drive action selection is less understood. We have investigated this question by combining whole-brain volumetric calcium imaging using light-field microscopy and an operant-conditioning task in larval zebrafish. We find global, recurring dynamics of brain states to exhibit pre-motor bifurcations toward mutually exclusive decision outcomes. These dynamics arise from a distributed network displaying trial-by-trial functional connectivity changes, especially between cerebellum and habenula, which correlate with decision outcome. Within this network the cerebellum shows particularly strong and predictive pre-motor activity (>10 s before movement initiation), mainly within the granule cells. Turn directions are determined by the difference neuroactivity between the ipsilateral and contralateral hemispheres, while the rate of bi-hemispheric population ramping quantitatively predicts decision time on the trial-by-trial level. Our results highlight a cognitive role of the cerebellum and its importance in motor planning.

The Neural Basis of Escape Behavior in Vertebrates.

Escape is one of the most studied animal behaviors, and there is a rich normative theory that links threat properties to evasive actions and their timing. The behavioral principles of escape are evolutionarily conserved and rely on elementary computational steps such as classifying sensory stimuli and executing appropriate movements. These are common building blocks of general adaptive behaviors. Here we consider the computational challenges required for escape behaviors to be implemented, discuss possible algorithmic solutions, and review some of the underlying neural circuits and mechanisms. We outline shared neural principles that can be implemented by evolutionarily ancient neural systems to generate escape behavior, to which cortical encephalization has been added to allow for increased sophistication and flexibility in responding to threat.

The Drosophila Mushroom Body: From Architecture to Algorithm in a Learning Circuit.

The Drosophila brain contains a relatively simple circuit for forming Pavlovian associations, yet it achieves many operations common across memory systems. Recent advances have established a clear framework for Drosophila learning and revealed the following key operations: a) pattern separation, whereby dense combinatorial representations of odors are preprocessed to generate highly specific, nonoverlapping odor patterns used for learning; b) convergence, in which sensory information is funneled to a small set of output neurons that guide behavioral actions; c) plasticity, where changing the mapping of sensory input to behavioral output requires a strong reinforcement signal, which is also modulated by internal state and environmental context; and d) modularization, in which a memory consists of multiple parallel traces, which are distinct in stability and flexibility and exist in anatomically well-defined modules within the network. Cross-module interactions allow for higher-order effects where past experience influences future learning. Many of these operations have parallels with processes of memory formation and action selection in more complex brains.

Basal Ganglia Circuits for Action Specification.

Behavior is readily classified into patterns of movements with inferred common goals-actions. Goals may be discrete; movements are continuous. Through the careful study of isolated movements in laboratory settings, or via introspection, it has become clear that animals can exhibit exquisite graded specification to their movements. Moreover, graded control can be as fundamental to success as the selection of which action to perform under many naturalistic scenarios: a predator adjusting its speed to intercept moving prey, or a tool-user exerting the perfect amount of force to complete a delicate task. The basal ganglia are a collection of nuclei in vertebrates that extend from the forebrain (telencephalon) to the midbrain (mesencephalon), constituting a major descending extrapyramidal pathway for control over midbrain and brainstem premotor structures. Here we discuss how this pathway contributes to the continuous specification of movements that endows our voluntary actions with vigor and grace.

What, If, and When to Move: Basal Ganglia Circuits and Self-Paced Action Initiation.

Deciding what to do and when to move is vital to our survival. Clinical and fundamental studies have identified basal ganglia circuits as critical for this process. The main input nucleus of the basal ganglia, the striatum, receives inputs from frontal, sensory, and motor cortices and interconnected thalamic areas that provide information about potential goals, context, and actions and directly or indirectly modulates basal ganglia outputs. The striatum also receives dopaminergic inputs that can signal reward prediction errors and also behavioral transitions and movement initiation. Here we review studies and models of how direct and indirect pathways can modulate basal ganglia outputs to facilitate movement initiation, and we discuss the role of cortical and dopaminergic inputs to the striatum in determining what to do and if and when to do it. Complex but exciting scenarios emerge that shed new light on how basal ganglia circuits modulate self-paced movement initiation.

Distinct Action Signals by Subregions in the Nucleus Accumbens during STOP-Change Performance.

The nucleus accumbens (NAc) is thought to contribute to motivated behavior by signaling the value of reward-predicting cues and the delivery of anticipated reward. The NAc is subdivided into core and shell, with each region containing different populations of neurons that increase or decrease firing to rewarding events. While there are numerous theories of functions pertaining to these subregions and cell types, most are in the context of reward processing, with fewer considering that the NAc might serve functions related to action selection more generally. We recorded from single neurons in the NAc as rats of both sexes performed a STOP-change task that is commonly used to study motor control and impulsivity. In this task, rats respond quickly to a spatial cue on 80% of trials (GO) and must stop and redirect planned movement on 20% of trials (STOP). We found that the activity of reward-excited neurons signaled accurate response direction on GO, but not STOP, trials and that these neurons exhibited higher precue firing after correct trials. In contrast, reward-inhibited neurons significantly represented response direction on STOP trials at the time of the instrumental response. Finally, the proportion of reward-excited to reward-inhibited neurons and the strength of precue firing decreased as the electrode traversed the NAc. We conclude that reward-excited cells (more common in core) promote proactive action selection, while reward-inhibited cells (more common in shell) contribute to accurate responding on STOP trials that require reactive suppression and redirection of behavior.

Neural Correlates of Online Action Preparation.

When performing movements in rapid succession, the brain needs to coordinate ongoing execution with the preparation of an upcoming action. Here we identify the processes and brain areas involved in this ability of online preparation. Human participants (both male and female) performed pairs of single-finger presses or three-finger chords in rapid succession, while 7T fMRI was recorded. In the overlap condition, they could prepare the second movement during the first response and in the nonoverlap condition only after the first response was completed. Despite matched perceptual and movement requirements, fMRI revealed increased brain activity in the overlap condition in regions along the intraparietal sulcus and ventral visual stream. Multivariate analyses suggested that these areas are involved in stimulus identification and action selection. In contrast, the dorsal premotor cortex, known to be involved in planning upcoming movements, showed no discernible signs of heightened activity. This observation suggests that the bottleneck during simultaneous action execution and preparation arises at the level of stimulus identification and action selection, whereas movement planning in the premotor cortex can unfold concurrently with the execution of a current action without requiring additional neural activity.

Clinical severity in Parkinson's disease is determined by decline in cortical compensation.

Dopaminergic dysfunction in the basal ganglia, particularly in the posterior putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e. bradykinesia) in Parkinson's disease. However, striatal dopamine loss fails to account for interindividual differences in motor phenotype and rate of decline, implying that the expression of motor symptoms depends on additional mechanisms, some of which may be compensatory in nature. Building on observations of increased motor-related activity in the parieto-premotor cortex of Parkinson patients, we tested the hypothesis that interindividual differences in clinical severity are determined by compensatory cortical mechanisms and not just by basal ganglia dysfunction. Using functional MRI, we measured variability in motor- and selection-related brain activity during a visuomotor task in 353 patients with Parkinson's disease (≤5 years disease duration) and 60 healthy controls. In this task, we manipulated action selection demand by varying the number of possible actions that individuals could choose from. Clinical variability was characterized in two ways. First, patients were categorized into three previously validated, discrete clinical subtypes that are hypothesized to reflect distinct routes of α-synuclein propagation: diffuse-malignant (n = 42), intermediate (n = 128) or mild motor-predominant (n = 150). Second, we used the scores of bradykinesia severity and cognitive performance across the entire sample as continuous measures. Patients showed motor slowing (longer response times) and reduced motor-related activity in the basal ganglia compared with controls. However, basal ganglia activity did not differ between clinical subtypes and was not associated with clinical scores. This indicates a limited role for striatal dysfunction in shaping interindividual differences in clinical severity. Consistent with our hypothesis, we observed enhanced action selection-related activity in the parieto-premotor cortex of patients with a mild-motor predominant subtype, both compared to patients with a diffuse-malignant subtype and controls. Furthermore, increased parieto-premotor activity was related to lower bradykinesia severity and better cognitive performance, which points to a compensatory role. We conclude that parieto-premotor compensation, rather than basal ganglia dysfunction, shapes interindividual variability in symptom severity in Parkinson's disease. Future interventions may focus on maintaining and enhancing compensatory cortical mechanisms, rather than only attempting to normalize basal ganglia dysfunction.

Biomechanical costs influence decisions made during ongoing actions.

Accurate interaction with the environment relies on the integration of external information about the spatial layout of potential actions and knowledge of their costs and benefits. Previous studies have shown that when given a choice between voluntary reaching movements, humans tend to prefer actions with lower biomechanical costs. However, these studies primarily focused on decisions made before the onset of movement ("decide-then-act" scenarios), and it is not known to what extent their conclusions generalize to many real-life situations, in which decisions occur during ongoing actions ("decide-while-acting"). For example, one recent study found that biomechanical costs did not influence decisions to switch from a continuous manual tracking movement to a point-to-point movement, suggesting that biomechanical costs may be disregarded in decide-while-acting scenarios. To better understand this surprising result, we designed an experiment in which participants were faced with the decision between continuing to track a target moving along a straight path or changing paths to track a new target that gradually moved along a direction that deviated from the initial one. We manipulated tracking direction, angular deviation rate, and side of deviation, allowing us to compare scenarios where biomechanical costs favored either continuing or changing the path. Crucially, here the choice was always between two continuous tracking actions. Our results show that in this situation decisions clearly took biomechanical costs into account. Thus we conclude that biomechanics are not disregarded during decide-while-acting scenarios but rather that cost comparisons can only be made between similar types of actions.NEW & NOTEWORTHY In this study, we aim to shed light on how biomechanical factors influence decisions made during ongoing actions. Previous work suggested that decisions made during actions disregard biomechanical costs, in contrast to decisions made before movement. Our results challenge that proposal and suggest instead that the effect of biomechanical factors is dependent on the types of actions being compared (e.g., continuous tracking vs. point-to-point reaching). These findings contribute to our understanding of the dynamic interplay between biomechanical considerations and action choices during ongoing interactions with the environment.

Evidence for a common mechanism supporting invigoration of action selection and action execution.

The speed, or vigor, of our movements can vary depending on circumstances. For instance, the promise of a reward leads to faster movements. Reward also leads us to move with a lower reaction time, suggesting that the process of action selection can also be invigorated by reward. It has been proposed that invigoration of action selection and of action execution might occur through a common mechanism, and thus these aspects of behavior might be coupled. To test this hypothesis, we asked participants to make reaching movements to "shoot" through a target at varying speeds to assess whether moving more quickly was also associated with more rapid action selection. We found that, when participants were required to move with a lower velocity, the speed of their action selection was also significantly slowed. This finding was recapitulated in a further dataset in which participants determined their own movement speed, but had to move slowly to stop their movement inside the target. By reanalyzing a previous dataset, we also found evidence for the converse relationship between action execution and action selection; when pressured to select actions more rapidly, people also executed movements with higher velocity. Our results establish that invigoration of action selection and action execution vary in tandem with one another, supporting the hypothesis of a common underlying mechanism.NEW & NOTEWORTHY We show that voluntary increases in the vigor of action execution lead action selection to also occur more rapidly. Conversely, hastening action selection by imposing a deadline to act also leads to increases in movement speed. These findings provide evidence that these two distinct aspects of behavior are modulated by a common underlying mechanism.

Why it hurts: with freedom comes the biological need for pain.

We argue that pain is not needed to protect the body from damage unless the organism is able to make free choices in action selection. Then pain (including its affective and evaluative aspects) provides a necessary prioritising motivation to select actions expected to avoid it, whilst leaving the possibility of alternative actions to serve potentially higher priorities. Thus, on adaptive grounds, only organisms having free choice over action selection should experience pain. Free choice implies actions must be selected following appraisal of their effects, requiring a predictive model generating estimates of action outcomes. These features give organisms anticipatory behavioural autonomy (ABA), for which we propose a plausible system using an internal predictive model, integrated into a system able to produce the qualitative and affective aspects of pain. Our hypothesis can be tested using behavioural experiments designed to elicit trade-off responses to novel experiences for which algorithmic (automaton) responses might be inappropriate. We discuss the empirical evidence for our hypothesis among taxonomic groups, showing how testing for ABA guides thinking on which groups might experience pain. It is likely that all vertebrates do and plausible that some invertebrates do (decapods, cephalopods and at least some insects).

Basal ganglia network dynamics and function: Role of direct, indirect and hyper-direct pathways in action selection.

Basal ganglia (BG) are a widely recognized neural basis for action selection, but its decision-making mechanism is still a difficult problem for researchers. Therefore, we constructed a spiking neural network inspired by the BG anatomical data. Simulation experiments were based on the principle of dis-inhibition and our functional hypothesis within the BG: the direct pathway, the indirect pathway, and the hyper-direct pathway of the BG jointly implement the initiation execution and termination of motor programs. Firstly, we studied the dynamic process of action selection with the network, which contained intra-group competition and inter-group competition. Secondly, we focused on the effects of the stimulus intensity and the proportion of excitation and inhibition on the GPi/SNr. The results suggested that inhibition and excitation shape action selection. They also explained why the firing rate of GPi/SNr did not continue to increase in the action-selection experiment. Finally, we discussed the experimental results with the functional hypothesis. Uniquely, this paper summarized the decision-making neural mechanism of action selection based on the direct pathway, the indirect pathway, and the hyper-direct pathway within BG.

Perceptual control or action-selection? Comment on: a perceptual control theory of emotional action.

The Perceptual Control Theory of Emotional Action provides a compelling view of the synergy between action and perception in the context of emotion. In this invited response, we outline three suggestions to further clarify and concretesise the theory in the hope that it can provide a solid basis for the theoretical, empirical, and clinical fields of emotion and emotion regulation. First, we emphasise the importance of concretesising these ideas in a way that is biologically plausible and testable in terms of its neuronal implementation, which has not been addressed in the main manuscript. Secondly, we highlight the challenges for this account to effectively describe core symptoms in emotional disorders, an essential step if the theory aims to foster the development of better-tuned neurocognitively grounded interventions. Finally, we take a leap on what action-oriented accounts of emotion can mean for the field of emotion regulation.

Comment on Albantakis et al. Computing the Integrated Information of a Quantum Mechanism. Entropy 2023, 25, 449.

Integrated information theory (IIT) is a powerful tool that provides a framework for evaluating consciousness, whether in the human brain or in other systems. In Computing the Integrated Information of a Quantum Mechanism, the authors extend IIT from digital gates to a quantum CNOT logic gate, and while they explicitly distinguish the analysis from quantum theories of consciousness, they nonetheless provide an analytical road map for extending IIT not only to other quantum mechanisms but also to hybrid computing structures like the brain. This comment provides additional information relating to an adiabatic quantum mechanical energy routing mechanism that is part of a hybrid biological computer that provides an action selection mechanism, which has been hypothesized to exist in the human brain and for which predicted evidence has been subsequently observed, and it hopes to motivate the further evaluation and extension of IIT not only to that hypothesized mechanism but also to other hybrid biological computers.

Coordinated Postnatal Maturation of Striatal Cholinergic Interneurons and Dopamine Release Dynamics in Mice.

Dynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical to action selection, motor learning, and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine (DA) neurons; however, little is known about its development. Here, we report that ChI spontaneous activity increases during postnatal development of male and female mice, concomitant with a decreased afterhyperpolarization (AHP). We characterized the postnatal development of four currents that contribute to the spontaneous firing rate of ChIs, including ISK, IA, Ih, and INaP We demonstrated that the developmental increase in INaP drives increased ChI firing rates during the postnatal period and can be reversed by the INaP inhibitor, ranolazine. We next addressed whether immature cholinergic signaling may lead to functional differences in DA release during the juvenile period. In the adult striatum, nicotinic acetylcholine receptors (nAChRs) prevent linear summation of DA release in response to trains of high-frequency stimuli. We show that, in contrast, during the second postnatal week, DA release linearly sums with trains of high-frequency stimuli. Consistently, nAChR antagonists exert little effect on dopamine release at postnatal day (P)10, but enhance the summation of evoked DA release in mice older than postnatal day P28. Together, these results reveal that postnatal maturation of ChI activity is due primarily to enhanced INaP and identify an interaction between developing cholinergic signaling and DA neurotransmission in the juvenile striatum.SIGNIFICANCE STATEMENT Motor skills and motivated behavior develop rapidly in juvenile rodents. Recent work has highlighted processes that contribute to the postnatal maturation of striatal principal neurons during development. The functional development of the striatal cholinergic interneuron (ChI), however, has been unexplored. In this study, we tracked the ontogeny of ChI activity and cellular morphology, as well as the developmental trajectory of specific conductances that contribute to the activity of these cells. We further report a link between cholinergic signaling and dopamine (DA) release, revealing a change in the frequency-dependence of DA release during the early postnatal period that is mediated by cholinergic signaling. This study provides evidence that striatal microcircuits are dynamic during the postnatal period and that they undergo coordinated maturation.

Prefronto-Striatal Structural Connectivity Mediates Adult Age Differences in Action Selection.

In complex everyday environments, action selection is critical for optimal goal-directed behavior. This refers to the process of choosing a proper action from the range of possible alternatives. The neural mechanisms underlying action selection and how these are affected by normal aging remain to be elucidated. In the present cross-sectional study, we studied processes of effector selection during a multilimb reaction time task in a lifespan sample of healthy human adults (N = 89; 20-75 years; 48 males, 41 females). Participants were instructed to react as quickly and accurately as possible to visually cued stimuli representing single-limb or combined upper and/or lower limb motions. Diffusion MRI was used to study structural connectivity between prefrontal and striatal regions as critical nodes for action selection. Behavioral findings revealed that increasing age was associated with slowing of action selection performance. At the neural level, aging had a negative impact on prefronto-striatal connectivity. Importantly, mediation analyses revealed that the negative association between action selection performance and age was mediated by prefronto-striatal connectivity, specifically the connections between left rostral medial frontal gyrus and left nucleus accumbens as well as right frontal pole and left caudate. These results highlight the potential role of prefronto-striatal white matter decline in poorer action selection performance of older adults.SIGNIFICANCE STATEMENT As a result of enhanced life expectancy, researchers have devoted increasing attention to the study of age-related alterations in cognitive and motor functions. Here we study associations between brain structure and behavior to reveal the impact of central neural white matter changes as a function of normal aging on action selection performance. We demonstrate the critical role of a reduction in prefronto-striatal structural connectivity in accounting for action selection performance deficits in healthy older adults. Preserving this cortico-subcortical pathway may be critical for behavioral flexibility and functional independence in older age.

Effect of behavioural practice targeted at the motor action selection network after stroke.

Motor action selection engages a network of frontal and parietal brain regions. After stroke, individuals activate a similar network, however, activation is higher, especially in the contralesional hemisphere. The current study examined the effect of practice on action selection performance and brain activation after stroke. Sixteen individuals with chronic stroke (Upper Extremity Fugl-Meyer motor score range: 18-61) moved a joystick with the more-impaired hand in two conditions: Select (externally cued choice; move right or left based on an abstract rule) and Execute (simple response; move same direction every trial). On Day 1, reaction time (RT) was longer in Select compared to Execute, which corresponded to increased activation primarily in regions in the contralesional action selection network including dorsal premotor, supplementary motor, anterior cingulate and parietal cortices. After 4 days of practice, behavioural performance improved (decreased RT), and only contralesional parietal cortex significantly increased during Select. Higher brain activation on Day 1 in the bilateral action selection network, dorsolateral prefrontal cortex and contralesional sensory cortex predicted better performance on Day 4. Overall, practice led to improved action selection performance and reduced brain activation. Systematic changes in practice conditions may allow the targeting of specific components of the motor network during rehabilitation after stroke.

Dissociable use-dependent processes for volitional goal-directed reaching.

Repetition of specific movement biases subsequent actions towards the practiced movement, a phenomenon known as use-dependent learning (UDL). Recent experiments that impose strict constraints on planning time have revealed two sources of use-dependent biases, one arising from dynamic changes occurring during motor planning and another reflecting a stable shift in motor execution. Here, we used a distributional analysis to examine the contribution of these biases in reaching. To create the conditions for UDL, the target appeared at a designated 'frequent' location on most trials, and at one of six 'rare' locations on other trials. Strikingly, the heading angles were bimodally distributed, with peaks at both frequent and rare target locations. Despite having no constraints on planning time, participants exhibited a robust bias towards the frequent target when movements were self-initiated quickly, the signature of a planning bias; notably, the peak near the rare target was shifted in the frequently practiced direction, the signature of an execution bias. Furthermore, these execution biases were not only replicated in a delayed-response task but were also insensitive to reward. Taken together, these results extend our understanding of how volitional movements are influenced by recent experience.

The Psychology of Reaching: Action Selection, Movement Implementation, and Sensorimotor Learning.

The study of motor planning and learning in humans has undergone a dramatic transformation in the 20 years since this journal's last review of this topic. The behavioral analysis of movement, the foundational approach for psychology, has been complemented by ideas from control theory, computer science, statistics, and, most notably, neuroscience. The result of this interdisciplinary approach has been a focus on the computational level of analysis, leading to the development of mechanistic models at the psychological level to explain how humans plan, execute, and consolidate skilled reaching movements. This review emphasizes new perspectives on action selection and motor planning, research that stands in contrast to the previously dominant representation-based perspective of motor programming, as well as an emerging literature highlighting the convergent operation of multiple processes in sensorimotor learning.

Application of the Catecholaminergic Neuron Electron Transport (CNET) Physical Substrate for Consciousness and Action Selection to Integrated Information Theory.

A newly discovered physical mechanism involving incoherent electron tunneling in layers of the protein ferritin that are found in catecholaminergic neurons (catecholaminergic neuron electron transport or CNET) is hypothesized to support communication between neurons. Recent tests further confirm that these ferritin layers can also perform a switching function (in addition to providing an electron tunneling mechanism) that could be associated with action selection in those neurons, consistent with earlier predictions based on CNET. While further testing would be needed to confirm the hypothesis that CNET allows groups of neurons to communicate and act as a switch for selecting one of the neurons in the group to assist in reaching action potential, this paper explains how that hypothesized behavior would be consistent with Integrated Information Theory (IIT), one of a number of consciousness theories (CTs). While the sheer number of CTs suggest that any one of them alone is not sufficient to explain consciousness, this paper demonstrates that CNET can provide a physical substrate and action selection mechanism that is consistent with IIT and which can also be applied to other CTs, such as to conform them into a single explanation of consciousness.