Modularity and robustness of frontal cortical networks.

Neural activity underlying short-term memory is maintained by interconnected networks of brain regions. It remains unknown how brain regions interact to maintain persistent activity while exhibiting robustness to corrupt information in parts of the network. We simultaneously measured activity in large neuronal populations across mouse frontal hemispheres to probe interactions between brain regions. Activity across hemispheres was coordinated to maintain coherent short-term memory. Across mice, we uncovered individual variability in the organization of frontal cortical networks. A modular organization was required for the robustness of persistent activity to perturbations: each hemisphere retained persistent activity during perturbations of the other hemisphere, thus preventing local perturbations from spreading. A dynamic gating mechanism allowed hemispheres to coordinate coherent information while gating out corrupt information. Our results show that robust short-term memory is mediated by redundant modular representations across brain regions. Redundant modular representations naturally emerge in neural network models that learned robust dynamics.

Hand Knob Area of Premotor Cortex Represents the Whole Body in a Compositional Way.

Decades after the motor homunculus was first proposed, it is still unknown how different body parts are intermixed and interrelated in human motor cortical areas at single-neuron resolution. Using multi-unit recordings, we studied how face, head, arm, and leg movements are represented in the hand knob area of premotor cortex (precentral gyrus) in people with tetraplegia. Contrary to traditional expectations, we found strong representation of all movements and a partially "compositional" neural code that linked together all four limbs. The code consisted of (1) a limb-coding component representing the limb to be moved and (2) a movement-coding component where analogous movements from each limb (e.g., hand grasp and toe curl) were represented similarly. Compositional coding might facilitate skill transfer across limbs, and it provides a useful framework for thinking about how the motor system constructs movement. Finally, we leveraged these results to create a whole-body intracortical brain-computer interface that spreads targets across all limbs.

Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems.

The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states, including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell-body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal-cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal-cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.

Control of working memory by phase-amplitude coupling of human hippocampal neurons.

Retaining information in working memory is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference1,2. However, how cognitive control regulates working memory storage is unclear. Here we show that interactions of frontal control and hippocampal persistent activity are coordinated by theta-gamma phase-amplitude coupling (TG-PAC). We recorded single neurons in the human medial temporal and frontal lobe while patients maintained multiple items in their working memory. In the hippocampus, TG-PAC was indicative of working memory load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. The spike timing of these PAC neurons was coordinated with frontal theta activity when cognitive control demand was high. By introducing noise correlations with persistently active neurons in the hippocampus, PAC neurons shaped the geometry of the population code. This led to higher-fidelity representations of working memory content that were associated with improved behaviour. Our results support a multicomponent architecture of working memory1,2, with frontal control managing maintenance of working memory content in storage-related areas3-5. Within this framework, hippocampal TG-PAC integrates cognitive control and working memory storage across brain areas, thereby suggesting a potential mechanism for top-down control over sensory-driven processes.

The Anatomy and Physiology of Claustrum-Cortex Interactions.

The claustrum is one of the most widely connected regions of the forebrain, yet its function has remained obscure, largely due to the experimentally challenging nature of targeting this small, thin, and elongated brain area. However, recent advances in molecular techniques have enabled the anatomy and physiology of the claustrum to be studied with the spatiotemporal and cell type-specific precision required to eventually converge on what this area does. Here we review early anatomical and electrophysiological results from cats and primates, as well as recent work in the rodent, identifying the connectivity, cell types, and physiological circuit mechanisms underlying the communication between the claustrum and the cortex. The emerging picture is one in which the rodent claustrum is closely tied to frontal/limbic regions and plays a role in processes, such as attention, that are associated with these areas.

Cortical feedback loops bind distributed representations of working memory.

Working memory-the brain's ability to internalize information and use it flexibly to guide behaviour-is an essential component of cognition. Although activity related to working memory has been observed in several brain regions1-3, how neural populations actually represent working memory4-7 and the mechanisms by which this activity is maintained8-12 remain unclear13-15. Here we describe the neural implementation of visual working memory in mice alternating between a delayed non-match-to-sample task and a simple discrimination task that does not require working memory but has identical stimulus, movement and reward statistics. Transient optogenetic inactivations revealed that distributed areas of the neocortex were required selectively for the maintenance of working memory. Population activity in visual area AM and premotor area M2 during the delay period was dominated by orderly low-dimensional dynamics16,17 that were, however, independent of working memory. Instead, working memory representations were embedded in high-dimensional population activity, present in both cortical areas, persisted throughout the inter-stimulus delay period, and predicted behavioural responses during the working memory task. To test whether the distributed nature of working memory was dependent on reciprocal interactions between cortical regions18-20, we silenced one cortical area (AM or M2) while recording the feedback it received from the other. Transient inactivation of either area led to the selective disruption of inter-areal communication of working memory. Therefore, reciprocally interconnected cortical areas maintain bound high-dimensional representations of working memory.

Activation and disruption of a neural mechanism for novel choice in monkeys.

Neural mechanisms that mediate the ability to make value-guided decisions have received substantial attention in humans and animals1-6. Experiments in animals typically involve long training periods. By contrast, choices in the real world often need to be made between new options spontaneously. It is therefore possible that the neural mechanisms targeted in animal studies differ from those required for new decisions, which are typical of human imaging studies. Here we show that the primate medial frontal cortex (MFC)7 is involved in making new inferential choices when the options have not been previously experienced. Macaques spontaneously inferred the values of new options via similarities with the component parts of previously encountered options. Functional magnetic resonance imaging (fMRI) suggested that this ability was mediated by the MFC, which is rarely investigated in monkeys3; MFC activity reflected different processes of comparison for unfamiliar and familiar options. Multidimensional representations of options in the MFC used a coding scheme resembling that of grid cells, which is well known in spatial navigation8,9, to integrate dimensions in this non-physical space10 during novel decision-making. By contrast, the orbitofrontal cortex held specific object-based value representations1,11. In addition, minimally invasive ultrasonic disruption12 of MFC, but not adjacent tissue, altered the estimation of novel choice values.

Neural responses in macaque prefrontal cortex are linked to strategic exploration.

Humans have been shown to strategically explore. They can identify situations in which gathering information about distant and uncertain options is beneficial for the future. Because primates rely on scarce resources when they forage, they are also thought to strategically explore, but whether they use the same strategies as humans and the neural bases of strategic exploration in monkeys are largely unknown. We designed a sequential choice task to investigate whether monkeys mobilize strategic exploration based on whether information can improve subsequent choice, but also to ask the novel question about whether monkeys adjust their exploratory choices based on the contingency between choice and information, by sometimes providing the counterfactual feedback about the unchosen option. We show that monkeys decreased their reliance on expected value when exploration could be beneficial, but this was not mediated by changes in the effect of uncertainty on choices. We found strategic exploratory signals in anterior and mid-cingulate cortex (ACC/MCC) and dorsolateral prefrontal cortex (dlPFC). This network was most active when a low value option was chosen, which suggests a role in counteracting expected value signals, when exploration away from value should to be considered. Such strategic exploration was abolished when the counterfactual feedback was available. Learning from counterfactual outcome was associated with the recruitment of a different circuit centered on the medial orbitofrontal cortex (OFC), where we showed that monkeys represent chosen and unchosen reward prediction errors. Overall, our study shows how ACC/MCC-dlPFC and OFC circuits together could support exploitation of available information to the fullest and drive behavior towards finding more information through exploration when it is beneficial.

Spatiotemporally distributed frontotemporal networks for sentence reading.

Reading a sentence entails integrating the meanings of individual words to infer more complex, higher-order meaning. This highly rapid and complex human behavior is known to engage the inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) in the language-dominant hemisphere, yet whether there are distinct contributions of these regions to sentence reading is still unclear. To probe these neural spatiotemporal dynamics, we used direct intracranial recordings to measure neural activity while reading sentences, meaning-deficient Jabberwocky sentences, and lists of words or pseudowords. We isolated two functionally and spatiotemporally distinct frontotemporal networks, each sensitive to distinct aspects of word and sentence composition. The first distributed network engages the IFG and MTG, with IFG activity preceding MTG. Activity in this network ramps up over the duration of a sentence and is reduced or absent during Jabberwocky and word lists, implying its role in the derivation of sentence-level meaning. The second network engages the superior temporal gyrus and the IFG, with temporal responses leading those in frontal lobe, and shows greater activation for each word in a list than those in sentences, suggesting that sentential context enables greater efficiency in the lexical and/or phonological processing of individual words. These adjacent, yet spatiotemporally dissociable neural mechanisms for word- and sentence-level processes shed light on the richly layered semantic networks that enable us to fluently read. These results imply distributed, dynamic computation across the frontotemporal language network rather than a clear dichotomy between the contributions of frontal and temporal structures.

Neural Representations of Post-Decision Accuracy and Reward Expectation in the Caudate Nucleus and Frontal Eye Field.

Performance monitoring that supports ongoing behavioral adjustments is often examined in the context of either choice confidence for perceptual decisions (i.e., "did I get it right?") or reward expectation for reward-based decisions (i.e., "what reward will I receive?"). However, our understanding of how the brain encodes these distinct evaluative signals remains limited because they are easily conflated, particularly in commonly used two-alternative tasks with symmetric rewards for correct choices. Previously we used a motion-discrimination task with asymmetric rewards to identify neural substrates of forming reward-biased perceptual decisions in the caudate nucleus (part of the striatum in the basal ganglia) and the frontal eye field (FEF, in prefrontal cortex). Here we leveraged this task design to partially decouple estimates of accuracy and reward expectation and examine their impacts on subsequent decisions and their representations in those two brain areas. We identified distinguishable representations of these two evaluative signals in individual caudate and FEF neurons, with regional differences in their distribution patterns and time courses. We observed that well-trained monkeys (both sexes) used both evaluative signals, infrequently but consistently, to adjust their subsequent decisions. We found further that these behavioral adjustments had reliable relationships with the neural representations of both evaluative signals in caudate, but not FEF. These results suggest that the cortico-striatal decision network may use diverse evaluative signals to monitor and adjust decision-making behaviors, adding to our understanding of the different roles that the FEF and caudate nucleus play in a diversity of decision-related computations.

Transcranial Alternating Current Stimulation over Frontal Eye Fields Mimics Attentional Modulation of Visual Processing.

Attentional control over sensory processing has been linked to neural alpha oscillations and related inhibition of cerebral cortex. Despite the wide consensus on the functional relevance of alpha oscillations for attention, precise neural mechanisms of how alpha oscillations shape perception and how this top-down modulation is implemented in cortical networks remain unclear. Here, we tested the hypothesis that alpha oscillations in frontal eye fields (FEFs) are causally involved in the top-down regulation of visual processing in humans (male and female). We applied sham-controlled, intermittent transcranial alternating current stimulation (tACS) over bilateral FEF at either 10 Hz (alpha) or 40 Hz (gamma) to manipulate attentional preparation in a visual discrimination task. Under each stimulation condition, we measured psychometric functions for contrast perception and introduced a novel linear mixed modeling approach for statistical control of neurosensory side effects of the electric stimulation. tACS at alpha frequency reduced the slope of the psychometric function, resulting in improved subthreshold and impaired superthreshold contrast perception. Side effects on the psychometric functions were complex and showed large interindividual variability. Controlling for the impact of side effects on the psychometric parameters by using covariates in the linear mixed model analysis reduced this variability and strengthened the perceptual effect. We propose that alpha tACS over FEF mimicked a state of endogenous attention by strengthening a fronto-occipitoparietal network in the alpha band. We speculate that this network modulation enhanced phasic gating in occipitoparietal cortex leading to increased variability of single-trial psychometric thresholds, measurable as a reduction of psychometric slope.

Biophysical Modeling of Frontocentral ERP Generation Links Circuit-Level Mechanisms of Action-Stopping to a Behavioral Race Model.

Human frontocentral event-related potentials (FC-ERPs) are ubiquitous neural correlates of cognition and control, but their generating multiscale mechanisms remain mostly unknown. We used the Human Neocortical Neurosolver's biophysical model of a canonical neocortical circuit under exogenous thalamic and cortical drive to simulate the cell and circuit mechanisms underpinning the P2, N2, and P3 features of the FC-ERP observed after Stop-Signals in the Stop-Signal task (SST; N = 234 humans, 137 female). We demonstrate that a sequence of simulated external thalamocortical and corticocortical drives can produce the FC-ERP, similar to what has been shown for primary sensory cortices. We used this model of the FC-ERP to examine likely circuit-mechanisms underlying FC-ERP features that distinguish between successful and failed action-stopping. We also tested their adherence to the predictions of the horse-race model of the SST, with specific hypotheses motivated by theoretical links between the P3 and Stop process. These simulations revealed that a difference in P3 onset between successful and failed Stops is most likely due to a later arrival of thalamocortical drive in failed Stops, rather than, for example, a difference in the effective strength of the input. In contrast, the same model predicted that early thalamocortical drives underpinning the P2 and N2 differed in both strength and timing across stopping accuracy conditions. Overall, this model generates novel testable predictions of the thalamocortical dynamics underlying FC-ERP generation during action-stopping. Moreover, it provides a detailed cellular and circuit-level interpretation that supports links between these macroscale signatures and predictions of the behavioral race model.

Ultrahigh Field fMRI Reveals Different Roles of the Temporal and Frontoparietal Cortices in Subjective Awareness.

A central question in consciousness theories is whether one is dealing with a dichotomous ("all-or-none") or a gradual phenomenon. In this 7T fMRI study, we investigated whether dichotomy or gradualness in fact depends on the brain region associated with perceptual awareness reports. Both male and female human subjects performed an emotion discrimination task (fear vs neutral bodies) presented under continuous flash suppression with trial-based perceptual awareness measures. Behaviorally, recognition sensitivity increased linearly with increased stimuli awareness and was at chance level during perceptual unawareness. Physiologically, threat stimuli triggered a slower heart rate than neutral ones during "almost clear" stimulus experience, indicating freezing behavior. Brain results showed that activity in the occipitotemporal, parietal, and frontal regions as well as in the amygdala increased with increased stimulus awareness while early visual areas showed the opposite pattern. The relationship between temporal area activity and perceptual awareness best fitted a gradual model while the activity in frontoparietal areas fitted a dichotomous model. Furthermore, our findings illustrate that specific experimental decisions, such as stimulus type or the approach used to evaluate awareness, play pivotal roles in consciousness studies and warrant careful consideration.

Covariations between pupil diameter and supplementary eye field activity suggest a role in cognitive effort implementation.

In both human and nonhuman primates (NHP), the medial prefrontal region, defined as the supplementary eye field (SEF), can indirectly influence behavior selection through modulation of the primary selection process in the oculomotor structures. To perform this oculomotor control, SEF integrates multiple cognitive signals such as attention, memory, reward, and error. As changes in pupil responses can assess these cognitive efforts, a better understanding of the precise dynamics by which pupil diameter and medial prefrontal cortex activity interact requires thorough investigations before, during, and after changes in pupil diameter. We tested whether SEF activity is related to pupil dynamics during a mixed pro/antisaccade oculomotor task in 2 macaque monkeys. We used functional ultrasound (fUS) imaging to examine temporal changes in brain activity at the 0.1-s time scale and 0.1-mm spatial resolution concerning behavioral performance and pupil dynamics. By combining the pupil signals and real-time imaging of NHP during cognitive tasks, we were able to infer localized cerebral blood volume (CBV) responses within a restricted part of the dorsomedial prefrontal cortex, referred to as the SEF, an area in which antisaccade preparation activity is also recorded. Inversely, SEF neurovascular activity measured by fUS imaging was found to be a robust predictor of specific variations in pupil diameter over short and long-time scales. Furthermore, we directly manipulated pupil diameter and CBV in the SEF using reward modulations. These results bring a novel understanding of the physiological links between pupil and SEF, but it also raises questions about the role of anterior cingulate cortex (ACC), as CBV variations in the ACC seems to be negligible compared to CBV variations in the SEF.

Feedback-related brain activity in individual decision: evidence from a gambling EEG study.

In this study, based on scalp electroencephalogram (EEG), we conducted cortical source localization and functional network analyses to investigate the underlying mechanism explaining the decision processes when individuals anticipate maximizing gambling benefits, particularly in situations where the decision outcomes are inconsistent with the profit goals. The findings shed light on the feedback monitoring process, wherein incongruity between outcomes and gambling goals triggers a more pronounced medial frontal negativity and activates the frontal lobe. Moreover, long-range theta connectivity is implicated in processing surprise and uncertainty caused by inconsistent feedback conditions, while middle-range delta coupling reflects a more intricate evaluation of feedback outcomes, which subsequently modifies individual decision-making for optimizing future rewards. Collectively, these findings deepen our comprehension of decision-making under circumstances where the profit goals are compromised by decision outcomes and provide electrophysiological evidence supporting adaptive adjustments in individual decision strategies to achieve maximum benefit.

Distinct and common mechanisms of cross-model semantic conflict and response conflict in an auditory relevant task.

The mechanisms of semantic conflict and response conflict in the Stroop task have mainly been investigated in the visual modality. However, the understanding of these mechanisms in cross-modal modalities remains limited. In this electroencephalography (EEG) study, an audiovisual 2-1 mapping Stroop task was utilized to investigate whether distinct and/or common neural mechanisms underlie cross-modal semantic conflict and response conflict. The response time data showed significant effects on both cross-modal semantic and response conflicts. Interestingly, the magnitude of semantic conflict was found to be smaller in the fast response time bins than in the slow response time bins, whereas no such difference was observed for response conflict. The EEG data demonstrated that cross-modal semantic conflict specifically increased the N450 amplitude. However, cross-modal response conflict specifically enhanced theta band power and theta phase synchronization between the medial frontal cortex (MFC) and lateral prefrontal electrodes as well as between the MFC and motor electrodes. In addition, both cross-modal semantic conflict and response conflict led to a decrease in P3 amplitude. Taken together, these findings provide cross-modal evidence for domain-specific mechanism in conflict detection and suggest both domain-specific and domain-general mechanisms exist in conflict resolution.

The dynamic causality brain network reflects whether the working memory is solidified.

Working memory, which is foundational to higher cognitive function, is the "sketchpad of volitional control." Successful working memory is the inevitable outcome of the individual's active control and manipulation of thoughts and turning them into internal goals during which the causal brain processes information in real time. However, little is known about the dynamic causality among distributed brain regions behind thought control that underpins successful working memory. In our present study, given that correct responses and incorrect ones did not differ in either contralateral delay activity or alpha suppression, further rooting on the high-temporal-resolution EEG time-varying directed network analysis, we revealed that successful working memory depended on both much stronger top-down connections from the frontal to the temporal lobe and bottom-up linkages from the occipital to the temporal lobe, during the early maintenance period, as well as top-down flows from the frontal lobe to the central areas as the delay behavior approached. Additionally, the correlation between behavioral performance and casual interactions increased over time, especially as memory-guided delayed behavior approached. Notably, when using the network metrics as features, time-resolved multiple linear regression of overall behavioral accuracy was exactly achieved as delayed behavior approached. These results indicate that accurate memory depends on dynamic switching of causal network connections and shifting to more task-related patterns during which the appropriate intervention may help enhance memory.

Dorsomedial frontal cortex damage impairs error-based, but not reinforcement-based motor learning in humans.

We adapt our movements to new and changing environments through multiple processes. Sensory error-based learning counteracts environmental perturbations that affect the sensory consequences of movements. Sensory errors also cause the upregulation of reflexes and muscle co-contraction. Reinforcement-based learning enhances the selection of movements that produce rewarding outcomes. Although some findings have identified dissociable neural substrates of sensory error- and reinforcement-based learning, correlative methods have implicated dorsomedial frontal cortex in both. Here, we tested the causal contributions of dorsomedial frontal to adaptive motor control, studying people with chronic damage to this region. Seven human participants with focal brain lesions affecting the dorsomedial frontal and 20 controls performed a battery of arm movement tasks. Three experiments tested: (i) the upregulation of visuomotor reflexes and muscle co-contraction in response to unpredictable mechanical perturbations, (ii) sensory error-based learning in which participants learned to compensate predictively for mechanical force-field perturbations, and (iii) reinforcement-based motor learning based on binary feedback in the absence of sensory error feedback. Participants with dorsomedial frontal damage were impaired in the early stages of force field adaptation, but performed similarly to controls in all other measures. These results provide evidence for a specific and selective causal role for the dorsomedial frontal in sensory error-based learning.

Transcranial magnetic stimulation on the right dorsal attention network modulates the center-surround profile of the attentional focus.

Psychophysical observations indicate that the spatial profile of visuospatial attention includes a central enhancement around the attentional focus, encircled by a narrow zone of reduced excitability in the immediate surround. This inhibitory ring optimally amplifies relevant target information, likely stemming from top-down frontoparietal recurrent activity modulating early visual cortex activations. However, the mechanisms through which neural suppression gives rise to the surrounding attenuation and any potential hemispheric specialization remain unclear. We used transcranial magnetic stimulation to evaluate the role of two regions of the dorsal attention network in the center-surround profile: the frontal eye field and the intraparietal sulcus. Participants performed a psychophysical task that mapped the entire spatial attentional profile, while transcranial magnetic stimulation was delivered either to intraparietal sulcus or frontal eye field on the right (Experiment 1) and left (Experiment 2) hemisphere. Results showed that stimulation of right frontal eye field and right intraparietal sulcus significantly changed the center-surround profile, by widening the inhibitory ring around the attentional focus. The stimulation on the left frontal eye field, but not left intraparietal sulcus, induced a general decrease in performance but did not alter the center-surround profile. Results point to a pivotal role of the right dorsal attention network in orchestrating inhibitory spatial mechanisms required to limit interference by surrounding distractors.

Dissociating the Contributions of Frontal Eye Field Activity to Spatial Working Memory and Motor Preparation.

Neurons within dorsolateral prefrontal cortex (PFC) of primates are characterized by robust persistent spiking activity exhibited during the delay period of working memory tasks. This includes the frontal eye field (FEF) where nearly half of the neurons are active when spatial locations are held in working memory. Past evidence has established the FEF's contribution to the planning and triggering of saccadic eye movements as well as to the control of visual spatial attention. However, it remains unclear whether persistent delay activity reflects a similar dual role in movement planning and visuospatial working memory. We trained male monkeys to alternate between different forms of a spatial working memory task which could dissociate remembered stimulus locations from planned eye movements. We tested the effects of inactivation of FEF sites on behavioral performance in the different tasks. Consistent with previous studies, FEF inactivation impaired the execution of memory-guided saccades (MGSs), and impaired performance when remembered locations matched the planned eye movement. In contrast, memory performance was largely unaffected when the remembered location was dissociated from the correct eye movement response. Overall, the inactivation effects demonstrated clear deficits in eye movements, regardless of task type, but little or no evidence of a deficit in spatial working memory. Thus, our results indicate that persistent delay activity in the FEF contributes primarily to the preparation of eye movements and not to spatial working memory.SIGNIFICANCE STATEMENT Many frontal eye field (FEF) neurons exhibit spatially tuned persistent spiking activity during the delay period of working memory tasks. However, the role of the FEF in spatial working memory remains unresolved. We tested the effects of inactivation of FEF sites on behavioral performance in different forms of a spatial working memory task, one of which dissociated the remembered stimulus locations from planned eye movements. We found that FEF inactivation produced clear deficits in eye movements, regardless of task type, but no deficit in spatial working memory when dissociated from those movements.