Perceptual Uncertainty Alternates Top-down and Bottom-up Fronto-Temporal Network Signaling during Response Inhibition.

Response inhibition is a primary executive control function that allows the withholding of inappropriate responses, and requires appropriate perception of the external environment to achieve a behavioral goal. It remains unclear, however, how response inhibition is achieved when goal-relevant information involves perceptual uncertainty. Twenty-six human participants of both sexes performed a go/no-go task where visually presented random-dot motion stimuli involved perceptual uncertainties. The right inferior frontal cortex (rIFC) was involved in response inhibition, and the middle temporal (MT) region showed greater activity when dot motions involved less uncertainty. A neocortical temporal region in the superior temporal sulcus (STS) specifically showed greater activity during response inhibition in more perceptually certain trials. In this STS region, activity was greater when response inhibition was successful than when it failed. Directional effective connectivity analysis revealed that, in more coherent trials, the MT and STS regions showed enhanced connectivity to the rIFC, whereas in less coherent trials, the signal direction was reversed. These results suggest that a reversible fronto-temporal functional network guides response inhibition and perceptual decision-making under perceptual uncertainty, and in this network, perceptual information in the MT is converted to control information in the rIFC via STS, enabling achievement of response inhibition.SIGNIFICANCE STATEMENT Response inhibition refers to withholding inappropriate behavior and is important for achieving goals. Often, however, decision must be made based on limited environmental evidence. We showed that successful response inhibition is guided by a neocortical temporal region that plays a hub role in converting perceived information coded in a posterior temporal region to control information coded in the PFC. Interestingly, when a perceived stimulus becomes more uncertain, the PFC supplements stimulus encoding in the temporal regions. Our results highlight fronto-temporal mechanisms of response inhibition in which conversion of stimulus-control information is regulated based on the uncertainty of environmental evidence.

Multimodal deep neural decoding reveals highly resolved spatiotemporal profile of visual object representation in humans.

Perception and categorization of objects in a visual scene are essential to grasp the surrounding situation. Recently, neural decoding schemes, such as machine learning in functional magnetic resonance imaging (fMRI), has been employed to elucidate the underlying neural mechanisms. However, it remains unclear as to how spatially distributed brain regions temporally represent visual object categories and sub-categories. One promising strategy to address this issue is neural decoding with concurrently obtained neural response data of high spatial and temporal resolution. In this study, we explored the spatial and temporal organization of visual object representations using concurrent fMRI and electroencephalography (EEG), combined with neural decoding using deep neural networks (DNNs). We hypothesized that neural decoding by multimodal neural data with DNN would show high classification performance in visual object categorization (faces or non-face objects) and sub-categorization within faces and objects. Visualization of the fMRI DNN was more sensitive than that in the univariate approach and revealed that visual categorization occurred in brain-wide regions. Interestingly, the EEG DNN valued the earlier phase of neural responses for categorization and the later phase of neural responses for sub-categorization. Combination of the two DNNs improved the classification performance for both categorization and sub-categorization compared with fMRI DNN or EEG DNN alone. These deep learning-based results demonstrate a categorization principle in which visual objects are represented in a spatially organized and coarse-to-fine manner, and provide strong evidence of the ability of multimodal deep learning to uncover spatiotemporal neural machinery in sensory processing.

Reversible Fronto-occipitotemporal Signaling Complements Task Encoding and Switching under Ambiguous Cues.

Adaptation to changing environments involves the appropriate extraction of environmental information to achieve a behavioral goal. It remains unclear how behavioral flexibility is guided under situations where the relevant behavior is ambiguous. Using functional brain mapping of machine learning decoders and directional functional connectivity, we show that brain-wide reversible neural signaling underpins task encoding and behavioral flexibility in ambiguously changing environments. When relevant behavior is cued ambiguously during behavioral shifting, neural coding is attenuated in distributed cortical regions, but top-down signals from the prefrontal cortex complement the coding. When behavioral shifting is cued more explicitly, modality-specialized occipitotemporal regions implement distinct neural coding about relevant behavior, and bottom-up signals from the occipitotemporal region to the prefrontal cortex supplement the behavioral shift. These results suggest that our adaptation to an ever-changing world is orchestrated by the alternation of top-down and bottom-up signaling in the fronto-occipitotemporal circuit depending on the availability of environmental information.

Cross-Hemispheric Complementary Prefrontal Mechanisms during Task Switching under Perceptual Uncertainty.

Flexible adaptation to changing environments is a representative executive control function implicated in the frontoparietal network that requires appropriate extraction of goal-relevant information through perception of the external environment. It remains unclear, however, how the flexibility is achieved under situations where goal-relevant information is uncertain. To address this issue, the current study examined neural mechanisms for task switching in which task-relevant information involved perceptual uncertainty. Twenty-eight human participants of both sexes alternated behavioral tasks in which they judged motion direction or color of visually presented colored dot stimuli that moved randomly. Task switching was associated with frontoparietal regions in the left hemisphere, and perception of ambiguous stimuli involved contralateral homologous frontoparietal regions. On the other hand, in stimulus-modality-dependent occipitotemporal regions, task coding information was increased during task switching. Effective connectivity analysis revealed that the frontal regions signaled toward the modality-dependent occipitotemporal regions when a relevant stimulus was more ambiguous, whereas the occipitotemporal regions signaled toward the frontal regions when the stimulus was more distinctive. These results suggest that complementary prefrontal mechanisms in the left and right hemispheres help to achieve a behavioral goal when the external environment involves perceptual uncertainty.SIGNIFICANCE STATEMENT In our daily life, environmental information to achieve a goal is not always certain, but we make judgments in such situations, and change our behavior accordingly. This study examined how the flexibility of behavior is achieved in a situation where goal-relevant information involves perceptual uncertainty. fMRI revealed that the lateral prefrontal cortex (PFC) in the left hemisphere is associated with behavioral flexibility, and the perception of ambiguous stimuli involves the PFC in the right hemisphere. These bilateral PFC signaled to stimulus-modality-dependent occipitotemporal regions, depending on perceptual uncertainty and the task to be performed. These top-down signals supplement task coding in the occipitotemporal regions, and highlight interhemispheric prefrontal mechanisms involved in executive control and perceptual decision-making.

Executive control by fronto-parietal activity explains counterintuitive decision behavior in complex value-based decision-making.

In real life, humans make decisions by taking into account multiple independent factors, such as delay and probability. Cognitive psychology suggests that cognitive control mechanisms play a key role when facing such complex task conditions. However, in value-based decision-making, it still remains unclear to what extent cognitive control mechanisms become essential when the task condition is complex. In this study, we investigated decision-making behaviors and underlying neural mechanisms using a multifactor gambling task where participants simultaneously considered probability and delay. Decision-making behavior in the multifactor task was modulated by both probability and delay. The behavioral effect of probability was stronger than delay, consistent with previous studies. Furthermore, in a subset of conditions that recruited fronto-parietal activations, reaction times were paradoxically elongated despite lower probabilistic uncertainty. Notably, such a reaction time elongation did not occur in control tasks involving single factors. Meta-analysis of brain activations suggested an interpretation that the paradoxical increase of reaction time may be associated with strategy switching. Consistent with this interpretation, logistic regression analysis of the behavioral data suggested a presence of multiple decision strategies. Taken together, we found that a novel complex value-based decision-making task cause prominent activations in fronto-parietal cortex. Furthermore, we propose that these activations can be interpreted as recruitment of cognitive control system in complex situations.

Self-Controlled Choice Arises from Dynamic Prefrontal Signals That Enable Future Anticipation.

Self-control allows humans the patience necessary to maximize reward attainment in the future. Yet it remains elusive when and how the preference to self-controlled choice is formed. We measured brain activity while female and male humans performed an intertemporal choice task in which they first received delayed real liquid rewards (forced-choice trial), and then made a choice between the reward options based on the experiences (free-choice trial). We found that, while subjects were awaiting an upcoming reward in the forced-choice trial, the anterior prefrontal cortex (aPFC) tracked a dynamic signal reflecting the pleasure of anticipating the future reward. Importantly, this prefrontal signal was specifically observed in self-controlled individuals, and moreover, interregional negative coupling between the prefrontal region and the ventral striatum (VS) became stronger in those individuals. During consumption of the liquid rewards, reduced ventral striatal activity predicted self-controlled choices in the subsequent free-choice trials. These results suggest that a well-coordinated prefrontal-striatal mechanism during the reward experience shapes preferences regarding the future self-controlled choice.SIGNIFICANCE STATEMENT Anticipating future desirable events is a critical mental function that guides self-controlled behavior in humans. When and how are the self-controlled choices formed in the brain? We monitored brain activity while humans awaited a real liquid reward that became available in tens of seconds. We found that the frontal polar cortex tracked temporally evolving signals reflecting the pleasure of anticipating the future reward, which was enhanced in self-controlled individuals. Our results highlight the contribution of the fronto-polar cortex to the formation of self-controlled preferences, and further suggest that future prospect in the prefrontal cortex (PFC) plays an important role in shaping future choice behavior.

Neural signals in amygdala predict implicit prejudice toward an ethnic outgroup.

Racial and ethnic prejudice is one of the most pressing problems in modern societies. Although previous social neuroscience research has suggested the amygdala as a key structure in racial prejudice, it still remains elusive whether the amygdala activity reflects negative attitudes toward an outgroup or other unrelated processes. The present study aims to rigorously test the role of the amygdala in negative prejudice toward an outgroup. Seventy Japanese individuals passively viewed images related to an ethnic outgroup (South Korea) inside a functional magnetic resonance imaging scanner. Using Multi-Voxel Pattern Analysis (MVPA), we found that Japanese individuals' level of implicit (but not explicit) evaluations of South Korea could be predicted from neural signals in the left amygdala. Our result further suggested that the medial and lateral parts of amygdala play different roles in implicit evaluations. In contrast to the MVPA findings, conventional univariate analyses failed to find any reliable relationship between brain activation and both implicit and explicit evaluations. Our findings provide evidence for the amygdala's role in representing an implicit form of prejudice and highlight the utility of the multivariate approach to reveal neural signatures of this complex social phenomenon.

The Stroop effect involves an excitatory-inhibitory fronto-cerebellar loop.

The Stroop effect is a classical, well-known behavioral phenomenon in humans that refers to robust interference between language and color information. It remains unclear, however, when the interference occurs and how it is resolved in the brain. Here we show that the Stroop effect occurs during perception of color-word stimuli and involves a cross-hemispheric, excitatory-inhibitory loop functionally connecting the lateral prefrontal cortex and cerebellum. Participants performed a Stroop task and a non-verbal control task (which we term the Swimmy task), and made a response vocally or manually. The Stroop effect involved the lateral prefrontal cortex in the left hemisphere and the cerebellum in the right hemisphere, independently of the response type; such lateralization was absent during the Swimmy task, however. Moreover, the prefrontal cortex amplified cerebellar activity, whereas the cerebellum suppressed prefrontal activity. This fronto-cerebellar loop may implement language and cognitive systems that enable goal-directed behavior during perceptual conflicts.

Decoding distributed oscillatory signals driven by memory and perception in the prefrontal cortex.

Sensory perception and memory recall generate different conscious experiences. Although externally and internally driven neural activities signifying the same perceptual content overlap in the sensory cortex, their distribution in the prefrontal cortex (PFC), an area implicated in both perception and memory, remains elusive. Here, we test whether the local spatial configurations and frequencies of neural oscillations driven by perception and memory recall overlap in the macaque PFC using high-density electrocorticography and multivariate pattern analysis. We find that dynamically changing oscillatory signals distributed across the PFC in the delta-, theta-, alpha-, and beta-band ranges carry significant, but mutually different, information predicting the same feature of memory-recalled internal targets and passively perceived external objects. These findings suggest that the frequency-specific distribution of oscillatory neural signals in the PFC serves cortical signatures responsible for distinguishing between different types of cognition driven by external perception and internal memory.

Functional heterogeneity in the left lateral posterior parietal cortex during visual and haptic crossmodal dot-surface matching.

BACKGROUND: Vision and touch are thought to contribute information to object perception in an independent but complementary manner. The left lateral posterior parietal cortex (LPPC) has long been associated with multisensory information processing, and it plays an important role in visual and haptic crossmodal information retrieval. However, it remains unclear how LPPC subregions are involved in visuo-haptic crossmodal retrieval processing. METHODS: In the present study, we used an fMRI experiment with a crossmodal delayed match-to-sample paradigm to reveal the functional role of LPPC subregions related to unimodal and crossmodal dot-surface retrieval. RESULTS: The visual-to-haptic condition enhanced the activity of the left inferior parietal lobule relative to the haptic unimodal condition, whereas the inverse condition enhanced the activity of the left superior parietal lobule. By contrast, activation of the left intraparietal sulcus did not differ significantly between the crossmodal and unimodal conditions. Seed-based resting connectivity analysis revealed that these three left LPPC subregions engaged distinct networks, confirming their different functions in crossmodal retrieval processing. CONCLUSION: Taken together, the findings suggest that functional heterogeneity of the left LPPC during visuo-haptic crossmodal dot-surface retrieval processing reflects that the left LPPC does not simply contribute to retrieval of past information; rather, each subregion has a specific functional role in resolving different task requirements.

Elucidating the role of the posterior medial frontal cortex in social conflict processing.

A fundamental function of the brain is learning via new information. Studies investigating the neural basis of information-based learning processes indicate an important role played by the posterior medial frontal cortex (pMFC) in representing conflict between an individual's expectation and new information. However, specific function of the pMFC in this process remains relatively indistinct. Particularly, it's unclear whether the pMFC plays a role in the detection of conflict of incoming information, or the update of their belief after new information is provided. In an fMRI scanner, twenty-eight Japanese students viewed scenarios depicting various pro-social/anti-social behaviors. Participants rated how likely Japanese and South Korean students would perform each behavior, followed by feedback of the actual likelihood. They were then asked to rerate the scenarios after the fMRI session. Participants updated their second estimates based on feedback, with estimate changes more pronounced for favorable feedback (e.g., higher likelihood of pro-social behavior than expected) despite nationality, indicating participants were willing to view other people favorably. The fMRI results demonstrated activity in a part of the pMFC, the dorsomedial prefrontal cortex (dmPFC), was correlated with social conflict (difference between participant's estimate and actual likelihood), but not the corresponding belief update. Importantly, activity in a different part within the dmPFC was more sensitive to unfavorable trials compared to favorable trials. These results indicate sensitivity in the pMFC (at least within the dmPFC) relates to conflict between desirable outcomes versus reality, as opposed to the associated update of belief.

Functional magnetic resonance imaging of macaque monkeys performing visually guided saccade tasks: comparison of cortical eye fields with humans.

The frontal and parietal eye fields serve as functional landmarks of the primate brain, although their correspondences between humans and macaque monkeys remain unclear. We conducted fMRI at 4.7 T in monkeys performing visually-guided saccade tasks and compared brain activations with those in humans using identical paradigms. Among multiple parietal activations, the dorsal lateral intraparietal area in monkeys and an area in the posterior superior parietal lobule in humans exhibited the highest selectivity to saccade directions. In the frontal cortex, the selectivity was highest at the junction of the precentral and superior frontal sulci in humans and in the frontal eye field (FEF) in monkeys. BOLD activation peaks were also found in premotor areas (BA6) in monkeys, which suggests that the apparent discrepancy in location between putative human FEF (BA6, suggested by imaging studies) and monkey FEF (BA8, identified by microstimulation studies) partly arose from methodological differences.

Exploring the neural basis of cognition: multi-modal links between human fMRI and macaque neurophysiology.

Although functional magnetic resonance imaging (fMRI) with sophisticated behavioral paradigms has enabled the investigation of increasingly higher-level cognitive functions in humans, these studies seem to lose touch with neurophysiological studies in macaque monkeys. The application of fMRI and other MRI-based techniques to macaque brains allows studies in the two species to be linked. fMRI in human and macaque subjects using equivalent cognitive tasks enables direct comparisons of the functional brain architecture, even for high-level cognitive functions. Combinations of functional or structural MRI and microelectrode techniques provide ways to explore functional brain networks at multiple spatiotemporal scales. These approaches would illuminate the neurophysiological underpinnings of human cognitive functions by integrating human functional neuroimaging with macaque single-unit recordings.

Large-scale network integration in the human brain tracks temporal fluctuations in memory encoding performance.

Although activation/deactivation of specific brain regions has been shown to be predictive of successful memory encoding, the relationship between time-varying large-scale brain networks and fluctuations of memory encoding performance remains unclear. Here, we investigated time-varying functional connectivity patterns across the human brain in periods of 30-40 s, which have recently been implicated in various cognitive functions. During functional magnetic resonance imaging, participants performed a memory encoding task, and their performance was assessed with a subsequent surprise memory test. A graph analysis of functional connectivity patterns revealed that increased integration of the subcortical, default-mode, salience, and visual subnetworks with other subnetworks is a hallmark of successful memory encoding. Moreover, multivariate analysis using the graph metrics of integration reliably classified the brain network states into the period of high (vs. low) memory encoding performance. Our findings suggest that a diverse set of brain systems dynamically interact to support successful memory encoding.

Visual perceptual training reconfigures post-task resting-state functional connectivity with a feature-representation region.

The neural mechanisms underlying visual perceptual learning (VPL) have typically been studied by examining changes in task-related brain activation after training. However, the relationship between post-task "offline" processes and VPL remains unclear. The present study examined this question by obtaining resting-state functional magnetic resonance imaging (fMRI) scans of human brains before and after a task-fMRI session involving visual perceptual training. During the task-fMRI session, participants performed a motion coherence discrimination task in which they judged the direction of moving dots with a coherence level that varied between trials (20, 40, and 80%). We found that stimulus-induced activation increased with motion coherence in the middle temporal cortex (MT+), a feature-specific region representing visual motion. On the other hand, stimulus-induced activation decreased with motion coherence in the dorsal anterior cingulate cortex (dACC) and bilateral insula, regions involved in decision making under perceptual ambiguity. Moreover, by comparing pre-task and post-task rest periods, we revealed that resting-state functional connectivity (rs-FC) with the MT+ was significantly increased after training in widespread cortical regions including the bilateral sensorimotor and temporal cortices. In contrast, rs-FC with the MT+ was significantly decreased in subcortical regions including the thalamus and putamen. Importantly, the training-induced change in rs-FC was observed only with the MT+, but not with the dACC or insula. Thus, our findings suggest that perceptual training induces plastic changes in offline functional connectivity specifically in brain regions representing the trained visual feature, emphasising the distinct roles of feature-representation regions and decision-related regions in VPL.

Locally induced neuronal synchrony precisely propagates to specific cortical areas without rhythm distortion.

Propagation of oscillatory spike firing activity at specific frequencies plays an important role in distributed cortical networks. However, there is limited evidence for how such frequency-specific signals are induced or how the signal spectra of the propagating signals are modulated during across-layer (radial) and inter-areal (tangential) neuronal interactions. To directly evaluate the direction specificity of spectral changes in a spiking cortical network, we selectively photostimulated infragranular excitatory neurons in the rat primary visual cortex (V1) at a supra-threshold level with various frequencies, and recorded local field potentials (LFPs) at the infragranular stimulation site, the cortical surface site immediately above the stimulation site in V1, and cortical surface sites outside V1. We found a significant reduction of LFP powers during radial propagation, especially at high-frequency stimulation conditions. Moreover, low-gamma-band dominant rhythms were transiently induced during radial propagation. Contrastingly, inter-areal LFP propagation, directed to specific cortical sites, accompanied no significant signal reduction nor gamma-band power induction. We propose an anisotropic mechanism for signal processing in the spiking cortical network, in which the neuronal rhythms are locally induced/modulated along the radial direction, and then propagate without distortion via intrinsic horizontal connections for spatiotemporally precise, inter-areal communication.

Altered KYN/TRP, Gln/Glu, and Met/methionine sulfoxide ratios in the blood plasma of medication-free patients with major depressive disorder.

Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS) is a comprehensive, quantitative, and high throughput tool used to analyze metabolite profiles. In the present study, we used CE-TOFMS to profile metabolites found in the blood plasma of 33 medication-free patients with major depressive disorder (MDD) and 33 non-psychiatric control subjects. We then investigated changes which occurred in the metabolite levels during an 8-week treatment period. The medication-free MDD patients and control subjects showed significant differences in their mean levels of 33 metabolites, including kynurenine (KYN), glutamate (Glu), glutamine (Gln), methionine sulfoxide, and methionine (Met). In particular, the ratios of KYN to tryptophan (TRP), Gln to Glu, and Met to methionine sulfoxide were all significantly different between the two groups. Among the 33 metabolites with altered levels in MDD patients, the levels of KYN and Gln, as well as the ratio of Gln to Glu, were significantly normalized after treatment. Our findings suggest that imbalances in specific metabolite levels may be involved in the pathogenesis of MDD, and provide insight into the mechanisms by which antidepressant agents work in MDD patients.

Associative-memory representations emerge as shared spatial patterns of theta activity spanning the primate temporal cortex.

Highly localized neuronal spikes in primate temporal cortex can encode associative memory; however, whether memory formation involves area-wide reorganization of ensemble activity, which often accompanies rhythmicity, or just local microcircuit-level plasticity, remains elusive. Using high-density electrocorticography, we capture local-field potentials spanning the monkey temporal lobes, and show that the visual pair-association (PA) memory is encoded in spatial patterns of theta activity in areas TE, 36, and, partially, in the parahippocampal cortex, but not in the entorhinal cortex. The theta patterns elicited by learned paired associates are distinct between pairs, but similar within pairs. This pattern similarity, emerging through novel PA learning, allows a machine-learning decoder trained on theta patterns elicited by a particular visual item to correctly predict the identity of those elicited by its paired associate. Our results suggest that the formation and sharing of widespread cortical theta patterns via learning-induced reorganization are involved in the mechanisms of associative memory representation.

A rapid presentation event-related functional magnetic resonance imaging study of response inhibition in macaque monkeys.

Rapid presentation event-related functional magnetic resonance imaging was applied to macaque monkeys performing a symmetrically rewarded go/no-go task, to investigate neural correlate of response inhibition. Sensorimotor activation related to the task performance was observed predominantly in the hemisphere contralateral to the response forelimb. Furthermore, no-go dominant activation possibly related to response inhibition, was observed in the ventral prefrontal cortex, in accordance with previous electrophysiological studies. These results show the feasibility of rapid presentation event-related functional magnetic resonance imaging in behaving monkeys.

Intrasulcal electrocorticography in macaque monkeys with minimally invasive neurosurgical protocols.

Electrocorticography (ECoG), multichannel brain-surface recording and stimulation with probe electrode arrays, has become a potent methodology not only for clinical neurosurgery but also for basic neuroscience using animal models. The highly evolved primate's brain has deep cerebral sulci, and both gyral and intrasulcal cortical regions have been implicated in important functional processes. However, direct experimental access is typically limited to gyral regions, since placing probes into sulci is difficult without damaging the surrounding tissues. Here we describe a novel methodology for intrasulcal ECoG in macaque monkeys. We designed and fabricated ultra-thin flexible probes for macaques with micro-electro-mechanical systems technology. We developed minimally invasive operative protocols to implant the probes by introducing cutting-edge devices for human neurosurgery. To evaluate the feasibility of intrasulcal ECoG, we conducted electrophysiological recording and stimulation experiments. First, we inserted parts of the Parylene-C-based probe into the superior temporal sulcus to compare visually evoked ECoG responses from the ventral bank of the sulcus with those from the surface of the inferior temporal cortex. Analyses of power spectral density and signal-to-noise ratio revealed that the quality of the ECoG signal was comparable inside and outside of the sulcus. Histological examination revealed no obvious physical damage in the implanted areas. Second, we placed a modified silicone ECoG probe into the central sulcus and also on the surface of the precentral gyrus for stimulation. Thresholds for muscle twitching were significantly lower during intrasulcal stimulation compared to gyral stimulation. These results demonstrate the feasibility of intrasulcal ECoG in macaques. The novel methodology proposed here opens up a new frontier in neuroscience research, enabling the direct measurement and manipulation of electrical activity in the whole brain.