Diurnal Variation of Brain Activity in the Human Suprachiasmatic Nucleus.

The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, we localized the SCN by employing an areal boundary mapping technique to resting-state functional images and investigated the SCN activity using perfusion imaging. In the first experiment (n = 27, including both sexes), we scanned each participant four times a day, every 6 h. Higher activity was observed at noon, while lower activity was recorded in the early morning. In the second experiment (n = 20, including both sexes), the SCN activity was measured every 30 min for 6 h from midnight to dawn. The results showed that the SCN activity gradually decreased and was not associated with the electroencephalography. Furthermore, the SCN activity was compatible with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of nocturnal and diurnal mammals and is modulated by physical lights rather than the local time.

Reduced gray matter volume in the default-mode network associated with insulin resistance.

Insulin resistance may lead to structural and functional abnormalities of the human brain. However, the mechanism by which insulin resistance impairs the brain remains elusive. In this study, we used two large neuroimaging databases to investigate the brain regions where insulin resistance was associated with the gray matter volume and to examine the resting-state functional connectivity between these brain regions and each hypothalamic nucleus. Insulin resistance was associated with reduced gray matter volume in the regions of the default-mode and limbic networks in the cerebral cortex in older adults. Resting-state functional connectivity was prominent between these networks and the paraventricular nucleus of the hypothalamus, a hypothalamic interface connecting functionally with the cerebral cortex. Furthermore, we found a significant correlation in these networks between insulin resistance-related gray matter volume reduction and network paraventricular nucleus of the hypothalamus resting-state functional connectivity. These results suggest that insulin resistance-related gray matter volume reduction in the default-mode and limbic networks emerged through metabolic homeostasis mechanisms in the hypothalamus.

Neural Basis of Social Influence of Observing Other's Perception in Dot-Number Estimation.

Our perceptions and decisions are often implicitly influenced by observing another's actions. However, it is unclear how observing other people's perceptual decisions without interacting with them can engage the processing of self-other discrepancies and change the observer's decisions. In this study, we employed functional magnetic resonance imaging and a computational model to investigate the neural basis of how unilaterally observing the other's perceptual decisions modulated one's own decisions. The experimental task was to discriminate whether the number of presented dots was higher or lower than a reference number. The participants performed the task solely while unilaterally observing the performance of another "participant," who produced overestimations and underestimations in the same task in separate sessions. Results of the behavioral analysis showed that the participants' decisions were modulated to resemble those of the other. Image analysis based on computational model revealed that the activation in the medial prefrontal cortex was associated with the discrepancy between the inferred participant's and the presented other's decisions. In addition, the number-sensitive region in the superior parietal region showed altered activation patterns after observing the other's overestimations and underestimations. The activity of the superior parietal region was not involved in assessing the observation of other's perceptual decisions, but it was engaged in plain numerosity perception. These results suggest that computational modeling can capture the neuro-behavioral processing of self-other discrepancies in perception followed by the activity modulation in the number-sensitive region in the task of dot-number estimation.

Role of right temporoparietal junction for counterfactual evaluation of partner's decision in ultimatum game.

Humans assess the distributions of resources based on their aversion to unfairness. If a partner distributes in an unfair manner even though the partner had a less unfair distribution option, a recipient will believe that the partner should have chosen the counterfactual option. In this study, we investigated the neural basis for fairness evaluation of actual and counterfactual options in the ultimatum game. In this task, a partner chose one distribution option out of two options, and a participant accepted or rejected the option. The behavioral results showed that the acceptance rate was influenced by counterfactual evaluation (CE), among others, as defined by the difference of monetary amount between the actual and counterfactual options. The functional magnetic resonance imaging results showed that CE was associated with the right ventral angular gyrus (vAG) that provided one of convergent inputs to the supramarginal gyrus related to decision utility, which reflects gross preferences for the distribution options. Furthermore, inhibitory repetitive transcranial magnetic stimulation administered to the right vAG reduced the behavioral component associated with CE. These results suggest that our acceptance/rejection of distribution options relies on multiple processes (monetary amount, disadvantageous inequity, and CE) and that the right vAG causally contributes to CE.

Behavioral and neuro-cognitive bases for emergence of norms and socially shared realities via dynamic interaction.

In the digital era, new socially shared realities and norms emerge rapidly, whether they are beneficial or harmful to our societies. Although these are emerging properties from dynamic interaction, most research has centered on static situations where isolated individuals face extant norms. We investigated how perceptual norms emerge endogenously as shared realities through interaction, using behavioral and fMRI experiments coupled with computational modeling. Social interactions fostered convergence of perceptual responses among people, not only overtly but also at the covert psychophysical level that generates overt responses. Reciprocity played a critical role in increasing the stability (reliability) of the psychophysical function within each individual, modulated by neural activity in the mentalizing network during interaction. These results imply that bilateral influence promotes mutual cognitive anchoring of individual views, producing shared generative models at the collective level that enable endogenous agreement on totally new targets-one of the key functions of social norms.

Hypothalamic interaction with reward-related regions during subjective evaluation of foods.

The reward system implemented in the midbrain, ventral striatum, orbitofrontal cortex, and ventromedial prefrontal cortex evaluates and compares various types of rewards given to the organisms. It has been suggested that autonomic factors influence reward-related processing via the hypothalamus, but how the hypothalamus modulates the reward system remains elusive. In this functional magnetic resonance imaging study, the hypothalamus was parcellated into individual hypothalamic nuclei performing different autonomic functions using boundary mapping parcellation analyses. The effective interaction during subjective evaluation of foods in a reward task was then investigated between the human hypothalamic nuclei and the reward-related regions. We found significant brain activity decrease in the paraventricular nucleus (PVH) and lateral nucleus in the hypothalamus in food evaluation compared with monetary evaluation. A psychophysiological interaction analysis revealed dual interactions between the PVH and (1) midbrain region and (2) ventromedial prefrontal cortex, with the former correlated with the stronger tendency of participants toward food-seeking. A dynamic causal modeling analysis further revealed unidirectional interactions from the PVH to the midbrain and ventromedial prefrontal cortex. These results suggest that the PVH in the human hypothalamus interacts with the reward-related regions in the cerebral cortex via multiple pathways (i.e., the midbrain pathway and ventromedial prefrontal pathway) to evaluate rewards for subsequent decision-making.

A causal role of anterior prefrontal-putamen circuit for response inhibition revealed by transcranial ultrasound stimulation in humans.

Stopping an inappropriate response requires the involvement of the prefrontal-subthalamic hyperdirect pathway. However, how the prefrontal-striatal indirect pathway contributes to stopping is poorly understood. In this study, transcranial ultrasound stimulation is used to perform interventions in a task-related region in the striatum. Functional magnetic resonance imaging (MRI) reveals activation in the right anterior part of the putamen during response inhibition, and ultrasound stimulation to the anterior putamen, as well as the subthalamic nucleus, results in significant impairments in stopping performance. Diffusion imaging further reveals prominent structural connections between the anterior putamen and the right anterior part of the inferior frontal cortex (IFC), and ultrasound stimulation to the anterior IFC also shows significant impaired stopping performance. These results demonstrate that the right anterior putamen and right anterior IFC causally contribute to stopping and suggest that the anterior IFC-anterior putamen circuit in the indirect pathway serves as an essential route for stopping.

Parallel cognitive processing streams in human prefrontal cortex: Parsing areal-level brain network for response inhibition.

Multiple cognitive processes are recruited to achieve adaptive behavior. However, it is poorly understood how such cognitive processes are implemented in temporal cascades of human cerebral cortical areas as processing streams to achieve behavior. In the present study, we identify cortical processing streams for response inhibition and examine relationships among the processing streams. Functional magnetic resonance imaging (MRI) and time-resolved single-pulse transcranial magnetic stimulation (TMS) reveal three distinct critical timings of transient disruption in the functionally essential cortical areas that belong to two distinct cerebrocortical networks. Furthermore, single-pulse TMS following suppression of the ventral posterior inferior frontal cortex (vpIFC) with repetitive TMS reveals information flow from the vpIFC to the presupplementary motor area (preSMA) within the same network but not to the dorsal posterior inferior frontal cortex (dpIFC) across different networks. These causal behavioral effects suggest two parallel processing streams (vpIFC-preSMA versus dpIFC-intraparietal sulcus) that act concurrently during response inhibition.

Time-varying measures of cerebral network centrality correlate with visual saliency during movie watching.

The extensive development of graph-theoretic analysis for functional connectivity has revealed the multifaceted characteristics of brain networks. Network centralities identify the principal functional regions, individual differences, and hub structure in brain networks. Neuroimaging studies using movie-watching have investigated brain function under naturalistic stimuli. Visual saliency is one of the promising measures for revealing cognition and emotions driven by naturalistic stimuli. This study investigated whether the visual saliency in movies was associated with network centrality. The study examined eigenvector centrality (EC), which is a measure of a region's influence in the brain network, and the participation coefficient (PC), which reflects the hub structure in the brain, was used for comparison. Static and time-varying EC and PC were analyzed by a parcel-based technique. While EC was correlated with brain activity in parcels in the visual and auditory areas during movie-watching, it was only correlated with parcels in the visual areas in the retinotopy task. In addition, high PC was consistently observed in parcels in the putative hub both during the tasks and the resting-state condition. Time-varying EC in the parietal parcels and time-varying PC in the primary sensory parcels significantly correlated with visual saliency in the movies. These results suggest that time-varying centralities in brain networks are distinctively associated with perceptual processing and subsequent higher processing of visual saliency.

Connectivity-based localization of human hypothalamic nuclei in functional images of standard voxel size.

Despite their critical roles in autonomic functions, individual hypothalamic nuclei have not been extensively investigated in humans using functional magnetic resonance imaging, partly due to the difficulty in resolving individual nuclei contained in the small structure of the hypothalamus. Areal parcellation analyses enable discrimination of individual hypothalamic nuclei but require a higher spatial resolution, which necessitates long scanning time or large amounts of data to compensate for the low signal-to-noise ratio in 3T or 1.5T scanners. In this study, we present analytic procedures to estimate likely locations of individual nuclei in the standard 2-mm resolution based on our higher resolution dataset. The spatial profiles of functional connectivity with the cerebral cortex for each nucleus in the medial hypothalamus were calculated using our higher resolution dataset. Voxels in the hypothalamus in standard resolution images from the Human Connectome Project (HCP) database that predominantly shared connectivity profiles with the same nucleus were subsequently identified. Voxels representing individual nuclei, as identified with the analytic procedures, were reproducible across 20 HCP datasets of 20 subjects each. Furthermore, the identified voxels were spatially separate. These results suggest that these analytic procedures are capable of refining voxels that represent individual hypothalamic nuclei in standard resolution. Our results highlight the potential utility of these procedures in various settings such as patient studies, where lengthy scans are infeasible.

Functional Organization for Response Inhibition in the Right Inferior Frontal Cortex of Individual Human Brains.

The right inferior frontal cortex (IFC) is critical to response inhibition. The right IFC referred in the human studies of response inhibition is located in the posterior part of the inferior frontal gyrus and the surrounding regions and consists of multiple areas that implement distinct functions. Recent studies using resting-state functional connectivity have parcellated the cerebral cortex and revealed across-subject variability of parcel-based cerebrocortical networks. However, how the right IFC of individual brains is functionally organized and what functional properties the IFC parcels possess regarding response inhibition remain elusive. In the present functional magnetic resonance imaging study, precision functional mapping of individual human brains was adopted to the parcels in the right IFC to evaluate their functional properties related to response inhibition. The right IFC consisted of six modules or subsets of subregions, and the spatial organization of the modules varied considerably across subjects. Each module revealed unique characteristics of brain activity and its correlation to behavior related to response inhibition. These results provide updated functional features of the IFC and demonstrate the importance of individual-focused approaches in studying response inhibition in the right IFC.

Dissociable Networks of the Lateral/Medial Mammillary Body in the Human Brain.

The mammillary body (MB) has been thought to implement mnemonic functions. Although recent animal studies have revealed dissociable roles of the lateral and medial parts of the MB, the dissociable roles of the lateral/medial MB in the human brain is still unclear. Functional connectivity using resting-state functional magnetic resonance imaging (fMRI) provides a unique opportunity to noninvasively inspect the intricate functional organization of the human MB with a high degree of spatial resolution. The present study divided the human MB into lateral and medial parts and examined their functional connectivity with the hippocampal formation, tegmental nuclei, and anterior thalamus. The subiculum of the hippocampal formation was more strongly connected with the medial part than with the lateral part of the MB, whereas the pre/parasubiculum was more strongly connected with the lateral part than with the medial part of the MB. The dorsal tegmental nucleus was connected more strongly with the lateral part of the MB, whereas the ventral tegmental nucleus showed an opposite pattern. The anterior thalamus was connected more strongly with the medial part of the MB. These results confirm the extant animal literature on the lateral/medial MB and provide evidence on the parallel but dissociable systems involving the MB that ascribe mnemonic and spatial-navigation functions to the medial and lateral MBs, respectively.

Network Centrality Reveals Dissociable Brain Activity during Response Inhibition in Human Right Ventral Part of Inferior Frontal Cortex.

The human right inferior frontal cortex (IFC) plays a critical role in response inhibition. It has also been demonstrated that the IFC is heterogeneous and that the ventral part of the IFC (vIFC) is more critical to inhibition of prepotent response tendency. Recent areal parcellation analyses based on resting-state functional connectivity have revealed that the right vIFC consists of multiple functional areas. In the present study, we characterized the parcellated areas (parcels) in the right vIFC using graph theory analysis, which characterizes local connectivity properties of a brain network by referring to its global structure of functional connectivity. Functional magnetic resonance imaging (MRI) scans were obtained during performance of a stop-signal task and during resting state. The cerebral cortex was parcellated into areas using resting-state functional connectivity. The parcels were then subjected to graph theory analysis to reveal central areas. Two parcels, ventral and dorsal, in the posterior part of the vIFC, exhibited significant brain activity during response inhibition. The ventral parcel exhibited a positive correlation between betweenness centrality and brain activity while the dorsal parcel did not. Correlations were significantly stronger in the ventral parcel. Moreover, the ventral parcel exhibited a negative correlation between brain activity during response inhibition and stop-signal reaction time (SSRT), a behavioral measure used to evaluate stopping performance. These dissociation results suggest that the ventral region in the vIFC plays a more central role in the brain network by increasing brain activity, which may further predict better performance of response inhibition.

Dissociable roles of left and right temporoparietal junction in strategic competitive interaction.

Although many studies have shown that the temporoparietal junction (TPJ) is involved in inferring others' beliefs, neural correlates of 'second-order' inferences (inferring another's inference about one's own belief) are still elusive. Here we report a functional magnetic resonance imaging experiment to examine the involvement of TPJ for second-order inferences. Participants played an economic game with three types of opponents: a human opponent outside the scanner, an artificial agent that followed a fixed probabilistic strategy according to a game-theoretic solution (FIX) and an artificial agent that adjusted its choices through a machine-learning algorithm (LRN). Participants' choice behaviors against the human opponent and LRN were similar but remarkably different from those against FIX. The activation of the left TPJ (LTPJ) was correlated with choice behavior against the human opponent and LRN but not against FIX. The overall activity pattern of the LTPJ for the human opponent was also similar to that for LRN but not for FIX. In contrast, the right TPJ (RTPJ) showed higher activation for the human opponent than FIX and LRN. These results suggest that, while the RTPJ is associated with the perception of human agency, the LTPJ is involved in second-order inferences in strategic decision making.

MRI-based visualization of rTMS-induced cortical plasticity in the primary motor cortex.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in cortical excitability for minutes to hours after the end of intervention. However, it has not been precisely determined to what extent cortical plasticity prevails spatially in the cortex. Recent studies have shown that rTMS induces changes in "interhemispheric" functional connectivity, the resting-state functional connectivity between the stimulated region and the symmetrically corresponding region in the contralateral hemisphere. In the present study, quadripulse stimulation (QPS) was applied to the index finger representation in the left primary motor cortex (M1), while the position of the stimulation coil was constantly monitored by an online navigator. After QPS application, resting-state functional magnetic resonance imaging was performed, and the interhemispheric functional connectivity was compared with that before QPS. A cluster of connectivity changes was observed in the stimulated region in the central sulcus. The cluster was spatially extended approximately 10 mm from the center [half width at half maximum (HWHM): approximately 3 mm] and was extended approximately 20 mm long in depth (HWHM: approximately 7 mm). A localizer scan of the index finger motion confirmed that the cluster of interhemispheric connectivity changes overlapped spatially with the activation related to the index finger motion. These results indicate that cortical plasticity in M1 induced by rTMS was relatively restricted in space and suggest that rTMS can reveal functional dissociation associated with adjacent small areas by inducing neural plasticity in restricted cortical regions.

More subjects are required for ventrolateral than dorsolateral prefrontal TMS because of intolerability and potential drop-out.

Transcranial magnetic stimulation (TMS) of the human lateral prefrontal cortex, particularly the ventral region, often causes considerable discomfort to subjects. To date, in contrast to abundant literature on stimulations to the dorsolateral prefrontal cortex, the ventrolateral prefrontal cortex has been less frequently stimulated, partly because some subjects are intolerable of stimulation to the ventrolateral prefrontal cortex. To predict the additional number of subjects required for the stimulation of the dorsolateral and ventrolateral prefrontal cortices, 20 young healthy subjects reported two evaluation scores: the discomfort caused by TMS and the resulting intolerability to complete the TMS experiments. Single-pulse stimulation (SPS) or theta-burst stimulation (TBS) was administered to the lateral prefrontal cortex. The high-resolution extended 10-20 system was used to provide accurate estimation of the voxelwise scores. The discomfort ratings with the SPS and TBS were relatively higher in the ventrolateral prefrontal cortex than those in the dorsolateral prefrontal cortex. Both the SPS and TBS elicited maximal discomfort at the stimulation position F8. The SPS and TBS to F8 under the standard TMS protocols were intolerable for approximately one half (11 and 10, respectively) of the subjects. The intolerability was further calculated for all voxels in the lateral prefrontal cortex, which enabled us to estimate the additional number of subjects required for specific target areas. These results suggest that prior knowledge of subjects' discomfort during stimulation of the lateral prefrontal cortex can be of practical use in the experimental planning of the appropriate number of recruited subjects and provide the database for the probability of intolerability that can be used to predict the additional number of subjects.

An Essential Role of the Intraparietal Sulcus in Response Inhibition Predicted by Parcellation-Based Network.

The posterior parietal cortex (PPC) features close anatomical and functional relationships with the prefrontal cortex. However, the necessity of the PPC in executive functions has been questioned. The present study used the stop-signal task to examine response inhibition, an executive function that inhibits prepotent response tendency. The brain activity and resting-state functional connectivity were measured to analyze a parcellation-based network that was aimed at identifying a candidate PPC region essential for response inhibition in humans. The intraparietal sulcus (IPS) was activated during response inhibition and connected with the inferior frontal cortex and the presupplementary motor area, the two frontal regions known to be necessary for response inhibition. Next, transcranial magnetic stimulation (TMS) was used to test the essential role of the IPS region for response inhibition. TMS over the IPS region prolonged the stop-signal reaction time (SSRT), the standard behavioral index used to evaluate stopping performance, when stimulation was applied 30-0 ms before stopping. On the contrary, stimulation over the temporoparietal junction region, an area activated during response inhibition but lacking connectivity with the two frontal regions, did not show changes in SSRT. These results indicate that the IPS identified using the parcellation-based network plays an essential role in executive functions.SIGNIFICANCE STATEMENT Based on the previous neuropsychological studies reporting no impairment in executive functions after lesions in the posterior parietal cortex (PPC), the necessity of PPC in executive functions has been questioned. Here, contrary to the long-lasting view, by using recently developed analysis in functional MRI ("parcellation-based network analysis"), we identified the intraparietal sulcus (IPS) region in the PPC as essential for response inhibition: one executive function to stop actions that are inaccurate in a given context. The necessity of IPS for response inhibition was further tested by an interventional technique of transcranial magnetic stimulation. Stimulation to the IPS disrupted the performance of stopping. Our findings suggest that the IPS plays essential roles in executive functions.

Deciding for others as a neutral party recruits risk-neutral perspective-taking: Model-based behavioral and fMRI experiments.

Risky decision making for others is ubiquitous in our societies. Whereas financial decision making for oneself induces strong concern about the worst outcome (maximin concern) as well as the expected value, behavioral and neural characteristics of decision making for others are less well understood. We conducted behavioral and functional magnetic resonance imaging (fMRI) experiments to examine the neurocognitive underpinnings of risky decisions for an anonymous other, using decisions for self as a benchmark. We show that, although the maximin concern affected both types of decisions equally strongly, decision making for others recruited a more risk-neutral computational mechanism than decision making for self. Specifically, participants exhibited more balanced information search when choosing a risky option for others. Activity of right temporoparietal junction (rTPJ, associated with cognitive perspective taking) was parametrically modulated by options' expected values in decisions for others, and by the minimum amounts in decisions for self. Furthermore, individual differences in self-reported empathic concern modified these attentional and neural processes. Overall, these results indicate that the typical maximin concern is attenuated in a risk-neutral direction in decisions for others as compared to self. We conjecture that, given others' diverse preferences, deciding as a neutral party may cognitively recruit such risk-neutrality.