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.

More widespread functionality of posterior language area in patients with brain tumors.

Damage to the posterior language area (PLA), or Wernicke's area causes cortical reorganization in the corresponding regions of the contralateral hemisphere. However, the details of reorganization within the ipsilateral hemisphere are not fully understood. In this context, direct electrical stimulation during awake surgery can provide valuable opportunities to investigate neuromodulation of the human brain in vivo, which is difficult through the non-invasive approaches. Thus, in this study, we aimed to investigate the characteristics of the cortical reorganization of the PLA within the ipsilateral hemisphere. Sixty-two patients with left hemispheric gliomas were divided into groups depending on whether the lesion extended to the PLA. All patients underwent direct cortical stimulation with a picture-naming task. We further performed functional connectivity analyses using resting-state functional magnetic resonance imaging (MRI) in a subset of patients and calculated betweenness centrality, an index of the network importance of brain areas. During direct cortical stimulation, the regions showing positive (impaired) responses in the non-PLA group were localized mainly in the posterior superior temporal gyrus (pSTG), whereas those in the PLA group were widely distributed from the pSTG to the posterior supramarginal gyrus (pSMG). Notably, the percentage of positive responses in the pSMG was significantly higher in the PLA group (47%) than in the non-PLA group (8%). In network analyses of functional connectivity, the pSMG was identified as a hub region with high betweenness centrality in both the groups. These findings suggest that the language area can spread beyond the PLA to the pSMG, a hub region, in patients with lesion progression to the pSTG. The change in the pattern of the language area may be a compensatory mechanism to maintain efficient brain networks.

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.

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.

Noninvasive intervention by transcranial ultrasound stimulation: Modulation of neural circuits and its clinical perspectives.

Low-intensity focused transcranial ultrasound stimulation (TUS) is an emerging noninvasive technique capable of stimulating both the cerebral cortex and deep brain structures with high spatial precision. This method is recognized for its potential to comprehensively perturb various brain regions, enabling the modulation of neural circuits, in a manner not achievable through conventional magnetic or electrical brain stimulation techniques. The underlying mechanisms of neuromodulation are based on a phenomenon where mechanical waves of ultrasound kinetically interact with neurons, specifically affecting neuronal membranes and mechanosensitive channels. This interaction induces alterations in the excitability of neurons within the stimulated region. In this review, we briefly present the fundamental principles of ultrasound physics and the physiological mechanisms of TUS neuromodulation. We explain the experimental apparatus and procedures for TUS in humans. Due to the focality, the integration of various methods, including magnetic resonance imaging and magnetic resonance-guided neuronavigation systems, is important to perform TUS experiments for precise targeting. We then review the current state of the literature on TUS neuromodulation, with a particular focus on human subjects, targeting both the cerebral cortex and deep subcortical structures. Finally, we outline future perspectives of TUS in clinical applications in psychiatric and neurological fields.

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.

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.

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.

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.

Striatal subdivisions that coherently interact with multiple cerebrocortical networks.

The striatum constitutes the cortical-basal ganglia loop and receives input from the cerebral cortex. Previous MRI studies have parcellated the human striatum using clustering analyses of structural/functional connectivity with the cerebral cortex. However, it is currently unclear how the striatal regions functionally interact with the cerebral cortex to organize cortical functions in the temporal domain. In the present human functional MRI study, the striatum was parcellated using boundary mapping analyses to reveal the fine architecture of the striatum by focusing on local gradient of functional connectivity. Boundary mapping analyses revealed approximately 100 subdivisions of the striatum. Many of the striatal subdivisions were functionally connected with specific combinations of cerebrocortical functional networks, such as somato-motor (SM) and ventral attention (VA) networks. Time-resolved functional connectivity analyses further revealed coherent interactions of multiple connectivities between each striatal subdivision and the cerebrocortical networks (i.e., a striatal subdivision-SM connectivity and the same striatal subdivision-VA connectivity). These results suggest that the striatum contains a large number of subdivisions that mediate functional coupling between specific combinations of cerebrocortical networks.

Functional subdivisions of the hypothalamus using areal parcellation and their signal changes related to glucose metabolism.

The hypothalamus consists of numerous nuclei, and is regarded as the highest center for various autonomic functions. Although each hypothalamic nucleus implements a distinct function, it remains difficult to investigate the human hypothalamus at the nucleus level. In the present high-resolution functional MRI study, we utilized areal parcellation to discriminate individual nuclei in the human hypothalamus based on areal profiles of resting-state functional connectivity. The areal parcellation detected ten foci that were expected to represent hypothalamic nuclei, and the locations of the foci were consistent with those of the hypothalamic nuclei identified in previous histological studies. Regions of interest (ROI) analyses revealed contrasting brain activity changes following glucose ingestion: decrease in the ventromedial hypothalamic nucleus and increase in the lateral hypothalamic area in parallel with blood glucose increase. Moreover, decreased brain activity in the arcuate nucleus predicted future elevation of blood insulin during the first 10 min after glucose ingestion. These results suggest that the hypothalamic nuclei can putatively be determined using areal parcellation, and that the ROI analysis of the human hypothalamic nuclei is useful for future scientific and clinical investigations into the autonomic functions.

Effects of rTMS of pre-supplementary motor area on fronto basal ganglia network activity during stop-signal task.

Stop-signal task (SST) has been a key paradigm for probing human brain mechanisms underlying response inhibition, and the inhibition observed in SST is now considered to largely depend on a fronto basal ganglia network consisting mainly of right inferior frontal cortex, pre-supplementary motor area (pre-SMA), and basal ganglia, including subthalamic nucleus, striatum (STR), and globus pallidus pars interna (GPi). However, causal relationships between these frontal regions and basal ganglia are not fully understood in humans. Here, we partly examined these causal links by measuring human fMRI activity during SST before and after excitatory/inhibitory repetitive transcranial magnetic stimulation (rTMS) of pre-SMA. We first confirmed that the behavioral performance of SST was improved by excitatory rTMS and impaired by inhibitory rTMS. Afterward, we found that these behavioral changes were well predicted by rTMS-induced modulation of brain activity in pre-SMA, STR, and GPi during SST. Moreover, by examining the effects of the rTMS on resting-state functional connectivity between these three regions, we showed that the magnetic stimulation of pre-SMA significantly affected intrinsic connectivity between pre-SMA and STR, and between STR and GPi. Furthermore, the magnitudes of changes in resting-state connectivity were also correlated with the behavioral changes seen in SST. These results suggest a causal relationship between pre-SMA and GPi via STR during response inhibition, and add direct evidence that the fronto basal ganglia network for response inhibition consists of multiple top-down regulation pathways in humans.

Changes in cerebro-cerebellar interaction during response inhibition after performance improvement.

It has been demonstrated that motor learning is supported by the cerebellum and the cerebro-cerebellar interaction. Response inhibition involves motor responses and the higher-order inhibition that controls the motor responses. In this functional MRI study, we measured the cerebro-cerebellar interaction during response inhibition in two separate days of task performance, and detected the changes in the interaction following performance improvement. Behaviorally, performance improved in the second day, compared to the first day. The psycho-physiological interaction (PPI) analysis revealed the interaction decrease from the right inferior frontal cortex (rIFC) to the cerebellum (lobule VII or VI). It was also revealed that the interaction increased from the same cerebellar region to the primary motor area. These results suggest the involvement of the cerebellum in response inhibition, and raise the possibility that the performance improvement was supported by the changes in the cerebro-cerebellar interaction.

Network-dependent modulation of brain activity during sleep.

Brain activity dynamically changes even during sleep. A line of neuroimaging studies has reported changes in functional connectivity and regional activity across different sleep stages such as slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. However, it remains unclear whether and how the large-scale network activity of human brains changes within a given sleep stage. Here, we investigated modulation of network activity within sleep stages by applying the pairwise maximum entropy model to brain activity obtained by functional magnetic resonance imaging from sleeping healthy subjects. We found that the brain activity of individual brain regions and functional interactions between pairs of regions significantly increased in the default-mode network during SWS and decreased during REM sleep. In contrast, the network activity of the fronto-parietal and sensory-motor networks showed the opposite pattern. Furthermore, in the three networks, the amount of the activity changes throughout REM sleep was negatively correlated with that throughout SWS. The present findings suggest that the brain activity is dynamically modulated even in a sleep stage and that the pattern of modulation depends on the type of the large-scale brain networks.

Bidirectional effects on interhemispheric resting-state functional connectivity induced by excitatory and inhibitory repetitive transcranial magnetic stimulation.

Several recent studies using functional magnetic resonance imaging (fMRI) have shown that repetitive transcranial magnetic stimulation (rTMS) affects not only brain activity in stimulated regions but also resting-state functional connectivity (RSFC) between the stimulated region and other remote regions. However, these studies have only demonstrated an effect of either excitatory or inhibitory rTMS on RSFC, and have not clearly shown the bidirectional effects of both types of rTMS. Here, we addressed this issue by performing excitatory and inhibitory quadripulse TMS (QPS), which is considered to exert relatively large and long-lasting effects on cortical excitability. We found that excitatory rTMS (QPS with interstimulus intervals of 5 ms) decreased interhemispheric RSFC between bilateral primary motor cortices, whereas inhibitory rTMS (QPS with interstimulus intervals of 50 ms) increased interhemispheric RSFC. The magnitude of these effects on RSFC was significantly correlated with that of rTMS-induced effects on motor evoked potential from the corresponding muscle. The bidirectional effects of QPS were also observed in the stimulation over prefrontal and parietal association areas. These findings provide evidence for the robust bidirectional effects of excitatory and inhibitory rTMSs on RSFC, and raise a possibility that QPS can be a powerful tool to modulate RSFC.

Functional relevance of micromodules in the human association cortex delineated with high-resolution FMRI.

Recent advancement of resting-state functional connectivity magnetic resonance imaging (MRI) has provided a method for drawing boundaries of brain areas. However, it remains to be elucidated how the parcellated areas in the association cortex relate to the spatial extent of the brain activation which ought to reflect a functional unit in the neural network supporting that particular function. To address this issue, in the present study, we first mapped boundaries and 2 adjacent activations in the human inferior frontal cortex, and then examined the spatial relationship between the boundaries and the 2 activations. The boundaries mapped with high-resolution functional magnetic resonance imaging revealed a collection of micromodules, the size of which was approximately only 12 mm on average, much smaller than the Brodmann areas. Each of the 2 activations associated with 2 functions, response inhibition and feedback processing, was smaller in size than the micromodules. By comparing the spatial patterns between the boundaries and the 2 activations, it was revealed that the brain activations were less likely to be located on the boundaries. These results suggest the functional relevance of the areas in the association cortex delineated by the boundary mapping method based on resting-state functional connectivity MRI.

Efficiency of go/no-go task performance implemented in the left hemisphere.

It is well known that the efficiency of response inhibition differs from person to person, but the neural mechanism that implements the efficiency is less understood. In the present fMRI study, we devised an index to evaluate the efficiency of response inhibition in the go/no-go task, and investigated the neural correlates of the efficiency of response inhibition. The human subjects who perform the go/no-go task with a shorter reaction time in go trials (Go-RT) and with a higher percentage of correct no-go trials (Nogo-PC) are thought to have the ability to conduct response inhibition more efficiently. To quantify the efficiency, we defined an efficiency index as the difference in the Nogo-PC between each subject and an ordinarily efficient subject, under the same Go-RT. An across-subject correlation analysis revealed that the brain activity in multiple regions in the left frontal and parietal cortex positively correlated with the efficiency index. Moreover, a test of hemispheric asymmetry with regard to the across-subject correlation revealed left-hemispheric dominance. The significant correlation in the left frontal and parietal regions complements the results of previous studies that used the stop-signal reaction time (SSRT), a well known index to evaluate the efficiency of response inhibition used in the stop-signal task. Our results also indicate that, although it is well known that the neural substrates for response inhibition common in a subject group exist dominantly in the right hemisphere, the neural substrates for efficiency exist dominantly in the left hemisphere.

Functional dissociation between anterior and posterior temporal cortical regions during retrieval of remote memory.

Retrieval of remote memory is considered to differentially involve the anterior and posterior temporal neocortices. Previous neuropsychological studies suggest that the different posterior temporal cortical regions are involved in the retrieval of remote memory of different categories of stimuli, whereas the anterior region is involved more generally in remote memory retrieval. In the present study, using functional magnetic resonance imaging of human brains, we tested this dissociation by examining the more precise characteristics of the anterior and posterior temporal cortical regions. Two categories of stimuli, faces and scenes, were used for paired stimuli to be retrieved, and the brain activity during retrieval of paired stimuli that were learned immediately before the scanning was compared with that during retrieval of paired stimuli that were learned ∼8 weeks earlier. We found that the different posterior temporal cortical regions were activated during retrieval of different categories of remote memory in a category-specific manner, whereas the anterior temporal cortical region was activated during retrieval of remote memory in a category-general manner. Furthermore, by applying a multivariate pattern analysis to psychophysiological interactions during retrieval of remote memory relative to recent memory, we revealed the significant interaction from the category-specific posterior temporal cortical regions to the category-general anterior temporal region. These results suggest that the posterior temporal cortical regions are involved in representation and retrieval of category-specific remote memory, whereas the anterior cortical temporal region is involved in category-general retrieval process of remote memory.

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.

Advantages of Using Both Voxel- and Surface-based Morphometry in Cortical Morphology Analysis: A Review of Various Applications.

Surface-based morphometry (SBM) is extremely useful for estimating the indices of cortical morphology, such as volume, thickness, area, and gyrification, whereas voxel-based morphometry (VBM) is a typical method of gray matter (GM) volumetry that includes cortex measurement. In cases where SBM is used to estimate cortical morphology, it remains controversial as to whether VBM should be used in addition to estimate GM volume. Therefore, this review has two main goals. First, we summarize the differences between the two methods regarding preprocessing, statistical analysis, and reliability. Second, we review studies that estimate cortical morphological changes using VBM and/or SBM and discuss whether using VBM in conjunction with SBM produces additional values. We found cases in which detection of morphological change in either VBM or SBM was superior, and others that showed equivalent performance between the two methods. Therefore, we concluded that using VBM and SBM together can help researchers and clinicians obtain a better understanding of normal neurobiological processes of the brain. Moreover, the use of both methods may improve the accuracy of the detection of morphological changes when comparing the data of patients and controls.In addition, we introduce two other recent methods as future directions for estimating cortical morphological changes: a multi-modal parcellation method using structural and functional images, and a synthetic segmentation method using multi-contrast images (such as T1- and proton density-weighted images).