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.

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.

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.

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.

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.

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).

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.

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.

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.

Skeletal muscle function and need for long-term care of urban elderly people in Japan (the Bunkyo Health Study): a prospective cohort study.

PURPOSE: The proportion of elderly individuals (age ≥65 years) in Japan reached 27.7% in 2017, the highest in the world. A serious social problem in a super-aged society is the rise in the number of elderly people who need long-term care (LTC), which is mainly due to cerebrovascular disease, dementia, age-related frailty, falls and fractures, and joint disease. We hypothesised that decreased muscle mass, muscle strength and insulin sensitivity are the common risk factors for these diseases related to needing LTC. We developed a prospective cohort study of elderly subjects in an urban community to test this hypothesis. The primary objective is to prospectively investigate associations between muscle mass, muscle strength, and insulin sensitivity and incidence of main disease and risk factors of needing LTC. The primary outcomes are the incidence of cerebrovascular disease and cognitive decline. PARTICIPANTS: Participants were 1629 people aged 65-84 years living in 13 communities in an urban area (Bunkyo-ku, Tokyo, Japan). Average age was 73.1±5.4 years. FINDINGS TO DATE: We obtained baseline data on cognitive function, cerebral small vessel disease (SVD) determined by brain MRI, body composition, bone mineral density, arteriosclerosis, physical function, muscle mass, muscle strength and insulin sensitivity. Mild cognitive impairment and dementia were observed in 18.1% and 3.3% of participants, respectively. The prevalence of cerebral SVD was 24.8%. These characteristics are similar to those previously reported in elderly Japanese subjects. FUTURE PLANS: We will ask participants about their health status, including incidence of cerebrovascular disease, falls, fractures and other diseases every year by mail. We plan to re-evaluate cognitive function, brain MRI parameters and other parameters at 5 and 10 years after the baseline evaluation. We will evaluate whether low muscle function (muscle mass, muscle strength or insulin sensitivity) is a risk factor for cognitive decline or cerebrovascular disease.

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.

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.