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The aging brain undergoes structural changes even in very healthy individuals. Quantifying these changes could help disentangle pathologic changes from those associated with the normal human aging process. Using longitudinal magnetic resonance imaging (MRI) data from 227 carefully selected healthy human cohort with age ranging from 50 to 80 years old at baseline scan, we quantified age-related volumetric changes in the brain of healthy human older adults. Longitudinally, the rates of tissue loss in total gray matter (GM) and white matter (WM) were 2497.5 and 2579.8 mm 3 per year, respectively. Across the whole brain, the rates of GM decline varied with regions in the frontal and parietal lobes having faster rates of decline, whereas some regions in the occipital and temporal lobes appeared relatively preserved. In contrast, cross-sectional changes were mainly observed in the temporal-occipital regions. Similar longitudinal atrophic changes were also observed in subcortical regions including thalamus, hippocampus, putamen, and caudate, whereas the pallidum showed an increasing volume with age. Overall, regions maturing late in development (frontal, parietal) are more vulnerable to longitudinal decline, whereas those that fully mature in the early stage (temporal, occipital) are mainly affected by cross-sectional changes in healthy older cohort. This may suggest that, for a successful healthy aging, the former needs to be maximally developed at an earlier age to compensate for the longitudinal decline later in life and the latter to remain relatively preserved even in old age, consistent with both concepts of reserve and brain maintenance., (Copyright © 2022 Bagarinao et al.)

Neuroimaging studies have shown that the brain is functionally organized into several large-scale brain networks. Within these networks are regions that are widely connected to several other regions within and/or outside the network. Regions that connect to several other networks, known as connector hubs, are believed to be crucial for information transfer and between-network communication within the brain. To identify regions with high between-network connectivity at the voxel level, we introduced a novel metric called functional connectivity overlap ratio (FCOR), which quantifies the spatial extent of a region's connection to a given network. Using resting state functional magnetic resonance imaging data, FCOR maps were generated for several well-known large-scale resting state networks (RSNs) and used to examine the relevant associations among different RSNs, identify connector hub regions in the cerebral cortex, and elucidate the hierarchical functional organization of the brain. Constructed FCOR maps revealed a strong association among the core neurocognitive networks (default mode, salience, and executive control) as well as among primary processing networks (sensorimotor, auditory, and visual). Prominent connector hubs were identified in the bilateral middle frontal gyrus, posterior cingulate, lateral parietal, middle temporal, dorsal anterior cingulate, and anterior insula, among others, regions mostly associated with the core neurocognitive networks. Finally, clustering the whole brain using FCOR features yielded a topological organization that arranges brain regions into a hierarchy of information processing systems with the primary processing systems at one end and the heteromodal systems comprising connector hubs at the other end., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2020. Published by Elsevier Inc.)

Healthy aging is associated with structural and functional changes in the brain even in individuals who are free of neurodegenerative diseases. Using resting state functional magnetic resonance imaging data from a carefully selected cohort of participants, we examined cross sectional changes in the functional organization of several large-scale brain networks over the adult lifespan and its potential association with general cognitive performance. Converging results from multiple analyses at the voxel, node, and network levels showed widespread reorganization of functional brain networks with increasing age. Specifically, the primary processing (visual and sensorimotor) and visuospatial (dorsal attention) networks showed diminished network integrity, while the so-called core neurocognitive (executive control, salience, and default mode) and basal ganglia networks exhibited relatively preserved between-network connections. The visuospatial and precuneus networks also showed significantly more widespread increased connectivity with other networks. Graph analysis suggested that this reorganization progressed towards a more integrated network topology. General cognitive performance, assessed by Addenbrooke's Cognitive Examination-Revised total score, was positively correlated with between-network connectivity among the core neurocognitive and basal ganglia networks and the integrity of the primary processing and visuospatial networks. Mediation analyses further indicated that the observed association between aging and relative decline in cognitive performance could be mediated by changes in relevant functional connectivity measures. Overall, these findings provided further evidence supporting widespread age-related brain network reorganization and its potential association with general cognitive performance during healthy aging.

Brain activity was recorded using a whole-head magnetoencephalography system followed by coherence analysis to assess neural connectivity in 10 healthy right-handed adults to clarify differences in neural connectivity in brain regions during action observation from several perspectives. The subjects were instructed to observe and memorize or imitate the hand action from a first-person or second-person visual perspective. The brain activity in coherence was modified among frontal and central, sensorimotor, and mirror neuron system-related regions based on the visual perspectives of finger movements. The regional activity in coherence changed similarly under the imitation and observation tasks compared with the condition of observing static hand figures. The information from different visual perspectives of body movements was processed in the frontal-central regions related to sensorimotor processes and partially in mirror neuron system.

This study aims to elucidate age-related intrinsic brain volume changes over the adult lifespan using an unbiased data-driven structural brain parcellation. Anatomical brain images from a cohort of 293 healthy volunteers ranging in age from 21 to 86 years were analyzed using independent component analysis (ICA). ICA-based parcellation identified 192 component images, of which 174 (90.6%) showed a significant negative correlation with age and with some components being more vulnerable to aging effects than others. Seven components demonstrated a convex slope with aging; 3 components had an inverted U-shaped trajectory, and 4 had a U-shaped trajectory. Linear combination of 86 components provided reliable prediction of chronological age with a mean absolute prediction error of approximately 7.2 years. Structural co-variation analysis showed strong interhemispheric, short-distance positive correlations and long-distance, inter-lobar negative correlations. Estimated network measures either exhibited a U- or an inverted U-shaped relationship with age, with the vertex occurring at approximately 45-50 years. Overall, these findings could contribute to our knowledge about healthy brain aging and could help provide a framework to distinguish the normal aging processes from that associated with age-related neurodegenerative diseases., (Copyright © 2017. Published by Elsevier Inc.)

Objective: Epileptic spikes are associated with rapidly changing brain activation involving the epileptic foci and other brain regions in the "epileptic network". We aim to resolve these activation changes using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings., Methods: Simultaneous EEG-fMRI recordings from 9 patients with epilepsy were used in the analysis. Our method employed the whole scalp EEG data to generate regressors for the analysis of fMRI data using the general linear model., Results: We were able to resolve, with milliseconds temporal resolution, changes in activation patterns involving suspected epileptic foci and other brain regions in the epileptic network during spike and slow wave. Using summary maps (called SSWAS maps) which show the activation frequency of voxels, we found that suspected epileptic foci tend to be significantly active during this interval. SSWAS maps also enabled the detection of the epileptic foci in 4 of 5 patients where the conventional event-timing-based analysis failed to identify., Conclusion: These findings demonstrated the efficacy of the method and the potential application of SSWAS maps to identify epileptic foci., Significance: The method could help resolve activation changes during epileptic spike and could provide insights into the underlying pathophysiology of these changes., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to investigate the clinically latent brain atrophy of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) harboring a mitochondrial DNA A3243G mutation (A3243G) and A3243G carriers without stroke-like episodes (SEs)., Methods: We used voxel-based morphometry (VBM) with magnetic resonance imaging to investigate gray matter (GM) and white matter (WM) volume reductions in four MELAS patients and in five A3243G carriers compared to 16 healthy controls. In addition, we investigated the regions of previous SEs using conventional MRI., Results: All four MELAS patients showed significant GM volume reductions in the left superior parietal lobule (SPL), right precuneus, right middle temporal gyrus (MTG), and bilateral posterior lobes of the cerebellum. These areas of GM volume reduction were beyond the regions of previous SEs. As for A3243G carriers, GM volume reductions in the left SPL, right precuneus, right MTG, and bilateral posterior lobes of the cerebellum were detected in three, one, two, and five subjects, respectively. All four MELAS patients showed significant WM volume reductions in the bilateral or unilateral temporal sub-gyral regions, which were included in the regions of previous SEs. No A3243G carriers showed WM volume reductions., Conclusion: The distribution patterns of GM volume reductions in VBM may reflect a common vulnerability of the brains among MELAS patients and A3243G carriers., (Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

The objective of this study was to investigate whether no-go potentials during go/no-go tasks were observed after painful stimulation using intraepidermal electrical stimulation. Event-related potentials were recorded by stimulating the medial or lateral side of the left-hand dorsum. Peak amplitudes of N2 and P3 were significantly larger in no-go trials than in go trials at frontocentral electrodes during go/no-go task, but the differences were not found during rest control and choice reaction time tasks. These characteristics of no-go-related potentials were very similar to event-related potential waveforms during visual, auditory, and somatosensory go/no-go tasks. We suggest that cortical activities relating to response inhibitory processing are not dependent on the sensory modality used.

Objective: We recorded event-related magnetic fields following a target stimulus followed by a masking stimulus to investigate the visual backward masking effect using a helmet-type magnetoencephalography system in humans., Methods: In the target stimulus with masking stimulus conditions, duration of the target stimulus was constant at 16 ms, and duration of the masking stimulus was altered (16, 48 and 144 ms). The target stimulus was masked by the 144-ms masking stimulus, but not by the 16-ms masking stimulus, and was obscured by the 48-ms masking stimulus. For control conditions (Single-condition), event-related magnetic fields were recorded following the sole presentation of the masking stimulus for 32, 64 or 160 ms., Results: One major response was obtained at 180 ms after the onset of the stimulation in each condition. The equivalent current dipole of one major response was estimated to lie in the occipital lobe, but there was a relatively large inter-individual difference. There was no significant difference in latency between the target stimulus with masking stimulus conditions and Single-conditions. In the target stimulus with masking stimulus conditions with the 48- and 144-ms masking stimulus, the root mean square value did not differ from that in the respective Single-condition, while the root mean square value for the target stimulus with masking stimulus conditions with the 16-ms masking stimulus was significantly smaller than that in the Single-condition with the 32-ms masking stimulus, but not different from that in the Single-condition with the 16-ms masking stimulus., Conclusions: The peak latency of one major response depended on the onset of the first stimulus for both the target stimulus with masking stimulus conditions and Single-condition, but the root mean square value depended on the duration of the masking stimulus. We concluded that the temporal information for the target stimulus was preserved during the masking effect, while the figural information was interrupted by the masking stimulus. Our results suggested that temporal factors for the stimulus were processed differently from those responsible for the object's recognition during backward masking.

We review the recent progress of electroencephalography (EEG) and magnetoencephalography (MEG) to elucidate pain perception mechanisms in humans, since EEG and MEG have an excellent temporal resolution in order of msec. MEG is more useful to detect activated areas following painful stimulation, because the spatial resolution of EEG is not very high. For recording activities following Adelta fiber stimulation relating to the first pain, painful CO2 laser stimulation is now widely used, but our new method, epidermal stimulation (ES), is also very useful. The primary small activity was recorded from the primary somatosensory cortex (SI), probably in area 1, in the hemisphere contralateral to the stimulation. Then, secondary somatosensory cortex (SII) and insula were activated with the second activity in SI. These 3 regions were activated in parallel with almost the same time period. This is a very characteristic finding in pain perception. Then, the cingulate cortex and medial temporal area (MT) around the amygdala and hippocampus were activated. In the hemisphere ipsilateral to the stimulation as well, the above regions were activated, except for SI. Therefore, we speculated that SI plays a main role in localization of the stimulus point, the SII and insula are important sites for pain perception, and the cingulate and MT are mainly responsible for cognitive or emotional aspects of pain perception. For recording activities following C fiber stimulation relating to the second pain, we recently developed a new method, that is, applying weaker CO2 laser stimuli to tiny areas of the skin. MEG findings following C fiber stimulation were also similar to those following Adelta fiber stimulation. However, the effects of sleep and attention on MEG following C fiber stimulation was much larger than that following Adelta fiber stimulation. This finding may suggest greater effects of cognitive or emotional functions on second pain than the first pain.

We investigated the event-related responses following subthreshold and suprathreshold stimulation with facial and non-facial figures using magnetoencephalography (MEG) and EEG recordings to clarify the physiological nature of subconscious perception. Event-related magnetic fields and potentials were recorded from the right hemisphere in eight healthy subjects. Three types of stimulus, i.e., facial image (Face), letters of the alphabet (Letters) and random patterns of dots (Dots), with different presentation periods, subthreshold (16 ms), intermediate (32 ms) and suprathreshold (48 ms) were visually presented in a random order. A psychological discrimination task using the same stimuli was also employed. Clear MEG and EEG responses were recorded for all the stimuli, but the amplitude of the responses was largest for Face and smallest for Dots even in the subthreshold stimulation. The equivalent current dipoles (ECDs) for Face were located around the fusiform gyrus, although the correlation coefficients for ECDs were low under subthreshold and intermediate conditions. The ECDs for Letters and Dots were not estimated with reliable correlation coefficients. The results from the psychological task correlated with the dominancy of face recognition. Face perception was processed differently in the subthreshold condition as well as suprathreshold condition. The subconscious recognition of face might be processed around the fusiform gyrus.

The present study recorded activities of magnetoencephalography (MEG) to the presentation of cards, and to the presentation of feedback signals in 12 normal subjects while they performed the Wisconsin Card Sorting Test (WCST), to observe temporal and spatial processing during the task. The MEG responses were compared between two different conditions in the presentation both of cards and of feedback signals: the cards proceeded by the first wrong [W1st(C)] and by the 4th correct feedback signals [C4th(C)]; and the feedback of the first wrong [W1st(FB)] and the 4th correct signals [C4th(FB)]. A multi-dipole model, brain electric source analysis (BESA), was used to explore the dipole sources responsible for the MEG activities. We found that MEG activity differences between the W1st(C) and the C4th(C) condition occurred in the period of 190-220 ms (M190 and M200), and 300-440 ms (M300 and M370) mainly at the supramarginal gyrus, the dorsolateral prefrontal, and the middle and inferior frontal gyrus. MEG differences between the W1st(FB) and the C4th(FB) condition occurred 460-640 ms (M460) after the presentation of the feedback signals, with the activation of the dorsolateral prefrontal cortex and the middle frontal cortex. No significant location differences were found between the frontal responses (M370) of the W1st(C) and M460 of the W1st(FB). Our results proved that the WCST task activates a broad frontal area and the parieto-frontal network across time streaming. Both shifting attention to the wrong feedback and enhanced visual working memory to the sorting shifting condition of the card presentation occur in the same areas at different time points.

Objectives: The effects of the proprioceptive activity of the proximal muscles on somatosensory evoked potentials (SEPs) were investigated, using vibratory stimulation of proximal muscle tendons., Methods: SEPs were recorded following electrical median nerve stimulation at the wrist during vibratory stimulation of tendon of pronator teres, biceps and trapezius muscles and fingers in 8 normal subjects., Results: The cortical SEP components, N20, P25 and N33 recorded from the parietal area, and P20 and N30 recorded from frontal area contralateral to the stimulated side, were markedly attenuated by vibratory stimulation applied to the fingers, but unaffected by vibratory stimulation of the proximal muscles., Conclusion: The proprioceptive afferent, especially group Ia muscle spindle afferent, in the relaxed proximal muscles is not likely to contribute to the gating of SEP following distal nerve stimulation.

Objective: We recorded vocalization related cortical potentials (VRCP) with complete masking of one's own voice, and separated the feedback auditory potentials following vocalization from the VRCP complex., Methods: We used 9 right-handed healthy subjects. We recorded VRCP during simple vowel vocalizing under two conditions, (1) without masking (control); (2) with masking. Electroencephalography (EEG) was recorded from seven areas, Fz, Cz, Pz, C3, C4, T3 and T4, of the International 10-20 system. The trigger point was the onset of vocalized sound recorded through a microphone., Results: In both control and masking conditions, similar negative potentials prior to the vocalization were observed. However, the amplitude just after the onset of vocalization was significantly smaller in the masking than the control condition. The difference waveform, obtained by subtracting the waveforms in the masking from those in the control condition, showed a simple negative peak after the vocalization onset., Conclusions: We considered that the difference waveform indicated the auditory evoked potentials following own voice in the auditory feedback process. Since there was no difference of the negative potentials before vocalization between the two conditions, we speculated that the masking effect on auditory feedback following vocalization was crucial, while its effect on the preparatory process of simple vocalization might be minimal.

Objectives: We investigated changes in the cortical silent period (CSP) following transcranial magnetic cortical stimulation (TCMS) during a standard paradigm which was designed to evoke contingent negative variation (CNV) in ten normal subjects., Methods: We recorded the motor evoked potentials (MEP) and CSP during the inter-stimulus interval (ISI) of a CNV paradigm in ten normal subjects. The CNV paradigm consisted of a visual warning stimulus (S1) followed by a visual response stimulus (S2). The CSP following TCMS on the hand motor area was recorded from mildly contracted first dorsal interosseous muscles., Results: The CSP was significantly shortened during the ISI (P < 0.01, t test) with a highly significant correlation with the TCMS timing during the ISI (P < 0.02, Spearman's correlation coefficient), while the MEP amplitude and latency were unchanged., Conclusions: The results suggested that shortening of the CSP was associated with neural processes related to preparation for voluntary movement during the paradigm.

The temporal and spatial processing of pain perception in human was traced by magnetoencephalography (MEG). We applied a painful CO2 laser beam to the forearm of 11 normal subjects, and estimated the activated areas using a single equivalent current dipole (ECD) at each time point, and a brain electric source analysis (BESA) as a spatio-temporal multiple source analysis method. The four-source model was found to be the most appropriate; sources 1 and 2 at the secondary sensory cortex (SII) contralateral and ipsilateral to the stimulation, and sources 3 and 4 at the anterior medial temporal area (probably the amygdalar nuclei or hippocampal formation) contralateral and ipsilateral to the stimulation, respectively. Activities in all 4 areas were temporally overlapped. Activity in the primary sensory cortex (SI) contralateral to the stimulated site was not identified. Activity in the cingulate cortex was also not clearly identified. These results are probably due to one or more of the following factors; (1) the cingulate cortex is too deep, (2) the ECDs generated in the cingulate cortex are mainly oriented radially, and (3) the ECDs generated in bilateral hemispheres interfere with each other. No significant or consistent magnetic fields were recorded after 500 msec following the stimulation, probably due to the complicated spatial and temporal overlapping of activities in multiple areas.

Visual evoked magnetic field (VEF) and visual evoked potentials (VEP) in response to pattern reversal left half-field central (0-2 degrees, 0-5 degrees) and to left half-field peripheral stimulation (2-15 degrees, 5-15 degrees) were simultaneously recorded in 10 normal subjects. The aim was to localize the origin of the largest wave around 100 ms. By comparing the magnetic evoked 100m wave and electric evoked P100 wave, we found that the response to the small central field (0-2 degrees) stimulation was clearly evident in the VEP and not in the VEF, while the response to the peripheral field (2-15 degrees, 5-15 degrees) stimulation was clearly present in both the VEP and VEF. Our findings show that in contrast to the already recognized predominantly macular origin of VEP activity, VEF activity has a peripheral rather than macular prevalence. Our VEF findings are related to the retinotopic organization of the visual cortex; the 100m dipole to the central field (0-5 degrees) was localized more (1.04 +/- 0.84 cm) posterior than was the 100m dipole to peripheral stimulation (5-15 degrees). The localization of 100m dipoles superimposed on magnetic resonance images (MRI) to central stimuli showed interindividual variations that were in agreement with the known variability of the central field representation in the striate cortex: on the convexity of the occipital pole, in the outer surface of the occipital lobe, and around the calcarine fissure of the right hemisphere. In contrast, following peripheral stimulation, the 100m dipole was located along the medial surface of the hemisphere or in the calcarine fissure. Our results suggest that the main origin of the largest wave around l00ms in response to pattern reversal stimuli is in the striate cortex.

We studied somatosensory evoked magnetic fields (SEFs) following stimulation of bilateral posterior tibial nerves ('bilateral' waveform) in normal subjects to determine the inter- and intra-hemispheric interference effects caused by activation of sensory areas in bilateral hemispheres. Activated areas in the primary and second sensory cortices (SI and SII) in each hemisphere following bilateral stimulation were clearly identified by estimation of the double best-fitted equivalent current dipoles (ECD) using the spherical head model, and the large inter-individual differences were identified. SEFs following the right posterior tibial nerve stimulation and those following the left stimulation were summated ('summated' waveform). The 'difference' waveform was induced by a subtraction of 'bilateral' waveforms from the 'summated' waveform. Short-latency deflections showed no consistent changes between the 'summated' and 'bilateral' waveforms, but the long-latency deflection, the N100m-P100m, in the 'bilateral' waveform was significantly (P < 0.02) reduced in amplitude as compared with the 'summated' waveform. The differences were clearly identified in the 'difference' waveform, in which the main deflections, U100m-D100m, were found. The ECDs of the short-latency deflections were located in SI contralateral to the stimulated nerve, but the ECDs of the N100m-P100m were located in bilateral SII which are considered to receive ascending signals from the body bilaterally. Therefore, some inhibitory interactions might take place in SII by receiving inputs from the body bilaterally.

The topography of somatosensory evoked magnetic fields (SEFs) following stimulation of the right and left posterior tibial nerves was investigated in 5 normal subjects (10 nerves). The main deflections N37m-P45m-N60m-P75m and their counterparts P37m-N45m-P60m-N75m were identified in the hemisphere contralateral to the stimulated nerve. Their equivalent current dipoles (ECDs) were located in the foot area of the primary sensory cortex (SI), probably in area 3b. Restricted minor deflections, P40m-N40m and N50m-P50m, were considered to be generated in area 1 in SI. As the generator sources of P37m-N37m, P40m-N40m and N45m-P45m were temporarily changed and interfered with each other, the direction of ECDs appeared to be rotated with the passage of time. Small middle-latency deflections, N100m-P100m, were clearly identified in 2 subjects. ECDs of these deflections were found in the second sensory cortex (SII), in both hemispheres, although they were clearer in the hemisphere contralateral to the stimulated nerve. In conclusion, short- and middle-latency SEFs are mainly generated in area 3b in SI contralateral to the stimulated nerve, and responses generated in area 1 of SI and SII affect the SEFs to some degree, but interindividual differences are large compared with SEFs evoked by upper limb stimulation.