Atypical Hierarchical Connectivity Revealed by Stepwise Functional Connectivity in Aging.

Hierarchical functional structure plays a crucial role in brain function. We aimed to investigate how aging affects hierarchical functional structure and to evaluate the relationship between such effects and molecular, microvascular, and cognitive features. We used resting-state functional magnetic resonance imaging (fMRI) data from 95 older adults (66.94 ± 7.23 years) and 44 younger adults (21.8 ± 2.53 years) and employed an innovative graph-theory-based analysis (stepwise functional connectivity (SFC)) to reveal the effects of aging on hierarchical functional structure in the brain. In the older group, an SFC pattern converged on the primary sensory-motor network (PSN) rather than the default mode network (DMN). Moreover, SFC decreased in the DMN and increased in the PSN at longer link-steps in aging, indicating a reconfiguration of brain hub systems during aging. Subsequent correlation analyses were performed between SFC values and molecular, microvascular features, and behavioral performance. Altered SFC patterns were associated with dopamine and serotonin, suggesting that altered hierarchical functional structure in aging is linked to the molecular fundament with dopamine and serotonin. Furthermore, increased SFC in the PSN, decreased SFC in the DMN, and accelerated convergence rate were all linked to poorer microvascular features and lower executive function. Finally, a mediation analysis among SFC features, microvascular features, and behavioral performance indicated that the microvascular state may influence executive function through SFC features, highlighting the interactive effects of SFC features and microvascular state on cognition.

Spatiotemporal dynamics of functional connectivity and association with molecular architecture in schizophrenia.

Schizophrenia is a self-disorder characterized by disrupted brain dynamics and architectures of multiple molecules. This study aims to explore spatiotemporal dynamics and its association with psychiatric symptoms. Resting-state functional magnetic resonance imaging data were collected from 98 patients with schizophrenia. Brain dynamics included the temporal and spatial variations in functional connectivity density and association with symptom scores were evaluated. Moreover, the spatial association between dynamics and receptors/transporters according to prior molecular imaging in healthy subjects was examined. Patients demonstrated decreased temporal variation and increased spatial variation in perceptual and attentional systems. However, increased temporal variation and decreased spatial variation were revealed in higher order networks and subcortical networks in patients. Specifically, spatial variation in perceptual and attentional systems was associated with symptom severity. Moreover, case-control differences were associated with dopamine, serotonin and mu-opioid receptor densities, serotonin reuptake transporter density, dopamine transporter density, and dopamine synthesis capacity. Therefore, this study implicates the abnormal dynamic interactions between the perceptual system and cortical core networks; in addition, the subcortical regions play a role in the dynamic interaction among the cortical regions in schizophrenia. These convergent findings support the importance of brain dynamics and emphasize the contribution of primary information processing to the pathological mechanism underlying schizophrenia.

Vascular feature as a modulator of the aging brain.

The cerebral functional reorganization and declined cognitive function of aging might associate with altered vascular features. Here, we explored the altered cerebral hierarchical functional network of 2 conditions (task-free and naturalistic stimuli) in older adults and its relationship with vascular features (systemic microvascular and perfusion features, measured by magnetic resonance imaging) and behavior. Using cerebral gradient analysis, we found that compressive gradient of resting-state mainly located on the primary sensory-motor system and transmodal regions in aging, and further compress in these regions under the continuous naturalistic stimuli. Combining cerebral functional gradient, vascular features, and cognitive performance, the more compressive gradient in the resting-state, the worse vascular state, the lower cognitive function in older adults. Further modulation analysis demonstrated that both vascular features can regulate the relationship between gradient scores in the insula and behavior. Interestingly, systemic microvascular oxygenation also can modulate the relationship between cerebral gradient and cerebral perfusion. Furthermore, the less alteration of the compressive gradient with naturalistic stimuli came with lower cognitive function. Our findings demonstrated that the altered cerebral hierarchical functional structure in aging was linked with changed vascular features and behavior, offering a new framework for studying the physiological mechanism of functional connectivity in aging.

Intranasal insulin ameliorates neurological impairment after intracerebral hemorrhage in mice.

In Alzheimer's disease and ischemic stroke, intranasal insulin can act as a neuroprotective agent. However, whether intranasal insulin has a neuroprotective effect in intracerebral hemorrhage and its potential mechanisms remain poorly understood. In this study, a mouse model of autologous blood-induced intracerebral hemorrhage was treated with 0.5, 1, or 2 IU insulin via intranasal delivery, twice per day, until 24 or 72 hours after surgery. Compared with saline treatment, 1 IU intranasal insulin treatment significantly reduced hematoma volume and brain edema after cerebral hemorrhage, decreased blood-brain barrier permeability and neuronal degeneration damage, reduced neurobehavioral deficits, and improved the survival rate of mice. Expression levels of p-AKT and p-GSK3ß were significantly increased in the perihematoma tissues after intranasal insulin therapy. Our findings suggest that intranasal insulin therapy can protect the neurological function of mice after intracerebral hemorrhage through the AKT/GSK3ß signaling pathway. The study was approved by the Ethics Committee of the North Sichuan Medical College of China (approval No. NSMC(A)2019(01)) on January 7, 2019.

Altered expression of DENND5B in patients with epilepsy and its regulation of seizures in mice.

Epilepsy is a high incidence neurological disease, and its repeated attacks cause serious physical and psychological damage to the patient. Differentially expressed in normal and neoplastic cells (DENN) domain containing 5B (DENND5B) is a lipoprotein binding protein that mediates synaptic vesicle transport and regulates neuroplasticity and lipid metabolism. Nevertheless, the effect of DENND5B on seizures remains unclear. We aimed to investigate the association of DENND5B with epilepsy, detect its expression and distribution in the nervous system, and explore its role in epileptogenesis through western blot, immunofluorescence staining, and behavioral studies. In this experiment, two C57BL/6 mice models, which induced seizures by pentylenetetrazole and kainic acid, were established. We observed that the expression of DENND5B was reduced in the brains of patients with temporal lobe epilepsy, and its expression was also similarly decreased in both chronic epileptic mice. The findings strongly suggest that DENND5B may be associated with epileptic seizures. Results of immunofluorescence showed that DENND5B was mainly expressed in the hippocampal region and co-located with neurons but not with astrocytes. Next, we used lentivirus to induce both lentiviral vector-mediated overexpression and knockdown of DENND5B in mice to test the change of susceptibility and severity of seizures in the two chronic seizure models. Knockdown of DENND5B was found to promote epileptic seizures, increase chronic spontaneous recurrent epileptic seizures and epileptic discharge, and reduce the incubation period. However, overexpression of DENND5B showed the opposite effect. These results suggest that DENND5B overexpression decreased the behavioral phenotype of epileptic seizures, but DENND5B downregulation had the opposite effect. In summary, our findings suggest that DENND5B can regulate epileptic seizures and may provide a new target for antiepileptic therapy.

Comparative Study of Brain fMRI of Olfactory Stimulation in Neuromyelitis Optica Spectrum Disease and Multiple Sclerosis.

Objective: To observe the characteristics of brain fMRI during olfactory stimulation in patients with neuromyelitis optica spectrum disease (NMOSD) and multiple sclerosis (MS), compare the differences of brain functional activation areas between patients with NMOSD and MS, and explore the characteristics of olfactory-related brain networks of NMOSD and MS. Methods: Nineteen patients with NMOSD and 16 patients with MS who met the diagnostic criteria were recruited, and 19 healthy controls matched by sex and age were recruited. The olfactory function of all participants was assessed using the visual analog scale (VAS). Olfactory stimulation was alternately performed using a volatile body (lavender and rose solution) and the difference in brain activation was evaluated by task-taste fMRI scanning simultaneously. Results: Activation intensity was weaker in the NMOSD group than in the healthy controls, including the left rectus, right superior temporal gyrus, and left cuneus. The activation intensity was stronger for the NMOSD than the controls in the left insula and left middle frontal gyrus (P < 0.05). Activation intensity was weaker in the MS group than the healthy controls in the bilateral hippocampus, right parahippocampal gyrus, right insula, left rectus gyrus, and right precentral gyrus, and stronger in the left paracentral lobule among the MS than the controls (P < 0.05). Compared with the MS group, activation intensity in the NMOSD group was weaker in the right superior temporal gyrus and left paracentral lobule, while it was stronger among the NMOSD group in the bilateral insula, bilateral hippocampus, bilateral parahippocampal gyrus, left inferior orbital gyrus, left superior temporal gyrus, left putamen, and left middle frontal gyrus (P < 0.05). Conclusion: Olfactory-related brain networks are altered in both patients, and there are differences between their olfactory-related brain networks. It may provide a new reference index for the clinical differentiation and disease evaluation of NMOSD and MS. Moreover, further studies are needed.

Individual differences in pain sensitivity in drug-naive patients with major depressive disorder: an fMRI study.

Patients with major depressive disorder (MDD) often report pain; however, the pain-related brain mechanism that contributes to MDD with pain remains largely unclear. In the current study, we aimed to observe the cortical responses by employing fMRI technique combined with thermal stimulation paradigm in 17 major depressive disorder patients with pain (MDDP), 19 major depressive disorder patients without pain (MDDNP), and 25 age- and gender-matched healthy control (HC) subjects. Participants completed the Hamilton Depression Rating Scale-17 (HAMD-17) and provided pain intensity ratings in response to noxious heat (51 °C) during task-fMRI scanning by visual analogue scale (VAS). In our results, there was no difference in pain intensity ratings during tonic heat stimulation between the HC group and MDDNP group (p > 0.05), while the MDDNP group had significantly higher HAMD scores compared with the HC group (p < 0.001). The MDDNP group had decreased brain activation in the postcentral gyrus (PCG) compared with the HC group, implying abnormal activation of the PCG may associate with the characterized depressive mood of painless MDD (p < 0.05). Additionally, there was no difference in HAMD scores between the MDDP group and MDDNP group (p > 0.05), while the MDDP group had significantly greater pain during tonic heat stimulation compared with the MDDNP group (p < 0.01). The MDDP group showed enhanced activation in the PCG compared with the MDDNP group (p < 0.05), which may relate to the abnormal regulation of pain in painful MDD. Our results suggested that higher PCG activation may play an important role in facilitating the occurrence of pain in depression.

Low-dose intranasal insulin improves cognitive function and suppresses the development of epilepsy.

Intranasal insulin exerts neuroprotective effects in a variety of neurological diseases. Whether intranasal insulin affects epileptic activity and whether it has neuroprotective effects in epileptic diseases is however still unknown. In this study we show that low-dose intranasal insulin inhibited kainic acid (KA)- or pentylenetetrazole (PTZ)-induced acute seizures and reduced epileptic discharge activities in mice, potentially by alleviating the increase in seizure-induced glutamate in the hippocampus. Meanwhile, intranasal insulin increased GABA levels and the activities of hippocampal theta, which may affect the excitability of the hippocampus. In chronic KA-induced epilepsy, low-dose intranasal insulin reduces the frequency of spontaneous recurrent seizures and epileptic discharges, while it increases theta energy and thereby improves spatial memory. Larger doses of intranasal insulin increased the frequency of seizures but did not aggravate cognitive impairment, suggesting that the frequency of seizures may not be related to impaired cognitive function. Overall, our findings show that low-dose intranasal insulin inhibits epileptic events and improves cognitive impairment in epileptic mice, suggesting that learning and memory can be improved by intranasal insulin. However, larger doses might increase the risk of epileptic seizures.

Dysfunctional white-matter networks in medicated and unmedicated benign epilepsy with centrotemporal spikes.

Benign epilepsy with centrotemporal spikes (BECT) is the most common childhood idiopathic focal epilepsy syndrome, which characterized with white-matter abnormalities in the rolandic cortex. Although diffusion tensor imaging research could characterize white-matter structural architecture, it cannot detect neural activity or white-matter functions. Recent studies demonstrated the functional organization of white-matter by using functional magnetic resonance imaging (fMRI), suggesting that it is feasible to investigate white-matter dysfunctions in BECT. Resting-state fMRI data were collected from 24 new-onset drug-naive (unmedicated [NMED]), 21 medicated (MED) BECT patients, and 27 healthy controls (HC). Several white-matter functional networks were obtained using a clustering analysis on voxel-by-voxel correlation profiles. Subsequently, conventional functional connectivity (FC) was calculated in four frequency sub-bands (Slow-5:0.01-0.027, Slow-4:0.027-0.073, Slow-3:0.073-0.198, and Slow-2:0.198-0.25 Hz). We also employed a functional covariance connectivity (FCC) to estimate the covariant relationship between two white-matter networks based on their correlations with multiple gray-matter regions. Compared with HC, the NMED showed increased FC and/or FCC in rolandic network (RN) and precentral/postcentral network, and decreased FC and/or FCC in dorsal frontal network, while these alterations were not observed in the MED group. Moreover, the changes exhibited frequency-specific properties. Specifically, only two alterations were shared in at least two frequency bands. Most of these alterations were observed in the frequency bands of Slow-3 and Slow-4. This study provided further support on the existence of white-matter functional networks which exhibited frequency-specific properties, and extended abnormalities of rolandic area from the perspective of white-matter dysfunction in BECT.

Abnormal asymmetry in benign epilepsy with unilateral and bilateral centrotemporal spikes: A combined fMRI and DTI study.

Benign epilepsy with centrotemporal spikes (BECTS) is the most common idiopathic focal childhood epilepsy associated with either unilateral or bilateral epileptic discharge. Asymmetry as an important characteristic of the human brain is beneficial for brain functions. However, little is known about on asymmetry of BECTS patients with different epileptic spikes pattern. In the present study, we investigated functional and structural asymmetries in unilateral spikes BECTS (U_BECTS) patients and bilateral spikes BECTS (B_BECTS) patients using resting state functional magnetic resonance images and diffusion tensor imaging. Compared with the controls, we observed a decreased voxel-mirrored interhemispheric functional connectivity (FC) in primary sensorimotor cortex (SM1) in U_BECTS and B_BECTS groups, and reduced fractional anisotropy (FA) values of the corpus callosum (CC) connecting bilateral SM1 were also observed in B_BECTS group. Further region-based FC map analysis of SM1 demonstrated increased functional asymmetry with ipsilateral hemisphere, contralateral hemisphere and the whole brain in U_BECTS and increased functional asymmetry with the contralateral hemisphere and the whole brain in B_BECTS groups. The correlation between functional asymmetry of SM1 and intelligence quotient scores was found in the U_BECTS group. The altered asymmetries of the SM1 further indicated the important role of SM1 in the pathophysiology of the BECTS. Furthermore, the B_BECTS group also showed abnormal voxel-mirrored interhemispheric FC in the temporal pole, the lobule IX of the cerebellum, the caudate and the occipital cortex relative to the controls. Altogether, our findings provide additional insight into the neuronal mechanism of BECTS with different epileptic spikes pattern and cognitive impairments with BECTS patients.

Altered Hippocampo-Cerebello-Cortical Circuit in Schizophrenia by a Spatiotemporal Consistency and Causal Connectivity Analysis.

In the current study, FOur-dimensional Consistency of local neural Activities (FOCA) analysis was used to investigate the local consistency by integrating the temporal and spatial information of the local region. In the current study, resting-state fMRI data of 69 schizophrenia patients and 70 healthy controls were collected. FOCA was utilized to investigate the local consistency. Moreover, Granger causal analysis was used to investigate causal functional connectivity among these areas, which exhibited significantly different local consistency between groups. Compared with the healthy controls, the schizophrenia patients exhibited increased local consistency in hippocampus, basal ganglia and cerebellum regions, and decreased local consistency in sensoriperceptual cortex. In addition, altered causal functional connectivity was observed in hippocampo-cerebello-cortical (occipital) circuit. These findings suggested that this circuit might play a role in the motor dysfunction in schizophrenia, and should be paid more attention in future.

The Multiple-Demand System in the Novelty of Musical Improvisation: Evidence from an MRI Study on Composers.

The multiple-demand (MD) system has proven to be associated with creating structured mental programs in comprehensive behaviors, but the functional mechanisms of this system have not been clarified in the musical domain. In this study, we explored the hypothesis that the MD system is involved in a comprehensive music-related behavior known as musical improvisation. Under a functional magnetic resonance imaging (fMRI) paradigm, 29 composers were recruited to improvise melodies through visual imagery tasks according to familiar and unfamiliar cues. We found that the main regions of the MD system were significantly activated during both musical improvisation conditions. However, only a greater involvement of the intraparietal sulcus (IPS) within the MD system was shown when improvising with unfamiliar cues. Our results revealed that the MD system strongly participated in musical improvisation through processing the novelty of melodies, working memory, and attention. In particular, improvising with unfamiliar cues required more musical transposition manipulations. Moreover, both functional and structural analyses indicated evidence of neuroplasticity in MD regions that could be associated with musical improvisation training. These findings can help unveil the functional mechanisms of the MD system in musical cognition, as well as improve our understanding of musical improvisation.

Altered functional and effective connectivity in anticorrelated intrinsic networks in children with benign childhood epilepsy with centrotemporal spikes.

There are 2 intrinsic networks in the human brain: the task positive network (TPN) and task negative network (alternately termed the default mode network, DMN) in which inverse correlations have been observed during resting state and event-related functional magnetic resonance imaging (fMRI). The antagonism between the 2 networks might indicate a dynamic interaction in the brain that is associated with development.To evaluate the alterations in the relations of the 2 networks in children with benign childhood epilepsy with centrotemporal spikes (BECTS), resting state fMRI was performed in 17 patients with BECTS and 17 healthy controls. The functional and effective connectivities of 29 nodes in the TPN and DMN were analyzed. Positive functional connectivity (FC) within the networks and negative FC between the 2 networks were observed in both groups.The patients exhibited increased FC within both networks, particularly in the frontoparietal nodes such as the left superior frontal cortex, and enhanced antagonism between the 2 networks, suggesting abnormal functional integration of the nodes of the 2 networks in the patients. Granger causality analysis revealed a significant difference in the degree of outflow to inflow in the left superior frontal cortex and the left ventral occipital lobe.The alterations observed in the combined functional and effective connectivity analyses might indicate an association of an abnormal ability to integrate information between the DMN and TPN and the epileptic neuropathology of BECTS and provide preliminary evidence supporting the occurrence of abnormal development in children with BECTS.

Complex discharge-affecting networks in juvenile myoclonic epilepsy: A simultaneous EEG-fMRI study.

Juvenile myoclonic epilepsy (JME) is a common subtype of idiopathic generalized epilepsies (IGEs) and is characterized by myoclonic jerks, tonic-clonic seizures and infrequent absence seizures. The network notion has been proposed to better characterize epilepsy. However, many issues remain not fully understood in JME, such as the associations between discharge-affecting networks and the relationships among resting-state networks. In this project, eigenspace maximal information canonical correlation analysis (emiCCA) and functional network connectivity (FNC) analysis were applied to simultaneous EEG-fMRI data from JME patients. The main findings of our study are as follows: discharge-affecting networks comprising the default model (DMN), self-reference (SRN), basal ganglia (BGN) and frontal networks have linear and nonlinear relationships with epileptic discharge information in JME patients; the DMN, SRN and BGN have dense/specific associations with discharge-affecting networks as well as resting-state networks; and compared with controls, significantly increased FNCs between the salience network (SN) and resting-state networks are found in JME patients. These findings suggest that the BGN, DMN and SRN may play intermediary roles in the modulation and propagation of epileptic discharges. These roles further tend to disturb the switching function of the SN in JME patients. We also postulate that emiCCA and FNC analysis may provide a potential analysis platform to provide insights into our understanding of the pathophysiological mechanism of epilepsy subtypes such as JME. Hum Brain Mapp 37:3515-3529, 2016. © 2016 Wiley Periodicals, Inc.

Effects of Cognitive Training on Resting-State Functional Connectivity of Default Mode, Salience, and Central Executive Networks.

Neuroimaging studies have documented that aging can disrupt certain higher cognitive systems such as the default mode network (DMN), the salience network and the central executive network (CEN). The effect of cognitive training on higher cognitive systems remains unclear. This study used a 1-year longitudinal design to explore the cognitive training effect on three higher cognitive networks in healthy older adults. The community-living healthy older adults were divided into two groups: the multi-domain cognitive training group (24 sessions of cognitive training over a 3-months period) and the wait-list control group. All subjects underwent cognitive measurements and resting-state functional magnetic resonance imaging scanning at baseline and at 1 year after the training ended. We examined training-related changes in functional connectivity (FC) within and between three networks. Compared with the baseline, we observed maintained or increased FC within all three networks after training. The scans after training also showed maintained anti-correlation of FC between the DMN and CEN compared to the baseline. These findings demonstrated that cognitive training maintained or improved the functional integration within networks and the coupling between the DMN and CEN in older adults. Our findings suggested that multi-domain cognitive training can mitigate the aging-related dysfunction of higher cognitive networks.

Altered Local Spontaneous Brain Activity in Juvenile Myoclonic Epilepsy: A Preliminary Resting-State fMRI Study.

Purpose. The purpose of this study was to evaluate the regional synchronization of brain in patients with juvenile myoclonic epilepsy (JME). Methods. Resting-state fMRI data were acquired from twenty-one patients with JME and twenty-two healthy subjects. Regional homogeneity (ReHo) was used to analyze the spontaneous activity in whole brain. Two-sample t-test was performed to detect the ReHo difference between two groups. Correlations between the ReHo values and features of seizures were calculated further. Key Findings. Compared with healthy controls, patients showed significantly increased ReHo in bilateral thalami and motor-related cortex regions and a substantial reduction of ReHo in cerebellum and occipitoparietal lobe. In addition, greater ReHo value in the left paracentral lobule was linked to the older age of onset in patients. Significance. These findings implicated the abnormality of thalamomotor cortical network in JME which were associated with the genesis and propagation of epileptiform activity. Moreover, our study supported that the local brain spontaneous activity is a potential tool to investigate the epileptic activity and provided important insights into understanding the pathophysiological mechanisms of JME.