Interregional metabolic connectivity of 2-deoxy-2[18 F]fluoro-D-glucose positron emission tomography in vagus nerve stimulation for pediatric patients with epilepsy: A retrospective cross-sectional study.

OBJECTIVE: With the recognition of epilepsy as a network disease that disrupts the organizing ability of resting-state brain networks, vagus nerve stimulation (VNS) may control epileptic seizures through modulation of functional connectivity. We evaluated preoperative 2-deoxy-2[18 F]fluoro-D-glucose (FDG) positron emission tomography (PET) in VNS-implanted pediatric patients with refractory epilepsy to analyze the metabolic connectivity of patients and its prognostic role in seizure control. METHODS: Preoperative PET data of 66 VNS pediatric patients who were followed up for a minimum of 1 year after the procedure were collected for the study. Retrospective review of the patients' charts was performed, and five patients with inappropriate PET data or major health issues were excluded. We conducted an independent component analysis of FDG-PET to extract spatial metabolic components and their activities, which were used to perform cross-sectional metabolic network analysis. We divided the patients into VNS-effective and VNS-ineffective groups (VNS-effective group, ≥50% seizure reduction; VNS-ineffective group, <50% reduction) and compared metabolic connectivity differences between groups using a permutation test. RESULTS: Thirty-four (55.7%) patients showed >50% seizure reduction from baseline frequency 1 year after VNS. A significant difference in metabolic connectivity evaluated by preoperative FDG-PET was noted between groups. Relative changes in glucose metabolism were strongly connected among the areas of brainstem, cingulate gyrus, cerebellum, bilateral insula, and putamen in patients with <50% seizure control after VNS. SIGNIFICANCE: This study shows that seizure outcome of VNS may be influenced by metabolic connectivity, which can be obtained from preoperative PET imaging. This study of metabolic connectivity analysis may contribute in further understanding of the mechanism of VNS in intractable seizures.

Analysis of structure-function network decoupling in the brain systems of spastic diplegic cerebral palsy.

Manifestation of the functionalities from the structural brain network is becoming increasingly important to understand a brain disease. With the aim of investigating the differential structure-function couplings according to network systems, we investigated the structural and functional brain networks of patients with spastic diplegic cerebral palsy with periventricular leukomalacia compared to healthy controls. The structural and functional networks of the whole brain and motor system, constructed using deterministic and probabilistic tractography of diffusion tensor magnetic resonance images and Pearson and partial correlation analyses of resting-state functional magnetic resonance images, showed differential embedding of functional networks in the structural networks in patients. In the whole-brain network of patients, significantly reduced global network efficiency compared to healthy controls were found in the structural networks but not in the functional networks, resulting in reduced structural-functional coupling. On the contrary, the motor network of patients had a significantly lower functional network efficiency over the intact structural network and a lower structure-function coupling than the control group. This reduced coupling but reverse directionality in the whole-brain and motor networks of patients was prominent particularly between the probabilistic structural and partial correlation-based functional networks. Intact (or less deficient) functional network over impaired structural networks of the whole brain and highly impaired functional network topology over the intact structural motor network might subserve relatively preserved cognitions and impaired motor functions in cerebral palsy. This study suggests that the structure-function relationship, evaluated specifically using sparse functional connectivity, may reveal important clues to functional reorganization in cerebral palsy. Hum Brain Mapp 38:5292-5306, 2017. © 2017 Wiley Periodicals, Inc.

Motor pathway injury in patients with periventricular leucomalacia and spastic diplegia.

Periventricular leucomalacia has long been investigated as a leading cause of motor and cognitive dysfunction in patients with spastic diplegic cerebral palsy. However, patients with periventricular leucomalacia on conventional magnetic resonance imaging do not always have motor dysfunction and preterm children without neurological abnormalities may have periventricular leucomalacia. In addition, it is uncertain whether descending motor tract or overlying cortical injury is related to motor impairment. To investigate the relationship between motor pathway injury and motor impairment, we conducted voxelwise correlation analysis using tract-based spatial statistics of white matter diffusion anisotropy and voxel-based-morphometry of grey matter injury in patients with periventricular leucomalacia and spastic diplegia (n = 43, mean 12.86 ± 4.79 years, median 12 years). We also evaluated motor cortical and thalamocortical connectivity at resting state in 11 patients using functional magnetic resonance imaging. The functional connectivity results of patients with spastic diplegic cerebral palsy were compared with those of age-matched normal controls. Since γ-aminobutyric acid(A) receptors play an important role in the remodelling process, we measured neuronal γ-aminobutyric acid(A) receptor binding potential with dynamic positron emission tomography scans (n = 27) and compared the binding potential map of the patient group with controls (n = 20). In the current study, white matter volume reduction did not show significant correlation with motor dysfunction. Although fractional anisotropy within most of the major white matter tracts were significantly lower than that of age-matched healthy controls (P < 0.05, family wise error corrected), fractional anisotropy mainly within the bilateral corticospinal tracts and posterior body and isthmus of the corpus callosum showed more significant correlation with motor dysfunction (P < 0.03) than thalamocortical pathways (P < 0.05, family-wise error corrected). Cortical volume of the pre- and post-central gyri and the paracentral lobule tended to be negatively correlated with motor function. The motor cortical connectivity was diminished mainly within the bilateral somatosensory cortex, paracentral lobule, cingulate motor area and visual cortex in the patient group. Thalamovisual connectivity was not diminished despite severe optic radiation injury. γ-Aminobutyric acid(A) receptor binding potential was focally increased within the lower extremity homunculus, cingulate cortex, visual cortex and cerebellum in the patient group (P < 0.05, false discovery rate corrected). In conclusion, descending motor tract injury along with overlying cortical volume reduction and reduced functional connectivity appears to be a leading pathophysiological mechanism of motor dysfunction in patients with periventricular leucomalacia. Increased regional γ-aminobutyric acid(A) receptor binding potential appears to result from a compensatory plasticity response after prenatal brain injury.

Regional cerebral blood flow changes and performance deficit during a sustained attention task in schizophrenia: (15) O-water positron emission tomography.

AIM: Attention deficit has been reported in both schizophrenia patients and patients with major depressive disorder (MDD). The aim of this study was to elucidate the deficits in sustained attention and associated neural network dysfunctions in schizophrenia patients and MDD patients, and to investigate the difference between the two patient groups. METHODS: Twelve schizophrenia patients, 12 patients with non-psychotic MDD, and 12 healthy control subjects participated in this study. A sustained attention to response task (SART) was used to measure attention capacity. Cerebral blood flow (CBF) during attention tasks was measured using H(2) (15) O positron emission tomography. Statistical parametric mapping and analysis of covariance were performed to compare the behavioral performance and CBF changes during SART among three groups. RESULTS: Behavioral performances were not significantly different among the three groups except for an increased commission error rate in the schizophrenia group. Regional CBF during SART was significantly reduced in the left inferior frontal gyrus, the left cuneus, and the right superior parietal lobule and increased in the right superior frontal gyrus and the right cuneus in the schizophrenia group compared to the healthy control group. In the MDD group, neither significant regional CBF difference nor behavioral deficit was found compared to the healthy control group. CONCLUSION: Behavioral performance deficit and perfusion changes in the prefrontal and parietal cortices during SART were observed only in the schizophrenia group. Prefrontal and parietal network dysfunction for sustained attention may be involved in the pathophysiology of schizophrenia.

Epidural grid, a new methodology of invasive intracranial EEG monitoring: A technical note and experience of a single center.

INTRODUCTION: Subdural grid monitoring (SDG) has the advantage to provide continuous coverage over a larger area of cortex, direct visualization of electrode location and functional mapping. However, SDG can cause direct irritation of the cortex or postoperative headaches due to cerebrospinal fluid (CSF) leakage. Epidural grid monitoring (EDG) without opening the dura is thought to reduce the possibility of these complications. We report our experience with EDG. METHODS: We described our surgical technique of EDG in invasive intracranial electroencephalography (iEEG) monitoring. A retrospective review of 30 patients who underwent grid placement of iEEG between March 2019 and December 2020 was performed to compare SDG and EDG. RESULTS: Of the 30 patients, 10 patients underwent SDG and 20 patients underwent EDG. There was no difference in age between SDG and EDG groups (p = 0.13). Also, there was no difference in the number of grid electrodes, craniotomy size, number of electrodes per craniotomy area and postoperative complication rate (p = 0.32, 0.84, 0.58 and 0.40). However, the maximum number of electrodes that have been undermined from the bone margin was much higher in SDG group (SDG 4.6 ± 2.2 vs. EDG 2.0 ± 0.9; p = 0.001). The demand for postoperative analgesics was significantly lower in EDG group (SDG 13.4 ± 9.1 vs. EDG 4.1 ± 4.3; p = 0.012); and the demand for postoperative antiemetics also tended to be low (SDG 4.6 ± 3.6 vs. EDG 1.8 ± 1.6; p = 0.078). CONCLUSIONS: There was no significant difference in craniotomy and electrode insertion between the two groups; however, the EDG group showed less postoperative headache and nausea. Though not in direct contact with the cortex, the quality of the electrophysiological signal received through the electrode in EDG is comparable to that of the SDG. The EDG enables to detect the onset of seizure and delineate the epileptogenic zone sufficiently. Moreover, functional mapping is possible with EDG. Therefore, EDG has the sufficient potential to replace SDG for monitoring of the lateral surface of brain.

Inter-species cortical registration between macaques and humans using a functional network property under a spherical demons framework.

Systematic evaluation of cortical differences between humans and macaques calls for inter-species registration of the cortex that matches homologous regions across species. For establishing homology across brains, structural landmarks and biological features have been used without paying sufficient attention to functional homology. The present study aimed to determine functional homology between the human and macaque cortices, defined in terms of functional network properties, by proposing an iterative functional network-based registration scheme using surface-based spherical demons. The functional connectivity matrix of resting-state functional magnetic resonance imaging (rs-fMRI) among cortical parcellations was iteratively calculated for humans and macaques. From the functional connectivity matrix, the functional network properties such as principal network components were derived to estimate a deformation field between the human and macaque cortices. The iterative registration procedure updates the parcellation map of macaques, corresponding to the human connectome project's multimodal parcellation atlas, which was used to derive the macaque's functional connectivity matrix. To test the plausibility of the functional network-based registration, we compared cortical registration using structural versus functional features in terms of cortical regional areal change. We also evaluated the interhemispheric asymmetry of regional area and its inter-subject variability in humans and macaques as an indirect validation of the proposed method. Higher inter-subject variability and interhemispheric asymmetry were found in functional homology than in structural homology, and the assessed asymmetry and variations were higher in humans than in macaques. The results emphasize the significance of functional network-based cortical registration across individuals within a species and across species.

Morphological alterations in the congenital blind based on the analysis of cortical thickness and surface area.

To explore the morphological aspects of the functional reorganization of the blind's visual cortex, we analyzed the regional cortical thickness and cortical surface area in the congenitally blind subjects (CB) compared to the late-onset blind (LB) and sighted controls (SC). Cortical thickness was calculated from high-resolution T1-weighted magnetic resonance images of 21 young CB (blind from birth, mean age=27.1 yr), 12 LB, and 35 young SC. Analysis of covariance of cortical layer thickness with global thickness, age, and gender as covariates was done node-by-node on the entire cortical surface. Further analysis of mean thickness and surface area was performed for 33 automatically parceled cortical regions. Voxel-based morphometry was also conducted to compare results with cortical thickness and surface area. We found increased cortical thickness in the regions involved in vision and eye movement, such as the pericalcarine sulcus, cingulate cortex, and right frontal eye field, but cortical thinning in the left somatosensory cortex and right auditory cortex of CB compared to SC. CB had significantly reduced surface extent in the primary and associated visual areas, which explains volumetric atrophies in the visual cortex of CB despite increased cortical thickness. Conversely, LB tended to have cortical thinning in the primary visual cortex with a slight or no significant reduction in the surface extent. These morphological alterations in CB may indicate cortical reorganization at the visual cortex in connection with other sensory cortices.

Volumetric abnormalities in connectivity-based subregions of the thalamus in patients with chronic schizophrenia.

OBJECTIVE: The thalamus, which consists of multiple subnuclei, has been of particular interest in the study of schizophrenia. This study aimed to identify abnormalities in the connectivity-based subregions of the thalamus in patients with schizophrenia. METHODS: Thalamic volume was measured by a manual tracing on superimposed images of T1-weighted and diffusion tensor images in 30 patients with schizophrenia and 22 normal volunteers. Cortical regional volumes automatically measured by a surface-based approach and thalamic subregional volumes measured by a connectivity-based technique were compared between the two groups and their correlations between the connected regions were calculated in each group. RESULTS: Volume reduction was observed in the bilateral orbitofrontal cortices and the left cingulate gyrus on the cortical side, whereas in subregions connected to the right orbitofrontal cortex and bilateral parietal cortices on the thalamic side. Significant volumetric correlations were identified between the right dorsal prefrontal cortex and its related thalamic subregion and between the left parietal cortex and its related thalamic subregion only in the normal group. CONCLUSIONS: Our results suggest that patients with schizophrenia have a structural deficit in the corticothalamic systems, especially in the orbitofrontal-thalamic system. Our findings may present evidence of corticothalamic connection problems in schizophrenia.

Reorganization of neural circuits in the blind on diffusion direction analysis.

The neural reorganization of the visual cortex of early blind individuals was evaluated using voxel-by-voxel analysis of diffusion tensor images with regard to the diffusion direction, diffusion anisotropy and diffusivity. Reduced anisotropy and increased diffusivity was found mainly in the visual pathways of 18 early blind individuals as opposed to 25 sighted individuals. Alteration of the diffusion direction was detected not only in the visual pathways but also in nonvisual pathways such as the u fibers of the parietal lobe, the sagittal striatum, the pulvinar and the inferior and superior longitudinal fasciculi. The alteration of regional diffusion direction, reduced anisotropy and increased diffusivity in early blind individuals imply the neural reorganization for functional adaptation to the loss of visual input during the early development period.

Neural responses to affective and cognitive theory of mind in children and adolescents with autism spectrum disorder.

Children and adolescents with Autism Spectrum Disorder (ASD) are characterized by an impaired Theory of Mind (ToM). Recent evidence suggested that two aspects of ToM (cognitive ToM versus affective ToM) are differentially impaired in individuals with ASD. In this study, we examined the neural correlates of cognitive and affective ToM in children and adolescents with ASD compared to typically developing children (TDCs). Twelve children and adolescents with ASD and 12 age, IQ matched TDCs participated in this functional MRI study. The ToM task involved the attribution of cognitive and affective mental states to a cartoon character based on verbal and eye-gaze cues. In cognitive ToM tasks, ASD participants recruited the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and superior temporal gyrus (STG) to a greater extent than did TDCs. In affective ToM tasks, both ASD and TDC participants showed more activation in the insula and other subcortical regions than in cognitive ToM tasks. Correlational analysis revealed that greater activation of the mPFC/ACC regions was associated with less symptom severity in ASD patients. In sum, our study suggests that the recruitment of additional prefrontal resources can compensate for the successful behavioral performance in the ToM task in ASD participants.

A network analysis of ¹5O-H2O PET reveals deep brain stimulation effects on brain network of Parkinson's disease.

PURPOSE: As Parkinson's disease (PD) can be considered a network abnormality, the effects of deep brain stimulation (DBS) need to be investigated in the aspect of networks. This study aimed to examine how DBS of the bilateral subthalamic nucleus (STN) affects the motor networks of patients with idiopathic PD during motor performance and to show the feasibility of the network analysis using cross-sectional positron emission tomography (PET) images in DBS studies. MATERIALS AND METHODS: We obtained [¹5O]H2O PET images from ten patients with PD during a sequential finger-to-thumb opposition task and during the resting state, with DBS-On and DBS-Off at STN. To identify the alteration of motor networks in PD and their changes due to STN-DBS, we applied independent component analysis (ICA) to all the cross-sectional PET images. We analysed the strength of each component according to DBS effects, task effects and interaction effects. RESULTS: ICA blindly decomposed components of functionally associated distributed clusters, which were comparable to the results of univariate statistical parametric mapping. ICA further revealed that STN-DBS modifies usage-strengths of components corresponding to the basal ganglia-thalamo-cortical circuits in PD patients by increasing the hypoactive basal ganglia and by suppressing the hyperactive cortical motor areas, ventrolateral thalamus and cerebellum. CONCLUSION: Our results suggest that STN-DBS may affect not only the abnormal local activity, but also alter brain networks in patients with PD. This study also demonstrated the usefulness of ICA for cross-sectional PET data to reveal network modifications due to DBS, which was not observable using the subtraction method.

Is the GABA System Related to the Social Competence Improvement Effect of Aripiprazole? An (18)F-Fluoroflumazenil PET Study.

OBJECTIVE: Patients with schizophrenia who are treated with aripiprazole experience some benefits including an improvement of social competence, but the underlying mechanism of this improvement has not been investigated yet. This study aimed to provide preliminary evidence that the GABA system may be involved in the effect of aripiprazole on social competence. METHODS: Seventeen outpatients with schizophrenia (9 taking aripiprazole and 8 taking risperidone) and 18 healthy controls underwent (18)F-fluoroflumazenil PET, and GABAA receptor binding potential was compared between the three groups. RESULTS: Voxelwise one-way ANOVA showed that GABAA receptor binding potentials in the right medial prefrontal cortex (p=0.04) and right dorsolateral prefrontal cortex (p=0.02) were significantly lower in the aripiprazole group than the risperidone group, and those in the left frontopolar cortex (p=0.03) and right premotor cortex (p=0.02) were significantly lower in the aripiprazole group than the risperidone and control groups. CONCLUSION: Our results suggest that aripiprazole administration results in increased GABA transmission in the prefrontal regions, and that these increases may be a neural basis of aripiprazole's clinical benefits on an improvement of social competence.

Increased GABA-A receptor binding and reduced connectivity at the motor cortex in children with hemiplegic cerebral palsy: a multimodal investigation using 18F-fluoroflumazenil PET, immunohistochemistry, and MR imaging.

UNLABELLED: γ-aminobutyric acid (GABA)-A receptor-mediated neural transmission is important to promote practice-dependent plasticity after brain injury. This study investigated alterations in GABA-A receptor binding and functional and anatomic connectivity within the motor cortex in children with cerebral palsy (CP). METHODS: We conducted (18)F-fluoroflumazenil PET on children with hemiplegic CP to investigate whether in vivo GABA-A receptor binding is altered in the ipsilateral or contralateral hemisphere of the lesion site. To evaluate changes in the GABA-A receptor subunit after prenatal brain injury, we performed GABA-A receptor immunohistochemistry using rat pups with a diffuse hypoxic ischemic insult. We also performed diffusion tensor MR imaging and resting-state functional MR imaging on the same children with hemiplegic CP to investigate alterations in anatomic and functional connectivity at the motor cortex with increased GABA-A receptor binding. RESULTS: In children with hemiplegic CP, the (18)F-fluoroflumazenil binding potential was increased within the ipsilateral motor cortex. GABA-A receptors with the α1 subunit were highly expressed exclusively within cortical layers III, IV, and VI of the motor cortex in rat pups. The motor cortex with increased GABA-A receptor binding in children with hemiplegic CP had reduced thalamocortical and corticocortical connectivity, which might be linked to increased GABA-A receptor distribution in cortical layers in rats. CONCLUSION: Increased expression of the GABA-A receptor α1 subunit within the ipsilateral motor cortex may be an important adaptive mechanism after prenatal brain injury in children with CP but may be associated with improper functional connectivity after birth and have adverse effects on the development of motor plasticity.

SENSE factors for reliable cortical thickness measurement.

The purposes of this study were to examine the effect of sensitivity encoding (SENSE) factors on cortical thickness measurements and to determine which SENSE factor to use to reliably measure cortical thickness in 3.0 T and 1.5 T T1-weighted MRI images. The 3D T1-TFE images were acquired from 11 healthy volunteers with 6 different SENSE acceleration factors from 1.0 (without SENSE acceleration) to 4.0 on a 1.5 T scanner, and 9 different SENSE factors from 1.0 to 6.0, plus a second-day 1.0 acquisition on a 3.0 T scanner. Cortical thickness was calculated for the entire cortical surface that was further subdivided into 33 regions. Repeated measures multivariate analysis of variance revealed that the main effect of SENSE factors (F=12.485, df=7, p=0.006) was a significant underestimation of cortical thickness at SENSE 5.0 (p=0.022) and 6.0 (p=0.011) at 3.0 T and at SENSE 4.0 (p<0.000) at 1.5 T. Repeated measures ANOVA showed that thickness measurements at the insula, superior temporal sulcus, the medial part of the superior frontal lobe, and cingulate cortex are highly affected by SENSE factors. SENSE factors affect thickness estimation more significantly at 1.5 T and thus 1.5 T imaging provides less reliable estimates using SENSE techniques. Faster imaging can be done without too much loss of reliability using a high SENSE factor, such as 3.0, at 3.0 T with acquisition time being inversely proportional to the SENSE factor.

Cortical surface-based analysis of 18F-FDG PET: measured metabolic abnormalities in schizophrenia are affected by cortical structural abnormalities.

The purpose of the study is to propose a new framework for surface-based statistical parametric mapping of PET images using MRI-based cortical surface analysis, including partial volume correction, intensity normalization and spatial normalization on the cortical surface. Maximum PET intensities along the path between inner and outer layer of the cortical gray matter are mapped onto the cortical surface to generate a metabolic activity surface map. For the partial volume correction, the metabolic activity surface map was divided by the partial volume effect map. The regional metabolic activity was normalized by the global activity iteratively calculated at the surface nodes, statistically independent of the group, as measured by F statistics. After surface-based spatial normalization, a statistical evaluation of both cortical thickness and cortical metabolic activity was conducted on the normalized surfaces of 16 patients with schizophrenia and 16 age- and gender-matched healthy controls. The patients with schizophrenia were found to have significant cortical thinning in the temporal and inferior frontal cortices. Accordingly, their PET imaging was significantly affected by the partial volume effect, indicating that partial volume correction could change the statistical results. After correction of the partial volume effects, the patients showed hyperactivity in the temporal cortex, whereas hypoactivity in the prefrontal cortex, predominantly in the left hemisphere. Our results demonstrate that anatomical factors affect an analysis for functional data from the PET, and therefore the importance of combining anatomy and function in the analysis of imaging data for schizophrenia should be considered.