Tamás Spisák

Autistic traits in neurotypical adults: correlates of graph theoretical functional network topology and white matter anisotropy patterns.

Attempts to explicate the neural abnormalities behind autism spectrum disorders frequently revealed impaired brain connectivity, yet our knowledge is limited about the alterations linked with autistic traits in the non-clinical population. In our study, we aimed at exploring the neural correlates of dimensional autistic traits using a dual approach of diffusion tensor imaging (DTI) and graph theoretical analysis of resting state functional MRI data. Subjects were sampled from a public neuroimaging dataset of healthy volunteers. Inclusion criteria were adult age (age: 18–65), availability of DTI and resting state functional acquisitions and psychological evaluation including the Social Responsiveness Scale (SRS) and Autistic Spectrum Screening Questionnaire (ASSQ). The final subject cohort consisted of 127 neurotypicals. Global brain network structure was described by graph theoretical parameters: global and average local efficiency. Regional topology was characterized by degree and efficiency. We provided measurements for diffusion anisotropy. The association between autistic traits and the neuroimaging findings was studied using a general linear model analysis, controlling for the effects of age, gender and IQ profile. Significant negative correlation was found between the degree and efficiency of the right posterior cingulate cortex and autistic traits, measured by the combination of ASSQ and SRS scores. Autistic phenotype was associated with the decrease of whole-brain local efficiency. Reduction of diffusion anisotropy was found bilaterally in the temporal fusiform and parahippocampal gyri. Numerous models describe the autistic brain connectome to be dominated by reduced long-range connections and excessive short-range fibers. Our finding of decreased efficiency supports this hypothesis although the only prominent effect was seen in the posterior limbic lobe, which is known to act as a connector hub. The neural correlates of the autistic trait in neurotypicals showed only limited similarities to the reported findings in clinical populations with low functioning autism.

Voxel-wise motion artifacts in population-level whole-brain connectivity analysis of resting-state fMRI

Functional Magnetic Resonance Imaging (fMRI) based brain connectivity analysis maps the functional networks of the brain by estimating the degree of synchronous neuronal activity between brain regions. Recent studies have demonstrated that “resting-state” fMRI-based brain connectivity conclusions may be erroneous when motion artifacts have a differential effect on fMRI BOLD signals for between group comparisons. A potential explanation could be that in-scanner displacement, due to rotational components, is not spatially constant in the whole brain. However, this localized nature of motion artifacts is poorly understood and is rarely considered in brain connectivity studies. In this study, we initially demonstrate the local correspondence between head displacement and the changes in the resting-state fMRI BOLD signal. Than, we investigate how connectivity strength is affected by the population-level variation in the spatial pattern of regional displacement. We introduce Regional Displacement Interaction (RDI), a new covariate parameter set for second-level connectivity analysis and demonstrate its effectiveness in reducing motion related confounds in comparisons of groups with different voxel-vise displacement pattern and preprocessed using various nuisance regression methods. The effect of using RDI as second-level covariate is than demonstrated in autism-related group comparisons. The relationship between the proposed method and some of the prevailing subject-level nuisance regression techniques is evaluated. Our results show that, depending on experimental design, treating in-scanner head motion as a global confound may not be appropriate. The degree of displacement is highly variable among various brain regions, both within and between subjects. These regional differences bias correlation-based measures of brain connectivity. The inclusion of the proposed second-level covariate into the analysis successfully reduces artifactual motion-related group differences and preserves real neuronal differences, as demonstrated by the autism-related comparisons.

Valproate treatment normalizes EEG functional connectivity in successfully treated idiopathic generalized epilepsy patients

AIM To investigate the effect of chronic VPA treatment of EEG functional connectivity in successfully treated idiopathic generalized epilepsy (IGE) patients. PATIENTS AND METHODS 19-channel waking, resting-state EEG records of 26 IGE patients were analyzed before treatment (IGE) and after the 90th day of treatment (VPA), in seizure-free condition. Three minutes of artifact-free EEG background activity (without epileptiform potentials) was analyzed for each patient in both conditions. A group of 26 age-matched healthy normative control persons (NC) was analyzed in the same way. All the EEG samples were processed to LORETA (Low Resolution Electromagnetic Tomography) to localize multiple distributed sources of EEG activity. Current source density time series were generated for 33 regions of interest (ROI) in each hemisphere for four frequency bands. Pearson correlation coefficients (R) were computed between all ROIs in each hemisphere, for four bands across the investigated samples. R values corresponded to intrahemispheric, cortico-cortical functional EEG connectivity (EEGfC). Group and condition differences were analyzed by statistical parametric network method. MAIN RESULTS p<0.05, corrected for multiple comparisons: (1) The untreated IGE group showed increased EEGfC in the delta and theta bands, and decreased EEGfC in the alpha band (as compared to the NC group); (2) VPA treatment normalized EEGfC in the delta, theta and alpha bands; and (3) degree of normalization depended on frequency band and cortical region. CONCLUSIONS VPA treatment normalizes EEGfC in IGE patients.

EEG functional connectivity of the intrahemispheric cortico-cortical network of idiopathic generalized epilepsy.

AIMS Intrahemispheric, cortico-cortical EEG functional connectivity (fC) was investigated in untreated patients with idiopathic generalized epilepsy (IGE) in this explorative study. PATIENTS AND METHODS Group comparison was carried out between 19, drug-naive IGE patients and 19, matched healthy persons. 90×2s of 19 channels waking, interictal background EEG signal (without epileptiform potentials) were processed to the LORETA (low resolution electromagnetic tomography) software to compute current source density for 2394 voxels representing parcels of the cerebral cortex for 25 very narrow bands of 1Hz bandwidth (VNBs) from 1 to 25Hz. EEG fC was investigated among the already localized sources. Pearson correlation coefficients (R) were computed among the 33 regions of interest (ROI) within the left and within the right hemisphere, separately. Group differences were computed by means of t-statistics. Corrected p<0.05 differences were accepted as statistically significant. MAIN RESULTS (1) The anatomical patterns of the fC differences showed great frequency-dependency. (2) Hemispheric asymmetry was prominent within most VNBs. (3) Decreased fC in the IGE group was found across all VNBs in the 1-6Hz frequency range as compared to mixed patterns comprising both increased and decreased fC at >6Hz frequencies. (4) In the 5-25Hz range, decreased fC dominated in the anterior, increased fC in the posterior parts of the cortex. (5) The results delineated an anterior and a posterior network. DISCUSSION (1) Decreased fC in the 1-6Hz band might indicate some relationship to yet hidden structure network abnormalities. (2) The anatomical patterns of fC indicate frequency-dependent, pathological coupling and decoupling processes in the interictal state. (3) The two networks might help to understand seizure liability and seizure precipitation in IGE. SIGNIFICANCE This is the first study to explore EEG fC in the interictal condition of IGE patients. The importance of EEG frequencies in evaluating fC in IGE was demonstrated and starting points for further research were given.

Gray Matter Atrophy Is Primarily Related to Demyelination of Lesions in Multiple Sclerosis: A Diffusion Tensor Imaging MRI Study

Objective: Cortical pathology, periventricular demyelination, and lesion formation in multiple sclerosis (MS) are related (Hypothesis 1). Factors in the cerebrospinal fluid close to these compartments could possibly drive the parallel processes. Alternatively, the cortical atrophy could be caused by remote axonal transection (Hypothesis 2). Since MRI can differentiate between demyelination and axon loss, we used this imaging modality to investigate the correlation between the pattern of diffusion parameter changes in the periventricular- and deep white matter and the gray matter atrophy. Methods: High-resolution T1-weighted, FLAIR, and diffusion MRI images were acquired in 52 RRMS patients and 50 healthy, age-matched controls. We used EDSS to estimate the clinical disability. We used Tract Based Spatial Statistics to compare diffusion parameters (fractional anisotropy, mean, axial, and radial diffusivity) between groups. We evaluated global brain, white, and gray matter atrophy with SIENAX. Averaged, standard diffusion parameters were calculated in four compartment: periventricular lesioned and normal appearing white matter, non-periventricular lesioned and normal appearing white matter. PLS regression was used to identify which diffusion parameter and in which compartment best predicts the brain atrophy and clinical disability. Results: In our diffusion tensor imaging study compared to controls we found extensive alterations of fractional anisotropy, mean and radial diffusivity and smaller changes of axial diffusivity (maximal p > 0.0002) in patients that suggested demyelination in the lesioned and in the normal appearing white matter. We found significant reduction in total brain, total white, and gray matter (patients: 718.764 ± 14.968, 323.237 ± 7.246, 395.527 ± 8.050 cm3, controls: 791.772 ± 22.692, 355.350 ± 10.929, 436.422 ± 12.011 cm3; mean ± SE), (p < 0.015; p < 0.0001; p < 0.009; respectively) of patients compared to controls. The PLS analysis revealed a combination of demyelination-like diffusion parameters (higher mean and radial diffusivity in patients) in the lesions and in the non-lesioned periventricular white matter, which best predicted the gray matter atrophy (p < 0.001). Similarly, EDSS was best predicted by the radial diffusivity of the lesions and the non-lesioned periventricular white matter, but axial diffusivity of the periventricular lesions also contributed significantly (p < 0.0001). Interpretation: Our investigation showed that gray matter atrophy and white matter demyelination are related in MS but white matter axonal loss does not significantly contribute to the gray matter pathology.

Increased resting-state EEG functional connectivity in benign childhood epilepsy with centro-temporal spikes

PURPOSE To explore intrahemispheric, cortico-cortical EEG functional connectivity (EEGfC) in benign childhood epilepsy with rolandic spikes (BECTS). METHODS 21-channel EEG was recorded in 17 non-medicated BECTS children and 19 healthy controls. 180s of spike- and artifact-free activity was selected for EEGfC analysis. Correlation of Low Resolution Electromagnetic Tomography- (LORETA-) defined current source density time series were computed between two cortical areas (region of interest, ROI). Analyses were based on broad-band EEGfC results. Groups were compared by statistical parametric network (SPN) method. Statistically significant differences between group EEGfC values were emphasized at p<0.05 corrected for multiple comparison by local false discovery rate (FDR). RESULTS (1) Bilaterally increased beta EEGfC occurred in the BECTS group as compared to the controls. Greatest beta abnormality emerged between frontal and frontal, as well as frontal and temporal ROIs. (2) Locally increased EEGfC emerged in all frequency bands in the right parietal area. CONCLUSIONS Areas of increased EEGfC topographically correspond to cortical areas that, based on relevant literature, are related to speech and attention deficit in BECTS children.

Population‐Level Correction of Systematic Motion Artifacts in fMRI in Patients with Ischemic Stroke

The aim of this study was to reveal potential sources of systematic motion artifacts in stroke functional magnetic resonance imaging (fMRI) focusing on those causing stimulus‐correlated motion on the individual‐level and separate the motion effect on the fMRI signal changing from the activation‐induced alteration at population level.

The Effect of Passive Movement for Paretic Ankle-Foot and Brain Activity in Post-Stroke Patients

Background: This study aims at investigating the short-term efficacy of the continuous passive motion (CPM) device developed for the therapy of ankle-foot paresis and to investigate by fMRI the blood oxygen level-dependent responses (BOLD) during ankle passive movement (PM). Methods: Sixty-four stroke patients were investigated. Patients were assigned into 2 groups: 49 patients received both 15 min manual and 30 min device therapy (M + D), while the other group (n = 15) received only 15 min manual therapy (M). A third group of stroke patients (n = 12) was investigated by fMRI before and immediately after 30 min CPM device therapy. There was no direct relation between the fMRI group and the other 2 groups. All subjects were assessed using the Modified Ashworth Scale (MAS) and a goniometer. Results: Mean MAS decreased, the ankles mean plantar flexion and dorsiflexion passive range of motion (PROM) increased and the equinovalgus improved significantly in the M + D group. In the fMRI group, the PM of the paretic ankle increased BOLD responses; this was observed in the contralateral pre- and postcentral gyrus, superior temporal gyrus, central opercular cortex, and in the ipsilateral postcentral gyrus, frontal operculum cortex and cerebellum. Conclusion: Manual therapy with CPM device therapy improved the ankle PROM, equinovalgus and severity of spasticity. The ankle PM increased ipsi- and contralateral cortical activation.

Uppermost synchronized generators of spike–wave activity are localized in limbic cortical areas in late-onset absence status epilepticus

PURPOSE Absence status (AS) epilepticus with generalized spike-wave pattern is frequently found in severely ill patients in whom several disease states co-exist. The cortical generators of the ictal EEG pattern and EEG functional connectivity (EEGfC) of this condition are unknown. The present study investigated the localization of the uppermost synchronized generators of spike-wave activity in AS. METHOD Seven patients with late-onset AS were investigated by EEG spectral analysis, LORETA (Low Resolution Electromagnetic Tomography) source imaging, and LSC (LORETA Source Correlation) analysis, which estimates cortico-cortical EEGfC among 23 ROIs (regions of interest) in each hemisphere. RESULTS All the patients showed generalized ictal EEG activity. Maximum Z-scored spectral power was found in the 1-6 Hz and 12-14 Hz frequency bands. LORETA showed that the uppermost synchronized generators of 1-6 Hz band activity were localized in frontal and temporal cortical areas that are parts of the limbic system. For the 12-14 Hz band, abnormally synchronized generators were found in the antero-medial frontal cortex. Unlike the rather stereotyped spectral and LORETA findings, the individual EEGfC patterns were very dissimilar. CONCLUSION The findings are discussed in the context of nonconvulsive seizure types and the role of the underlying cortical areas in late-onset AS. The diversity of the EEGfC patterns remains an enigma. Localizing the cortical generators of the EEG patterns contributes to understanding the neurophysiology of the condition.

Purkinje cell number-correlated cerebrocerebellar circuit anomaly in the valproate model of autism

While cerebellar alterations may play a crucial role in the development of core autism spectrum disorder (ASD) symptoms, their pathophysiology on the function of cerebrocerebellar circuit loops is largely unknown. We combined multimodal MRI (9.4 T) brain assessment of the prenatal rat valproate (VPA) model and correlated immunohistological analysis of the cerebellar Purkinje cell number to address this question. We hypothesized that a suitable functional MRI (fMRI) paradigm might show some altered activity related to disrupted cerebrocerebellar information processing. Two doses of maternal VPA (400 and 600 mg/kg, s.c.) were used, and while the higher VPA dose induced a global decrease in whole brain volume, the lower dose induced a focal gray matter density decrease in the cerebellum and brainstem. Increased cortical BOLD responses to whisker stimulation were detected in both VPA groups, but it was more pronounced and extended to cerebellar regions in the 400 mg/kg VPA group. Immunohistological analysis revealed a decreased number of Purkinje cells in both VPA groups. In a detailed analysis, we revealed that the Purkinje cell number interacts with the cerebral BOLD response distinctively in the two VPA groups that highlights atypical function of the cerebrocerebellar circuit loops with potential translational value as an ASD biomarker.