Hypothalamic Inflammation in Human Obesity Is Mediated by Environmental and Genetic Factors.

Obesity is associated with hypothalamic inflammation (HI) in animal models. In the current study, we examined the mediobasal hypothalamus (MBH) of 57 obese human subjects and 54 age- and sex- matched nonobese control subjects by MRI and analyzed the T2 hyperintensity as a measure of HI. Obese subjects exhibited T2 hyperintensity in the left but not the right MBH, which was strongly associated with systemic low-grade inflammation. MRS revealed the number of neurons in the left hypothalamic region to be similar in obese versus control subjects, suggesting functional but not structural impairment due to the inflammatory process. To gain mechanistic insights, we performed nutritional analysis and 16S rDNA microbiome sequencing, which showed that high-fat diet induces reduction of Parasutterella sp. in the gut, which is significantly correlated with MBH T2 hyperintensity. In addition to these environmental factors, we found subjects carrying common polymorphisms in the JNK or the MC4R gene to be more susceptible to HI. Finally, in a subgroup analysis, bariatric surgery had no effect on MBH T2 hyperintensity despite inducing significant weight loss and improvement of peripheral insulin sensitivity. In conclusion, obesity in humans is associated with HI and disturbances in the gut-brain axis, which are influenced by both environmental and genetic factors.

Differences in hemispherical thalamo-cortical causality analysis during resting-state fMRI.

Thalamus is a very important part of the human brain. It has been reported to act as a relay for the messaging taking place between the cortical and sub-cortical regions of the brain. In the present study, we analyze the functional network between both hemispheres of the brain with the focus on thalamus. We used conditional Granger causality (CGC) and time-resolved partial directed coherence (tPDC) to investigate the functional connectivity. Results of CGC analysis revealed the asymmetry between connection strengths of the bilateral thalamus. Upon testing the functional connectivity of the default-mode network (DMN) at low-frequency fluctuations (LFF) and comparing coherence vectors using Spearman's rank correlation, we found that thalamus is a better source for the signals directed towards the contralateral regions of the brain, however, when thalamus acts as sink, it is a better sink for signals generated from ipsilateral regions of the brain.

White matter microstructural changes of thalamocortical networks in photosensitivity and idiopathic generalized epilepsy.

PURPOSE: Photosensitivity or photoparoxysmal response (PPR) is an electroencephalography trait that is highly associated with idiopathic generalized epilepsies (IGEs) and characterized by changes in cortical excitability in response to photic stimulation. Studying functional and structural changes of PPR might provide important insights into the pathogenesis of IGE. Recent studies revealed a functional network consisting of occipital, parietal, and precentral areas that might be implicated in PPR. Herein, we investigate the microstructural changes associated with PPR. METHODS: Twelve healthy subjects with PPR, nine patients with IGE and PPR (IGE-PPR group), and 18 healthy controls were studied with diffusion magnetic resonance imaging. Tract-based spatial statistics were used to test for regional differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity between groups. KEY FINDINGS: Subjects with PPR exhibited higher FA in the right precentral juxtacortical white matter and higher MD in lateral occipital areas relative to controls. Patients with IGE-patients showed additional increases in regional FA in the thalamus and juxtacortical precentral and parietal areas. Both subjects with PPR and patients with IGE-PPR presented axial and radial diffusivity changes in the occipital regions. SIGNIFICANCE: Our results show that PPR is associated with subcortical microstructural changes in precentral, parietal, and occipital regions. The coexistence of PPR and IGE is associated with white matter abnormalities in the thalamus and precuneus. PPR and epilepsy share similar functional and structural networks in widespread cortical and subcortical areas.

Simultaneous EEG-fMRI in drug-naive children with newly diagnosed absence epilepsy.

PURPOSE: In patients with idiopathic generalized epilepsy (IGE), blood oxygen level dependent (BOLD) EEG during functional MRI (EEG-fMRI) has been successfully used to link changes in regional neuronal activity to the occurrence of generalized spike-and-wave (GSW) discharges. Most EEG-fMRI studies have been performed on adult patients with long-standing epilepsy who were on antiepileptic medication. Here, we applied EEG-fMRI to investigate BOLD signal changes during absence seizures in children with newly diagnosed childhood absence epilepsy (CAE). METHODS: Ten drug-naive children with newly diagnosed CAE underwent simultaneous EEG-fMRI. BOLD signal changes associated with ictal EEG activity (i.e., periods of three per second GSW) were analyzed in predefined regions-of-interests (ROIs), including the thalamus, the precuneus, and caudate nucleus. RESULTS: In 6 out of 10 children, EEG recordings showed periods of three per second GSW during fMRI. Three per second GSW were associated with regional BOLD signal decreases in parietal areas, precuneus, and caudate nucleus along with a bilateral increase in the BOLD signal in the medial thalamus. Taking into account the normal delay in the hemodynamic response, temporal analysis showed that the onset of BOLD signal changes coincided with the onset of GSW. DISCUSSION: In drug-naive individuals with CAE, ictal three per second GSW are associated with BOLD signal changes in the same striato-thalamo-cortical network that changes its regional activity during primary and secondary generalized paroxysms in treated adults. No BOLD signal changes in the striato-thalamo-cortical network preceded the onset of three per second GSW in unmediated children with CAE.

Changes in activity of striato-thalamo-cortical network precede generalized spike wave discharges.

The pathophysiology of generalized spike wave discharges (GSW) is not completely understood. Thalamus, basal ganglia and neocortex have been implicated in the generation of GSW, yet the specific role of each structure remains to be clarified. In six children with idiopathic generalized epilepsy (IGE), we performed combined EEG-fMRI to identify GSW-related changes in blood oxygen level-dependent (BOLD) signal in the striato-thalamo-cortical network. In all patients, within-subject analysis demonstrated BOLD signal changes that preceded the GSW. An increase in BOLD signal in the medial thalamus started 6 s before the onset of the GSW. Decreases in cortical BOLD signal were mainly found in frontoparietal areas and precuneus starting 6 to 3 s before the GSW. All patients showed a decrease in BOLD signal in the head of the caudate nucleus with a variable onset. The temporospatial pattern of BOLD signal changes suggests that GSW on the cortical surface is preceded by a sequence of neuronal events in the thalamo-cortical-striatal network. Approximately 6 s before the GSW, the thalamus shows an increase in neuronal activity along with regional decreases in cortical activity. These changes in thalamo-cortical activity are followed by a deactivation of the caudate nucleus. These early changes in BOLD signal may reflect changes in neuronal activity that contribute to the generation of GSW and may contribute to the transition from a normal to a generalized hypersynchronous pattern of neuronal activity. Our preliminary findings warrant further studies on a larger number of patients to explore the influence of age, medication and type of epileptic syndrome.

Different neuronal networks are associated with spikes and slow activity in hypsarrhythmia.

PURPOSE: West syndrome is a severe epileptic encephalopathy of infancy characterized by a poor developmental outcome and hypsarrhythmia. The pathogenesis of hypsarrhythmia is insufficiently understood. METHODS: We investigated eight patients with infantile spasms and hypsarrhythmia (group I) and 8 children with complex partial seizures (group II) using simultaneous recordings of electroencephalogram (EEG) and functional MRI. Hemodynamic responses to epileptiform discharges and slow wave activity (EEG delta power) were analyzed separately. RESULTS: In group I (mean age, 7.82 +/- 2.87 months), interictal spikes within the hypsarrhythmia were associated with positive blood oxygenation level-dependent (BOLD) changes in the cerebral cortex (especially occipital areas). This was comparable with cortical positive BOLD responses in group II (mean age, 20.75 +/- 12.52 months). Slow wave activity in group I correlated significantly with BOLD signal in voxels, which were localized in brainstem, thalamus, as well as different cortical areas. There was no association between BOLD effect and EEG delta power in group II. Moreover, as revealed by group analysis, group I differed from group II according to correlations between BOLD signal and slow wave activity in putamen and brainstem. CONCLUSIONS: This study demonstrates that multifocal interictal spikes and high-amplitude slow wave activity within the hypsarrhythmia are associated with the activation of different neuronal networks. Although spikes caused a cortical activation pattern similar to that in focal epilepsies, slow wave activity produced a hypsarrhythmia-specific activation in cortex and subcortical structures such as brainstem, thalamus, and putamen.