Alterations in intra- and internetwork functional connectivity associated with levetiracetam treatment in temporal lobe epilepsy.

OBJECTIVE: Levetiracetam (LEV) is an antiepileptic drug with a novel pharmacological mechanism. Advances in functional magnetic resonance imaging (fMRI) enable researchers to explore the cognitive effects of antiepileptic drugs on the living brain. This study aimed to explore how the functional connectivity patterns of the cognitive networks changed in association with LEV treatment. METHODS: Patients with temporal lobe epilepsy (TLE), including both users and nonusers of LEV, were included in this study along with healthy controls. Core cognitive networks were extracted using an independent component analysis approach. Functional connectivity patterns within and between networks were investigated. The relationships between functional connectivity patterns and clinical characteristics were also examined. RESULTS: The patterns of intranetwork connectivity in the default mode network (DMN), left executive control network (lECN), and dorsal attention network (DAN) differed among the three groups. The internetwork interactions did not show intergroup differences once corrected for multiple comparisons. No correlation between functional connectivity and clinical characteristics was found in patients with TLE. CONCLUSIONS: Changes in intranetwork connectivity are a key effect of LEV administration. SIGNIFICANCE: Alterations in intranetwork connectivity patterns may underlie the cognitive effects of LEV administration; this finding improves our understanding of the neural mechanisms of LEV therapy.

Temporal lobe epilepsy: decreased thalamic resting-state functional connectivity and their relationships with alertness performance.

OBJECTIVES: Studies have provided evidence regarding the pathology of the thalamus in patients with temporal lobe epilepsy (TLE). The thalamus, particularly the right thalamus, is one of the subcortical structures that are most uniformly accepted as being significantly involved in alertness. Moreover, alertness impairment in epilepsy has been reported. This study aimed to investigate alterations in thalamic resting-state functional connectivity (FC) and their relationships with alertness performance in patients with TLE; an issue that has not yet been addressed. METHODS: A total of 15 patients with right TLE (rTLE) and 16 healthy controls were recruited for the present study. All of the participants underwent a resting-state functional magnetic resonance imaging (fMRI) scan and the attention network test (ANT). Whole-brain voxel-wise FC analyses were applied to extract the thalamic resting-state functional networks in the patients with rTLE and healthy controls, and the differences between the two groups were evaluated. Correlation analyses were employed to examine the relationships between alterations in thalamic FC and alertness performance in patients with rTLE. RESULTS: Compared to the healthy controls, the FC within and between the bilateral thalamus was decreased in the patients with rTLE. Moreover, in the patient group, the bilateral anterior cingulate cortex (ACC) and subcortical regions, including the bilateral brainstem, cerebellum, putamen, right caudate nucleus, and amygdala, exhibited decreased FC with the ipsilateral thalamus (p<0.05, AlphaSim corrected, cluster size>44) but not with the contralateral thalamus (p<0.05, AlphaSim corrected, cluster size>43). The intrinsic and phasic alertness performances of the patients were impaired (p=0.001 and p<0.001, respectively) but not correlated with decreased thalamic FC. Meanwhile, the alertness performance was not altered in right TLE but was negatively correlated with decreased thalamic FC with ACC (p<0.05). CONCLUSIONS: Our findings highlight the functional importance of the thalamus in TLE pathology and suggest that damage to the thalamic resting-state functional networks, particularly ipsilateral to the epileptogenic focus, is present in patients with TLE.

Alteration of functional connectivity within visuospatial working memory-related brain network in patients with right temporal lobe epilepsy: a resting-state fMRI study.

PURPOSE: This study aimed to investigate the resting-state brain network related to visuospatial working memory (VSWM) in patients with right temporal lobe epilepsy (rTLE). The functional mechanism underlying the cognitive impairment in VSWM was also determined. METHOD: Fifteen patients with rTLE and 16 healthy controls matched for age, gender, and handedness underwent a 6-min resting-state functional MRI session and a neuropsychological test using VSWM_Nback. The VSWM-related brain network at rest was extracted using multiple independent component analysis; the spatial distribution and the functional connectivity (FC) parameters of the cerebral network were compared between groups. Behavioral data were subsequently correlated with the mean Z-value in voxels showing significant FC difference during intergroup comparison. RESULTS: The distribution of the VSWM-related resting-state network (RSN) in the group with rTLE was virtually consistent with that in the healthy controls. The distribution involved the dorsolateral prefrontal lobe and parietal lobe in the right hemisphere and the partial inferior parietal lobe and posterior lobe of the cerebellum in the left hemisphere (p<0.05, AlphaSim corrected). Between-group differences suggest that the group with rTLE had a decreased FC within the right superior frontal lobe (BA8), right middle frontal lobe, and right ventromedial prefrontal lobe compared with the controls (p<0.05, AlphaSim corrected). The regions of increased FC in rTLE were localized within the right superior frontal lobe (BA11), right superior parietal lobe, and left posterior lobe of the cerebellum (p<0.05, AlphaSim corrected). Moreover, patients with rTLE performed worse than controls in the VSWM_Nback test, and there were negative correlations between ACCmeanRT (2-back) and the mean Z-value in the voxels showing decreased or increased FC in rTLE (p<0.05). CONCLUSION: The results suggest that the alteration of the VSWM-related RSN might underpin the VSWM impairment in patients with rTLE and possibly implies a functional compensation by enlarging the FC within the ipsilateral cerebral network.

Expression of laminin ß1 and integrin α2 in the anterior temporal neocortex tissue of patients with intractable epilepsy.

We investigated the expression of laminin ß1 and integrin α2 in the anterior temporal neocortex tissue of patients with intractable epilepsy and explored the role of these molecules in the pathogenesis of this disease. Immunohistochemistry and immunofluorescence were used to test the expression of laminin ß1 and integrin α2 in samples (from the brain bank of our department, n=32) of surgically removed anterior temporal neocortex tissues from intractable epilepsy patients, and the results were compared with those of controls (n=10). We found that laminin ß1 and integrin α2 protein expression was significantly increased in the anterior temporal neocortex as compared with controls (immunohistochemistry optical density: laminin ß1 = 0.36 ± 0.01 vs. 0.10 ± 0.03 for control; integrin α2=0.42 ± 0.02 vs. 0.04 ± 0.01 for control; p<.05). Immunofluorescence staining indicated that laminin ß1 and integrin α2 accumulated in the plasma membrane and cytoplasm, with strong fluorescence intensity in the anterior temporal neocortex tissue of patients with intractable epilepsy. Thus, our work demonstrates that laminin ß1 and integrin α2 expression is elevated in the anterior temporal neocortex tissue from patients with intractable epilepsy.

Granulocyte colony-stimulating factor and stromal cell-derived factor-1 combination therapy: A more effective treatment for cerebral ischemic stroke.

BACKGROUND: Drugs that promote angiogenesis include statins, recombinant human granulocyte colony-stimulating factor, and stromal cell-derived factor-1. Low doses of atorvastatin could significantly increase the vascular expressions of endothelial growth factor, and the number of peripheral blood endothelial progenitor cells (EPCs), thus improving angiogenesis and local blood flow. G-CSF is an EPC-mobilization agent used in ischemia studies for targeting angiogenesis after cerebral ischemia via EPCs. In previous clinical trials, consistent conclusions have not been reached about the effectiveness of G-CSF on ischemic stroke. Therefore, the therapeutic effect of G-CSF and its combination with other medicines need further experimental verification. It is known that atorvastatin, rhG-CSF, and SDF-1 are considered the most promising neuroprotective candidates, but a comprehensive comparison of their effects is lacking. AIMS: To compare the effects of atorvastatin, stromal cell-derived factor-1, and recombinant human granulocyte colony-stimulating factor on ischemic stroke. METHODS: Adult male Sprague-Dawley rats were randomly allocated to three groups: normal, sham-operated, and middle cerebral artery occlusion operated. Middle cerebral artery occlusion operated rats were further allocated into saline, atorvastatin, recombinant human granulocyte colony-stimulating factor, and recombinant human granulocyte colony-stimulating factor + stromal cell-derived factor-1 groups. Neurological function evaluation, cerebral infarction and the blood-brain barrier integrity analysis, identification of angiogenic factors, assessment of angiogenesis, expression of growth-associated protein-43, neuroglobin, glial cell-derived neurotrophic factor, and cleaved caspase 3, were performed. RESULTS: Compared with atorvastatin or recombinant human granulocyte colony-stimulating factor alone, recombinant human granulocyte colony-stimulating factor + stromal cell-derived factor-1 treatment improved neurological performance, reduced cerebral infarction and blood-brain barrier disruption after stroke, and increased the content of stromal cell-derived factor-1, vascular endothelial growth factor, monocyte chemotactic protein 1, and basic fibroblast growth factor in peripheral blood. In addition, recombinant human granulocyte colony-stimulating factor + stromal cell-derived factor-1 promoted greater angiogenesis than atorvastatin or recombinant human granulocyte colony-stimulating factor alone and increased the expression of growth-associated protein-43, neuroglobin, and glial cell-derived neurotrophic factor, while decreasing the levels of cleaved caspase 3 in the brain after ischemic stroke. CONCLUSIONS: Combination therapy with recombinant human granulocyte colony-stimulating factor and stromal cell-derived factor-1 is more effective than atorvastatin or recombinant human granulocyte colony-stimulating factor alone in protecting against stroke-induced damage and could be an optimal therapeutic strategy for stroke.

Expression of laminin beta1 in hippocampi of patients with intractable epilepsy.

We investigated laminin beta1 expression in the hippocampi of patients with intractable epilepsy and explored the role of laminin beta1 in the pathogenesis of this condition. Fluorescence quantitative PCR, immunofluorescence, immunohistochemistry and Western blotting were used to measure laminin beta1 expression in surgically removed hippocampi of patients with intractable epilepsy, and the results were compared with control hippocampi. Fluorescence quantitative PCR showed increased expression of laminin beta1 mRNA in patient hippocampi compared with control tissues. Immunohistochemical staining demonstrated that laminin beta1 protein expression was significantly increased in patient hippocampi, and immunofluorescence microscopy showed accumulation of laminin beta1 in the cell membrane and cytoplasm of patient hippocampi. These findings were confirmed by Western blotting of protein preparations from patient hippocampi. Elevated expression of laminin beta1 mRNA and protein in the hippocampus suggests that laminin beta1 may play a role in the development of epileptic seizures in patients with intractable epilepsy.

Reduced self-regulation of cerebrum contributes to executive impairment in patients with temporal lobe epilepsy.

The aim of this study was to investigate the role of self-regulation of cerebrum in the executive impairment. 22 subjects were enrolled were assessed by a neuropsychological test of executive function using attentional networks test and the cerebral activity was evaluated by functional magnetic resonance imaging. The patients with TLE had a longer reaction time than controls (P < 0.05). Moreover, the healthy controls showed more right hemisphere lateralized activation in incongruent tasks. Finally, both positively and negatively correlated cerebral areas were found in the healthy controls but only negatively correlated cerebral areas were found in the TLE patients. Reduced cerebral lead to areas and lack of activation of right midline positively self-regulatory cerebral areas may executive impairment in TLE patients.