Xiaosong He

Presurgical thalamic “hubness” predicts surgical outcome in temporal lobe epilepsy

Objective: To characterize the presurgical brain functional architecture presented in patients with temporal lobe epilepsy (TLE) using graph theoretical measures of resting-state fMRI data and to test its association with surgical outcome. Methods: Fifty-six unilateral patients with TLE, who subsequently underwent anterior temporal lobectomy and were classified as obtaining a seizure-free (Engel class I, n = 35) vs not seizure-free (Engel classes II–IV, n = 21) outcome at 1 year after surgery, and 28 matched healthy controls were enrolled. On the basis of their presurgical resting-state functional connectivity, network properties, including nodal hubness (importance of a node to the network; degree, betweenness, and eigenvector centralities) and integration (global efficiency), were estimated and compared across our experimental groups. Cross-validations with support vector machine (SVM) were used to examine whether selective nodal hubness exceeded standard clinical characteristics in outcome prediction. Results: Compared to the seizure-free patients and healthy controls, the not seizure-free patients displayed a specific increase in nodal hubness (degree and eigenvector centralities) involving both the ipsilateral and contralateral thalami, contributed by an increase in the number of connections to regions distributed mostly in the contralateral hemisphere. Simulating removal of thalamus reduced network integration more dramatically in not seizure-free patients. Lastly, SVM models built on these thalamic hubness measures produced 76% prediction accuracy, while models built with standard clinical variables yielded only 58% accuracy (both were cross-validated). Conclusions: A thalamic network associated with seizure recurrence may already be established presurgically. Thalamic hubness can serve as a potential biomarker of surgical outcome, outperforming the clinical characteristics commonly used in epilepsy surgery centers.

Reduced thalamocortical functional connectivity in temporal lobe epilepsy.

In temporal lobe epilepsy (TLE), the thalamus is well known for its role in the propagation and spread of epileptiform activity. However, the integrity of thalamocortical functional connectivity (FC) in TLE and its relation to specific seizure patterns have not yet been determined. We address these issues with resting‐state functional magnetic resonance imaging (fMRI).

The Temporal Instability of Resting State Network Connectivity in Intractable Epilepsy

Focal epilepsies, such as temporal lobe epilepsy (TLE), are known to disrupt network activity in areas outside the epileptogenic zone [Tracy et al., 2015]. We devised a measure of temporal instability of resting state functional connectivity (FC), capturing temporal variations of BOLD correlations between brain regions that is less confounded than the “sliding window” approach common in the literature.

Gray Matter Abnormalities in Temporal Lobe Epilepsy: Relationships with Resting-State Functional Connectivity and Episodic Memory Performance.

Temporal lobe epilepsy (TLE) affects multiple brain regions through evidence from both structural (gray matter; GM) and functional connectivity (FC) studies. We tested whether these structural abnormalities were associated with FC abnormalities, and assessed the ability of these measures to explain episodic memory impairments in this population. A resting-state and T1 sequences were acquired on 94 (45 with mesial temporal pathology) TLE patients and 50 controls, using magnetic resonance imaging (MRI) technique. A voxel-based morphometry analysis was computed to determine the GM volume differences between groups (right, left TLE, controls). Resting-state FC between the abnormal GM volume regions was computed, and compared between groups. Finally, we investigated the relation between EM, GM and FC findings. Patients with and without temporal pathology were analyzed separately. The results revealed reduced GM volume in multiple regions in the patients relative to the controls. Using FC, we found the abnormal GM regions did not display abnormal functional connectivity. Lastly, we found in left TLE patients, verbal episodic memory was associated with abnormal left posterior hippocampus volume, while in right TLE, non-verbal episodic memory was better predicted by resting-state FC measures. This study investigated TLE abnormalities using a multi-modal approach combining GM, FC and neurocognitive measures. We did not find that the GM abnormalities were functionally or abnormally connected during an inter-ictal resting state, which may reflect a weak sensitivity of functional connectivity to the epileptic network. We provided evidence that verbal and non-verbal episodic memory in left and right TLE patients may have distinct relationships with structural and functional measures. Lastly, we provide data suggesting that in the setting of occult, non-lesional right TLE pathology, a coupling of structural and functional abnormalities in extra-temporal/non-ictal regions is necessary to produce reductions in episodic memory recall. The latter, in particular, demonstrates the complex structure/function interactions at work when trying to understand cognition in TLE, suggesting that subtle network effects can emerge bearing specific relationships to hemisphere and the type of pathology.

Predicting the laterality of temporal lobe epilepsy from PET, MRI, and DTI: A multimodal study.

Pre-surgical evaluation of patients with temporal lobe epilepsy (TLE) relies on information obtained from multiple neuroimaging modalities. The relationship between modalities and their combined power in predicting the seizure focus is currently unknown. We investigated asymmetries from three different modalities, PET (glucose metabolism), MRI (cortical thickness), and diffusion tensor imaging (DTI; white matter anisotropy) in 28 left and 30 right TLE patients (LTLE and RTLE). Stepwise logistic regression models were built from each modality separately and from all three combined, while bootstrapped methods and split-sample validation verified the robustness of predictions. Among all multimodal asymmetries, three PET asymmetries formed the best predictive model (100% success in full sample, >95% success in split-sample validation). The combinations of PET with other modalities did not perform better than PET alone. Probabilistic classifications were obtained for new clinical cases, which showed correct lateralization for 7/7 new TLE patients (100%) and for 4/5 operated patients with discordant or non-informative PET reports (80%). Metabolism showed closer relationship with white matter in LTLE and closer relationship with gray matter in RTLE. Our data suggest that metabolism is a powerful modality that can predict seizure laterality with high accuracy, and offers high value for automated predictive models. The side of epileptogenic focus can affect the relationship of metabolism with brain structure. The data and tools necessary to obtain classifications for new TLE patients are made publicly available.

From “rest” to language task: Task activation selects and prunes from broader resting-state network: Language Network Spatial Configuration Change

Resting‐state networks (RSNs) show spatial patterns generally consistent with networks revealed during cognitive tasks. However, the exact degree of overlap between these networks has not been clearly quantified. Such an investigation shows promise for decoding altered functional connectivity (FC) related to abnormal language functioning in clinical populations such as temporal lobe epilepsy (TLE). In this context, we investigated the network configurations during a language task and during resting state using FC. Twenty‐four healthy controls, 24 right and 24 left TLE patients completed a verb generation (VG) task and a resting‐state fMRI scan. We compared the language network revealed by the VG task with three FC‐based networks (seeding the left inferior frontal cortex (IFC)/Broca): two from the task (ON, OFF blocks) and one from the resting state. We found that, for both left TLE patients and controls, the RSN recruited regions bilaterally, whereas both VG‐on and VG‐off conditions produced more left‐lateralized FC networks, matching more closely with the activated language network. TLE brings with it variability in both task‐dependent and task‐independent networks, reflective of atypical language organization. Overall, our findings suggest that our RSN captured bilateral activity, reflecting a set of prepotent language regions. We propose that this relationship can be best understood by the notion of pruning or winnowing down of the larger language‐ready RSN to carry out specific task demands. Our data suggest that multiple types of network analyses may be needed to decode the association between language deficits and the underlying functional mechanisms altered by disease. Hum Brain Mapp 38:2540–2552, 2017.

Frontal gray matter abnormalities predict seizure outcome in refractory temporal lobe epilepsy patients

Developing more reliable predictors of seizure outcome following temporal lobe surgery for intractable epilepsy is an important clinical goal. In this context, we investigated patients with refractory temporal lobe epilepsy (TLE) before and after temporal resection. In detail, we explored gray matter (GM) volume change in relation with seizure outcome, using a voxel-based morphometry (VBM) approach. To do so, this study was divided into two parts. The first one involved group analysis of differences in regional GM volume between the groups (good outcome (GO), e.g., no seizures after surgery; poor outcome (PO), e.g., persistent postoperative seizures; and controls, N = 24 in each group), pre- and post-surgery. The second part of the study focused on pre-surgical data only (N = 61), determining whether the degree of GM abnormalities can predict surgical outcomes. For this second step, GM abnormalities were identified, within each lobe, in each patient when compared with an ad hoc sample of age-matched controls. For the first analysis, the results showed larger GM atrophy, mostly in the frontal lobe, in PO patients, relative to both GO patients and controls, pre-surgery. When comparing pre-to-post changes, we found relative GM gains in the GO but not in the PO patients, mostly in the non-resected hemisphere. For the second analysis, only the frontal lobe displayed reliable prediction of seizure outcome. 81% of the patients showing pre-surgical increased GM volume in the frontal lobe became seizure free, post-surgery; while 77% of the patients with pre-surgical reduced frontal GM volume had refractory seizures, post-surgery. A regression analysis revealed that the proportion of voxels with reduced frontal GM volume was a significant predictor of seizure outcome (p = 0.014). Importantly, having less than 1% of the frontal voxels with GM atrophy increased the likelihood of being seizure-free, post-surgery, by seven times. Overall, our results suggest that using pre-surgical GM abnormalities within the frontal lobe is a reliable predictor of seizure outcome post-surgery in TLE. We believe that this frontal GM atrophy captures seizure burden outside the pre-existing ictal temporal lobe, reflecting either the development of epileptogenesis or the loss of a protective, adaptive force helping to control or limit seizures. This study provides evidence of the potential of VBM-based approaches to predict surgical outcomes in refractory TLE candidates.

Task activation and functional connectivity show concordant memory laterality in temporal lobe epilepsy

OBJECTIVE In epilepsy, asymmetries in the organization of mesial temporal lobe (MTL) functions help determine the cognitive risk associated with procedures such as anterior temporal lobectomy. Past studies have investigated the change/shift in a visual episodic memory laterality index (LI) in mesial temporal lobe structures through functional magnetic resonance imaging (fMRI) task activations. Here, we examine whether underlying task-related functional connectivity (FC) is concordant with such standard fMRI laterality measures. METHODS A total of 56 patients with temporal lobe epilepsy (TLE) (Left TLE [LTLE]: 31; Right TLE [RTLE]: 25) and 34 matched healthy controls (HC) underwent fMRI scanning during performance of a scene encoding task (SET). We assessed an activation-based LI of the hippocampal gyrus (HG) and parahippocampal gyrus (PHG) during the SET and its correspondence with task-related FC measures. RESULTS Analyses involving the HG and PHG showed that the patients with LTLE had a consistently higher LI (right-lateralized) than that of the HC and group with RTLE, indicating functional reorganization. The patients with RTLE did not display a reliable contralateral shift away from the pathology, with the mesial structures showing quite distinct laterality patterns (HG, no laterality bias; PHG, no evidence of LI shift). The FC data for the group with LTLE provided confirmation of reorganization effects, revealing that a rightward task LI may be based on underlying connections between several left-sided regions (middle/superior occipital and left medial frontal gyri) and the right PHG. The FCs between the right HG and left anterior cingulate/medial frontal gyri were also observed in LTLE. Importantly, the data demonstrate that the areas involved in the LTLE task activation shift to the right hemisphere showed a corresponding increase in task-related FCs between the hemispheres. SIGNIFICANCE Altered laterality patterns based on mesial temporal lobe epilepsy (MTLE) pathology manifest as several different phenotypes, varying according to side of seizure onset and the specific mesial structures involved. There is good correspondence between task LI activation and FC patterns in the setting of LTLE, suggesting that reliable visual episodic memory reorganization may require both a shift in nodal activation and a change in nodal connectivity with mesial temporal structures involved in memory.

Ripple oscillations in the left temporal neocortex are associated with impaired verbal episodic memory encoding

BACKGROUND We sought to determine if ripple oscillations (80-120 Hz), detected in intracranial electroencephalogram (iEEG) recordings of patients with epilepsy, correlate with an enhancement or disruption of verbal episodic memory encoding. METHODS We defined ripple and spike events in depth iEEG recordings during list learning in 107 patients with focal epilepsy. We used logistic regression models (LRMs) to investigate the relationship between the occurrence of ripple and spike events during word presentation and the odds of successful word recall following a distractor epoch and included the seizure onset zone (SOZ) as a covariate in the LRMs. RESULTS We detected events during 58,312 word presentation trials from 7630 unique electrode sites. The probability of ripple on spike (RonS) events was increased in the SOZ (p < 0.04). In the left temporal neocortex, RonS events during word presentation corresponded with a decrease in the odds ratio (OR) of successful recall, however, this effect only met significance in the SOZ (OR of word recall: 0.71, 95% confidence interval (CI): 0.59-0.85, n = 158 events, adaptive Hochberg, p < 0.01). Ripple on oscillation (RonO) events that occurred in the left temporal neocortex non-SOZ also correlated with decreased odds of successful recall (OR: 0.52, 95% CI: 0.34-0.80, n = 140, adaptive Hochberg, p < 0.01). Spikes and RonS that occurred during word presentation in the left middle temporal gyrus (MTG) correlated with the most significant decrease in the odds of successful recall, irrespective of the location of the SOZ (adaptive Hochberg, p < 0.01). CONCLUSION Ripples and spikes generated in the left temporal neocortex are associated with impaired verbal episodic memory encoding. Although physiological and pathological ripple oscillations were not distinguished during cognitive tasks, our results show an association of undifferentiated ripples with impaired encoding. The effect was sometimes specific to regions outside the SOZ, suggesting that widespread effects of epilepsy outside the SOZ may contribute to cognitive impairment.