Functional connectivity between mesial temporal and default mode structures may help lateralize surgical temporal lobe epilepsy.

OBJECTIVE: The most common surgically treatable epilepsy syndrome is mesial temporal lobe epilepsy (mTLE). Preoperative noninvasive lateralization of mTLE is challenging in part due to rapid contralateral seizure spread. Abnormal connections in both the mesial temporal lobe and resting-state networks have been described in mTLE, but it is unclear if connectivity between these networks may aid in lateralization. METHODS: In 52 patients with left mTLE (LmTLE) or right mTLE (RmTLE) and 52 matched control subjects, the authors acquired 20 minutes of resting-state functional MRI (fMRI) and evaluated functional connectivity of bilateral hippocampi and amygdalae with selected resting-state networks. They used Pearson correlation, network-based statistic, and dynamic causal modeling. Also, to evaluate the clinical utility of a resting-state connectivity model in lateralizing unilateral presurgical mTLE patients, they used receiver operating characteristic curve analysis. RESULTS: RmTLE patients demonstrated decreased nondirected connectivity between the right hippocampus and default mode network compared with LmTLE patients and control subjects. Network-based statistic analysis revealed that the network with most decreased connectivity that distinguished LmTLE from RmTLE patients included the right hippocampus and amygdala, right lateral orbitofrontal cortices, and bilateral inferior parietal lobules, precuneus, and medial orbitofrontal cortices. Dynamic causal modeling analysis revealed that cross-hemispheric connectivity between hippocampi and amygdalae was predominantly inward toward the epileptogenic side. A regression model incorporating these connectivity patterns was used to accurately lateralize mTLE patients with an area under the receiver operating characteristic curve of 0.87. CONCLUSIONS: Evaluating fMRI connectivity between mesial temporal structures and default mode network may aid in mTLE lateralization, reduce need for intracranial monitoring, and guide surgical planning.

Temporal lobe epilepsy lateralisation and surgical outcome prediction using diffusion imaging.

OBJECTIVE: We sought to augment the presurgical workup of medically refractory temporal lobe epilepsy by creating a supervised machine learning technique that uses diffusion-weighted imaging to classify patient-specific seizure onset laterality and surgical outcome. METHODS: 151 subjects were included in this analysis: 62 patients (aged 18-68 years, 36 women) and 89 healthy controls (aged 18-71 years, 47 women). We created a supervised machine learning technique that uses diffusion-weighted metrics to classify subject groups. Specifically, we sought to classify patients versus healthy controls, unilateral versus bilateral temporal lobe epilepsy, left versus right temporal lobe epilepsy and seizure-free versus not seizure-free surgical outcome. We then reduced the dimensionality of derived features with community detection for ease of interpretation. RESULTS: We classified the subject groups in withheld testing data sets with a cross-fold average testing areas under the receiver operating characteristic curve of 0.745 for patients versus healthy controls, 1.000 for unilateral versus bilateral seizure onset, 0.662 for left versus right seizure onset, 0.800 for left-sided seizure-free vsersu not seizure-free surgical outcome and 0.775 for right-sided seizure-free versus not seizure-free surgical outcome. CONCLUSIONS: This technique classifies important clinical decisions in the presurgical workup of temporal lobe epilepsy by generating discerning white-matter features. We believe that this work augments existing network connectivity findings in the field by further elucidating important white-matter pathology in temporal lobe epilepsy. We hope that this work contributes to recent efforts aimed at using diffusion imaging as an augmentation to the presurgical workup of this devastating neurological disorder.

SEEG Functional Connectivity Measures to Identify Epileptogenic Zones: Stability, Medication Influence, and Recording Condition.

BACKGROUND AND OBJECTIVES: Functional connectivity (FC) measures can be used to differentiate epileptogenic zones (EZs) from non-EZs in patients with medically refractory epilepsy. Little work has been done to evaluate the stability of stereo-EEG (SEEG) FC measures over time and their relationship with antiseizure medication (ASM) use, a critical confounder in epilepsy FC studies. We aimed to answer the following questions: Are SEEG FC measures stable over time? Are they influenced by ASMs? Are they affected by patient data collection state? METHODS: In 32 patients with medically refractory focal epilepsy, we collected a single 2-minute prospective SEEG resting-state (awake, eyes closed) data set and consecutive 2-minute retrospective pseudo-rest (awake, eyes open) data sets for days 1-7 postimplantation. ASM dosages were recorded for days 1-7 postimplantation and drug load score (DLS) per day was calculated to standardize and compare across patients. FC was evaluated using directed and nondirected measures. Standard clinical interpretation of ictal SEEG was used to classify brain regions as EZs and non-EZs. RESULTS: Over 7 days, presumed EZs consistently had higher FC than non-EZs when using between imaginary coherence (ImCoh) and partial directed coherence (PDC) inward strength, without accounting for DLS. These measures were demonstrated to be stable over a short-term period of 3 consecutive days with the same DLS. Between ImCoh FC differences between EZs and non-EZs were reduced with DLS decreases, whereas other measures were not affected by DLS. FC differences between EZs and non-EZs were seen during both resting-state and pseudo-rest conditions; ImCoh values were strongly correlated between the 2 conditions, whereas PDC values were not. DISCUSSION: Inward and nondirected SEEG FC is higher in presumed EZs vs non-EZs and measures are stable over time. However, certain measures may be affected by ASM dose, as between ImCoh differences between EZs and non-EZs are less pronounced with lower doses, and other measures such as PDC are poorly correlated across recording conditions. These findings allow novel insight into how SEEG FC measures may aid surgical localization and how they are influenced by ASMs and other factors.

Role of the Nucleus Basalis as a Key Network Node in Temporal Lobe Epilepsy.

OBJECTIVE: To determine whether the nucleus basalis of Meynert (NBM) may be a key network structure of altered functional connectivity in temporal lobe epilepsy (TLE), we examined fMRI with network-based analyses. METHODS: We acquired resting-state fMRI in 40 adults with TLE and 40 matched healthy control participants. We calculated functional connectivity of NBM and used multiple complementary network-based analyses to explore the importance of NBM in TLE networks without biasing our results by our approach. We compared patients to controls and examined associations of network properties with disease metrics and neurocognitive testing. RESULTS: We observed marked decreases in connectivity between NBM and the rest of the brain in patients with TLE (0.91 ± 0.88, mean ± SD) vs controls (1.96 ± 1.13, p < 0.001, t test). Larger decreases in connectivity between NBM and fronto-parietal-insular regions were associated with higher frequency of consciousness-impairing seizures (r = -0.41, p = 0.008, Pearson). A core network of altered nodes in TLE included NBM ipsilateral to the epileptogenic side and bilateral limbic structures. Furthermore, normal community affiliation of ipsilateral NBM was lost in patients, and this structure displayed the most altered clustering coefficient of any node examined (3.46 ± 1.17 in controls vs 2.23 ± 0.93 in patients). Abnormal connectivity between NBM and subcortical arousal community was associated with modest neurocognitive deficits. Finally, a logistic regression model incorporating connectivity properties of ipsilateral NBM successfully distinguished patients from control datasets with moderately high accuracy (78%). CONCLUSIONS: These results suggest that while NBM is rarely studied in epilepsy, it may be one of the most perturbed network nodes in TLE, contributing to widespread neural effects in this disabling disorder.

People with mesial temporal lobe epilepsy have altered thalamo-occipital brain networks.

While temporal lobe epilepsy (TLE) is a focal epilepsy, previous work demonstrates that TLE causes widespread brain-network disruptions. Impaired visuospatial attention and learning in TLE may be related to thalamic arousal nuclei connectivity. Our prior preliminary work in a smaller patient cohort suggests that patients with TLE demonstrate abnormal functional connectivity between central lateral (CL) thalamic nucleus and medial occipital lobe. Others have shown pulvinar connectivity disturbances in TLE, but it is incompletely understood how TLE affects pulvinar subnuclei. Also, the effects of epilepsy surgery on thalamic functional connectivity remains poorly understood. In this study, we examine the effects of TLE on functional connectivity of two key thalamic arousal-nuclei: lateral pulvinar (PuL) and CL. We evaluate resting-state functional connectivity of the PuL and CL in 40 patients with TLE and 40 controls using fMRI. In 25 patients, postoperative images (>1 year) were also compared with preoperative images. Compared to controls, patients with TLE exhibit loss of normal positive connectivity between PuL and lateral occipital lobe (p < 0.05), and a loss of normal negative connectivity between CL and medial occipital lobe (p < 0.01, paired t-tests). FMRI amplitude of low-frequency fluctuation (ALFF) in TLE trended higher in ipsilateral PuL (p = 0.06), but was lower in the lateral occipital (p < 0.01) and medial occipital lobe in patients versus controls (p < 0.05, paired t-tests). More abnormal ALFF in the ipsilateral lateral occipital lobe is associated with worse preoperative performance on Rey Complex Figure Test Immediate (p < 0.05, r = 0.381) and Delayed scores (p < 0.05, r = 0.413, Pearson's Correlations). After surgery, connectivity between PuL and lateral occipital lobe remains abnormal in patients (p < 0.01), but connectivity between CL and medial occipital lobe improves and is no longer different from control values (p > 0.05, ANOVA, post hoc Fischer's LSD). In conclusion, thalamic arousal nuclei exhibit abnormal connectivity with occipital lobe in TLE, and some connections may improve after surgery. Studying thalamic arousal centers may help explain distal network disturbances in TLE.

Seizure-onset regions demonstrate high inward directed connectivity during resting-state: An SEEG study in focal epilepsy.

OBJECTIVE: In patients with medically refractory focal epilepsy, stereotactic-electroencephalography (SEEG) can aid in localizing epileptogenic regions for surgical treatment. SEEG, however, requires long hospitalizations to record seizures, and ictal interpretation can be incomplete or inaccurate. Our recent work showed that non-directed resting-state analyses may identify brain regions as epileptogenic or uninvolved. Our present objective is to map epileptogenic networks in greater detail and more accurately identify seizure-onset regions using directed resting-state SEEG connectivity. METHODS: In 25 patients with focal epilepsy who underwent SEEG, 2 minutes of resting-state, artifact-free, SEEG data were selected and functional connectivity was estimated. Using standard clinical interpretation, brain regions were classified into four categories: ictogenic, early propagation, irritative, or uninvolved. Three non-directed connectivity measures (mutual information [MI] strength, and imaginary coherence between and within regions) and four directed measures (partial directed coherence [PDC] and directed transfer function [DTF], inward and outward strength) were calculated. Logistic regression was used to generate a predictive model of ictogenicity. RESULTS: Ictogenic regions had the highest and uninvolved regions had the lowest MI strength. Although both PDC and DTF inward strengths were highest in ictogenic regions, outward strengths did not differ among categories. A model incorporating directed and nondirected connectivity measures demonstrated an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.88 in predicting ictogenicity of individual regions. The AUC of this model was 0.93 when restricted to patients with favorable postsurgical seizure outcomes. SIGNIFICANCE: Directed connectivity measures may help identify epileptogenic networks without requiring ictal recordings. Greater inward but not outward connectivity in ictogenic regions at rest may represent broad inhibitory input to prevent seizure generation.

Altered habenula to locus coeruleus functional connectivity in past anorexia nervosa suggests correlation with suicidality: a pilot study.

PURPOSE: Despite anorexia nervosa having the highest mortality rate of mental illnesses, little is known regarding the brain mechanisms involved. Given that lack of interest for food in anorexic patients is related to alterations in the reward system, we tested the hypothesis that patients with past anorexia nervosa (pAN) have altered resting state functional connectivity (RSFC) between the habenula (a major component of the reward system) and its targets. METHODS: RSFC between the habenula and major targets (locus coeruleus, median and dorsal raphe nuclei, substantia nigra, and ventral tegmental area) was studied in 14 psychiatric inpatients with pAN and 14 psychiatric inpatient controls (PC, never-anorexic patients in same clinic, matched for comorbidities). Next, we tested possible correlations between RSFC and suicidal ideation, depression, and anxiety as determined by self-report questionnaires. RESULTS: Left habenula/locus coeruleus RSFC was lower in pAN patients compared to PC. The left habenula/locus coeruleus RSFC was positively correlated with suicidal ideation (past 2 months) in pAN patients, but not in controls. CONCLUSIONS: pAN patients showed long lasting alterations in habenular connectivity. This may have clinical implications, possibly including future evaluation of the habenula as a therapeutic target and the need to carefully monitor suicidality in pAN patients. NO LEVEL OF EVIDENCE: Basic science.