Verbal Learning and Longitudinal Hippocampal Network Connectivity in Temporal Lobe Epilepsy Surgery.

Introduction: Learning new verbal information can be impaired in 20-40% of patients after mesial temporal lobe resection. In recent years, understanding epilepsy as a brain network disease, and investigating the relationship between large-scale resting networks and cognition has led to several advances. Aligned studies suggest that it is the integrity of the hippocampal connectivity with these large-scale networks what is relevant for cognition, with evidence showing a functional and structural heterogeneity along the long axis hippocampus bilaterally. Objective: Our aim is to examine whether pre-operative resting-state connectivity along the long hippocampal axis is associated with verbal learning decline after anterior temporal lobe resection. Methods: Thirty-one patients with epilepsy who underwent an anterior temporal lobe resection were pre-surgically scanned at 3-tesla, and pre/post-surgery evaluated for learning deficits using the Rey Auditory Verbal Learning Task (RAVLT). Eighteen controls matched by age, gender and handedness were also scanned and evaluated with the RAVLT. We studied the functional connectivity along the (anterior/posterior) long axis hippocampal subregions and resting-state functionally-defined brain networks involved in learning [executive (EXE), dorsal attention (DAN) and default-mode (DMN) networks]. Functional connectivity differences between the two groups of patients (learning intact or with learning decline) and controls were investigated with MANOVA and discriminant analysis. Results: There were significant differences in the pattern of hippocampal connectivity among the groups. Regarding the anterior connectivity hippocampal pattern, our data showed an increase of connectivity in the pathological side with the DAN (p = 0.011) and the EXE (p = 0.008) when comparing learning-decline vs. learning-intact patients. Moreover, the non-pathological side showed an increase in the anterior connectivity pattern with the DAN (p = 0.027) between learning-decline vs. learning-intact patients. In contrast, the posterior hippocampus showed a reduction of connectivity in the learning-decline patients with the DMN, both in the pathological (p = 0.004) and the non-pathological sides (p = 0.036). Finally, the discriminant analysis based on the pre-operative connectivity pattern significantly differentiated the learning-decline patients from the other groups (p = 0.019). Conclusion: Our findings reveal bilateral connectivity disruptions along the longitudinal axis of the hippocampi with resting-state networks, which could be key to identify those patients at risk of verbal learning decline after epilepsy surgery.

Mapping connectivity fingerprints for presurgical evaluation of temporal lobe epilepsy.

BACKGROUND: Surgery may render temporal lobe epilepsy (TLE) patients seizure-free. However, TLE is a heterogenous entity and surgical prognosis varies between patients. Network-based biomarkers have been shown to be altered in TLE patients and hold promise for classifying TLE subtypes and improving pre-surgical prognosis. The aim of the present study is to investigate a network-based biomarker, the weighted degree of connectivity (wDC), on an individual level, and its relation to TLE subtypes and surgical prognosis. METHODS: Thirty unilateral TLE patients undergoing the same surgical procedure (anterior temporal resection) and 18 healthy controls were included. All patients were followed-up in the same center for a mean time of 6.85 years and classified as seizure-free (SF) and non seizure-free (non-SF). Using pre-surgical resting state functional MRI, whole brain wDC values for patients and controls were calculated. Then, we divided both temporal lobes in three Regions-of-interest (ROIs) -mesial, pole and lateral- as these areas are known to behave differently in seizure onset and propagation, delimiting different TLE profiles. The wDC values for the defined ROIs of each individual patient were compared with the healthy group. RESULTS: After surgery, 14 TLE patients remained SF. As a group, patients had higher wDC than controls in both the temporal pole (p < 0.05) as well as in the mesial regions (p < 0.002) of the to-be-resected temporal lobe. When comparing between SF and non-SF patients, a step-wise binary logistic regression model including all the ROIs, showed that having an increased wDC of the temporal pole (p < 0.05) and the mesial area (p < 0.05) of the to-be-resected temporal lobe was associated with seizure freedom long-term after surgery. CONCLUSIONS: This study provides a network-based presurgical biomarker that could pave the way towards personalized prediction. In patients with TLE undergoing anterior temporal resections, having an increased wDC at rest could be a signature of the epileptogenic area, and could help identifying those patients who would benefit most from surgery.

Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.

Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.

Theta rhythm supports hippocampus-dependent integrative encoding in schematic/semantic memory networks.

Integrating new information into existing schematic/semantic structures of knowledge is the basis of learning in our everyday life as it enables structured representation of information and goal-directed behaviour in an ever-changing environment. However, how schematic/semantic mnemonic structures aid the integration of novel elements remains poorly understood. Here, we showed that the ability to integrate novel picture information into learned structures of picture associations that overlapped by the same picture scene (i.e., simple network) or by a conceptually related picture scene (i.e., schematic/semantic network) is hippocampus-dependent, as patients with lesions at the medial temporal lobe (including the hippocampus) were impaired in inferring novel relations between pictures within these memory networks. We also found more persistent and widespread scalp EEG theta oscillations (3-5 Hz) while participants integrated novel pictures into schematic/semantic memory networks than into simple networks. On the other hand, greater neural similarity was observed between EEG patterns elicited by novel and related events within simple networks than between novel and related events within schematic/semantic memory networks. These findings have important implications for our understanding of the neural mechanisms that support the development and organization of structures of knowledge.

Hippocampal microstructural architecture and surgical outcome: Hippocampal diffusivity could predict seizure relapse.

PURPOSE: Our aim was to study the microstructural architecture of the contralateral hippocampus to the affected side in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and its relation with surgical outcome. METHOD: We included 33 consecutive patients evaluated in our epilepsy surgery program during a five-year period. They underwent a presurgical MRI with volumetric T1 and diffusion weighted sequences. 22 patients with TLE-HS (13 women, 12 right TLE-HS) were finally selected. Median follow-up after surgery was 6.25 years (4.5-8.83 years). We segmented the hippocampal subfields of the contralateral hippocampus using FreeSurfer and calculated the fractional anisotropy (FA) and the mean diffusivity (MD) of each subfield. We also scanned 18 healthy age-matched controls. RESULTS: After surgery, 50 % of the patients (n = 11) remained seizure-free (SF) following surgery. Comparing non-SF to SF patients, the MD showed increased values of the CA1 (p = 0.035), the molecular layer (p = 0.010) and the dentate gyrus (p = 0.041) in the healthy hippocampus. Using a cut-off point for a survival analysis, we found that patients with lower values of MD of the molecular layer and the CA1 remained SF during long-term post-operative follow-up (p < 0.0001). CONCLUSIONS: The contralateral hippocampal internal microstructure may have be implicated in post-surgery seizure freedom in patients with TLE-HS.

Autobiographical memory in epileptic patients after temporal lobe resection or bitemporal hippocampal sclerosis.

The human hippocampus is believed to be a crucial node in the neural network supporting autobiographical memory retrieval. Structural mesial temporal damage associated with temporal lobe epilepsy (TLE) provides an opportunity to systematically investigate and better understand the local and distal functional consequences of mesial temporal damage in the engagement of the autobiographical memory network. We examined 19 TLE patients (49.21 ± 11.55 years; 12 females) with unilateral mesial TLE (MTLE; 12 with anterior temporal lobe resection: 6 right MTLE, 6 left MTLE) or bilateral mesial TLE (7 BMTLE) and 18 matched healthy subjects. We used functional MRI (fMRI) with an adapted autobiographical memory paradigm and a specific neuropsychological test (Autobiographical Memory Interview, AMI). While engaged in the fMRI autobiographical memory paradigm, all groups activated a large fronto-temporo-parietal network. However, while this network was left lateralized for healthy participants and right MTLE patients, left MTLE and patients with BMTLE also showed strong activation in right temporal and frontal regions. Moreover, BMTLE and left MTLE patients also showed significant mild deficits in episodic autobiographical memory performance measured with the AMI test. The right temporal and extra-temporal fMRI activation, along with the impairment in autobiographical memory retrieval found in left MTLE and BMTLE patients suggest that alternate brain areas-other than the hippocampus-may also support this process, possibly due to neuroplastic effects.

Antithyroid antibodies as a potential marker of autoimmune-mediated late onset temporal lobe epilepsy.

UNLABELLED: In one third of patients with epilepsy starting in adulthood the aetiology remains undetermined. Some patients with late onset temporal lobe epilepsy (TLE) together with memory decline have elevated antithyroid antibodies. PURPOSE: To compare the prevalence of antithyroid antibodies (aTR-ab) in adult onset temporal lobe epilepsy (TLE) patients with known and unknown TLE aetiology (N=42). Moreover, the sera of these patients was also assayed for antinuclear antibodies (ANA), anticardiolipin antibodies (ACL), anti glutamic acid decarboxylase antibodies (GAD) and antiglidadin antibodies. RESULTS: Positive aTR-ab in the sera of patients with unknown aetiology was 11/23 (47.8%) vs. 1/19 (4.3%) in the group with known aetiology (p=0.005). In 9/11 (81%) a pre-existing autoimmune disease was confirmed. Nine (81%) were women and five (45%) had memory impairment. There were 5/11 (45%) pharmacoresistant patients, and corticosteroid treatment was initiated in 3/5 with cognitive and seizure improvement. The results of other immunological tests were only remarkable for antiGAD antibodies with 3/11 (27%) positive patients, but this subgroup does not have any significant clinical differential feature. CONCLUSIONS: Late-onset TLE with positive aTR-ab tends to be middle-aged women with nonpharmacoresistant cryptogenic epilepsy plus cognitive decline and other associated autoimmune diseases. It could be advisable to test aTR-ab in TLE patients with an unknown aetiology, in order to improve diagnosis and resulting treatment.