Association Between Microstructural Asymmetry of Temporal Lobe White Matter and Memory Decline After Anterior Temporal Lobectomy.

BACKGROUND AND OBJECTIVES: Risk for memory decline is a substantial concern in patients with temporal lobe epilepsy (TLE) undergoing anterior temporal lobectomy (ATL). Although prior studies have identified associations between memory and integrity of white matter (WM) networks within the medial temporal lobe (MTL) preoperatively, we contribute a study examining whether microstructural asymmetry of deep and superficial WM networks within the MTL predicts postoperative memory decline. METHODS: Patients with drug-resistant TLE were recruited from 2 epilepsy centers in a prospective longitudinal study. All patients completed preoperative T1 and diffusion-weighted MRI (DWI) as well as preoperative and postoperative neuropsychological testing. Preoperative fractional anisotropy (FA) of the WM directly beneath the neocortex (i.e., superficial WM [SWM]) and of deep WM tracts associated with memory were calculated. Asymmetry was calculated for hippocampal volume and FA of each WM tract or region and examined in linear and logistic regressions with preoperative to postoperative memory change as the primary outcome. RESULTS: Data were analyzed from 42 patients with TLE (19 left TLE [LTLE], 23 right TLE [RTLE]) who underwent ATL. Leftward FA asymmetry of the entorhinal SWM was associated with decline on prose and associative recall in LTLE, whereas leftward FA asymmetry of the uncinate fasciculus (UNC) was associated with decline on prose recall only. After controlling for preoperative memory score and hippocampal volume, leftward FA asymmetry of the entorhinal SWM uniquely contributed to decline in both prose and associative recall (ß = -0.46; SE 0.14 and ß = -0.68; SE 0.22, respectively) and leftward FA asymmetry of the UNC uniquely contributed to decline in prose recall (ß = -0.31; SE 0.14). A model combining asymmetry of hippocampal volume and entorhinal FA correctly classified memory outcomes in 79% of patients with LTLE for prose (area under the curve [AUC] 0.89; sensitivity 82%; specificity 75%) and 81% of patients for associative (AUC 0.79; sensitivity 83%; specificity 80%) recall. Entorhinal SWM asymmetry was the strongest predictor in both models. DISCUSSION: Preoperative asymmetry of deep WM and SWM integrity within the MTL is a strong predictor of postoperative memory decline in TLE, suggesting that surgical decision-making may benefit from considering each patient's WM network adequacy and reserve in addition to hippocampal integrity. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that preoperative asymmetry of deep WM and SWM integrity within the MTL is a predictor of postoperative memory decline.

Impaired Behavioral Pattern Separation in Refractory Temporal Lobe Epilepsy and Mild Cognitive Impairment.

OBJECTIVE: Episodic memory impairment and hippocampal pathology are hallmark features of both temporal lobe epilepsy (TLE) and amnestic mild cognitive impairment (aMCI). Pattern separation (PS), which enables the distinction between similar but unique experiences, is thought to contribute to successful encoding and retrieval of episodic memories. Impaired PS has been proposed as a potential mechanism underling episodic memory impairment in aMCI, but this association is less established in TLE. In this study, we examined behavioral PS in patients with TLE and explored whether profiles of performance in TLE are similar to aMCI. METHOD: Patients with TLE, aMCI, and age-matched, healthy controls (HCs) completed a modified recognition task that relies on PS for the discrimination of highly similar lure items, the Mnemonic Similarity Task (MST). Group differences were evaluated and relationships between clinical characteristics, California Verbal Learning Test-Second Edition scores, and MST performance were tested in the TLE group. RESULTS: Patients with TLE and aMCI demonstrated poorer PS performance relative to the HCs, but performance did not differ between the two patient groups. Neither the side of seizure focus nor having hippocampal sclerosis affected performance in TLE. However, TLE patients with clinically defined memory impairment showed the poorest performance. CONCLUSION: Memory performance on a task that relies on PS was disrupted to a similar extent in TLE and aMCI. The MST could provide a clinically useful tool for measuring hippocampus-dependent memory impairments in TLE and other neurological disorders associated with hippocampal damage.

Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment.

Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle-associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop-gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4-aminopyridine and 3,4-diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live-cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild-type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of off-label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures. Aminopyridine treatment may extend to patients with pathogenic variants in VAMP2 and other genes influencing presynaptic function or GABAergic tone, and tested in vitro before treatment.

The white matter connectome as an individualized biomarker of language impairment in temporal lobe epilepsy.

OBJECTIVE: The distributed white matter network underlying language leads to difficulties in extracting clinically meaningful summaries of neural alterations leading to language impairment. Here we determine the predictive ability of the structural connectome (SC), compared with global measures of white matter tract microstructure and clinical data, to discriminate language impaired patients with temporal lobe epilepsy (TLE) from TLE patients without language impairment. METHODS: T1- and diffusion-MRI, clinical variables (CVs), and neuropsychological measures of naming and verbal fluency were available for 82 TLE patients. Prediction of language impairment was performed using a robust tree-based classifier (XGBoost) for three models: (1) a CV-model which included demographic and epilepsy-related clinical features, (2) an atlas-based tract-model, including four frontotemporal white matter association tracts implicated in language (i.e., the bilateral arcuate fasciculus, inferior frontal occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus), and (3) a SC-model based on diffusion MRI. For the association tracts, mean fractional anisotropy was calculated as a measure of white matter microstructure for each tract using a diffusion tensor atlas (i.e., AtlasTrack). The SC-model used measurement of cortical-cortical connections arising from a temporal lobe subnetwork derived using probabilistic tractography. Dimensionality reduction of the SC was performed with principal components analysis (PCA). Each model was trained on 49 patients from one epilepsy center and tested on 33 patients from a different center (i.e., an independent dataset). Randomization was performed to test the stability of the results. RESULTS: The SC-model yielded a greater area under the curve (AUC; .73) and accuracy (79%) compared to both the tract-model (AUC: .54, p < .001; accuracy: 70%, p < .001) and the CV-model (AUC: .59, p < .001; accuracy: 64%, p < .001). Within the SC-model, lateral temporal connections had the highest importance to model performance, including connections similar to language association tracts such as links between the superior temporal gyrus to pars opercularis. However, in addition to these connections many additional connections that were widely distributed, bilateral and interhemispheric in nature were identified as contributing to SC-model performance. CONCLUSION: The SC revealed a white matter network contributing to language impairment that was widely distributed, bilateral, and lateral temporal in nature. The distributed network underlying language may be why the SC-model has an advantage in identifying sub-components of the complex fiber networks most relevant for aspects of language performance.

Acute pediatric traumatic brain injury severity predicts long-term verbal memory performance through suppression by white matter integrity on diffusion tensor imaging.

Mediation analysis was used to investigate the role of white matter integrity in the relationship between injury severity and verbal memory performance in participants with chronic pediatric traumatic brain injury (TBI). DTI tractography was used to measure fractional anisotropy (FA) within the corpus callosum, fornix, cingulum bundles, perforant pathways, and uncinate fasciculi. Injury severity was indexed using Glasgow Coma Scale (GCS) scores obtained at the time of the injury. Verbal memory was measured by performance on the long-delay free recall (LDFR) trial of the California Verbal Learning Test-Children's version. Participants were between the ages of 10-18 and included 21 children with TBI (injured before age 9) and 19 typically-developing children (TDC). Children with TBI showed lower FA across all pathways and poorer LDFR performance relative to TDC. Within the TBI group, mediation analysis revealed neither a significant total effect of GCS on LDFR nor significant direct effects of GCS on LDFR across pathways; however, the indirect effects of GCS on LDFR through FA of the corpus callosum, left perforant pathway, and left uncinate fasciculus were significant and opposite in sign to their respective direct effects. These results suggests that the predictive validity of GCS for LDFR is initially suppressed by the substantial variance accounted for by FA, which is uncorrelated with GCS, and the predictive validity of GCS increases only when FA is considered, and the opposing path is controlled. These findings illustrate the complex associations between acute injury severity, white matter pathways, and verbal memory several years following pediatric TBI.

The impact of cerebrovascular risk factors on postoperative memory decline in patients with left temporal lobe epilepsy.

Cerebrovascular risk factors (CVRFs) and comorbid cardiovascular and metabolic disease have been linked to accelerated cognitive aging and dementia in the general population; however, the contribution of these comorbidities to the risk of post anterior temporal lobectomy (ATL) memory decline has been unexamined. We explored the effects of CVRFs on postoperative verbal memory decline in a cohort of 22 patients with left temporal lobe epilepsy (LTLE) who completed pre- and one-year postsurgical neuropsychological testing. Diagnoses of interest included preoperative cardiovascular and metabolic disorders, as well as CVRFs [pulse pressure proxy, body mass index (BMI), and fasting glucose]. Twenty-three percent of patients had a history of cardiovascular disease, 9% of metabolic disorders, and 38% had a BMI indicating overweight or obese status. Higher preoperative BMI and glucose were associated with greater decline in verbal memory. The association between BMI and memory decline remained significant after controlling for age and left hippocampal volume. These findings suggest that modifiable health-related risk factors, including CVRFs, may impact the risk of postoperative cognitive decline, and that BMI in particular could be an important factor to consider and/or target for intervention early in clinical care to protect cognitive health.

Auditory attention in autism spectrum disorder: An exploration of volumetric magnetic resonance imaging findings.

Studies have shown that individuals with autism spectrum disorder (ASD) tend to perform significantly below typically developing individuals on standardized measures of attention, even when controlling for IQ. The current study sought to examine within ASD whether anatomical correlates of attention performance differed between those with average to above-average IQ (AIQ group) and those with low-average to borderline ability (LIQ group) as well as in comparison to typically developing controls (TDC). Using automated volumetric analyses, we examined regional volume of classic attention areas including the superior frontal gyrus, anterior cingulate cortex, and precuneus in ASD AIQ (n = 38) and LIQ (n = 18) individuals along with 30 TDC. Auditory attention performance was assessed using subtests of the Test of Memory and Learning (TOMAL) compared among the groups and then correlated with regional brain volumes. Analyses revealed group differences in attention. The three groups did not differ significantly on any auditory attention-related brain volumes; however, trends toward significant size-attention function interactions were observed. Negative correlations were found between the volume of the precuneus and auditory attention performance for the AIQ ASD group, indicating larger volume related to poorer performance. Implications for general attention functioning and dysfunctional neural connectivity in ASD are discussed.