Human visuoperceptual functions can be divided according to their neuroanatomical substrates: processing 'what' an object is depends largely on ventral occipitotemporal regions, whereas processing 'where' an object is relies more on dorsal occipitoparietal regions. Although much is known regarding the mature incarnation of this ventral/ dorsal dissociation, little is known about how it develops. The current study addressed this with two experiments that involved both typically-developing children and healthy adults, as well as adult individuals with Williams Syndrome (WS), a genetically-based neurodevelopmental disorder for which dissociations in ventral-dorsal stream processing have been reported. The first experiment examined behavioral performance on two matched tasks differing only in their instructions: attend to stimulus identity (face identity-matching; ventral stream) or to stimulus position (face location-matching; dorsal stream). The second experiment examined patterns of brain activation on these same tasks using functional magnetic resonance imaging (FMRI) with each of the three populations. By virtue of including both typical adults and children (chronological age, CA, and mental age, MA, controls for the WS participants) in addition to WS participants, these experiments were well poised to provide both insight into the normal development of ventral and dorsal stream processing, and critical information regarding the integrity of these systems in WS. Thirty-three individuals with WS (age M̲ = 27.2 years), 19 MA controls (age M̲ = 9.0 years), and 24 CA controls (age ̲M̲ = 20.7 years) participated in the behavioral experiment. Although overall, typical children (MA controls) responded less accurately and more slowly than adults (CA controls), like adults, their performance did not differ across the identity- and location-matching tasks. By contrast, WS participants showed a pronounced and selective deficit in location-matching when compared with MA controls, but comparable performance on identity- matching. This finding in WS provides empirical support for numerous reports of face processing skills that far exceed general spatial ability in WS. This dissociation is not observed during the course of normal development. Based on this finding, it was hypothesized that the subsequent brain imaging experiment would reveal differentially impacted function in the ventral and dorsal visual streams in WS when compared with typically- developing participants. In the second experiment, both cognitive and FMRI data were collected from a second set of participants: 15 with WS (age M̲ = 30.1 years), 16 MA controls (age M̲ = 8.9 years), and 17 CA controls (age M̲ = 31.0 years; individually age- and gender-matched to the WS participants). In accordance with their cognitive profile (performance on both tasks that had not quite reached the level of CA controls) MA controls recruited many of the same regions as CA controls, but also differed from them in certain key task-related regions. These regions included the face-preferring temporal fusiform gyrus of the left hemisphere (LH) during identity-matching and superior parietal cortex in the LH during location- matching. Given that most critical task-related regions reside in the right hemisphere (RH) (RH fusiform gyrus for face discrimination, RH parietal cortex for location processing), these findings appear to reflect protracted maturation of task-sensitive regions in the nondominant hemisphere. When compared with profiles of activation in MA and CA controls, brain response in WS participants was abnormal. In accordance with their profound location- matching deficits, WS participants showed a striking lack of location-matching activation in parietal cortex, a finding that isconsistent with a dorsal stream deficit hypothesized in this disorder. However, at variance with hypotheses of spared face discrimination and ventral stream function in WS, the brain response was also abnormal for face identity-matching, even though cognitively, WS participants performed this task at the level of MA controls. Abnormalities in WS manifested as a poorly modulated response of the fusiform gyrus, a lack of response in the amygdala, and surprisingly, an abnormally heightened response in a portion of parietal cortex that was not engaged by the task in MA or CA controls. The latter two findings are of particular interest because they may relate to an unusually strong preference for face -to-face social interaction (often described as "hypersociability") that has been described in the WS population

Objective

Emerging research highlights the importance of basal-temporal cortex, centered on the fusiform gyrus, to both pre-surgical naming ability and post-surgical naming outcomes in temporal lobe epilepsy (TLE). In this study, we investigate whether integrity of the white matter network that interconnects this basal region to the distributed language network affects naming ability and risk for post-surgical naming decline.

Methods

Patients with drug-resistant TLE were recruited from two epilepsy centers in a prospective longitudinal study. The pre-surgical dataset included 50 healthy controls, 47 left TLE (L-TLE), and 41 right TLE (R-TLE) patients. All participants completed pre-surgical T1- and diffusion-weighted MRI (dMRI), as well as neuropsychological tests of auditory and visual naming. Nineteen L-TLE and 18 R-TLE patients underwent anterior temporal lobectomy (ATL) and also completed post-surgical neuropsychological testing. Pre-surgical fractional anisotropy (FA) of the white matter directly beneath the fusiform neocortex (i.e., superficial white matter; SWM) and of deep white matter tracts with connections to the basal-temporal cortex [inferior longitudinal fasciculus (ILF) and inferior frontal occipital fasciculus (IFOF)] was calculated. Clinical variables, hippocampal volume, and FA of each white matter tract or region were examined in linear regressions with naming scores, or change in naming scores, as the primary outcomes.

Results

Pre-surgically, higher FA in the bilateral ILF, bilateral IFOF, and left fusiform SWM was associated with better visual and auditory naming scores (all ps < 0.05 with FDR correction). In L-TLE, higher pre-surgical FA was also associated with less naming decline post-surgically, but results varied across tracts. When including only patients with typical language dominance, only integrity of the right fusiform SWM was associated with less visual naming decline (p = .0018).

Discussion

Although a broad network of white matter network matter may contribute to naming ability pre-surgically, the reserve capacity of the contralateral (right) fusiform SWM may be important for mitigating visual naming decline following ATL in L-TLE. This shows that the study of the structural network interconnecting the basal-temporal region to the wider language network has implications for understanding both pre- and post-surgical naming in TLE.

OBJECTIVE:To identify distinct cognitive phenotypes in temporal lobe epilepsy (TLE) and evaluate patterns of white matter (WM) network alterations associated with each phenotype. METHODS:Seventy patients with TLE were characterized into 4 distinct cognitive phenotypes based on patterns of impairment in language and verbal memory measures (language and memory impaired, memory impaired only, language impaired only, no impairment). Diffusion tensor imaging was obtained in all patients and in 46 healthy controls (HC). Fractional anisotropy (FA) and mean diffusivity (MD) of the WM directly beneath neocortex (i.e., superficial WM [SWM]) and of deep WM tracts associated with memory and language were calculated for each phenotype. Regional and network-based SWM analyses were performed across phenotypes. RESULTS:The language and memory impaired group and the memory impaired group showed distinct patterns of microstructural abnormalities in SWM relative to HC. In addition, the language and memory impaired group showed widespread alterations in WM tracts and altered global SWM network topology. Patients with isolated language impairment exhibited poor network structure within perisylvian cortex, despite relatively intact global SWM network structure, whereas patients with no impairment appeared similar to HC across all measures. CONCLUSIONS:These findings demonstrate a differential pattern of WM microstructural abnormalities across distinct cognitive phenotypes in TLE that can be appreciated at both the regional and network levels. These findings not only help to unravel the underlying neurobiology associated with cognitive impairment in TLE, but they could also aid in establishing cognitive taxonomies or in the prediction of cognitive course in TLE.

Objective

Individuals with temporal lobe epilepsy (TLE) often experience diminished quality of life (QoL). Although comorbid depression is one of the most recognized predictors of poor QoL in TLE, impairments in verbal memory (VM) and executive functioning (EF), have also been identified as risk factors, independent of other biological and psychosocial factors. In this study, we examine the contribution of depression, VM, and EF to QoL in 52 well-characterized medically-refractory TLE patients.

Methods

Quality of life was assessed with the Quality of Life in Epilepsy (QOLIE-31) questionnaire and depression symptomatology was evaluated with the Beck Depression Inventory-II (BDI-II). Tests of VM included the California Verbal Learning Test-Second Edition and the Wechsler Memory Scale-Third Edition, Logical Memory and Verbal Paired Associates subtests. Tests of EF included the D-KEFS Category Switching and Color Word Interference Tests, and the Trail Making Test. Using these measures, a principal component (PC) was derived for VM and for EF. Hierarchical multiple linear regression analysis was used to evaluate the unique contributions of BDI-II Score, VM PC, and EF PC to the QOLIE-31 Total Score, while controlling for important clinical and demographic variables. Post-hoc analyses were also performed to examine the contribution of each variable to specific QOLIE subscales.

Results

Of the clinical variables, only number of antiepileptic drugs contributed to QOLIE scores. As expected, severity of depressive symptoms was the most significant predictor of QOLIE Total Score, explaining 43.4% of the variance in total QoL. The VM PC did not contribute to the QOLIE Total Score. Rather, our EF PC emerged as an important predictor of QoL, explaining an additional 5% of the variance, after controlling for clinical variables, depression severity, and VM performance.

Significance

These findings suggest that a combination of clinical, affective, and cognitive factors influence QoL in patients with TLE. Designing interventions with careful attention to depression and EF may be needed to optimize QoL in patients with refractory TLE and potentially other epilepsy syndromes.

Objectives

Temporal lobe epilepsy (TLE) is known to affect large-scale gray and white matter networks, and these network changes likely contribute to the verbal memory impairments observed in many patients. In this study, we investigate multimodal imaging patterns of brain alterations in TLE and evaluate the sensitivity of different imaging measures to verbal memory impairment.

Methods

Diffusion tensor imaging (DTI), volumetric magnetic resonance imaging (vMRI), and resting-state functional MRI (rs-fMRI) were evaluated in 46 patients with TLE and 33 healthy controls to measure patterns of microstructural, structural, and functional alterations, respectively. These measurements were obtained within the white matter directly beneath neocortex (ie, superficial white matter [SWM]) for DTI and across neocortex for vMRI and rs-fMRI. The degree to which imaging alterations within left medial temporal lobe/posterior cingulate (LMT/PC) and left lateral temporal regions were associated with verbal memory performance was evaluated.

Results

Patients with left TLE and right TLE both demonstrated pronounced microstructural alterations (ie, decreased fractional anisotropy [FA] and increased mean diffusivity [MD]) spanning the entire frontal and temporolimbic SWM, which were highly lateralized to the ipsilateral hemisphere. Conversely, reductions in cortical thickness in vMRI and alterations in the magnitude of the rs-fMRI response were less pronounced and less lateralized than the microstructural changes. Both stepwise regression and mediation analyses further revealed that FA and MD within SWM in LMT/PC regions were the most robust predictors of verbal memory, and that these associations were independent of left hippocampal volume.

Significance

These findings suggest that microstructural loss within the SWM is pronounced in patients with TLE, and injury to the SWM within the LMT/PC region plays a critical role in verbal memory impairment.

Objective

Diffusion tensor imaging (DTI) has become a popular tool for delineating the location and extent of white matter injury in temporal lobe epilepsy (TLE). However, DTI yields nonspecific measures that are confounded by changes occurring within both the intracellular and extracellular environments. This study investigated whether an advanced diffusion method, restriction spectrum imaging (RSI) could provide a more robust measure of white matter injury in TLE relative to DTI due to RSI's ability to separate intraaxonal diffusion (i.e., neurite density; ND) from diffusion associated with extraaxonal factors (e.g., inflammation; crossing fibers).

Methods

RSI and DTI scans were obtained on 21 patients with TLE and 11 age-matched controls. RSI-derived maps of ND, isotropic-hindered (IH) and isotropic-free (IF) water, and crossing fibers (CFs) were compared to DTI-derived fractional anisotropy (FA) maps. Voxelwise and tract-based analyses were performed comparing patients with TLE to controls on each diffusion metric.

Results

Reductions in FA were seen primarily in frontotemporal white matter in TLE, and they were most pronounced proximal to the seizure focus. Reductions in ND corresponded to those seen in the FA maps; however, ND reductions were greater in magnitude, more lateralized to the epileptogenic hemisphere, and showed a broader pattern. Increases in IF/IH and effects from CFs also contributed to reduced FA in the ipsilateral parahippocampal cingulum and fornix, with decreases in IH extending into extratemporal regions. Reduced ND of the uncinate fasciculus was associated with longer disease duration, whereas FA was not associated with any clinical variables.

Significance

RSI may provide a more specific measure of white matter pathology in TLE, distinguishing regions primarily affected by axonal/myelin loss from those where CFs and increases in extracellular water also play a role. By providing a more specific measure of axonal/myelin loss, RSI-derived ND may better reflect overall white matter burden in epilepsy.

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 (β = -0.46; SE 0.14 and β = -0.68; SE 0.22, respectively) and leftward FA asymmetry of the UNC uniquely contributed to decline in prose recall (β = -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.

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.

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.

This study explored the relationships among multimodal imaging, clinical features, and language impairment in patients with left temporal lobe epilepsy (LTLE). Fourteen patients with LTLE and 26 controls underwent structural MRI, functional MRI, diffusion tensor imaging, and neuropsychological language tasks. Laterality indices were calculated for each imaging modality and a principal component (PC) was derived from language measures. Correlations were performed among imaging measures, as well as to the language PC. In controls, better language performance was associated with stronger left-lateralized temporo-parietal and temporo-occipital activations. In LTLE, better language performance was associated with stronger right-lateralized inferior frontal, temporo-parietal, and temporo-occipital activations. These right-lateralized activations in LTLE were associated with right-lateralized arcuate fasciculus fractional anisotropy. These data suggest that interhemispheric language reorganization in LTLE is associated with alterations to perisylvian white matter. These concurrent structural and functional shifts from left to right may help to mitigate language impairment in LTLE.