Does bilingualism increase brain or cognitive reserve in patients with temporal lobe epilepsy?

OBJECTIVE: Bilingual healthy adults have been shown to exhibit an advantage in executive functioning (EF) that is associated with microstructural changes in white matter (WM) networks. Patients with temporal lobe epilepsy (TLE) often show EF deficits that are associated with WM compromise. In this study, we investigate whether bilingualism can increase cognitive reserve and/or brain reserve in bilingual patients with TLE, mitigating EF impairment and WM compromise. METHODS: Diffusion tensor imaging was obtained in 19 bilingual and 26 monolingual patients with TLE, 12 bilingual healthy controls (HC), and 21 monolingual HC. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated for the uncinate fasciculus (Unc) and cingulum (Cing), superior frontostriatal tract (SFS), and inferior frontostriatal tract (IFS). Measures of EF included Trail Making Test-B (TMT-B) and Delis-Kaplan Executive Function System Color-Word Inhibition/Switching. Analyses of covariance were conducted to compare FA and MD of the Unc, Cing, SFS, and IFS and EF performance across groups. RESULTS: In bilingual patients, FA was lower in the ipsilateral Cing and Unc compared to all other groups. For both patient groups, MD of the ipsilateral Unc was higher relative to HC. Despite more pronounced reductions in WM integrity, bilingual patients performed similarly to monolingual TLE and both HC groups on EF measures. By contrast, monolingual patients performed worse than HC on TMT-B. In addition, differences in group means between bilingual and monolingual patients on TMT-B approached significance when controlling for the extent of WM damage (P = .071; d = 0.62), suggesting a tendency toward higher performance for bilingual patients. SIGNIFICANCE: Despite poorer integrity of regional frontal lobe WM, bilingual patients performed similarly to monolingual patients and HC on EF measures. These findings align with studies suggesting that bilingualism may provide a protective factor for individuals with neurological disease, potentially through reorganization of EF networks that promote greater cognitive reserve.

Multimodal imaging of language reorganization in patients with left temporal lobe epilepsy.

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.

Frontolimbic brain networks predict depressive symptoms in temporal lobe epilepsy.

Psychiatric co-morbidities in epilepsy are of great concern. The current study investigated the relative contribution of structural and functional connectivity (FC) between medial temporal (MT) and prefrontal regions in predicting levels of depressive symptoms in patients with temporal lobe epilepsy (TLE). Twenty-one patients with TLE [11 left TLE (LTLE); 10 right TLE (RTLE)] and 20 controls participated. Diffusion tensor imaging was performed to obtain fractional anisotropy (FA) of the uncinate fasciculus (UF), and mean diffusivity (MD) of the amygdala (AM) and hippocampus (HC). Functional MRI was performed to obtain FC strengths between the AM and HC and prefrontal regions of interest including anterior prefrontal (APF), orbitofrontal, and inferior frontal regions. Participants self-reported depression symptoms on the Beck Depression Inventory-II. Greater depressive symptoms were associated with stronger FC of ipsilateral HC-APF, lower FA of the bilateral UF, and higher MD of the ipsilateral HC in LTLE, and with lower FA of the contralateral UF in RTLE. Regression analyses indicated that FC of the ipsilateral HC-APF was the strongest contributor to depression in LTLE, explaining 68.7% of the variance in depression scores. Both functional and microstructural measures of frontolimbic dysfunction were associated with depressive symptoms. These connectivity variables may be moderating which patients present with depression symptoms. In particular, FC MRI may provide a more sensitive measure of depression-related dysfunction, at least in patients with LTLE. Employing sensitive measures of frontolimbic network dysfunction in TLE may help provide new insight into mood disorders in epilepsy that could eventually guide treatment planning.

ERP abnormalities elicited by word repetition in fragile X-associated tremor/ataxia syndrome (FXTAS) and amnestic MCI.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder caused by FMR1 gene premutations, typically associated with frontal-subcortical type cognitive impairments. High prevalence (~50%) of superimposed Alzheimer׳s pathology has been reported in FMR1 premutation carriers, and standardized neuropsychological tests have not yielded any robust discriminators between FXTAS and Alzheimer׳s disease (AD) dementia. The similarities/differences in memory processes between FXTAS and early AD remain underexplored. METHODS: 32-channel event-related potentials (ERPs) were obtained from a semantic judgment task in which semantically congruous (50%) and incongruous pairs repeat pseudorandomly. The N400 and late positive component (LPC) of 25 FXTAS patients (M(age)=71.2, MMSE=26.6) were compared to a matched group of 25 patients with MCI or early AD (1 mild AD dementia, 24 amnestic MCI, of whom 18 later converted to AD; M(age)=73.4, MMSE=26.4), and 25 healthy elderly. RESULTS: Both patient groups showed similar reductions in the N400 repetition effect and N400 congruity effect amplitudes, compared to controls, reflecting abnormal semantic priming and repetition priming. The MCI/AD group, however, had significantly smaller LPC word repetition effects and poorer learning and memory on the CVLT than FXTAS. The LPC and N400 repetition effects both correlated with verbal memory across all subjects, but only N400 correlated with memory in FXTAS. CONCLUSION: FXTAS patients show relative sparing of the LPC repetition effect, and less disruption of explicit memory than prodromal/early AD. N400 abnormalities in FXTAS appear to account for much of their mild impairments in verbal learning and memory.

White matter microstructure complements morphometry for predicting verbal memory in epilepsy.

Verbal memory is the most commonly impaired cognitive domain in patients with temporal lobe epilepsy (TLE). Although damage to the hippocampus and adjacent temporal lobe structures is known to contribute to memory impairment, little is known of the relative contributions of white versus gray matter structures, or whether microstructural versus morphometric measures of temporal lobe pathology are stronger predictors of impairment. We evaluate whether measures of temporal lobe pathology derived from diffusion tensor imaging (DTI; microstructural) versus structural MRI (sMRI; morphometric) contribute the most to memory performances in TLE, after controlling for hippocampal volume (HCV). DTI and sMRI were performed on 26 patients with TLE and 35 controls. Verbal memory was measured with the Logical Memory (LM) subtest of the Wechsler Memory Scale-III. Hierarchical regression analyses were performed to examine unique contributions of DTI and sMRI measures to verbal memory with HCV entered in block 1. In patients, impaired recall was associated with increased mean diffusivity (MD) of multiple fiber tracts that project through the temporal lobes. In addition, increased MD of the left cortical and bilateral pericortical white matter was associated with impaired recall. After controlling for left HCV, only microstructural measures of white matter pathology contributed to verbal recall. The best predictive model included left HCV and MD of the left inferior longitudinal fasciculus (ILF) and pericortical white matter beneath the left entorhinal cortex. This model explained 60% of the variance in delayed recall and revealed that MD of the left ILF was the strongest predictor. These data reveal that white matter microstructure within the temporal lobe can be used in conjunction with left HCV to enhance the prediction of verbal memory impairment, and speak to the complementary nature of DTI and sMRI for understanding cognitive dysfunction in epilepsy and possibly other memory disorders.

Alterations in functional connectivity between the hippocampus and prefrontal cortex as a correlate of depressive symptoms in temporal lobe epilepsy.

Depression is a common comorbidity in temporal lobe epilepsy (TLE) that is thought to have a neurobiological basis. This study investigated the functional connectivity (FC) of medial temporal networks in depression symptomatology of TLE and the relative contribution of structural versus FC measures. Volumetric MRI and functional connectivity MRI (fcMRI) were performed on nineteen patients with TLE and 20 controls. The hippocampi and amygdalae were selected as seeds, and five prefrontal and five cingulate regions of interest (ROIs) were selected as targets. Low-frequency blood-oxygen-level-dependent signals were isolated from fcMRI data, and ROIs with synchronous signal fluctuations with the seeds were identified. Depressive symptoms were measured by the Beck Depression Inventory-II. The patients with TLE showed greater ipsilateral hippocampal atrophy (HA) and reduced FC between the ipsilateral hippocampus and the ventral posterior cingulate cortex (vPCC). Neither HA nor hippocampal-vPCC FC asymmetry was a robust contributor to depressive symptoms. Rather, hippocampal-anterior prefrontal FC was a stronger contributor to depressive symptoms in left TLE (LTLE). Conversely, right amygdala FC was correlated with depressive symptoms in both patient groups, with a positive and negative correlation in LTLE and right TLE (RTLE), respectively. Frontolimbic network dysfunction is a strong contributor to levels of depressive symptoms in TLE and a better contributor than HA in LTLE. In addition, the right amygdala may play a role in depression symptomatology regardless of the side of the epileptogenic focus. These findings may inform the treatment of depressive symptoms in TLE and inspire future research to help guide surgical planning.

Functional connectivity of the hippocampus in temporal lobe epilepsy: feasibility of a task-regressed seed-based approach.

OBJECTIVE: Resting-state functional connectivity (FC) has revealed marked network dysfunction in patients with temporal lobe epilepsy (TLE) compared to healthy controls. However, the nature and the location of these changes have not been fully elucidated nor confirmed by other methodologies. We assessed the presence of hippocampal FC changes in TLE based on the low frequency residuals of task-related functional magnetic resonance imaging data after the removal of task-related activation [i.e., task-regressed functional connectivity MRI (fcMRI)]. METHOD: We employed a novel, task-regressed approach to quantify hippocampal FC, and compare hippocampal FC in 17 patients with unilateral TLE (9 left) with 17 healthy controls. RESULTS: Our results suggest widespread FC reductions in the mesial cortex associated with the default mode network (DMN), and some local FC increases in the lateral portions of the right hemisphere. We found more pronounced FC decreases in the left hemisphere than in the right, and these FC decreases were greatest in patients with left TLE. Moreover, the FC reductions observed between the hippocampus and posterior cingulate, inferior parietal, paracentral regions are in agreement with previous resting state studies. CONCLUSIONS: Consistent with the existing literature, FC reductions in TLE appear widespread with prominent reductions in the medial portion of the DMN. Our data expand the literature by demonstrating that reductions in FC may be greatest in the left hemisphere and in patients with left TLE. Overall, our findings suggest that task-regressed FC is a viable alternative to resting state and that future studies may extract similar information on network connectivity from already existing datasets.

The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT.

BACKGROUND: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes. OBJECTIVE: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure. METHODS: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days. RESULTS: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group. CONCLUSIONS: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure.

MRI analysis in temporal lobe epilepsy: cortical thinning and white matter disruptions are related to side of seizure onset.

PURPOSE: Past studies reported more widespread structural brain abnormalities in patients with left compared to right temporal lobe epilepsy (TLE), but the profile of these differences remains unknown. This study investigated the relationship between cortical thinning, white matter compromise, epilepsy variables, and the side of seizure onset, in patients with TLE. METHODS: We performed diffusion tensor imaging tractography and cortical thickness analyses of 18 patients with left TLE (LTLE), 18 patients with right TLE (RTLE), and 36 controls. We investigated the relationship among brain structural abnormalities, side of seizure onset, age of seizure onset, and disease duration. KEY FINDINGS: Patients with TLE displayed cortical thinning and white matter compromise, predominately on the side ipsilateral to the seizure onset. Relative to RTLE, patients with LTLE showed more widespread abnormalities, particularly in white matter fiber tracts. Greater compromise in white matter integrity was associated with earlier age of seizure onset, whereas cortical thinning was marginally associated with disease duration. SIGNIFICANCE: These data support previous findings of LTLE showing greater structural compromise than RTLE, and suggest that mechanisms may not be uniform for gray and white matter compromise in patients with LTLE and RTLE. These results may indicate that LTLE is different from RTLE, possibly due to greater vulnerability of the left hemisphere to early injury and the progressive effects of seizures.

fMRI congruous word repetition effects reflect memory variability in normal elderly.

Neural circuits mediating repetition effect for semantically congruous words on functional MRI were investigated in seventeen normal elderly (mean age=70). Participants determined if written words were semantically congruent (50% probability) with spoken statements. Subsequent cued-recall revealed robust explicit memory only for congruous items (83% versus 8% for incongruous). Event-related BOLD responses to New>Old congruous words were found in the left>right cingulate and fusiform gyri, left parahippocampal cortex, middle and inferior frontal gyri (IFG). A group with above-median subsequent recall had markedly more widespread BOLD responses than a Low-Recall subgroup, with larger responses in the left medial temporal lobe (LMTL), IFG, and bilateral cingulate gyri. The magnitude of LMTL activation (New-Old) correlated with subsequent cued-recall, while the spatial extent of LMTL activation (New>Old) correlated with recall and recognition. Both magnitude and spatial extent of left fusiform activation correlated with subsequent recall/recognition. A neural circuit of left-hemisphere brain regions, many identified as P600 generators by invasive electrophysiological studies, was activated by New>Old congruous words, likely mediating successful verbal encoding.

A componential analysis of proverb interpretation in patients with frontal lobe epilepsy and temporal lobe epilepsy: relationships with disease-related factors.

The ability to interpret nonliteral, metaphoric language was explored in patients with frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE), and matched control participants, to determine (1) if patients with FLE were impaired in their interpretations relative to those with TLE and controls, and (2) if disease-related variables (e.g., age of seizure onset) predicted performances in either patient group. A total of 22 patients with FLE, 20 patients with TLE, and 23 controls were administered a test of proverb interpretation to assess their ability to grasp the abstract meaning of nonliteral language. Participants were presented with a series of proverbs and asked to provide an oral interpretation of each. Responses to each proverb were scored according to their accuracy and level of abstractness. Patients with FLE, but not TLE, were impaired relative to controls in their overall interpretation of proverbs. However, a subgroup analysis revealed that only patients with left FLE showed impaired interpretation accuracy relative to the other groups, whereas patients with both left FLE and left TLE showed impaired abstraction. Patients with FLE were also impaired when they were asked to select the best interpretation of the proverb from response alternatives. In patients with FLE, only a left-sided seizure focus was associated with poorer performance. In patients with TLE, both an early age of onset and a left-sided seizure focus predicted poorer performance. Overall, FLE patients exhibit greater impairment than TLE patients in interpreting proverbs. However, the nature and disease-specific correlates of impaired performances in proverb interpretation differ between the groups.

Absent event-related potential (ERP) word repetition effects in mild Alzheimer's disease.

OBJECTIVE: We hypothesized that an ERP word repetition paradigm, which reliably elicits and modulates the P600 and N400 components, would be particularly sensitive to the memory deficits and altered synaptic plasticity in mild Alzheimer's disease (AD). The P600 (a late positive component, or 'LPC'), and the N400, are sensitive indices of memory encoding and semantic processing, respectively. METHODS: We studied 11 patients with mild AD (mean MMSE=22.9) and 11 elderly (mean age=77.1) normal controls (NC) on a paradigm in which semantically 'congruous' category statement/exemplar pairs (50%) and 'incongruous' category statement/non-exemplar pairs (50%) repeat at 10-140 s intervals. A minimum of 19 channels ERP data were recorded and submitted to split-plot ANOVAs. RESULTS: Normal ERP data showed: (1) a significant word repetition effect for congruous words, with a wide-spread late positivity between approximately 300 and 800 ms post-stimulus (P600) that is larger for New than Old words; (2) a significant N400 repetition effect for incongruous words, with a right posterior negativity that is reduced for Old relative to New words. By contrast, neither of these word repetition effects was reliably present in the mild AD group. Good group discrimination was achieved by requiring that both these repetition effects were > or = the 10th percentile, with 100% sensitivity and 82% specificity. CONCLUSIONS: We found significant abnormalities of the N400 and P600 in mild AD, with both potentials showing markedly reduced sensitivity to word repetition. SIGNIFICANCE: The absence of normal N400 and LPC/P600 word repetition effects suggests impaired functioning of their neural generators, several of which are located in medial temporal lobe predilection sites (e.g. anterior fusiform, parahippocampal gyrus, hippocampus) for AD/tau pathology.

Vagus nerve stimulation use and effect in epilepsy: what have we learned?

Vagus nerve stimulation (VNS) for epilepsy has been available in the United States for 8 years. Pivotal randomized, blinded clinical trials leading to FDA approval in patients age 12 and older with refractory partial seizures have not been performed for other age groups or epilepsy syndromes. This practical review takes stock of the current information about VNS use and efficacy in various types of epilepsy. We review the evidence for commonly used stimulation parameters, end of battery life, predictors of response including duration of epilepsy, seizure type/epilepsy syndrome, bihemispheric seizures, age at implant, and prior cranial surgery. We review adverse events and VNS effects on respiratory patterns, cardiac function, and mood and behavior. With the recent U.S. approval of VNS for treatment-resistant depression, we anticipate that lessons learned from treating patients with epilepsy will be useful to physicians using VNS to treat patients with depression and possibly other conditions.

Discriminating patients with frontal-lobe epilepsy and temporal-lobe epilepsy: utility of a multilevel design fluency test.

Patients with frontal-lobe epilepsy (FLE) or temporal-lobe epilepsy (TLE) and matched control participants were given a design fluency test that assessed nonverbal fluency and switching ability. Patients with FLE generated fewer designs in the switching condition relative to the TLE patients and controls, whereas group differences did not emerge in the basic fluency conditions. When the side of the seizure focus and the presence or absence of a structural lesion were considered in patients with FLE, only those with left-lesional FLE generated fewer designs than controls did in the switching condition. Furthermore, patients with left-lesional and nonlesional FLE produced a greater proportion of set-loss errors than did controls. These results indicate that patients with FLE are impaired when they must simultaneously generate new designs and engage in cognitive switching; however, the pattern of impairment may depend on the side of the seizure focus and the presence of a structural lesion.

Response inhibition and set shifting in patients with frontal lobe epilepsy or temporal lobe epilepsy.

Patients with frontal lobe epilepsy (FLE), patients with temporal lobe epilepsy (TLE), and matched controls were administered a test of response inhibition and set shifting (switching) (Color Word Interference Test, CWIT). Patients with FLE were impaired relative to the controls across all conditions of the CWIT, with the FLE patients showing disproportionate impairment in the Inhibition and Inhibition/Switching conditions. In contrast, the TLE patients did not differ from controls. Further analysis of the patient groups revealed that patients with left FLE were impaired relative to those with right FLE, left TLE, and right TLE in the Inhibition condition. In the Inhibition/Switching condition, patients with left FLE and left TLE were impaired relative to their right-sided counterparts. Finally, performance by the TLE group in the Inhibition/Switching condition was correlated with seizure frequency. These data suggest that patients with FLE, but not TLE, show impaired inhibition and set shifting relative to controls. In addition, side of the seizure focus and seizure frequency may contribute to executive dysfunction in patients with epilepsy.

Reduced sensitivity of the N400 and late positive component to semantic congruity and word repetition in left temporal lobe epilepsy.

We studied 14 patients with well-characterized refractory temporal lobe epilepsy (TLE), 7 with right temporal lobe epilepsy (RTE) and 7 with left temporal lobe epilepsy (LTE), on a word repetition ERP experiment. Much prior literature supports the view that patients with left TLE are more likely to develop verbal memory deficits, often attributable to left hippocampal sclerosis. Our main objectives were to test if abnormalities of the N400 or Late Positive Component (LPC, P600) were associated with a left temporal seizure focus, or left temporal lobe dysfunction. A minimum of 19 channels of EEG/EOG data were collected while subjects performed a semantic categorization task. Auditory category statements were followed by a visual target word, which were 50% "congruous" (category exemplars) and 50% "incongruous" (non-category exemplars) with the preceding semantic context. These auditory-visual pairings were repeated pseudo-randomly at time intervals ranging from approximately 10-140 seconds later. The ERP data were submitted to repeated-measures ANOVAs, which showed the RTE group had generally normal effects of word repetition on the LPC and the N400. Also, the N400 component was larger to incongruous than congruous new words, as is normally the case. In contrast, the LTE group did not have statistically significant effects of either word repetition or congruity on their ERPs (N400 or LPC), suggesting that this ERP semantic categorization paradigm is sensitive to left temporal lobe dysfunction. Further studies are ongoing to determine if these ERP abnormalities predict hippocampal sclerosis on histopathology, or outcome after anterior temporal lobectomy.