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Cognitive slowing is a known but comparatively under-investigated neuropsychological complication of the epilepsies in relation to other known cognitive comorbidities such as memory, executive function and language. Here we focus on a novel metric of processing speed, characterize its relative salience compared to other cognitive difficulties in epilepsy, and explore its underlying neurobiological correlates. Research participants included 55 patients with temporal lobe epilepsy (TLE) and 58 healthy controls from the Epilepsy Connectome Project (ECP) who were administered a battery of tests yielding 14 neuropsychological measures, including selected tests from the NIH Toolbox-Cognitive Battery, and underwent 3T MRI and resting state fMRI. TLE patients exhibited a pattern of generalized cognitive impairment with very few lateralized abnormalities. Using the neuropsychological measures, machine learning (Support Vector Machine binary classification model) classified the TLE and control groups with 74% accuracy with processing speed (NIH Toolbox Pattern Comparison Processing Speed Test) the best predictor. In TLE, slower processing speed was associated predominantly with decreased local gyrification in regions including the rostral and caudal middle frontal gyrus, inferior precentral cortex, insula, inferior parietal cortex (angular and supramarginal gyri), lateral occipital cortex, rostral anterior cingulate, and medial orbital frontal regions, as well as three small regions of the temporal lobe. Slower processing speed was also associated with decreased connectivity between the primary visual cortices in both hemispheres and the left supplementary motor area, as well as between the right parieto-occipital sulcus and right middle insular area. Overall, slowed processing speed is an important cognitive comorbidity of TLE associated with altered brain structure and connectivity.

AbstractThe Epilepsy Connectome Project examines the differences in connectomes between temporal lobe epilepsy (TLE) patients and healthy controls. Using these data, the effective connectivity of the default mode network (DMN) in patients with left TLE compared with healthy controls was investigated using spectral dynamic causal modeling (spDCM) of resting-state functional magnetic resonance imaging data. Group comparisons were made using two parametric empirical Bayes (PEB) models. The first level of each PEB model consisted of each participant's spDCM. Two different second-level models were constructed: the first comparing effective connectivity of the groups directly and the second using the Rey Auditory Verbal Learning Test (RAVLT) delayed free recall index as a covariate at the second level to assess effective connectivity controlling for the poor memory performance of left TLE patients. After an automated search over the nested parameter space and thresholding parameters at 95% posterior probability, both models revealed numerous connections in the DMN, which lead to inhibition of the left hippocampal formation. Left hippocampal formation inhibition may be an inherent result of the left temporal epileptogenic focus as memory differences were controlled for in one model and the same connections remained. An excitatory connection from the posterior cingulate cortex to the medial prefrontal cortex was found to be concomitant with left hippocampal formation inhibition in TLE patients when including RAVLT delayed free recall at the second level.

AbstractThe National Institutes of Health-sponsored Epilepsy Connectome Project aims to characterize connectivity changes in temporal lobe epilepsy (TLE) patients. The magnetic resonance imaging protocol follows that used in the Human Connectome Project, and includes 20 min of resting-state functional magnetic resonance imaging acquired at 3T using 8-band multiband imaging. Glasser parcellation atlas was combined with the FreeSurfer subcortical regions to generate resting-state functional connectivity (RSFC), amplitude of low-frequency fluctuations (ALFFs), and fractional ALFF measures. Seven different frequency ranges such as Slow-5 (0.01–0.027 Hz) and Slow-4 (0.027–0.073 Hz) were selected to compute these measures. The goal was to train machine learning classification models to discriminate TLE patients from healthy controls, and to determine which combination of the resting state measure and frequency range produced the best classification model. The samples included age- and gender-matched groups of 60 TLE patients and 59 healthy controls. Three traditional machine learning models were trained: support vector machine, linear discriminant analysis, and naive Bayes classifier. The highest classification accuracy was obtained using RSFC measures in the Slow-4 + 5 band (0.01–0.073 Hz) as features. Leave-one-out cross-validation accuracies were ∼83%, with receiver operating characteristic area-under-the-curve reaching close to 90%. Increased connectivity from right area posterior 9-46v in TLE patients contributed to the high accuracies. With increased sample sizes in the near future, better machine learning models will be trained not only to aid the diagnosis of TLE, but also as a tool to understand this brain disorder.

AbstractConscious perception relies on interactions between spatially and functionally distinct modules of the brain at various spatiotemporal scales. These interactions are altered by anesthesia, an intervention that leads to fading consciousness. Relatively little is known about brain functional connectivity and its anesthetic modulation at a fine spatial scale. Here, we used functional imaging to examine propofol-induced changes in functional connectivity in brain networks defined at a fine-grained parcellation based on a combination of anatomical and functional features. Fifteen healthy volunteers underwent resting-state functional imaging in wakeful baseline, mild sedation, deep sedation, and recovery of consciousness. Compared with wakeful baseline, propofol produced widespread, dose-dependent functional connectivity changes that scaled with the extent to which consciousness was altered. The dominant changes in connectivity were associated with the frontal lobes. By examining node pairs that demonstrated a trend of functional connectivity change between wakefulness and deep sedation, quadratic discriminant analysis differentiated the states of consciousness in individual participants more accurately at a fine-grained parcellation (e.g., 2000 nodes) than at a coarse-grained parcellation (e.g., 116 anatomical nodes). Our study suggests that defining brain networks at a high granularity may provide a superior imaging-based distinction of the graded effect of anesthesia on consciousness.

Introduction:Patients with large vessel occlusion stroke (LVO) benefit from thrombolysis before thrombectomy. Previous meta-analysis suggested superiority of tenecteplase over alteplase in achieving good clinical outcome at 3 months.Aim:We aimed to compare clinical outcomes after tenecteplase 0.25 mg/kg versus alteplase in patients with LVO.Methods:An experienced librarian searched PubMed and Scopus databases through July 13, 2022 for randomized controlled trials comparing tenecteplase with alteplase in patients with LVO. We included trials using 0.25 mg/kg tenecteplase dose, reporting blindly assessed pre-specified clinical outcomes at 3-4 months among patients with LVO. Two authors independently reviewed eligibility and extracted the data. We used RevMan 5.4 and random effect models with inverse variance weights to calculate odds ratios (OR) and 95% confidence intervals (CI). This systematic review is registered (CRD42022349414).Results:From 585 retrieved abstracts, 3 trials and 1 pooled secondary analysis involving 704 unique patients met the inclusion criteria. Among patients with LVO, tenecteplase 0.25mg/kg is not superior to alteplase in achieving good clinical outcome (defined as modified Rankin Scale [mRS] 0-2, OR 1.82 (95% CI 0.91-3.65, panel A); nor all-cause mortality, OR 0.75 (95% CI 0.49-1.13, panel B); while tenecteplase increases the odds of excellent outcome (mRS 0-1), OR 1.52 (95% CI 1.11-2.09, panel C), and odds of functional improvement (defined as a shift on the ordinal mRS), OR 1.54 (95% CI 1.07-2.20, panel D). High heterogeneity was present (I2 =70%) for the good clinical outcome.Conclusion:Tenecteplase is not superior over alteplase in achieving good clinical outcome. Tenecteplase, as compared to alteplase, increases the odds of functional improvement and excellent outcome. These findings support bridging tenecteplase in patients with LVO.

The term “Wernicke's area” is most often used as an anatomical label for the gyri forming the lower posterior left sylvian fissure. Although traditionally this region was held to support language comprehension, modern imaging and neuropsychological studies converge on the conclusion that this region plays a much larger role in speech production. This evidence is briefly reviewed, and a simple schematic model of posterior cortical language processing is described.

We examined whether individual neuronal architecture obtained from the brain connectome can be used to estimate the surgical success of anterior temporal lobectomy (ATL) in patients with temporal lobe epilepsy (TLE).

Language dominance and factors that influence language lateralization were investigated in right-handed, neurologically normal subjects (n = 100) and right-handed epilepsy patients (n = 50) using functional MRI. Increases in blood oxygenation-dependent signal during a semantic language activation task relative to a non-linguistic, auditory discrimination task provided an index of language system lateralization. As expected, the majority of both groups showed left hemisphere dominance, although a continuum of activation asymmetry was evident, with nearly all subjects showing some degree of right hemisphere activation. Using a categorical dominance classification, 94% of the normal subjects were considered left hemisphere dominant and 6% had bilateral, roughly symmetric language representation. None of the normal subjects had rightward dominance. There was greater variability of language dominance in the epilepsy group, with 78% showing left hemisphere dominance, 16% showing a symmetric pattern and 6% showing right hemisphere dominance. Atypical language dominance in the epilepsy group was associated with an earlier age of brain injury and with weaker right hand dominance. Language lateralization in the normal group was weakly related to age, but was not significantly related to sex, education, task performance or familial left-handedness.

Background and objective: The intracarotid amobarbital procedure, or Wada test, is the method of choice to determine hemispheric representation of language, and is routinely used in the presurgical evaluation for intractable epilepsy. Some investigators perform comprehensive language assessments, but others base language lateralization solely on speech arrest. This study sought to determine whether speech arrest alone during Wada testing provides valid data regarding language lateralization. Methods: The subjects (previously reported) were 21 patients evaluated for intractable epilepsy, who underwent language lateralization by Wada testing and functional MRI (FMRI). For each patient, language representation was determined by calculating: (1) a Wada laterality index based exclusively on speech arrest; (2) a Wada laterality index based on comprehensive language assessment; and (3) an FMRI laterality quotient. Correlation coefficients and categorical classifications were analyzed. Results: There was no significant correlation between the Wada laterality quotient derived from duration of speech arrest and either the comprehensive Wada language laterality score (r= .35,p= .12) or FMRI language laterality score (r= .32,p= .16). Categorical classification as left, right or bilateral language also showed marked discordance between speech arrest and the other two methods. Conclusion: Duration of speech arrest during Wada testing is not a valid measure of language dominance.

LESIONS involving the dorsolateral prefrontal lobes may produce deficits on conceptual reasoning (CR) tasks in humans. Such deficits can also occur with subcortical lesions involving the basal ganglia, thalamus, or cerebellum, suggesting a common, yet widespread, neural network supporting this executive function. Here we report the results of a whole brain functional magnetic resonance imaging (fMRI) experiment in healthy volunteers while performing a CR task. Compared to a sensorimotor control condition, the CR task resulted in discrete subcortical activation sites primarily involving the right basal ganglia, right thalamus and left lateral cerebellum. Cortical activation was present in multiple systems, including the dorsolateral prefrontal and inferior frontal/insular areas; posterior parietal, superior extrastriate, and premotor areas; inferior extrastriate and middle temporal regions; and midline pre-supplementary motor and anterior cingulate regions. Our findings provide strong evidence that CR is mediated by interacting neural systems involving the cerebral cortex, basal ganglia, thalamus, and cerebellum.

OBJECTIVE: To develop a procedure for noninvasive measurement of language lateralization with functional magnetic resonance imaging (MRI). DESIGN: Functional neuroimaging using time-series echo-planar MRI. SETTING: University medical center research facility. SUBJECTS: Five healthy, right-handed, young adults. MAIN OUTCOME MEASURES: Number of MRI voxels in left and right hemispheres showing task-related signal increases during two contrasting auditory processing tasks. The nonlinguistic task involved processing of pure tones, while the linguistic task involved processing of single words based on semantic content. RESULTS: The pure-tone processing task activated temporal lobe auditory areas and dorsolateral frontal regions bilaterally. Using this task as a control condition, the semantic processing task resulted in lateralized activity in distributed regions of the left hemisphere. A significant effect of task on intrahemispheric activity pattern was demonstrated in every subject. Results were reproduced in preliminary studies of test-retest reliability. CONCLUSIONS: The results demonstrate the lateralized anatomy of semantic linguistic systems in contrast to nonlinguistic auditory sensory processors and introduce a task subtraction technique adapted for functional MRI as a noninvasive measure of language lateralization.

The neuropsychological complications of temporal lobe epilepsy are characterized by a spectrum of reproducible cognitive phenotypes that vary in the presence, type and degree of impairment. The nature of the disruptions to the neuropsychological networks that underlie these phenotypes remain to be characterized and represent the subject of this investigation.

We thank Papanicolaou et al. for the comment on our article,1and agree that important issues were raised regarding thresholding methods in functional MRI (fMRI).2However, the original estimate of the number of studies potentially affected was substantially lowered.3,4Imprecision is part of every diagnostic test; its presence in thresholded fMRI activation maps is unlikely to lead to spurious lateralized correlations between cognitive tasks and blood oxygenation level–dependent signal, or to agreement between fMRI and other investigations. As Papanicolaou et al. note, laterality measures are likely robust to the occurrence of false-positive clusters, since they are derived from side-to-side ratios.

Perception of speech is effortless under most circumstances; this may explain why the complexity of this cognitive process is so often unappreciated. While most other sounds in the environment are acoustically very distinctive, the 30 or 40 speech sounds people make are discriminable only by rapid analysis of rather subtle acoustic cues. Given the importance of language, it seems plausible not only that our auditory system evolved a degree of specialization for handling such analyses, but also that this specialization should assimilate substantial neural resources. Recent work in comparative physiology and human brain imaging suggests, in fact, that much of the superior temporal gyrus in humans is devoted to this perceptual feat.