Cognitive phenotype of juvenile absence epilepsy: An investigation of patients and unaffected siblings

Objective: The cognitive profile of juvenile absence epilepsy (JAE) remains largely uncharacterized. This study aimed to: (1) elucidate the neuropsychological profile of JAE; (2) identify familial cognitive traits by investigating unaffected JAE siblings; (3) establish the clinical meaningfulness of JAE-associated cognitive traits; (4) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome-specific, by comparing JAE to juvenile myoclonic epilepsy (JME); and (5) identify relationships between cognitive abilities and clinical characteristics. Methods: We investigated 123 participants—23 patients with JAE, 16 unaffected siblings of JAE patients, 45 healthy controls, and 39 patients with JME—who underwent a comprehensive neuropsychological test battery including measures within four cognitive domains: attention/psychomotor speed, language, memory, and executive function. We correlated clinical measures with cognitive performance data to decode effects of age at onset and duration of epilepsy. Results: Cognitive performance in individuals with JAE was reduced compared to controls across attention/psychomotor speed, language, and executive function domains; those with ongoing seizures additionally showed lower memory scores. Patients with JAE and their unaffected siblings had similar language impairment compared to controls. Individuals with JME had worse response inhibition than those with JAE. Across all patients, those with older age at onset had better attention/psychomotor speed performance. Significance: JAE is associated with wide-ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including language, attention, and executive function. JAE siblings share impairment with patients on linguistic measures, indicative of a familial trait. Executive function subdomains may be differentially affected across the IGE spectrum. Cognitive abilities are detrimentally modulated by an early age at seizure onset

Thalamus and focal to bilateral seizures: A multiscale cognitive imaging study.

OBJECTIVE: To investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e., focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality. METHODS: FBTCS occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three patients (29%) had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12-derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality. RESULTS: Individuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamotemporal and thalamomotor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS. CONCLUSIONS: In TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamotemporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization

Effect of Anti-seizure Medications on Functional Anatomy of Language: A Perspective From Language Functional Magnetic Resonance Imaging

BACKGROUND In epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined. METHODS Here, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine/oxcarbazepine, eslicarbazepine, valproic acid; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (n = 180). "Drug load" was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication. RESULTS In people taking "moderate" ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking "severe" ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with "moderate" ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex. CONCLUSION Our study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect

Effect of Anti-seizure Medications on Functional Anatomy of Language: A Perspective From Language Functional Magnetic Resonance Imaging

Background: In epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined. Methods: Here, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine/oxcarbazepine, eslicarbazepine, valproic acid; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (n = 180). "Drug load" was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication. Results: In people taking "moderate" ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking "severe" ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with "moderate" ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex. Conclusion: Our study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect

Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy

Cognitive impairment is a common comorbidity of epilepsy, and adversely impacts people with both frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). While its neural substrates have been extensively investigated in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE, and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE, and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devise a multiscale approach to map brain activation and deactivation during cognition, and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems, and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, and reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE were broadly similar to those in TLE, but some patterns were syndrome-specific: altered default-mode deactivation was more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands was more marked in TLE. Functional abnormalities in FLE and TLE appeared overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies, and sheds light on system behavior that may be amenable to future remediation strategies

Acoustic Noise Alters Selective Attention Processes as Indicated by Direct Current (DC) Brain Potential Changes

Acoustic environmental noise, even of low to moderate intensity, is known to adversely affect information processing in animals and humans via attention mechanisms. In particular, facilitation and inhibition of information processing are basic functions of selective attention. Such mechanisms can be investigated by analyzing brain potentials under conditions of externally directed attention (intake of environmental information) versus internally directed attention (rejection of environmental stimuli and focusing on memory/planning processes). This study investigated brain direct current (DC) potential shifts—which are discussed to represent different states of cortical activation—of tasks that require intake and rejection of environmental information under noise. It was hypothesized that without background noise rejection tasks would show more positive DC potential changes compared to intake tasks and that under noise both kinds of tasks would show positive DC shifts as an expression of cortical inhibition caused by noise. DC potential shifts during intake and rejection tasks were analyzed at 16 standard locations in 45 persons during irrelevant speech or white noise vs. control condition. Without noise, rejection tasks were associated with more positive DC potential changes compared to intake tasks. During background noise, however, this difference disappeared and both kinds of tasks led to positive DC shifts. Results suggest—besides some limitations—that noise modulates selective attention mechanisms by switching to an environmental information processing and noise rejection mode, which could represent a suggested “attention shift”. Implications for fMRI studies as well as for public health in learning and performance environments including susceptible persons are discussed

Assessment of lateralization of language function in epilepsy patients using high-density scalp-derived event-related potentials (ERPs)

Epilepsiechirurgie ist eine effektive und sichere Behandlungsmöglichkeit für Patienten mit medikamentös therapierefraktären Anfallsleiden. Bei 60-80% dieser Epilepsiepatienten kann durch einen neurochirurgischen Eingriff Anfallsfreiheit erzielt werden. Ziel eines solchen epilepsiechirurgischen Eingriffes ist es, die epileptogene Zone zu entfernen, ohne postoperative motorische oder neuropsychologische Defizite insbesondere Sprach- oder Gedächtnisstörungen zu verursachen.^ ^Dementsprechend ist es notwendig, im Rahmen einer sorgfältigen präoperativen Abklärung die essentiellen Hirnareale und deren Verbindungen zu lokalisieren, die für motorische, visuelle, sowie Sprach- und Gedächtnisfunktion verantwortlich sind. Die funktionelle Magnetresonanztomographie (fMRT) stellt den klinischen Standard für die Beurteilung der Sprachlateralisation dar, aber dennoch kommt es nach einem epilepsiechirurgischen Eingriff bei etwa einem Drittel der Patienten zu Defiziten bei Sprache und verbalem Gedächtnis, was die Notwendigkeit der weiteren Verbesserung nichtinvasiver Methoden verdeutlicht. Im Gegensatz zum fMRT bieten ereigniskorrelierte Potentiale (event-related potentials; ERPs) eine besonders hohe zeitliche Auflösung, was eine Echtzeit-Analyse der neuronalen Aktivität kognitiver Prozesse ermöglicht.^ ^ Bestimmte ERP-Komponenten, insbesondere die negative Komponente um und nach 400 ms nach Stimulus onset, stehen in engem Zusammenhang mit Sprachverarbeitung. Der anatomische Ursprung dieser ERP-Komponenten wird temporalen und frontotemporalen Hirnregionen der dominanten Hemisphäre zugeordnet. Ziel der vorliegenden Arbeit war es demnach, ERPs von räumlich hochauflösenden EEG-Ableitungen der Kopfoberfläche als neues nicht-invasives Verfahren zur Beurteilung der Sprachlateralisation im Rahmen der prächirurgischen Epilepsiediagnostik zu prüfen. Bei 36 Epilepsiepatienten sowie 37 gesunden Kontrollpersonen wurde ein 64-Kanal Oberflächen-EEG abgeleitet, während drei unterschiedliche, visuell präsentierte Sprachaufgaben vorgegeben wurden: Eine Kurzzeit-Sprachgedächtnisaufgabe (Differenzierung von gemerkten vs.^ ^unbekannten Wörtern), eine phonologische Aufgabe (Erkennung von Reim bei Vorgabe von Wortpaaren) und eine semantische Aufgabe (Differenzierung von Wörtern vs Pseudowörtern). ERPs wurden im 300 ms 800 ms Zeitfenster analysiert. Bei den Epilepsiepatienten wurde routinemäßig ein Sprach-fMRT durchgeführt. Die Amplituden der sprachbezogenen ERPs waren sowohl bei Patienten als auch bei Kontrollpersonen in allen drei Sprachaufgaben über der linken Hemisphäre signifikant negativer als über der rechten Hemisphäre. Individuell berechnete Lateralisations-Indizes zeigten die höchste Übereinstimmung der ERP-Lateralisation mit den fMRT-Ergebnissen bei der Pseudowort-Aufgabe. Diese Ergebnisse legen nahe, dass Sprachmapping basierend auf ERPs die prächirurgische Epilepsiediagnostik weiter verbessern kann.Epilepsy surgery represents a safe and effective treatment option for patients suffering from refractory focal epilepsies. The goals of epilepsy surgery are twofold: On one hand, the epileptogenic zone needs to be removed, giving seizure freedom. On the other hand, eloquent cortex, such as areas responsible for language and memory function, needs to be spared to avoid neuropsychological deficits following surgery. Thus, the accurate localization of essential brain regions and their critical connections, which are responsible for language and memory, is of utmost importance. Language functional magnetic resonance imaging (fMRI) represents the current clinical standard for assessment of language lateralization in presurgical epilepsy evaluation. Nevertheless, language or verbal memory deficits occur in about one third of patients following epilepsy surgery which highlights the need for further improvement of noninvasive methods.^ ^In contrast to fMRI and positron emission tomography (PET) studies, event-related potentials (ERPs) studies offer a very high temporal resolution, thus allowing a real-time analysis of the neural processes elicited during cognitive tasks. Certain ERP components, especially the negative component around and after 400 ms, are strongly related to language processing and are supposed to arise from temporal and frontotemporal regions of the dominant hemisphere. The aim of this thesis was therefore to investigate the possibility to use high-density scalp-derived ERPs as a noninvasive tool to assess language lateralization in presurgical epilepsy evaluation. Scalp EEG was recorded from 64 locations in 36 consecutive epilepsy patients and 37 controls during three visually presented language tasks: A short-term language memory task (differentiation memorized vs.^ ^unknown words), a phonological task (detection of rhymes in word pairs), and a semantic decision task (differentiation words vs. pseudowords). ERPs were analyzed in the 300 ms800 ms epoch. Language fMRI was routinely obtained in patients. vii Amplitudes of language-related ERPs were significantly more negative over the left compared to the right hemisphere in all three tasks in patients and controls. Individual laterality indices were calculated and showed highest concordance with fMRI results for the Word/Pseudoword Task. Thus, results suggest that ERP-derived language maps might contribute to further improve the standard of presurgical workup in epilepsy patients.submitted by Karin TrimmelZusammenfassung in deutscher SpracheMedizinische Universität Wien, Dissertation, 2017OeB

Heart Rate Variability: Clinical Applications and Interaction between HRV and Heart Rate

Over the last decades, assessment of heart rate variability (HRV) has increased in various fields of research. HRV describes changes in heartbeat intervals, which are caused by autonomic neural regulation, i.e. by the interplay of the sympathetic and the parasympathetic nervous systems. The most frequent application of HRV is connected to cardiological issues, most importantly to the monitoring of post-myocardial infarction patients and the prediction of sudden cardiac death. Analysis of HRV is also frequently applied in relation to diabetes, renal failure, neurological and psychiatric conditions, sleep disorders, psychological phenomena such as stress, as well as drug and addiction research including alcohol and smoking. The widespread application of HRV measurements is based on the fact that they are noninvasive, easy to perform, and in general reproducible – if carried out under standardized conditions. However, the amount of parameters to be analysed is still rising. Well-established time domain and frequency domain parameters are discussed controversially when it comes to their physiological interpretation and their psychometric properties like reliability and validity, and the sensitivity to cardiovascular properties of the variety of parameters seems to be a topic for further research. Recently introduced parameters like pNNxx and new dynamic methods such as approximate entropy and detrended fluctuation analysis offer new potentials and warrant standardization. However, HRV is significantly associated with average heart rate (HR) and one can conclude that HRV actually provides information on two quantities, i.e. on HR and its variability. It is hard to determine which of these two plays a principal role in the clinical value of HRV. The association between HRV and HR is not only a physiological phenomenon but also a mathematical one which is due to non-linear (mathematical) relationship between RR interval and HR. If one normalizes HRV to its average RR interval, one may get ‘pure’ variability free from the mathematical bias. Recently, a new modification method of the association between HRV and HR has been developed which enables us to completely remove the HRV dependence on HR (even the physiological one), or conversely enhance this dependence. Such an approach allows us to explore the HR contribution to the clinical significance of HRV, i.e. whether HR or its variability plays a main role in the HRV clinical value. This Research Topic covers recent advances in the application of HRV, methodological issues, basic underlying mechanisms as well as all aspects of the interaction between HRV and HR

Naming fMRI-guided white matter language tract volumes influence naming decline after temporal lobe resection.

OBJECTIVE The aim of this study was to explore the relation of language functional MRI (fMRI)-guided tractography with postsurgical naming decline in people with temporal lobe epilepsy (TLE). METHODS Twenty patients with unilateral TLE (9 left) were studied with auditory and picture naming functional MRI tasks. Activation maxima in the left posterobasal temporal lobe were used as seed regions for whole-brain fibre tractography. Clinical naming performance was assessed preoperatively, 4 months, and 12 months following temporal lobe resection. Volumes of white matter language tracts in both hemispheres as well as tract volume laterality indices were explored as moderators of postoperative naming decline using Pearson correlations and multiple linear regression with other clinical variables. RESULTS Larger volumes of white matter language tracts derived from auditory and picture naming maxima in the hemisphere of subsequent surgery as well as stronger lateralization of picture naming tract volumes to the side of surgery correlated with greater language decline, which was independent of fMRI lateralization status. Multiple regression for picture naming tract volumes was associated with a significant decline of naming function with 100% sensitivity and 93% specificity at both short-term and long-term follow-up. INTERPRETATION Naming fMRI-guided white matter language tract volumes relate to postoperative naming decline after temporal lobe resection in people with TLE. This can assist stratification of surgical outcome and minimize risk of postoperative language deficits in TLE