Dataset Information

Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.

ABSTRACT: OBJECTIVE:Juvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected siblings, and (b) validate those as endophenotypes of JME. METHODS:This prospective cross-sectional investigation included 32 patients with JME, 12 unaffected siblings, and 26 controls, comparable for age, sex, handedness, language laterality, neuropsychological performance, and anxiety and depression scores. We investigated patterns of motor system activation during episodic memory encoding and verb generation functional magnetic resonance imaging (fMRI) tasks. RESULTS:During both tasks, patients and unaffected siblings showed increased activation of motor system areas compared to controls. Effects were more prominent during memory encoding, which entailed hand motion via joystick responses. Subgroup analyses identified stronger activation of the motor cortex in JME patients with ongoing seizures compared to seizure-free patients. Receiver-operating characteristic curves, based on measures of motor activation, accurately discriminated both patients with JME and their siblings from healthy controls (area under the curve: 0.75 and 0.77, for JME and a combined patient-sibling group against controls, respectively; P < .005). SIGNIFICANCE:Motor system hyperactivation represents a cognitive, domain-independent endophenotype of JME. We propose measures of motor system activation as quantitative traits for future genetic imaging studies in this syndrome.

SUBMITTER: Caciagli L

PROVIDER: S-EPMC7681252 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.

Caciagli Lorenzo L Wandschneider Britta B Centeno Maria M Vollmar Christian C Vos Sjoerd B SB Trimmel Karin K Long Lili L Xiao Fenglai F Lowe Alexander J AJ Sidhu Meneka K MK Thompson Pamela J PJ Winston Gavin P GP Duncan John S JS Koepp Matthias J MJ

Epilepsia 20200625 7

<h4>Objective</h4>Juvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected ...[more]

PMID: 32584424

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Project description:ObjectiveGeneralized epilepsy syndromes often confer multiple types of seizures, but it is not known if these seizures activate separate or overlapping brain networks. Recently, we reported that mice with a juvenile myoclonic epilepsy mutation (Gabra1[A322D]) exhibited both absence and myoclonic generalized seizures. Here, we determined the time course of sensorimotor cortex activation and the spatial distribution of spike voltage during these two seizures.MethodsWe implanted Gabra1+/A322D mice with multiple electroencephalography (EEG) electrodes over bilateral somatosensory cortex barrel fields (S1) and anterior (aM1) and posterior (pM1) motor cortices and recorded absence seizures/spike-wave discharges (SWDs) and myoclonic seizures. We used nonlinear-association analyses and cross-correlation calculations to determine the strength, leading regions, and time delays of cortical coupling from the preictal to ictal states and within the spike and interspike periods. The distribution of spike voltage was also measured in SWDs and myoclonic seizures.ResultsEEG connectivity among all electrode pairs increased at the onset of both SWDs and myoclonic seizures. Surprisingly, during spikes of both seizure types, S1 led M1 with similar delay times. Myoclonic seizure spikes started more focally than SWD spikes, with a significant majority appearing first only in S1 electrodes, whereas a substantial fraction of SWD spikes were detected first in S1 and at least one M1 electrode. The absolute voltage of myoclonic seizure spikes was significantly higher than that of SWD spikes, and there was a greater relative voltage over M1 during myoclonic seizure spikes than in the first one to two SWD spikes.SignificanceThe leading sites in S1 and similar delay times suggest both SWDs and myoclonic seizures activate overlapping networks in sensorimotor cortex and thus, therapeutically targeting of this network could potentially treat both seizures. Spike focality, absolute voltage, and voltage distribution provide insight into neuronal activation during these two seizure types.

Project description:ObjectiveAccording to Panksepp's hierarchical emotion model, emotion processing relies on three functionally and neuroanatomically distinct levels. These levels comprise subcortical networks (primary level), the limbic system (secondary level), and the neocortex (tertiary level) and are suggested to serve differential emotional processing. We aimed to validate and extend previous evidence of discrete and dimensional emotion processing in patient with juvenile myoclonic epilepsy (JME).MethodsWe recorded brain activity of patients with JME and healthy controls in response to lexical decisions to words reflecting the discrete emotion fear and the affective dimension negativity previously suggested to rely on different brain regions and to reflect different levels of processing. In all study participants, we tested verbal cognitive functions, as well as the relationship of psychiatric conditions, seizure types and duration of epilepsy and emotional word processing.ResultsIn support of the hierarchical emotion model, we found an interaction of discrete emotion and affective dimensional processing in the right amygdala likely to reflect secondary level processing. Brain activity related to affective dimensional processing was found in the right inferior frontal gyrus and is suggested to reflect tertiary level processing. Psychiatric conditions, type of seizure nor mono- vs. polytherapy and duration of epilepsy within patients did not have any effect on the processing of emotional words. In addition, no differences in brain activity or response times between patients and controls were observed, despite neuropsychological testing revealed slightly decreased verbal intelligence, verbal fluency and reading speed in patients with JME.SignificanceThese results were interpreted to be in line with the hierarchical emotion model and to highlight the amygdala's role in processing biologically relevant stimuli, as well as to suggest a semantic foundation of affective dimensional processing in prefrontal cortex. A lack of differences in brain activity of patients with JME and healthy controls in response to the emotional content of words could point to unaffected implicit emotion processing in patients with JME.

Project description:ObjectiveTo study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME).MethodsPeople with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females.ResultsWe included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001).SignificanceIn people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments.

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Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.

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Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.

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