Risktaking Behavior in Juvenile Myoclonic Epilepsy
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FULL-LENGTH ORIGINAL RESEARCH Risk-taking behavior in juvenile myoclonic epilepsy *†Britta Wandschneider, *†Maria Centeno, *†‡Christian Vollmar, *†Jason Stretton, §Jonathan O’Muircheartaigh, *†Pamela J. Thompson, ¶Veena Kumari, *†Mark Symms, §Gareth J. Barker, *†John S. Duncan, #Mark P. Richardson, and *†Matthias J. Koepp Epilepsia, 0(0):1–8, 2013 doi: 10.1111/epi.12413 SUMMARY Objective: Patients with juvenile myoclonic epilepsy (JME) often present with risk-tak- ing behavior, suggestive of frontal lobe dysfunction. Recent studies confirm functional and microstructural changes within the frontal lobes in JME. This study aimed at char- acterizing decision-making behavior in JME and its neuronal correlates using functional magnetic resonance imaging (fMRI). Methods: We investigated impulsivity in 21 JME patients and 11 controls using the Iowa Gambling Task (IGT), which measures decision making under ambiguity. Perfor- mance on the IGT was correlated with activation patterns during an fMRI working memory task. Results: Both patients and controls learned throughout the task. Post hoc analysis revealed a greater proportion of patients with seizures than seizure-free patients hav- ing difficulties in advantageous decision making, but no difference in performance between seizure-free patients and controls. Functional imaging of working memory networks showed that overall poor IGT performance was associated with an increased Dr. Wandschneider is activation in the dorsolateral prefrontal cortex (DLPFC) in JME patients. Impaired registrar in neurology learning during the task and ongoing seizures were associated with bilateral medial and is pursuing a PhD prefrontal cortex (PFC) and presupplementary motor area, right superior frontal at the UCL Institute of gyrus, and left DLPFC activation. Neurology. Significance: Our study provides evidence that patients with JME and ongoing seizures learn significantly less from previous experience. Interictal dysfunction within “nor- mal” working memory networks, specifically, within the DLPFC and medial PFC struc- tures, may affect their ability to learn. KEY WORDS: Impulsivity, Frontal lobe function, Functional imaging, Working memory. Juvenile myoclonic epilepsy (JME) is the most common Accepted September 12, 2013. idiopathic epilepsy syndrome (Berg et al., 2010). Patients *Department of Clinical and Experimental Epilepsy, UCL Institute of have been described as “immature” with impaired experi- † Neurology, London, United Kingdom; Epilepsy Society MRI Unit, ence-related learning (Janz, 1985; De Araujo Filho & Epilepsy Society, Chalfont St Peter, United Kingdom; ‡Department of Neurology, Epilepsy Center, University of Munich, Munich, Germany; Yacubian, 2013), suggestive of frontal lobe dysfunction. Departments of §Neuroimaging, ¶Psychology, and #Clinical Neuroscien- This is corroborated by reports on impaired working mem- ’ ces, Institute of Psychiatry, King s College London, London, United Kingdom ory (WM) and executive functions (Wandschneider et al., Address correspondence to Matthias Koepp, UCL Institute of Neurol- ogy, 33 Queen Square, London WC1N 3BG, U.K. E-mail: m.koepp@ucl. 2012) and functional and microstructural changes within ac.uk the medial and dorsolateral prefrontal cortex (DLPFC) © 2013 The Authors. Epilepsia published by Wiley Periodicals, Inc. on (Vollmar et al., 2011; O’Muircheartaigh et al., 2011). behalf of International League Against Epilepsy. The Iowa Gambling Task (IGT) was developed for This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in patients with lesions within the prefrontal cortex (PFC) any medium, provided the original work is properly cited. presenting with impulsive decision making irrespective of 1 2 B. Wandschneider et al. possible future consequences (Bechara et al., 1994). Previ- could not be obtained. Performance was correlated with ous studies investigated the relationship of decision making activations during an fMRI WM task (n-back). Imaging data with performance in other cognitive domains of the PFC, sets from two controls and two patients were excluded such as executive functions (EFs) and working memory because of lack of activations during fMRI. In one patient (WM), arguing for a dissociation of decision-making abili- and two HCs, we could not record the dot back performance ties from other cognitive prefrontal lobe functions (Toplak due to joystick failure. et al., 2010). However, there is also evidence for an asym- Patients had a typical history of JME and had been diag- metrical relationship of decision making and WM in healthy nosed by experienced epileptologists according to the Inter- subjects (Suhr & Hammers, 2010) and in patients with fron- national League Against Epilepsy (ILAE) Classification tal lobe lesions (Bechara et al., 1998; Manes et al., 2002), (Berg et al., 2010). All clinical MRI scans were normal on but also in nonlesional frontal lobe disorders (Duarte et al., qualitative analysis. Fourteen patients had been seizure-free 2012). Working memory performance may not depend on for at least 12 months (see Table S1 for further clinical intact decision-making abilities, but WM dysfunction can details). No patient experienced a seizure during the assess- mediate impaired decision making. Lesions or dysfunction ment. of the anterior ventromedial prefrontal cortex (VMPFC) and orbitofrontal cortex seem to be associated with impaired Standardized frontal lobe tests decision making only, whereas pathology in the posterior A battery of standardized tests assessing frontal lobe (VMPFC) is associated with both WM and decision making functions was administered to all participants. It included impairment and the DLPFC with WM impairment only the following: (Bechara et al., 1998; Brand et al., 2007). 1 Letter and category fluency. The letters “F,”“A,” and “S” These observations are corroborated by a recent func- were presented for letter fluency, and the categories tional MRI (fMRI) study investigating neuronal correlates “animals,”“fruits,” and “vegetables” for categorical of decision making during the IGT in healthy controls fluency. The number of words produced for each letter or (Li et al., 2010). category within one minute was totaled to provide an Cortical activation patterns underlying decision making average score for letters and categories. include the following: (1) the DLPFC for WM, in order to 2 The Digit Span subtest of the Wechsler Adult Intelligence provide online knowledge during the decision-making Scale (WAIS-III; Wechsler, 1981) for working memory; process; (2) insula and posterior cingulate for emotional 3 The Trail Making Test (Reitan & Wolfson, 1985) for feedback; (3) medial orbitofrontal cortex to interlink the (a) Psychomotor speed: Total time to complete part A. previous two processes; and (4) ventral striatum and supple- (b) Mental flexibility: A score was derived by subtract- mentary motor area (SMA) to carry out decisions (Li et al., ing the time to complete for part A from the time to 2010). Impulsive decision making in the IGT has been complete part B. reported recently in JME (Zamarian et al., 2013), and was specifically evident if seizures were poorly controlled. Iowa Gambling Task We aimed to investigate the underlying mechanisms of In a computerized IGT version (Bechara, 2007), subjects decision-making behavior in JME, in particular to elucidate chose from four decks of cards (A–D) with a total of 100 which part of the WM network, as defined by fMRI, is cards. All decks awarded virtual monetary gains and losses. associated with IGT performance (Li et al., 2010). The aim was to gain as much money as possible. Decks A and B were associated with higher gains and penalties, Methods indicative of disadvantageous choices. Decks C and D were associated with lower gains and penalties (advantageous This study was approved by the UCL Hospital Research choices). Ethics Committee. Written informed consent was obtained Before commencing the IGT, participants were instructed from all study participants. that their aim was to gain as much money as possible and to Twenty-one JME patients and 11 healthy controls (HC), avoid losing money. However, they were not informed matched for gender (JME: 12 female, HC: 6; Pearson chi- about the IGT’s contingencies and had to learn them by square p = 0.888), age (JME: median 33.5 [range: 22–64] feedback from their card choices, that is, their monetary years; HC: 28 [24–32]; Mann-Whitney U = 70.500, gains and losses. N1 = 21, N2 = 11, p = 0.074), and IQ (JME: median 109 [range: 77–118]; HC: 113 [107–116]; Mann-Whitney Scores of IGT performance U = 51.000, N1 = 20, N2 = 7, p = 0.314) were assessed 1 The total number of card selections from the disadvan- with the IGT. With regard to educational exposure, 10 tageous decks (A and B) and the total number of patients were postgraduate, two obtained A-levels, six Gen- selections from the advantageous decks (C and D) were eral Certificate of Secondary Education (GCSE), and in counted. Subsequently, an overall net score was derived three patients, information about educational exposure by subtracting the total number of disadvantageous from Epilepsia, 0(0):1–8, 2013 doi: 10.1111/epi.12413 3 Impulsivity in Idiopathic Epilepsy advantageous choices (C + D À [A + B]). Net scores delay of the original occurrence (0-, 1-, or 2-back) and above zero indicate that subjects select advanta- respond by moving a joystick corresponding to the location geously; net scores