Executive function and risk-taking behaviour in JME

Behavioural studies on executive functions, such as planning, response inhibition, cognitive flexibility and verbal fluency describe varying degrees of impairment. Amongst these, verbal fluency is most consistently affected (Devinsky et al., 1997; Pascalicchio et al., 2007; Piazzini et al., 2008; Sonmez et al., 2004; Thomas et al., 2014; Wandschneider et al., 2012).

Few studies relate executive functions to findings on structural, functional and metabolic imaging. In a quantitative MR spectroscopy (MRS) study, Savic and colleagues (2004) compared patients with either JME or GGE with generalized tonic clonic seizures (GTCS) to a group of healthy controls. N-acetyl aspartate (NAA) is a neuron specific metabolite. Reduced levels can be associated with neuronal dysfunction or damage (Savic et al., 2000). Within the frontal lobes, NAA concentrations were reduced in the JME group in relation to both healthy controls and GTCS patients. In addition, JME patients with low frontal NAA concentrations showed frontal lobe dysfunction on a brief neuropsychological assessment. In contrast, frontal lobe functions were spared in JME patients with normal NAA concentrations, GTCS patients and controls. Hence, although a prefrontal neuronal lesion may be present in some JME patients, JME seems to be a heterogeneous condition. Low NAA levels did not correlate with any other clinical parameter, such as current seizure frequency or seizure number over lifetime.

Pulsipher et al. (2009) aimed to investigate the integrity of thalamo-frontocortical networks in relation to executive function in recent onset JME. Twenty JME patients within 12 months of diagnosis were compared to an epilepsy control group of 12 patients with recent onset Benign Childhood Epilepsy with Centrotemporal Spikes (BECTS) and 51 healthy controls. Participants were assessed with three subtests of the Delis-Kaplan Executive Function System (D-

KEFS) and a questionnaire for parents, the Behavior Rating Inventory of Executive Function (BRIEF). JME patients performed less well than controls on D-KEFS Inhibition. Behavioral Regulation and Metacognition scores of the BRIEF were also significantly lower in the JME group. Quantitative MRI measurements revealed smaller thalamic volumes and greater frontal CSF in JME patients than in healthy controls and BECTS-patients. Thalamic and frontal volumes predicted D-KEFS performance only for the JME group.

In a resting FDG-PET study (McDonald et al., 2006), regional cerebral rates of glucose uptake values (rCMRGlc) were regressed on various executive function test scores in patients with frontal lobe epilepsy, JME and healthy controls. In the JME group, frontal hypometabolic values predicted impairment on measures of figural fluency and cognitive flexibility.

O’Muircheartaigh and colleagues (2011) reported subtle dysfunctions in verbal fluency, comprehension and expression, mental flexibility and response inhibition in a cohort of 28 JME patients. In a structural and diffusion tensor MRI (DTI) study, voxel-based morphometry revealed reductions in grey matter volume in the supplementary motor area and posterior cingulate cortex. Fractional anisotropy (FA) in the supplementary motor area predicted performance in tasks of word naming and expression. Grey matter volumes of the posterior cingulate cortex and FA correlated with scores on the mental flexibility task. The authors describe their JME cohort as relatively high functioning but with neuropsychological evaluation revealing subtle cognitive impairments.

Another frontal lobe function, engaging working memory networks, the orbitofrontal cortex and SMA, is decision making. Impaired experienced-related learning and impulsive decision-making have been described in a behavioural study in JME patients (Zamarian et al., 2013). A recent fMRI study investigated

impulsivity in JME using the Iowa Gambling Task (IGT), which is a measure of decision-making under ambiguity, and correlated IGT performance with activation patterns during a working memory task (Wandschneider et al., 2013) (Figure 1.1). Subjects are instructed to choose from four decks of cards, which award virtual monetary gains and losses. Card deck choices are indicative of either advantageous or disadvantageous long-term choices, however participants are not informed about the IGT’s contingencies. Apart from overall advantageous or disadvantageous decision-making, learning from previous card choices can be assessed. The authors report overall no differences in card-choices and both groups, JME patients and healthy controls learned throughout the task. However, post hoc analysis revealed a greater proportion of patients with seizures than seizure-free patients having difficulties in advantageous decision-making and learn less from previous experience than both seizure-free patients and controls. Overall poor IGT performance was associated with increased activation within the dorsolateral prefrontal cortex (DLPFC). Impaired learning and ongoing seizures were associated with bilateral mesial prefrontal cortex and SMA, right superior frontal gyrus and left DLPFC activation. Findings suggest a dysfunction within macroscopically “normal” working memory networks, which implicates decision-making particularly in patients with poor seizure control.

Figure 1.1 (Wandschneider et al., 2013). Association of working memory network activation with learning in patients. A subgroup analysis in patients with ongoing seizures showed a bilateral medial prefrontal cortex and pre-SMA, a left dorsolateral prefrontal cortex (DLPFC), and right superior frontal gyrus activation in nonlearners compared to learners. (p < 0.005 unc.) (sz, seizures).

1.3.7.3

Possible confounds of cognitive function

Cognitive abilities of patients with epilepsy in general can be modulated by disease activity, subclinical epileptiform discharges, and medication. Evidence for GGE and JME in particular is outlined.

Disease activity

Parameters of disease activity include seizure frequency and disease duration. Pascalicchio and colleagues (2007) reported a positive correlation of disease duration and the risk of cognitive impairment in JME. Vollmar and colleagues