Neuroimaging of epilepsy: disease severity, cognitive comorbidities and endophenotypes

Epilepsy is a common neurological disorder complicated by cognitive and psycho- social comorbidities. Magnetic resonance imaging (MRI) investigations characterise brain networks in vivo, providing measurable traits (biomarkers) of pathological processes with biological validity and high reproducibility, thereby shedding light on the pathological mechanisms of epilepsy and its comorbidities. In this PhD thesis, functional and structural MRI have been employed to detect potential biomarkers in relation to three specific domains of epilepsy: (1) disease severity in temporal lobe epilepsy (TLE), (2) cognitive network dysfunction in frontal lobe epilepsy (FLE), and (3) heritable phenotypes (endophenotypes) in the prototypical generalised epilepsy syndrome, juvenile myoclonic epilepsy (JME). The first project focused on determinants of disease severity in TLE: (a) disease progression and (b) secondary generalised (focal to bilateral) tonic-clonic seizures. In Study 1, I applied a meta-analytical approach on previous structural MRI studies in TLE (n>1500), providing comprehensive evidence for hippocampal and extra- hippocampal cumulative atrophy. In Study 2, I captured functional MRI (fMRI) markers of secondarily-generalised tonic-clonic seizures in TLE, identifying abnormal activation, task-modulated connectivity and network-based centrality of the thalamus. The second project investigated the neural correlates of cognitive dysfunction in FLE. Using neuropsychometry and four fMRI tasks addressing working memory and expressive language, I detected derangements of fronto-temporo-parietal activation, independent of seizure focus lateralisation, and impaired deactivation of task- negative networks. The third project investigated patients with JME and their unaffected siblings to identify imaging endophenotypes of JME, i.e. heritable traits associated with the disease at the population-level, co-segregating in families with affected members. Study 1 validated indicators of motor system activation during language and episodic memory fMRI as suitable endophenotypes. Study 2 investigated structure and function of the mesiotemporal lobe, showing abnormalities of hippocampal morphometry common to patients and siblings and associated with reorganisation of memory fMRI activation, implying prenatal neurodevelopmental mechanisms

Labour Activism and Social Movement Unionism in the Gig Economy. Food Delivery Workers Struggles in Italy

This article aims to explore the forms of collective actions that are emerging in new sectors of digital capitalism. In particular, it enquires into the mobilisation of food delivery workers that has been developing since 2016 in four Italian cities: Milan, Turin, Bologna and Florence. Despite the high level of precarisation and atomisation that characterise this subset of gig economy jobs, the so-called riders were able to organise into self-organised workers' collectives, which not only gave rise to many protest events, but also drew the attention of the institutions and the media. What are the conditions and the strategies that made this possible? And, more broadly, what does this case tell us about the possibility of labour activism in gig economy work? We argue that the high level of activation of food delivery workers is to be related to their capability to provide resources for reconstructing social ties among workers and, in turn, for translating them into political engagement and contentious action. This is realised through the combination of three factors that will be scrutinised in the paper. The analysis points out that although precarisation creates significant obstacles to organisation and mobilisation, collective action does actually take place also in the gig economy, in certain conditions

Labour Activism and Social Movement Unionism in the Gig Economy. Food Delivery Workers Struggles in Italy

This article aims to explore the forms of collective actions that are emerging in new sectors of digital capitalism. In particular, it enquires into the mobilisation of food delivery workers that has been developing since 2016 in four Italian cities: Milan, Turin, Bologna and Florence. Despite the high level of precarisation and atomisation that characterise this subset of gig economy jobs, the so-called riders were able to organise into self-organised workers' collectives, which not only gave rise to many protest events, but also drew the attention of the institutions and the media. What are the conditions and the strategies that made this possible? And, more broadly, what does this case tell us about the possibility of labour activism in gig economy work? We argue that the high level of activation of food delivery workers is to be related to their capability to provide resources for reconstructing social ties among workers and, in turn, for translating them into political engagement and contentious action. This is realised through the combination of three factors that will be scrutinised in the paper. The analysis points out that although precarisation creates significant obstacles to organisation and mobilisation, collective action does actually take place also in the gig economy, in certain conditions

Quantitative susceptibility mapping identifies hippocampal and other subcortical grey matter tissue composition changes in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is associated with widespread brain alterations. Using quantitative susceptibility mapping (QSM) alongside transverse relaxation rate ( ), we investigated regional brain susceptibility changes in 36 patients with left-sided (LTLE) or right-sided TLE (RTLE) secondary to hippocampal sclerosis, and 27 healthy controls (HC). We compared three susceptibility calculation methods to ensure image quality. Correlations of susceptibility and with age of epilepsy onset, frequency of focal-to-bilateral tonic–clonic seizures (FBTCS), and neuropsychological test scores were examined. Weak-harmonic QSM (WH-QSM) successfully reduced noise and removed residual background field artefacts. Significant susceptibility increases were identified in the left putamen in the RTLE group compared to the LTLE group, the right putamen and right thalamus in the RTLE group compared to HC, and a significant susceptibility decrease in the left hippocampus in LTLE versus HC. LTLE patients who underwent epilepsy surgery showed significantly lower left-versus-right hippocampal susceptibility. Significant changes were found between TLE and HC groups in the amygdala, putamen, thalamus, and in the hippocampus. Specifically, decreased R2* was found in the left and right hippocampus in LTLE and RTLE, respectively, compared to HC. Susceptibility and were significantly correlated with cognitive test scores in the hippocampus, globus pallidus, and thalamus. FBTCS frequency correlated positively with ipsilateral thalamic and contralateral putamen susceptibility and with in bilateral globi pallidi. Age of onset was correlated with susceptibility in the hippocampus and putamen, and with in the caudate. Susceptibility and changes observed in TLE groups suggest selective loss of low-myelinated neurons alongside iron redistribution in the hippocampi, predominantly ipsilaterally, indicating QSM's sensitivity to local pathology. Increased susceptibility and in the thalamus and putamen suggest increased iron content and reflect disease severity

Verbal fluency functional magnetic resonance imaging detects anti-seizure effects and affective side effects of perampanel in people with focal epilepsy

Perampanel, a noncompetitive antagonist of the postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but is also known to increase feelings of anger. Using statistical parametric mapping-derived measures of activation and task-modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency functional magnetic resonance imaging (fMRI) twice, before and after the add-on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity-matched for clinical characteristics, who had two scans but no change in anti-seizure medication (ASM) regimen in-between. After commencing perampanel, individuals had higher task-related activations in left orbitofrontal cortex (OFC), fewer task-related activations in the subcortical regions including the left thalamus and left caudate, and lower task-related thalamocaudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between the left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic-clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC)

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

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

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