Fisiopatologia della risposta fotoparossistica nella Epilessia Mioclonica Giovanile: studio EEG e Risonanza Magnetica funzionale

L'Epilessia Mioclonica Giovanile (JME) è una sindrome elettro-clinica, classificata tra le epilessie generalizzate genetiche, che presenta esordio tipicamente in età giovanile ed è caratterizzata da crisi miocloniche, tonico-cloniche e talora assenze tipiche. Le anomalie elettroencefalografiche di più frequente riscontro sono rappresentate da complessi punta/polipunta-onda a 3-6 Hz. La fotosensibilità è un fenotipo particolarmente frequente nei pazienti JME, con prevalenza variabile fra il 30% e il 90% a seconda delle casistiche (Wolf & Goosses, 1986; Appleton et al. 2000). Con approcci neurofisiologici classici, la fisiopatologia della fotosensibilità nella JME non è ancora stata chiarita. L’utilizzo di un approccio innovativo e multimodale, quale l’associazione di EEG e Risonanza Magnetica funzionale (EEG-fMRI) consente di mappare l’attivazione funzionale (tramite misura del c.d. segnale blood-oxygen-level-dependent- BOLD) specifica di aree cerebrali in concomitanza temporale con anomalie elettroencefalografiche selezionate dallo sperimentatore: un’analisi del pattern di attivazioni/deattivazioni in relazione allo stimolo luminoso e alle anomalie epilettiformi foto-indotte può aiutare a chiarire i networks coinvolti nella generazione della scarica epilettiforme. Per il presente studio sono stati reclutati venti soggetti, dieci pazienti JME e dieci controlli sani. Gli obiettivi sono rappresentati da: (1) caratterizzazione delle mappe fMRI in pazienti e controlli in risposta a un protocollo di stimolazione luminosa intermittente (SLI) a bassa luminanza; (2) identificazione dell’andamento temporale del segnale BOLD, nel sottogruppo di pazienti foto-sensibili, in relazione alla comparsa di risposta fotoparossistica nel tracciato EEG. Come ulteriore sotto-analisi, abbiamo validato il nostro metodo di SLI a bassa luminanza e luce rossa (lunghezza d’onda = 680 nm), effettuata durante la risonanza tramite occhialini LCD RM-compatibili, rispetto al protocollo di stimolazione con luce stroboscopica convenzionalmente utilizzato durante EEG di routine. Nei controlli sani abbiamo rilevato, in corrispondenza della stimolazione luminosa, l’attivazione delle aree visive striate ed extrastriate e del putamen, e la deattivazione di aree cerebrali deputate alla preparazione ed attuazione del movimento. Nei pazienti si è identificato l’attivazione della aree visive, in maniera meno marcata rispetto ai controlli, e la deattivazione delle aree costituenti il c.d. default mode network. Il task di stimolazione luminosa a bassa luminanza ha determinato la comparsa di risposta fotoparossistica (PPR) nel tracciato EEG nel 70% dei pazienti. In tali soggetti, l’analisi temporale del segnale BOLD in intervalli antecedenti e successivi alla risposta fotoparossistica (PPR) ha mostrato l’attivazione del putamen prima della PPR, seguita dall’attivazione di aree motorie e del talamo poco dopo l’anomalia; successivamente, sono stati osservati soprattutto fenomeni di deattivazione a carico di aree motorie, caudato-putamen bilateralmente e default mode network nella sua componente anteriore. Nella sotto-analisi comparativa delle metodiche di stimolazione luminosa, la tecnica a bassa luminanza con luce rossa è risultata più provocativa della metodica SLI convenzionale, confermando l’utilità di tale approccio per questa categoria di pazienti. I risultati da noi ottenuti suggeriscono che, nel contesto dell’alterazione della connettività funzionale tra aree visive e aree motorie, recentemente identificata nella JME, un ruolo significativo possa essere svolto dai circuiti dei nuclei dalla base. La complessa sequenza di attivazioni e deattivazioni, riscontrata in corrispondenza delle risposte fotoparossistiche, potrebbe rappresentare la manifestazione dell’alterazione della connettività del sistema striato-talamo-corticale, verosimile base fisiopatologica della JME

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

Reversible MRI abnormalities in mesial temporal lobe epilepsy: a case report

The question regarding the existence of abnormalities in the neuroimaging exams immediately after status epilecticus or epileptic seizures, but showing complete reversibility after a proper antiepileptic therapy, has long been debated. The first reports attempting to demonstrate their existence date back to the 1980s, and relied upon computed tomography as the imaging method of choice. After the introduction of MRI, a more appropriate characterization of these abnormalities was obtained along with the description of their most frequent features: (a) T2 signal hyperintensity in the white matter and, occasionally, (b) reduced apparent diffusion coefficient (ADC) and increased signal in DWI sequences.The MRI abnormalities induced by epileptic activity pose a broad differential diagnosis including infections, inflammatory autoimmune encephalopathies, neoplasms. It remains a diagnosis of exclusion and requires proper diagnostic iter in order to reduce the risk of misdiagnosis and unnecessary intervention.In this case report, a thorough presentation will be outlined about MRI alterations in the left mesial temporal lobe, which resulted completely reversible after a proper antiepileptic therapy

Human Learning of Hierarchical Graphs

Humans are constantly exposed to sequences of events in the environment. Those sequences frequently evince statistical regularities, such as the probabilities with which one event transitions to another. Collectively, inter-event transition probabilities can be modeled as a graph or network. Many real-world networks are organized hierarchically and understanding how humans learn these networks is an ongoing aim of current investigations. While much is known about how humans learn basic transition graph topology, whether and to what degree humans can learn hierarchical structures in such graphs remains unknown. We investigate how humans learn hierarchical graphs of the Sierpi\'nski family using computer simulations and behavioral laboratory experiments. We probe the mental estimates of transition probabilities via the surprisal effect: a phenomenon in which humans react more slowly to less expected transitions, such as those between communities or modules in the network. Using mean-field predictions and numerical simulations, we show that surprisal effects are stronger for finer-level than coarser-level hierarchical transitions. Surprisal effects at coarser levels of the hierarchy are difficult to detect for limited learning times or in small samples. Using a serial response experiment with human participants (n=$100$), we replicate our predictions by detecting a surprisal effect at the finer-level of the hierarchy but not at the coarser-level of the hierarchy. To further explain our findings, we evaluate the presence of a trade-off in learning, whereby humans who learned the finer-level of the hierarchy better tended to learn the coarser-level worse, and vice versa. Our study elucidates the processes by which humans learn hierarchical sequential events. Our work charts a road map for future investigation of the neural underpinnings and behavioral manifestations of graph learning.Comment: 22 pages, 10 figures, 1 tabl

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

The Impact of Temporal Lobe Epilepsy Surgery on Picture Naming and its Relationship to Network Metric Change

Background: Anterior temporal lobe resection (ATLR) is a successful treatment for medically-refractory temporal lobe epilepsy (TLE). In the language-dominant hemisphere, 30%- 50% of individuals experience a naming decline which can impact upon daily life. Measures of structural networks are associated with language performance pre-operatively. It is unclear if analysis of network measures may predict post-operative decline. Methods: White matter fibre tractography was performed on preoperative diffusion MRI of 44 left lateralised and left resection individuals with TLE to reconstruct the preoperative structural network. Resection masks, drawn on co-registered pre- and post-operative T1-weighted MRI scans, were used as exclusion regions on pre-operative tractography to estimate the post-operative network. Changes in graph theory metrics, cortical strength, betweenness centrality, and clustering coefficient were generated by comparing the estimated pre- and post-operative networks. These were thresholded based on the presence of the connection in each patient, ranging from 75% to 100% in steps of 5%. The average graph theory metric across thresholds was taken. We incorporated leave-one-out cross-validation with smoothly clipped absolute deviation (SCAD) least absolute shrinkage and selection operator (LASSO) feature selection and a support vector classifier to assess graph theory metrics on picture naming decline. Picture naming was assessed via the Graded Naming Test preoperatively and at 3 and 12 months post-operatively and the outcome was classified using the reliable change index (RCI) to identify clinically significant decline. The best feature combination and model was selected using the area under the curve (AUC). The sensitivity, specificity and F1-score were also reported. Permutation testing was performed to assess the machine learning model and selected regions difference significance. Results: A combination of clinical and graph theory metrics were able to classify outcome of picture naming at 3 months with an AUC of 0.84. At 12 months, change in strength to cortical regions was best able to correctly classify outcome with an AUC of 0.86. Longitudinal analysis revealed that betweenness centrality was the best metric to identify patients who declined at 3 months, who will then continue to experience decline from 3-12 months. Both models were significantly higher AUC values than a random classifier. Conclusion: Our results suggest that inferred changes of network integrity were able to correctly classify picture naming decline after ATLR. These measures may be used to prospectively to identify patients who are at risk of picture naming decline after surgery and could potentially be utilised to assist tailoring the resection in order to prevent this decline