Autism Spectrum Disorders: from clinical identification to neuroimaging detection of brain abnormalities.

Abstract This thesis collects doctoral studies about early autism spectrum disorders (ASD) clinical identification and early ASD detection of brain magnetic resonance imaging (MRI) abnormalities. The work has been organized in five parts. In particular, the first report regards a screening population program for early ASD identification, purposely suited by Prof. Muratori and its research group and carried out by pediatricians of ASL 1 in all children of Massa-Carrara district twice, i.e. at 12 and 18 months of age. The second work is a retrospective study about growth of head circumference (HC) during the first 14 months of age, in children with ASD compared to typical developing children. Respect to anthropometric measurement of control group, courtesy provided by pediatricians Dr. Becattini and Dr. Soldateschi, children subsequently diagnosed as ASD show in the first six months of life significantly excessive growth of HC. Nevertheless, the mechanism for ASD brain enlargement remains to be elucidated and it is unknown whether brain enlargement is a cause or consequence of ASD. The third report analyzes the capacity of CBCL parent-report questionnaire to discriminate between ASD patients, subjects with other psychiatric disorders and typical children and investigates on its possible use as a ASD screening instrument for children between 18 and 60 months of ages. The fourth research is implemented in cooperation with the Natbrainlab laboratory (Institute of Psychiatry, King’s College Hospital London), directed by Dr. Marco Catani, with the aim of detecting structural connectivity differences between ASD patients and control subjects by means diffusion tensor imaging (DTI) measurements. The fifth and last study stems from the strong collaboration with the Istituto Nazionale di Fisica Nucleare (INFN) and concerns a structural MRI investigation on female children with ASD, a population poorly investigated in ASD neuroimaging studies and, for this reason, considered as “research orphan”. Riassunto Questa tesi raccoglie gli studi effettuati nel corso del dottorato riguardanti il riconoscimento clinico precoce dei disturbi dello spettro autistico (DSA) e l’identificazione precoce tramite risonanza magnetica (RM), delle anomalie cerebrali nei pazienti DSA. Il lavoro è stato organizzato in cinque parti. In particolare, il primo resoconto riguarda un programma di screening per l’identificazione precoce dei DSA, messo a punto dal Prof. Muratori e dal suo gruppo di ricerca e condotto dai pediatri di libera scelta della ASL 1 con una duplice valutazione, effettuata a 12 e a 18 mesi di vita in tutti i bambini della provincia di Massa-Carrara. Il secondo lavoro è uno studio retrospettivo sulla crescita della circonferenza cranica (CC) nei primi 14 mesi di vita in bambini con DSA confrontati con bambini con uno sviluppo tipico. Rispetto alle misure antropometriche del gruppo di controllo, cortesemente fornite dai pediatri Dott.ssa Becattini e Dott. Soldateschi, i bambini successivamente diagnosticati come DSA mostrano nei primi sei mesi di vita una crescita significativamente maggiore della CC. Tuttavia, il meccanismo alla base dell’aumento cerebrale e il suo ruolo nell’eziopatogenesi dei DSA rimangono argomenti da chiarire. La terza ricerca analizza la capacità del questionario CBCL compilato dai genitori di discriminare tra pazienti con DSA, soggetti con altri disturbi psichiatrici e bambini con sviluppo tipico e indaga inoltre il suo possibile utilizzo come strumento di screening per i DSA nei bambini di età compresa tra i 18 e i 60 mesi. Il quarto lavoro è stato progettato in collaborazione con il laboratorio Natbrainlab (Institute of Psychiatry, King’s College Hospital London), diretto dal Dott. Marco Catani, ed ha lo scopo di individuare eventuali differenze nella connettività strutturale tra i pazienti DSA e i soggetti di controllo attraverso misure derivate dall’imaging del tensore di diffusione (DTI). Il quinto e ultimo studio nasce dalla forte collaborazione con l’Istituto Nazionale di Fisica Nucleare (INFN) e riguarda un’indagine di RM strutturale focalizzata sulle bambine con DSA, una popolazione scarsamente presa in considerazione dagli studi di neuroimmagine nei DSA e pertanto considerata “research orphan”

Umorismo e ironia in Albert Camus: immagini capovolte di un’etica

Alla luce delle teorie su umorismo e ironia fra Ottocento e Novecento, l’intervento intende indagare le modalità dell’umorismo e dell’ironia in Albert Camus, in particolare riferendosi al testo La caduta. Camus, attraverso la riflessione digressiva del personaggio – che, quanto più scompone e giudica, con abilità dialettica, una posizione di potere, tanto più tende a confermarla – si fa carico di una contraddizione, di una struttura doppia, per esprimere il proprio disagio verso la società nichilista a lui contemporanea e rivelarne il fallimento. L’umorismo in Camus sorge nella logica della “transizione”, della crisi, della necessità di affermare nuovi valori morali e un nuovo linguaggio. Si vuole pertanto esaminarne il processo al fine di mostrare come, nell’Autore, l’umorismo – e soprattutto un’ironia (di tipo filosofico, di matrice kierkegaardiana, della quale è investito negativamente il personaggio) capace di cogliere il vano, l’assurdo e la follia dell’esistenza ma senza risolverli in mediazione, piuttosto rinforzandoli – diventi in ultima istanza mezzo critico per consolidare l’etica della rivolta, che è etica del limite e della misura.Alla luce delle teorie su umorismo e ironia fra Ottocento e Novecento, l’intervento intende indagare le modalità dell’umorismo e dell’ironia in Albert Camus, in particolare riferendosi al testo La caduta. Camus, attraverso la riflessione digressiva del personaggio – che, quanto più scompone e giudica, con abilità dialettica, una posizione di potere, tanto più tende a confermarla – si fa carico di una contraddizione, di una struttura doppia, per esprimere il proprio disagio verso la società nichilista a lui contemporanea e rivelarne il fallimento. L’umorismo in Camus sorge nella logica della “transizione”, della crisi, della necessità di affermare nuovi valori morali e un nuovo linguaggio. Si vuole pertanto esaminarne il processo al fine di mostrare come, nell’Autore, l’umorismo – e soprattutto un’ironia (di tipo filosofico, di matrice kierkegaardiana, della quale è investito negativamente il personaggio) capace di cogliere il vano, l’assurdo e la follia dell’esistenza ma senza risolverli in mediazione, piuttosto rinforzandoli – diventi in ultima istanza mezzo critico per consolidare l’etica della rivolta, che è etica del limite e della misura

One-class support vector machines identify the language and default mode regions as common patterns of structural alterations in young children with autism spectrum disorders

The identification of reliable brain endophenotypes of autism spectrum disorders (ASD) has been hampered to date by the heterogeneity in the neuroanatomical abnormalities detected in this condition. To handle the complexity of neuroimaging data and to convert brain images in informative biomarkers of pathology, multivariate analysis techniques based on Support Vector Machines (SVM) have been widely used in several disease conditions. They are usually trained to distinguish patients from healthy control subjects by making a binary classification. Here, we propose the use of the One-Class Classification (OCC) or Data Description method that, in contrast to two-class classification, is based on a description of one class of objects only. This approach, by defining a multivariate normative rule on one class of subjects, allows recognizing examples from a different category as outliers. We applied the OCC to 314 regional features extracted from brain structural Magnetic Resonance Imaging (MRI) scans of young children with ASD (21 males and 20 females) and control subjects (20 males and 20 females), matched on age [range: 22-72 months of age; mean = 49 months] and non-verbal intelligence quotient (NVIQ) [range: 31-123; mean = 73]. We demonstrated that a common pattern of features characterize the ASD population. The OCC SVM trained on the group of ASD subjects showed the following performances in the ASD vs. controls separation: the area under the receiver operating characteristic curve (AUC) was 0.74 for the male and 0.68 for the female population, respectively. Notably, the ASD vs. controls discrimination results were maximized when evaluated on the subsamples of subjects with NVIQ = 70, leading to AUC = 0.81 for the male and AUC = 0.72 for the female populations, respectively. Language regions and regions from the default mode network-posterior cingulate cortex, pars opercularis and pars triangularis of the inferior frontal gyrus, and transverse temporal gyrus-contributed most to distinguishing individuals with ASD from controls, arguing for the crucial role of these areas in the ASD pathophysiology. The observed brain patterns associate preschoolers with ASD independently of their age, gender and NVIQ and therefore they are expected to constitute part of the ASD brain endophenotype

Inter-method reliability of brainstem volume segmentation algorithms in preschoolers with ASD

Introduction: The brainstem has a potential role in the pathophysiology of Autism Spectrum Disorders (ASD) (Roger, 2013). In particular, alterations in brainstem volume and their relationship with sensory/motor abnormalities have been suggested (Trevarthen & Delafield-Butt, 2013). However, the findings in volume alterations of subjects with ASD with respect to matched controls are controversial both in adults and children cohorts (Hardan, 2001; Piven, 1992; Kleiman, 1992). Moreover, the contribution to variability of brainstem volume measurements performed with different automated methods is still unclear. Methods: T1-weighted MRI brain scans of a cohort of 80 preschoolers (20 male controls, 20 male subjects with ASD, 20 female controls, 20 female subjects with ASD, mean age controls 49 months, std 12 months, mean age ASD 49 months, std 14) were processed with three different automated methods to measure the brainstem volume: Freesurfer 5.3 (Fischl, 2002), FSL-FIRST (Patenaude, 2011) and ANTs (Avants, 2011). Analysis of variance was then carried out taking into account gender and total brain volume in order to investigate potential brainstem volume differences between controls/ASD subjects for each method. A direct comparison of brainstem volume assessments in native space was then performed to assess inter-method reliability (correlation has been calculated by Pearson coefficient) and Dice similarity indexes were calculated to evaluate the segmentation agreement across methods. Results:The brainstem volume measurements are reported in scatter plots in Fig. 1 to show the agreement in terms of volume (in mm3) between different methods. The color represents the Dice similarity index (range 0-1 were 1 means total agreement) of the brainstem segmentations obtained by the methods under investigation. In Fig. 2 four examples of brainstem segmentations with the different methods are shown in sagittal view (brainstem segmentations are reported in red, green, blue for Freesurfer, FSL-FIRST and ANTs respectively). Pearson correlation coefficient between FSL-FIRST and Freesurfer brainstem volume assessments was 0.27 (p-value=0.02). It was 0.51 (p-value0.05).Conclusions:The inter-method reliability of automated algorithms for brainstem volume assessment is limited (the mean Dice similarity index barely reaches 0.8 in just one out of 3 comparisons). Inconsistencies across previous studies on brainstem and more in general the lack of evidence for brain biomarkers in ASD may in part be a result of this poor agreements in the extraction of structural features with different methods. Inter-method brainstem volume differences can be attributed to varying definitions of brainstem structure, the use of different templates (e.g. in our study only ANTs processed the brain scans by using an age-specific brain template) and the varying effects of imaging artifacts and acquisition settings. This study suggests that research on brain structure alterations should cross-validate findings across multiple methods before providing biological interpretations

How attention to faces and objects changes over time in toddlers with autism spectrum disorders: Preliminary evidence from an eye tracking study

Further understanding of the longitudinal changes in visual pattern of toddlers with autism spectrum disorders (ASDs) is needed. We examined twelve 19 to 33-month-old toddlers at their first diagnosis (mean age: 25.1 months) and after six months (mean age: 31.7 months) during two initiating joint attention (IJA) tasks using eye tracking. Results were compared with the performance of age-matched typically developing (TD) toddlers evaluated at a single time-point. Autistic toddlers showed longitudinal changes in the visual sensory processing of the IJA tasks, approaching TD performance with an improvement in the ability to disengage and to explore the global space. Findings suggest the use of eye tracking technology as an objective, non-intrusive, adjunctive tool to measure outcomes in toddlers with ASD

Temporal lobe connects regression and macrocephaly to autism spectrum disorders

Interictal electroencephalogram (EEG) abnormalities are frequently associated with autism spectrum disorders (ASD), although their relationship with the clinical features of ASD, particularly the regressive onset, remains controversial. The aim of this study was to investigate whether the characteristics of interictal EEG abnormalities might help to distinguish and predict definite phenotypes within the heterogeneity of ASD. We reviewed the awake and sleep interictal EEGs of 220 individuals with idiopathic ASD, either with or without a history of seizures. EEG findings were analyzed with respect to a set of clinical variables to explore significant associations. A brain morphometry study was also carried out on a subgroup of patients. EEG abnormalities were seen in 154/220 individuals (70 %) and were mostly focal (p < 0.01) with an anterior localization (p < 0.001). They were detected more frequently during sleep (p < 0.01), and were associated with a regressive onset of ASD (p < 0.05), particularly in individuals with focal temporal localization (p < 0.05). This association was also stronger in regressive patients with concurrent macrocephaly, together with a relative volumetric reduction of the right temporal cortex (p < 0.05). Indeed, concurrence of temporal EEG abnormalities, regression and macrocephaly might possibly define a distinct endophenotype of ASD. EEG-based endophenotypes could be useful to untangle the complexity of ASD, helping to establish anatomic or pathophysiologic subtypes of the disorder

The Broad Autism (Endo)Phenotype: Neurostructural and Neurofunctional Correlates in Parents of Individuals with Autism Spectrum Disorders

Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with an early-onset and a strong genetic component in their pathogenesis. According to genetic and epidemiological data, ASD relatives present personality traits similar to, but not as severe as the defining features of ASD, which have been indicated as the "Broader Autism Phenotype" (BAP). BAP features seem to be more prevalent in first-degree relatives of individuals with ASD than in the general population. Characterizing brain profiles of relatives of autistic probands may help to understand ASD endophenotype. The aim of this review was to provide an up-to-date overview of research findings on the neurostructural and neurofunctional substrates in parents of individuals with ASD (pASD). The primary hypothesis was that, like for the behavioral profile, the pASD express an intermediate neurobiological pattern between ASD individuals and healthy controls. The 13 reviewed studies evaluated structural magnetic resonance imaging (MRI) brain volumes, chemical signals using magnetic resonance spectroscopy (MRS), task-related functional activation by functional magnetic resonance imaging (fMRI), electroencephalography (EEG), or magnetoencephalography (MEG) in pASD.The studies showed that pASD are generally different from healthy controls at a structural and functional level despite often not behaviorally impaired. More atypicalities in neural patterns of pASD seem to be associated with higher scores at BAP assessment. Some of the observed atypicalities are the same of the ASD probands. In addition, the pattern of neural correlates in pASD resembles that of adult individuals with ASD, or it is specific, possibly due to a compensatory mechanism. Future studies should ideally include a group of pASD and HC with their ASD and non-ASD probands respectively. They should subgrouping the pASD according to the BAP scores, considering gender as a possible confounding factor, and correlating these scores to underlying brain structure and function. These types of studies may help to understand the genetic mechanisms involved in the various clinical dimension of ASD

Moving Toward Telehealth Surveillance Services for Toddlers at Risk for Autism During the COVID-19 Pandemic

Since 2016, the project "Early Bird Diagnostic Protocol for Autism Spectrum Disorders (ASD)" funded by the Italian Ministry of Health has been operative at IRCCS Fondazione Stella Maris (FSM), Pisa (IT), with the main aim of developing early age-specific diagnostic protocols by longitudinally enrolling two different populations at risk for ASD: (i) toddlers with older siblings with ASD (FR) and (ii) toddlers referred by a child psychiatrist or pediatrician for suspected ASD (CR). On January 30, 2020, when the World Health Organization declared the outbreak of coronavirus disease 2019 (COVID-19), 136 patients (85 FR; 51 CR; 93 males; 43 females) had been enrolled in the project with 324 completed time points and 64 still missing. Considering both the huge psychological burden on families with toddlers at risk for ASD during the lockdown and the longitudinal studies reporting the positive "surveillance effect" in terms of a better outcome in at-risk toddlers, our priority has been to maintain regular contact and support to enrolled families. To do this, the research team, being authorized for smart-working research activities, has set up a detailed remote surveillance protocol (RSP). The RSP includes three online interviews and one online video registration of parent-child play. In the current community case study, the authors report the telehealth procedure and discuss possible future directions in developing remote assessment and new evaluation modalities for ecological parent-child play video recordings in at-risk populations. Hopefully, the surveillance protocol will further improve our ability to detect risk and activate early tailored intervention