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HORIZONS IN NEUROSCIENCE RESEARCH

HORIZONS IN NEUROSCIENCE RESEARCH VOLUME 31

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HORIZONS IN NEUROSCIENCE RESEARCH

HORIZONS IN NEUROSCIENCE RESEARCH VOLUME 31

ANDRES COSTA AND

EUGENIO VILLALBA EDITORS

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Copyright © 2017 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470 E-mail: [email protected]

NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data ISBN:  H%RRN ISSN: 2159-113X

Published by Nova Science Publishers, Inc. † New York

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CONTENTS Preface Chapter 1

Chapter 2

Chapter 3

vii Cognitive-Behavioral Interventions for Promoting Adaptive Skills of Children with Rare Genetic Syndromes: A Selective Overview Fabrizio Stasolla, Viviana Perilli, Alessandro O. Caffò and Fiora D'Amico The Effects of Valproate and Levetiracetam as a Monotherapy on Vitamin D Status in Epileptic Children Teodoro Durá-Travé, Fidel Gallinas-Victoriano, María Urretavizcaya-García, Lotfi Ahmed-Mohamed, Sergio Aguilera-Albesa and María Eugenia Yoldi-Petri Cerebral Blood Flow Mediated Rapid Vascular Reactivity Mapping and Effects of Age and Smoking Yongxia Zhou

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Contents

Chapter 4

Neurofilaments in Brain and Spinal Cord Ischemia Lenka Fialová

Chapter 5

Beneficial Effects of Noise on Visual Acuity without Consciousness Hitoshi Sasaki, Hideaki Saito and Takuya Ishida

Chapter 6

Chapter 7

Chapter 8

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117

Psychodynamics and the PlaymoCase: Novel Aspects for Playing and Projective Testing Martin H. Maurer

147

Implicit Natural Morphosyntactic Learning Is the Learning of What? Jean A. Rondal

171

A Few Remarks on Spatial Frequency Filtered Images Bernt Christian Skottun

193

Index

209

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PREFACE This book provides readers with the latest developments in neurosciences research. Chapter One provides a selective overview of the empirical contributions available in the last decade for promoting independence and self-determination of children with rare genetic syndromes and severe to profound developmental disabilities through cognitive-behavioral interventions and assistive technology-based programs. Chapter Two evaluates the influence of VPA and LEV as monotherapy on vitamin D status among children with epilepsy. Chapter Three characterizes the intercorrelations and different factors contributing to whole brain voxel-wise blood flow measures based on standard imaging metrics. Chapter Four summarizes current knowledge about the determination of individual subunits of the neurofilament triplet in cerebral and spinal cord ischemia. Chapter Five provides a new approach to the restoration of degraded visual functions and expands our knowledge of perception and consciousness. Chapter Six describes PlaymoCase as a means of a play-therapeutic approach with the regard to its content and its relationship to the Operationalized Psychodynamic Diagnosis in Childhood and Adolescence in the revised version (OPD-CA2). Chapter Seven discusses structural linguists and how speaking amounts to transforming a structural order into a linear one, and understanding a sentence to turning a linear order into a structural one. Chapter Eight investigates the responses

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to images of human faces in which the spatial Fourier spectra have been manipulated. Chapter 1 - This chapter provides the reader with a selective overview of the empirical contributions available in the last decade for promoting independence and self-determination of children with rare genetic syndromes and severe to profound developmental disabilities through cognitive-behavioral interventions and assistive technology-based programs. Four syndromes were considered, namely (a) Angelman, (b) Cornelia de Lange, (c) fragile X, and (d) Rett. Thirty studies were retained and 1322 participants were involved. Results were largely positive, although few failures occurred. Psychological and rehabilitative implications of the findings were discussed, and some useful recommendations for future research and practice were outlined. Chapter 2 - Introduction. Many classic antiepileptic drugs (AEDs) may cause vitamin D deficiency (e.g., valproate). Levetiracetam (LEV) is a more recent AED widely used in paediatric epilepsy. Adult studies suggest no vitamin D-lowering effect of LEV treatment, but there are few studies in children. Objectives. The aim of this study is to evaluate the influence of VPA and LEV as monotherapy on vitamin D status among children with epilepsy. Material & Methods. A cross-sectional clinical (seizure types, aetiology of epilepsy, dosage, drug levels, and duration of AEDs) and blood testing (calcium, phosphorous, 25-OHD and PTH) study was accomplished in 90 epileptic children (AEDs group: 59 receiving VPA, and 31 receiving LEV) and a control group (244 healthy subjects). Serum 25-OHD levels were categorized as low (>20 ng/ml), borderline (20-29 ng/ml), or normal (>30 ng/ml). Results. The aetiology of epilepsy was idiopathic in 69 patients (76.7%), cryptogenic in 12 patients (13.3%), and symptomatic in 9 patients (10%). The average dosage of VPA and LEV was 20.7 ± 4.7 mg/kg/d and 24.1 ± 7.9 mg/kg/d, respectively. The mean duration of VPA therapy was 2.5 ± 1.4 years, and for LEV was 2.3 ± 1.6 years. Drug levels of VPA and LEV were 72.1 ± 25.9 mcg/ml and 7.7 ± 4.0 mcg/ml, respectively.

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Calcium and 25-OHD levels were significantly higher (p < 0.05) in the control group. There was a negative correlation (p < 0.01) between 25OHD and VPA levels (r = -0.442). There was not any correlation between 25-OHD and LEV levels and length of AEDs therapy (VPA or LEV). Vitamin D deficiency was significantly higher (p < 0.05) in VPA (24.1%) and LEV (35.5%) groups than in control group (14%). The multiple logistic regression analysis showed that VPA monotherapy (OR: 1.9, CI 95%: 1.1-3.8) and specially LEV monotherapy (OR: 3.3, CI 95%: 1.5-7.5) were associated with an increased risk of vitamin D deficiency. Conclusion. The prevalence of vitamin D deficiency is common in children with epilepsy taking VPA or LEV. Hence, vitamin D status of children treated with VPA and LEV should be regularly monitored, and vitamin D supplements on an individual basis should be considered. Chapter 3 - Section I: CBF and Pseudo-CBF. The purpose of this section is to characterize the intercorrelations and different factors contributing to whole brain voxel-wise blood flow measures based on standard imaging metrics. Cerebral blood flow (CBF) measured with PET [15-O] tracer as well as the kinetic parameters for quantifying PiB betaamyloid tracer flow rate (R1, pseudo-CBF) and tracer distribution volume ratio (DVR) choosing cerebellum as reference region were introduced. Significant voxel-wise correlations between [15-O] CBF and PiB-R1 images across subjects (N = 93) were found mostly for the whole sample group, and more significant in the PiB- sub-group in comparison to the PiB+ sub-group. Non-negative matrix factorization to the CBF data showed different CBF spatial distributions with higher visual CBF in PiB+ group in contrast to higher frontal and visual CBF in APOE4+ group. Mild correlations between CBF and BOLD-based default mode network (DMN) using functional connectivity with fMRI (fcMRI) were found from clusters in the posterior cingulate, frontal and premotor and subcortical thalamic regions (uncorrected P < 0.05) based on either whole-brain voxel-wise correlations or between CBF and functional activity. Linear mixed effects modeling was performed to predict CBF by baseline age and sex effects, adding modulation factors by PiB beta-amyloid uptake level (measured as mean DVR cortical values) and APOE status as well as longitudinal rate of

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CBF change. Significantly lower CBF with age were found in all brain regions, especially at cortical and sub-cortical gray matter regions (P < 0.01, cluster corrected). Longitudinal interval effects showed CBF decrement in frontal, temporal, posterior cingulate, and caudate regions, accompanied with CBF decrement in subcortical putamen and pallidum as well as cerebellar regions at follow-up times. Mild APOE and PiB effects based on CBF were observed. LME modeling of PiB R1 transport rate showed significantly lower R1 with age in all brain regions, especially at cerebellum, cortical and sub-cortical gray matter regions (P < 0.01, cluster corrected). Longitudinal interval effects showed pseudo-CBF decreases in small clusters from frontal including superior and anterior cingulate, precentral and inferior frontal portions, post-central and temporal regions. Mild APOE and PiB effects based on R1 were observed as well. The authors’ results demonstrated slightly different age, sex and genetic effects to the standard CBF and pseudo-CBF (R1) measures, although two measures were significantly correlated in majority of brain regions, including especially the frontal cortex. Section II: CBF-Based Rapid Vascular Reactivity Measure. Endothelial cells produce a variety of vasodilators, among which is nitric oxide, but also vasoconstrictors such as endothelia. Reactive oxygen species such as the superoxide radical anion (O2), occurring in cigarette smoke, are well known to dysregulate the normal vasodilatory response of the endothelium to increased demand for blood flow. Endothelial dysfunction is believed to be the earliest initiator of atherogenesis followed by the well-known sequelae leading to neurovascular and heart disease. In this section, both phase-based velocimetry and magnitude-based breath holding index (BHI) quantifications including slope, normalized BHI and delay parameters were explored with individual and average fitting algorithms and metrics, and to further demonstrate vascular reactivity (VR) changes in response to apnea in smokers and elderly population. Vascular reactivity was assessed in a subset of patients (18 nonsmokers and 17 smokers) drawn from a larger study designed to evaluate the effects of smoking and age on a variety of peripheral and central nervous systematic vascular measures in 169 subjects without

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symptomatic cardiovascular disease conducted at 3T field strength. Subjects underwent an apnea paradigm consisting of a single 30-second normal breathing baseline period followed by three repeated blocks of a 30-second breath-holds, each separated by a 90-second normal breathing recovery period. Blood flow velocity in the superior sagittal sinus (SSS) during the 6-min apnea paradigm was quantified using in-house developed non-gated phase-contrast BRISK acquisition scheme with BRISK k-space sampling and view sharing achieving a temporal resolution of 2s. Sequence parameters included flip angle = 15°, bandwidth-347 Hz/pixel, TE/TR = 6.5/31.25 ms, VENC = 50 cm/s, FOV = 220×220×5 mm3, resolution = 1.15×1.15×5 mm3. The data were evaluated in terms of the slope of the velocity, magnitude and delay parameters versus time curve, expressed as cm/s2, referred to as BHI slope. Normalized BHI and slope parameters of velocimetry and magnitudebased methods were highly correlated (r ≥ 0.44, P ≤ 0.01). The authors found significantly lower BHI (i.e., reduced neurovascular reactivity, P ≤ 0.01) based on velocimetry in smokers and elderly participants. Marginally smoking effects observed between smokers and non-smokers (P = 0.05 for slope and P = 0.05 for BHI) based on magnitude method. Furthermore, the dynamic delay time parameter in brain SSS based on velocimetry correlated significantly with peripheral VR reflecting arterial stiffness measured as iliofemoral and total pulse-wave velocity (|r|≥0.4, P≤0.01), as well as with pulsatility index (r = 0.37, P = 0.03) from the large cohort. The authors' results suggests that BHI-based VR may be a useful test to evaluate subjects with presymptomatic vascular disease and may be applicable to other subject groups at risk of developing neurovascular disease such as those with hypertension or hypercholesterolemia. Finally BHI scan can be easily and quickly implemented to these patients compared to other VR methods as the data take only minutes to acquire without any imposed challenges. Chapter 4 - A neurofilament (NF) represents an important structure of the cytoskeleton specific for nervous tissue. Axonal injury is associated with the disruption of axonal cytoskeletal structures and their release into the extracellular space. Neurofilaments are investigated as biomarkers of

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axonal damage in various neurological diseases. Strokes are a group of diseases in which the neurofilament examination in cerebrospinal fluid (CSF) and blood are intensively studied. This chapter summarizes current knowledge about the determination of individual subunits of the neurofilament triplet in cerebral and spinal cord ischemia. Most of the studies showed the increase of light and heavy subunits of neurofilaments in CSF and serum in patients with these neurological disorders. Some studies demonstrated a potential prognostic significance of NF levels in CSF and serum. Results from studies suggested a certain benefit of the neurofilament examination in ischemic cerebral ischemia. However, studies on larger groups of patients will be needed for final evaluation of neurofilaments as biomarkers in these disorders. Chapter 5 - In many nonlinear systems, specific levels of noise enhance the detection of subliminal signals via stochastic resonance. The improved detection of a weak visual signal in the presence of noise was previously demonstrated in humans. In the authors’ present study, they conducted two experiments to investigate whether visual acuity can be improved by noise. The authors used a Landolt ring as the signal and random dots as noise, and participants were asked to identify the location of the gap in the Landolt ring in a four-alternative forced-choice procedure. In Experiment 1, the authors analyzed data from 12 healthy participants who observed visual signals and noise presented on a computer display positioned 210 cm away. The correct response rate increased significantly with the addition of non-zero intensity noise but decreased with more intense and less intense noise. However, the self-reported confidence scores did not exhibit systematic changes as a function of noise intensity, except in catch trials. In Experiment 2, the authors analyzed data from 10 participants who observed a computer display positioned 600 cm away. The noise intensity was aligned according to the noise threshold for each participant. There was a significant increase in the correct response rate when the noise intensity was near the threshold level. The response latencies were the shortest with noise at near-threshold intensity. These findings strongly suggest that visual acuity is improved by the presence of

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weak noise and that visual signals are detected without conscious experiences. This study provides a new approach to the restoration of degraded visual functions and expands the authors’ knowledge of perception and consciousness. Chapter 6 - The PlaymoCase is a novel tool for play and play therapy, consisting of a defined set of small plastic figures, including human beings of different sex, age, and profession, animals, plants, tools, furniture, elements of the fantastic world, and other material. The composition of the material is based on psychological aspects. In the present chapter, the PlaymoCase is described as a means of a play-therapeutic approach with the regard to its content and its relationship to the Operationalized Psychodynamic Diagnosis in Childhood and Adolescence in the revised version (OPD-CA2). The OPD-CA2 is an effective instrument for recognizing and describing psychodynamics. It is used in the diagnostic process of mental disorders and is an important part of therapy planning. In an interdisciplinary and methodological understanding, OPD-CA2 can also describe interactions between the patient and the therapist. The OPD-CA2 is based on a semi-structured interview, its findings are based on observation of game and behavior as well as therapeutic conversation and scenic understanding. It can describe the axes structure, conflict, relationship, and treatment requirements. In the present chapter the authors describe a semi-standardized setting and report several clinical cases. Chapter 7 - According to structural linguists, speaking amounts to transforming a structural order into a linear one, and understanding a sentence to turning a linear order into a structural one. Traditional psycholinguistics has it that the linguistic categories, formal rules, and syntagmatic hierarchies of phrase structure grammars have psychological reality. This belief can be contrasted on several grounds, theoretical as well as empirical. The paradigm of implicit learning may allow solving the long-standing conundrum regarding morphosyntactic development and functioning. It is argued, however, that it needs to integrate a reappraisal of the role of relational semantics. The chapter details this proposal and justifies it both logically and empirically.

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Chapter 8 - A number of investigators have employed high- and lowpass filtered images in order to assess the importance of spatial frequency in visual perception. However, simply filtering the images causes the maximum amplitudes in low-pass filtered images to be larger than those in highpas filtered images. Some investigators have sought to adjust the filtered images for average luminance and some have also equated the images for the RootMean Square of the luminance values. Images of human faces of these kinds are here examined in order to determine to what extent these procedures manage to equate the images for amplitude. It is found that while such adjustments make the maximum amplitudes equal in low- and high-pass filtered images they leave the sums of the amplitudes highly unequal. These observations mean, therefore, that in the case of images of human faces it is difficult to filter images for spatial frequency without also introducing differences in amplitudes.

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In: Horizons in Neuroscience Research. Vol. 31 ISBN: 978-1-53612-375-3 Editors: A. Costa and E. Villalba © 2017 Nova Science Publishers, Inc.

Chapter 1

COGNITIVE-BEHAVIORAL INTERVENTIONS FOR PROMOTING ADAPTIVE SKILLS OF CHILDREN WITH RARE GENETIC SYNDROMES: A SELECTIVE OVERVIEW Fabrizio Stasolla1,*, Viviana Perilli1, Alessandro O. Caffò2 and Fiora D'Amico3 1

Department of Neurosciences, University of Bari, Italy 2 Department of Educational Sciences, Psychology, Communication, University of Bari, Italy 3 San Raffaele Medical Care Center, Modugno, Italy

ABSTRACT This chapter provides the reader with a selective overview of the empirical contributions available in the last decade for promoting independence and self-determination of children with rare genetic syndromes and severe to profound developmental disabilities through

*

Corresponding author: Fabrizio Stasolla ([email protected]).

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Fabrizio Stasolla, Viviana Perilli, Alessandro O. Caffò et al. cognitive-behavioral interventions and assistive technology-based programs. Four syndromes were considered, namely (a) Angelman, (b) Cornelia de Lange, (c) fragile X, and (d) Rett. Thirty studies were retained and 1322 participants were involved. Results were largely positive, although few failures occurred. Psychological and rehabilitative implications of the findings were discussed, and some useful recommendations for future research and practice were outlined.

1. INTRODUCTION Children with severe to profound developmental disabilities are frequently described as isolated and passive towards the outside world. Due to congenital or acquired brain injuries, they might have intellectual delays, motor impairments, communication disorders and sensorial deficits. Furthermore, they may exhibit challenging behaviors and present both feeding or breathing abnormalities, needing special medical care. Additionally, learning difficulties may be realized as a consequence of their withdrawal and few capacities of constructive engagement and positive interaction. In fact, they constantly rely on caregivers and parents' assistance. Accordingly, one of the main rehabilitative goals is their independence and self-determination with the surrounding environment [14]. That is, by promoting the autonomous responding of children with multiple disabilities, one may argue that their quality of life may be significantly improved (e.g., with positive outcomes on their social image, desirability and status), and caregivers' burden may be relevantly reduced [5-8]. One of the basic causes of severe to profound developmental disabilities are rare genetic syndromes (e.g., Angelman, Cornelia de Lange). Mutations and/or deletions of genes and chromosomes may determine the aforementioned disabilities with negative consequences on both children and families. One way to overcome this issue is the use of cognitive-behavioral interventions aimed at enhancing the opportunities of positive interactions. Within this framework, the use of assistive technology-based programs (AT) may be viewed as a great educational and

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Cognitive-Behavioral Interventions …

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rehabilitative resource for ensuring participants with independent responding [9-11]. Despite this consideration, few and sparse empirical studies are available in the current literature [12]. In light of the above, the first objective of the current chapter was to systematically compare both cognitive-behavioral and AT-based programs for teaching adaptive skills to children and/or adolescents (i.e., age ranging between 3 and 19 years old) affected by four rare syndromes, namely (a) Angelman, (b) Cornelia de Lange, (c) fragile X, and (d) Rett syndromes, which may seriously be deleterious for those children and hamper their quality of life. Consequently, the second objective of the chapter was to provide the reader with a selective overview of the published evidences in the last decade (i.e., time range 2005-2017) within this topic and to emphasize strengths and weakness of the retained studies. Although some differences occurred among the cited syndromes with regard to the found contributions (i.e., by searching in Scopus 23, 13, 12, 3 documents were recorded by matching cognitive-behavioral interventions and Angelman, Cornelia de Lange, fragile X, and Rett syndromes respectively as keywords), the literature is still limited. The third objective was to outline some useful AT-based strategies for enabling children with the reviewed rare syndromes to manage pleasant and/or desired events in the everyday life. Finally, some helpful guidelines for future research and practice were critically discussed.

2. METHOD A computerized search was performed in Scopus using “Angelman, Cornelia de Lange, fragile X, Rett syndromes, behavioral, cognitivebehavioral and assistive technology-based interventions, severe to profound developmental disabilities, self-determination, independence, and quality of life” as keywords, within 2005-2017 range time interval. A manual search was conducted as completion. Including criteria concerned empirical studies involving (a) children with Angelman, Cornelia de Lange, fragile X, or Rett syndromes, (b) severe to profound developmental

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and/or intellectual disabilities, (c) chronological age included between 3 and 19 years old, and (d) a behavioral, cognitive-behavioral or AT-based rehabilitative program. Excluding criteria referred to (a) review and conference papers, (b) theoretical and/or descriptive/illustrative contributions without any interventions, (c) adults aged over 19 years, (d) other developmental disabilities and/or different genetic syndromes (e.g., autism spectrum disorders, cerebral palsy, Down and/or Williams syndromes), since their inclusion would exceed the objectives of the current chapter. Accordingly, 30 studies were reviewed with 1322 participants involved. The empirical contributions were briefly described, within each category, with the objectives, the participants, the procedures, and the main results emphasized. A synoptic tab (i.e., Table 1) aimed at summarizing and providing a general picture of the selected articles was additionally inserted. Table 1. Summary of the reviewed studies displayed in alphabetic order and grouped according to the examined genetic syndrome Authors Syndromes Participants Ages Cossu et al. [34] Cornelia de 1 5 Lange Curie et al. [41] Fragile X 14 22.2

Interventions Outcomes Neuropsychological One Positive

Fabio et al. [51] Rett

34

13.9

Cognitive Training

Fabio et al. [52] Rett

114

14.1

Fabio et al. [53] Rett

1

21

Fabio et al. [54] Fabio et al. [55] Fichtner & Tiger [23] Hall et al. [33]

10 10 3

9-26 5-26 10-17

RARS Scale Assessment Communication training Cognitive Training Cognitive Task Social Approaches

Cornelia de 54 Lange Heald et al. [19] Angelman 4

13.88

Rett Rett Angelman

5-10

Visual Paradigm

Informant-based measures Behavioral

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Fourteen Positive Twenty-one Positive One hundred Positive One Positive Ten Positive Ten Positive Three Positive Fifty-four Positive Four Positive

Cognitive-Behavioral Interventions … Authors Syndromes Participants Ages Hessl et al. [40] Fragile X 63 19.3 Joleff et al. [22] Fragile X

7

Kurtz et al. [42] Fragile X

9

Lanovaz et al. [35] Lee et al. [39]

Cornelia de 1 Lange Fragile X 65

Interventions Cognitive Battery

5

8-18

Outcomes Sixty-three Positive Five Positive

16

Nine Positive One positive

Communication training 6.2-15.9 Parent Training Behavioral

8.5-11.7 Cognitive Battery

Moss et al. [32] Cornelia de 130 Lange Neul et al. [49] Rett 638

17.9

Questionnaire

4-4.5

Parisi et al. [31] Corneli de Lange Quest et al. [50] Rett

4

4-5

5

17.8

Radstaake et al. [24] Radstaake et al. [25] Radstaake et al. [26] Roberts et al. [20] Stasolla et al. [44] Stasolla et al. [45] Stasolla & Caffò[56] Stasolla et al. [57] Stasolla et al. [58] Summers [21]

Angelman

7

7-14

Longitudinal Investigation CognitiveBehavioral Functional Assessment Toilet Training

Angelman

3

9-12

Angelman

4

6-10

Angelman

56

7-12

Fragile X

2

8.7-9.7

Fragile X

3

9.57

Rett

2

12-17

Rett

3

9.36

Rett

3

10.83

Angelman

4

3.1-9.2

Tonnsen et al. [43]

Fragile X

55

3-6

Sixty-five Positive Thirty Negative Forty-eight Negative Four Positive Five Positive

Seven Positive Functional Analysis Three Positive Communication Four Training Positive CognitiveFifty-six Behavioral Positive Assistive Two Positive Technology Assistive Three Technology Positive Assistive Two Positive Technology PECS and VOCA Three Positive Assistive Three Technology Positive Applied Behavior Four Analysis Positive Experimental Fifty-five Paradigm Positive

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3. LITERATURE OVERVIEW 3.1. Angelman Syndrome Angelman syndrome (AS) is a neuro-developmental disorder caused by maternal deletion or mutation of the ubiquitin-protein ligase (i.e., UBE3A) enzyme encoded by the UBE3A gene, situated on the 15th chromosome, first described by Angelman [13]. Its prevalence is approximately of 1 in 52000 live births, and the phenotype is commonly characterized by microcephaly, frequent tongue protrusion, excessive laughing, jerky and stiff gait. Lack of speech, hyperactivity, and sleep abnormalities are usually included [14-16]. Essentially, children with AS regularly need adult driven attention due to significant developmental and intellectual delays. Consequently, rehabilitative interventions are focused on promoting the independence and self-determination of AS children for improving their quality of life. Beside the assessment of sleep disorders and genetic basis, the applied research within this framework focused on the implications for intervention, diagnosis, and prognosis of autism spectrum disorders and intellectual disabilities connected to the syndrome [17-18]. Eight studies were retained within this section with 88 participants involved [19-26]. For instance, Heald, Allen, Villa, and Oliver [19] exposed four AS children who were aged between 5 and 10 years old to a multiple schedule arrangement, in which social reinforcement and extinction, cued using a novel stimulus, were systematically alternated. Twenty-five to 35 discrimination training sessions were carried out and levels of social (i.e., approach) behaviors were recorded for two participants. All children showed capacities of discrimination between reinforcement and extinction after 16-20 intervention sessions. Reversal effects for both participants whom the experimental design was implemented were emphasized. Data suggested that with a repeated training program, the use of a novel stimulus may be useful (i.e., as a cue) for differentiating the adult availability by AS children.

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Roberts et al. [20] assessed an intervention for evaluating the behavioral and emotional functioning of sibling of children with a severe to profound developmental disability and chronic condition (i.e., Angelman syndrome). Specifically, a six-week manual-based, cognitivebehavioral group support program, aimed at enhancing siblings' perceived social support, self-esteem, problem-solving skills, adaptive and coping behaviors, was implemented. Fifty-six children aged 7-12 were assigned to either the experimental group (i.e., provided with the above described intervention) or the control group. The primary dependent variable (i.e., outcome) was siblings' emotional and behavioral functioning. Additional dependent variables considered were the siblings' self-esteem, perceived social support, coping and adaptive behaviors. A three month follow-up was conducted. The experimental group evinced few emotional, adaptive, coping, and behavioral difficulties with regard to the control group. The follow-up confirmed the trend. Summers [21] examined the impact of teaching approaches based on the principles of applied behavior analysis (ABA) recruiting four AS children aged between 3.1 and 9.2 years. They were systematically compared to a control group constituted by other children with AS who were individually matched on the basis of chronological age, gender, and molecular sub-type. The experimental group received two-to-three weeks ABA-based intervention sessions per week over a 1-year period. Standardized measures of cognitive, adaptive, and language functioning were recorded at initial baseline and after 1 year. Although no statistical differences emerged between groups neither at baseline nor after one year, some improved trends were observed for cognitive and adaptive outcomes within the experimental group. Joleff, Emmerson, Ryan, and Mc Conachie [22] attempted to establish whether there was a difference in communication phenotypes to parallel the different genetic mechanisms causing AS. The working hypothesis investigated was that children and young adults with the classic genetic deletion would have lower capacities of developmental skills than those with non-deletion AS. Seven children/adolescents with the classic deletion were matched for age and gender with participants with imprinting defects

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or parental small deletion in the UBE3A gene. A significant group difference was detected for five of the nine dependent variables. Higher levels of cognitive, communication, motor, and adaptive skills were recorded in the control group. Fichtner and Tiger [23] evaluated the effects of a training program for teaching 3 boys with AS to discriminate appropriate from inappropriate times to initiate interactions. During baseline, attention was delivered according to social initiations provided with a continuous reinforcement schedule. Periods of initiations' extinction were systematically alternated. During the intervention a discrimination training was implemented through the presentation of a salient discriminative stimulus, prompting the occurrence of initiations, and providing reinforcements during reinforcement periods and withdrawing the stimulus during extinction periods. Results showed that the three participants learned to differentiate social approaches and generalized the learning process with caregivers and at their homes. Radstaake et al. [24] implemented a toilet training protocol for fostering the urinary continence of seven children with AS. Data were collected with an AB design during baseline, training, generalization, and follow-up. A response restriction strategy was adapted. Participants were trained in their natural environment, were prompted to void and along with improving continence, the interval between voids was enlarged and timeon toilet reduced. During generalization five children had less than two accidents and one to six correct voids per day. During baselines, more accidents and/or less correct voids occurred. Two individuals augmented their correct voids during the training, although various accidents were recorded. The participants consolidated their learning after 3-18 months. Radstaake et al. [25] implemented a functional analysis and a functional communication training for explaining the challenging behavior and promoting communication skills of three children with AS. Both protocols were assessed in the classroom by their teachers. Replacement behavior was prompted on the onset of precursor behavior. The challenging behavior was maintained either by tangible items or by task escape. Social contact with the teacher was a precursor of the challenging

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behavior for one child. All the children significantly decreased their challenging behavior once the functional training was introduced. Functional equivalence of both challenging and replacement behavior was evinced. Radstaake, Didden, Oliver, Allen, and Curfs [26] assessed the functions of challenging behavior in four children with AS. Additionally, a function communication training with precursor-based prompting was adopted. An ABAB reversal design was implemented. The effect sizes were considered. Burst analysis depicted tendencies in precursor behaviors surrounding target behaviors. Challenging behavior was maintained by either social attention or access to tangible items and task escape. Burst analysis indicated physical and eye contact and reaching for tangibles as precursors. The size effects were small to large.

3.2. Cornelia De Lange Syndrome Cornelia de Lange syndrome (CdL) is a rare genetic disorder characterized by multiple abnormalities and severe to profound intellectual disabilities. The phenotype includes microcephaly, growth failure, distinctive faces, development delays for hands and feet, excessive growth of hair. Autism spectrum disorders are commonly described and associated to CdL syndrome. However, self-injuries have a higher prevalence as well as impulsive behavior if compared with individuals affected by traditional autism spectrum disorders. Additionally, attention deficits and hyperactivity disorders are embedded. The diagnosis of the syndrome is based upon clinical grounds because neither biochemical nor chromosomal markers are available [27-30]. Therefore, rehabilitative interventions for fostering their adaptive skills and improving their quality of life are mandatory. Five studies were retained in this section, with 190 participants recruited [31-35]. For example, Parisi, Di Filippo, and Roccella [31] reported four case studies (i.e., two males and two females) aged of 4 and 5 years old, and described clinical characteristics including autism spectrum disorders, lack

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of speech, incapacities of adequate social interactions with peers and adults, epilepsy. The authors recommended psycho-educational and cognitive-behavioral specific interventions, structured environments, the use of visual, verbal, and communicative cues for simplifying their daily activities. The intentionality of expressive communication was improved. Direct contact with nature and enjoyment for their rural landscapes were enhanced. Future research perspectives suggested to evaluate the behavioral phenotype through diagnostic algorithms for autism with a detailed phenomenology of the impulsive behavior. Systematic comparisons between CdL individuals and other intellectual disabilities may be useful for a complete understanding of the CdL behavioral phenotype. Moss, Oliver, Nelson, Richard, and Hall [32] examined 130 individuals with CdL syndrome, with a mean age of 17.19, who were compared to participants with fragile X syndrome, and autism spectrum disorders. Using the Social Communication Questionnaire, the proportion meeting cutoff for autism spectrum disorders and autism in CdL participants was 78.6 and 45.6 respectively. Domain and item analysis indicated differing, atypical autism spectrum disorders profiles in CdL syndrome. A limited association between adaptive behavior and autism spectrum disorder was found. The authors argued on the implications for future research and practice in CdL syndrome and on the conceptualization for autism spectrum disorders. Hall, Arron, Sloneem, and Oliver [33] compared 54 individuals with CdL with 46 participants with intellectual disabilities of mixed etiology who were similar in terms of degree of intellectual delays, mobility, age, and gender, using the informant-based measure of health problems, sleep, and self-injuries. Results showed that participants with CdL experienced a significant higher level of health problems, with a prevalence of eye and gastrointestinal difficulties. Sleep disorders were closely linked to selfinjuries among CdL individuals, and skin abnormalities were associated with self-injuries severity. A new distinctive pattern of clinical features for CdL syndrome was described, and a regular assessment for health and appropriate intervention was solicited.

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Cossu, Nava, Leoni, and Piccardi [34] described a moderate case of CdL syndrome, who was exposed to a neuropsychological rehabilitative program structured across patient's specific strength and weakness areas focused on improving cognitive and adaptive skills. To optimize the learning process of CdL children, a multidimensional neuropsychological approach was recommended, involving both developmental abilities and disabilities related to the global reality of the child. Lanovaz, Rapp, and Maciw [35] attempted to reduce the stereotypic behavior in a CdL individual through behavioral interventions. Specifically, non-contingent reinforcement alone and combined with a differential reinforcement of alternative behavior (DRA) were both applied by using an alternating treatment single subject design. The targeted behavior concerned sitting on mouthing and tapping. Data emphasized that non-contingent reinforcement alone decreased mouthing, whereas access to tactile stimuli did not. The combined non-contingent reinforcement with DRA significantly diminished mouthing and tapping, increasing the adaptive behavior.

3.3. Fragile X Syndrome Fragile X syndrome (FXS) is a neuro-developmental disorder caused by an excessive length of the repetitive sequence of trinucletotides (CGG) in a single gene (FMR1), situated in the long arm of chromosome X. It represents one of the most frequent cause of severe to profound developmental disabilities. Its prevalence is estimated in 1 every 3600 males, and 1 every 8000 females. The phenotype is commonly described with aggression, hyperactivity, inattention, ASD. Additionally, learning difficulties, seizures, anxiety, gaze-avoidance, self-injuries, impulsivity are usually included. Long and narrow visage, large ears, prominent jaw and foreheads are basic physical features with its full mutation (i.e., mosaic) [36-38]. Seven studies were reviewed in this sub-section with 211 participants involved [39-45].

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Lee, Martin, Berry-Kravis, and Losh [39] recruited 65 individuals with FXS who were aged between 8.5 and 11.7 years for the characterization and the comparison of individual ASD phenotypes across development as well as the conceptualization of idiopathic ASD over the time. The participants completed a battery of cognitive, diagnostic, and language assessments at two time points (mean 25 years apart). Non parametric test considered variations in diagnostic classification in FXS over the time, and hierarchical linear modeling and repeated measures assessed variations in ASD symptoms in FXS over the time. Furthermore, ANCOVAs compared ASD symptom severity and component phenotypes in boys with FXS alone, FXS and ASD, and idiopathic ASD over the time. Results showed that ASD significantly increased in children with FXS over the time, and developmental predictors varied based on the domain of symptoms assessed. The higher overlapping was recorded between boys with FXS and ASD, and idiopathic ASD in the domain of social reciprocal communication across time points, whereas boys with idiopathic ASD emphasized greatest impairment in restricted and repetitive behaviors at the second time point. Accordingly, it was argued that ASD symptoms increased with age, and social language impairments emerged as a potential core shared feature of FXS and ASD that may help understanding the molecular genetic variation related to phenotype variance. Data were useful for planning specific interventions for subgroups of children with different phenotypes. Hessl et al. [40] validated the Toolbox Cognitive Battery on a sample of 63 participants with FXS (mean age 19.3), with a mean mental age of 5.3. The battery was aimed at measuring processing speed, executive functions, episodic memory, word/letter reading, receptive vocabulary, and working memory. The dependent variable assessed were its feasibility, reliability, construct validity, ecological validity, and syndrome differences and profiles, once the sample was compared to individuals with Down syndrome, and idiopathic intellectual disabilities. Data revealed the battery feasibility (except for working memory), its reliability and both construct and ecological validity. Syndrome/group comparison outlined relevant

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deficits on attention and inhibitory control, and reading weakness for children FXS. Curie et al. [41] developed a novel visual analogical paradigm, inspired by the Progressive Raven's Matrices, for evaluating reasoning and inhibition abilities by individuals with intellectual disabilities. Fourteen patients with FXS with a full mutation were involved. Their mean age and ranges were 22.2, 14.5, and 31.5. They were compared with a group of individuals with Down syndrome, and a group of ARX mutated patients. A behavior analysis for the specific task (i.e., completion of the figure according to Raven's Matrices) with a reaction time and a rate error analysis was performed in 96 healthy controls (adults and typically developed children older than 4 years), and 41 genetically determined patients with intellectual disabilities (i.e., FXS, Down syndrome, and ARX syndrome). Moreover, an eye-tracking analysis was conducted in order to establish and quantify the cognitive strategies adopted to solve the task. Although participants with intellectual disabilities performed lower and were slower than the chronological age-matched healthy controls, data suggested that the effect of inhibition on error rate was greater than matrix complexity effect in individuals with intellectual disabilities, opposite to the findings in adult healthy controls. FXS were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis pointed out that FXS individuals used a response-based strategy. Conversely, the adults’ healthy controls adopted a matrix-based strategy. The new paradigm provided an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for behavioral interventions in this specific population. Kurtz, Chin, Robinson, O'Connor, and Hagopian [42] presented a functional analysis of the challenging behavior through a consecutive caseseries analysis involving nine children with FXS, aged between 6.2 and 15.9, who exhibited ASD, ADHD, mood, and oppositional defiant disorders. Functional assessment, consistent with previous findings, evinced that the challenging behavior was maintained by task escape and access to tangible items. Parent training-based intervention revealed a

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significant reduction of the challenging behavior among all the participants involved, who generalized the learning process from clinical settings to their homes, schools, and communities. An unique effective behavioral analysis phenotype for FXS individuals was demonstrated. Tonnsen, Grefer, Hatton, and Roberts [43] examined the attention problems and inhibitory control in 3-6 years old children with FXS, through an experimental paradigm and parent-reports of attention problems. Fifty-five participants were recruited. During a first step, 14 children with FXS were compared to a matched-age control group for assessing the attention control. During a second step, 41 new participants with FXS were considered for analyzing patterns of developmental changes in an expanded longitudinal sample. Across both steps, participants with FXS showed relevant impairments in inhibitory control and parent-reported attention problems. Inhibitory control was linked to lower mental age. Although parent-reported attention problems were stable across ages, inhibitory control improved with time. Children with higher ADHD symptoms displayed initially poorer inhibitory control. However, these trajectories improved more rapidly with age. Early intervention, including multi-method assessment and targeted treatments, was indicated as the more effective and successful among FXS population. Stasolla et al. [44] enabled two boys with FXS who were aged of 8.7 and 9.7 respectively and presented severe to profound intellectual and developmental disabilities to perform an occupational task (i.e., insert an object in a container) and make choices among preferred stimuli through an assistive technology-based intervention (i.e., optic sensors as photocells and a battery-powered system control unit). Further objectives of the studies consisted of reducing challenging behavior (i.e., mouthing and eye poking), and increasing indices of happiness as outcome measure of participants' quality of life. The study was carried out through a nonconcurrent multiple baseline across participants experimental design with a systematic cross-over, allowing the inversion between behavioral responses and environmental consequences. Thus, colored lights and vibrations on one hand or preferred music and familiar voices on the other could be selected contingent to the exhibition of adaptive responding,

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based upon the object inserted in the container (i.e., left or right container), according to the experimental phase. A maintenance phase was additionally assessed for documenting the consolidation of the learning process at two-ended weeks from the final intervention. Results showed that both children learned to use the technological supports for selecting a preferred event or another, depending upon the behavioral response and the experimental condition. Intervals with indices of happiness increased and stereotypic behaviors were reduced during the intervention phases, if compared to the baselines. During the maintenance, both participants consolidated their learning. Stasolla, Perilli, Damiani, and Albano [45] extended the previous findings of Stasolla et al. [44] above reported, by recruiting three new boys with FXS (mean age of 9.57) exposed to a similar intervention program with three different containers. A single subject reversal design with triple AB sequence was adopted. Intervals with indices of happiness and intervals with stereotypic behaviors (i.e., mouthing and flapping) were recorded. A three month follow-up was conducted. Furthermore, 30 parents of children with severe to profound developmental disabilities were involved in a social validation assessment as external and expert raters. All the participants improved their performances during intervention phases and consolidated the learning process during the follow-up. Social raters formally endorsed the use of technology and considered it as suitable, effective, and useful for daily settings.

3.4. Rett Syndrome Rett syndrome (RS) is a progressive neurodevelopmental disorder, X linked, caused by genetic mutations in the methyl-cytosine-phosphateguanine binding protein 2 (MECP2) gene, fixed in the Xq28 chromosome, primarily occurring in females. Its prevalence is estimated to be 1 every 8000 female life births. It includes four main stages (i.e., stagnation, regression, stationary, and motor deterioration), and is commonly characterized by a gradual impairment in cognitive, social, communicative,

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and motor functions. After an apparent regular and normal birth, a general arrest of child's development is recorded. A loss of acquired adapted functions (e.g., language and social interactions) are observed. Stereotypic hand-related movements (e.g., tipping, and washing) are additionally detected. Apraxia, hyperventilation, seizures, ataxia, physical decline, motor deterioration, failing locomotion, and withdrawal are frequently described. Girls with RS usually present severe to profound intellectual disabilities [46-48]. Ten studies were included in the current sub-section, with 833 participants involved [49-58]. Neul et al. [49] examined the achievement of adaptive skills or abilities in classic RS, and assessed phenotype-genotype relations of 542 girls with classic RS, ad 96 girls with atypical RS, who presented a mean age of 4 and 4.5 years old at the beginning of the study respectively. Gross and fine motor skills, expressive and receptive communication abilities were considered within a longitudinal investigation, which lasted 7 years. Data were analyzed for age at acquisition and loss of developmental features, and for genotype-phenotype effects. Acquired, loss, and retained skills were compared between groups with better or poorer functional scores. A general linear model was used to establish whether the mean age of acquisition or loss of a developmental adaptive skill differed by mutation type. Results revealed that early developmental skills or abilities were acquired albeit late than normal. Complex motor and communication capacities were delayed or lacking. Clinical severity was less in those achieving the respective skill. Quest, Byiers, Payen, and Symons [50] used direct behavioral observation to quantify and compare the frequency of hand-related stereotyped behavior and signs of negative affect during periods of presumed high and low stress conditions associated with functional analysis by 5 girls with RS, who were aged between 4 and 47 years (i.e., mean age 17.8). Negative effect was more likely to be observed during negative reinforcement (i.e., stress conditions) for all participants whereas hand stereotypic behaviors did not differ across conditions for any of the participant. Although preliminary, data suggested that hand stereotyped behavior was not a valid predictor for stress conditions in females with RS.

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Otherwise, one could argue that the approach used was not sufficient to evoke a stress response. Fabio et al. [51] investigated whether behaviors and brain activity were modified by cognitive training in RS. Two basic experimental conditions were assessed, namely (a) short term training (i.e., 30 minutes of training), and (b) long term training (i.e., 5 days of training). Thirty-four girls (mean age 13.9, with ranges varying between 5 and 36 years old) were divided in two groups: a training group (i.e., 21 participants), who were exposed to a long term training, and a control group (i.e., 13 participants), who were exposed to a short term training. A modified version of the Raven's Matrices, with colored and larger items for individuals with RS was used. Eye-gazing and quantitative electro-encephalogram (QEEG) data were recorded as dependent variables. A gold eye-tracker and a wearable EEG equipment were adopted. The control group showed a habituation effect, decreased beta activity, and right asymmetry. The experimental group looked faster and longer at the target, with an increased beta activity observed, and a reduced theta activity. A leftward asymmetry was reestablished. A long cognitive training was helpful for promoting brain and behavioral responses among individuals with RS. Fabio et al. [52] evaluated a cohort of 114 girls with RS (age ranged from 2 and 36 years, mean age 14.1 years) with a detailed scale, which measured the different impairments caused by the syndrome, namely the Rett Assessment Rating Scale (i.e., RARS). The sample included a wide subsets of the different mutations, and a strong correlation genotypephenotype was described accordingly. Specific variants of the syndrome were assessed, and a remarkable difference emerged by comparing mutations truncating the protein before or after the nuclear localization signal. Such difference prevalently concerned the motor functions and the independence of the patient, involving the management of life skills. Fabio, Castelli, Marchetti, and Antonietti [53] described a case-report of a woman with RS, who was 21 year old for investigating the opportunity of training communication abilities. The participant was trained in a cognitive rehabilitation paradigm, based upon Feuerstein's principles of behavior modification. The objective was to teaching reading and writing

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basic abilities. Data emphasized the learning process and corroborated the method's validity. Specifically, the woman profitably learned to communicate with others by composing words with her forefinger on an alphabetic table. Caution was undoubtedly needed before generalizing the results because the assessment was carried out on a unique participant and further extensions were warmly warranted. Fabio, Antonietti, Cstelli, and Marchetti [54] investigated attention and communication abilities in girls with RS. A sample of 10 participants (age ranges included between 9 and 26 years old) were matched with 10 controls on their mental age. Both attention and non-verbal communication abilities were examined. Attention assessments were carried out by coding six and mutually exclusive categories. Non-verbal communication assessments were conducted on the basis of joint attention and requesting. Results evinced that girls with RS presented specific impairments in the ability of selectively attending to relevant stimuli, and gave attention to irrelevant information sources. Non-verbal communication skills were partially compromised in girls with RS. Fabio, Giannatiempo, Antonietti, and Budden [55] proposed to 10 girls with RS (age ranging between 5 and 26 years), who were matched to 10 controls, a cognitive task in which a complex stimulus was showed followed by individual stimuli presented with confounding items. Participants were requested to correctly discriminate the presented stimuli from confounding items. Two basic experimental conditions were created, namely (a) stereotyped behaviors containment, and (b) no stereotyped behaviors containment. Girls with RS quickly learned in the containment condition if compared to the no containment condition, although no statistical differences were recorded with regard to the number of correct responses between conditions. Stasolla and Caffò [56] fostered locomotion fluency and enhanced object manipulation of two girls with RS who were aged of 12 and 17 years old respectively through a microswitch-based program. The technology consisted of a wobble microswitch (i.e., a touch ball sensitive microswitch which requested to be pulled, pushed or moved side way to be activated), and optic sensors (i.e., photocells) for improving locomotion

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fluency (i.e., four forward steps to be performed within a 3 second time interval). Both microswitches were connected to a battery-powered system control unit and preferred stimuli (except for baselines). Indices of happiness as outcome measure of participants' quality of life as well as indices of stereotypic behaviors such as hand washing and body rocking were additionally recorded. The study was carried out according to a multiple probe design across behaviors for each participant, where the adaptive behaviors were learned first singly and finally combined and systematically and randomly alternated across 5 min sessions. Both girls significantly improved their overall performance with an increased number of adaptive behaviors, an augmented percentage of intervals with indices of happiness and a reduced percentage of stereotypic behaviors during intervention phases. Stasolla et al. [57] systematically compared PECS and VOCA strategies for promoting communication skills of three girls with RS, who were aged of 9.2, 8.4, and 10.5 (mean age of 9.36 years). Indices of happiness and stereotyped behaviors (i.e., hand tipping and body rocking) were monitored. Phases 1, 2, and 3 of the PECS protocol were implemented. VOCA device consisted of a rectangular 70x50 cm keyboard provided with sensitive areas to be activated through touch screen modality. The study was carried out through an alternating treatment single-subject experimental design, where both strategies were randomly and systematically alternated across 10 min sessions. Results revealed that both strategies were effective and suitable for improving communication strategies for all the participants. Indices of happiness were contingently augmented and stereotyped behaviors diminished. Stasolla et al. [58] enabled choice-making and occupation for three girls with RS who were aged of 9.6, 12.4, and 10.5 (mean age 10.83) respectively, through an assistive technology-based program. The technology consisted of six photocells fixed in three different containers (i.e., two for each container), which were available in front of the participants during the sessions, a laptop placed behind the containers, visible but inaccessible to the participants, an interface connecting the photocells to the laptop, and familiar objects such as little bottles, compact

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discs, and audiotapes. The girls were requested to insert familiar objects in the containers for getting independent access to preferred stimuli contingently. Based upon the insertion of the object in a container or in another, and the implemented experimental condition participants could receive 10 s of preferred songs, videos, or colored lights, except for baselines. Body rocking, hand washing and mouthing stereotypic behaviors and indices of happiness were recorded during the sessions. Results showed the consolidation of learning and an improved quality of life closed linked to the sessions for all participants involved. The girls could make choices among preferred selected stimuli.

4. DISCUSSION Data of the reviewed studies showed that the outcomes were largely positive, although few failures occurred (i.e., 7.94%). Cognitive-behavioral interventions, behavioral programs, and assistive technology-based treatments were effective and suitable for promoting independence and self-determination of individuals with rare genetic syndromes and severe to profound developmental and intellectual disabilities. Children exposed to those strategies gradually acquired awareness of their own behavior and played an active role towards their environment. Consequently, their passivity, isolation and challenging behaviors were prevented. Whenever available, indices of happiness as outcomes measure of participants' quality of life were encouraging, and external expert raters involved in social validation assessments formally endorsed the rehabilitative approaches and corroborated the interventions' clinical validity. Specific genotypephenotype connections were established and new pattern of clinical frameworks were evinced for each rare genetic syndrome considered. The results were widely supported by previous findings [59-64] and suggested the following considerations. First, cognitive-behavioral interventions seemed to be useful, helpful, effective, and suitable for promoting independence and self-determination of children with rare genetic syndrome and severe to profound

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developmental disabilities. Thus, by enhancing the awareness of their own behaviors, the rehabilitative programs promoted new adaptive skills. The participants' active role towards the outside world was fostered accordingly. Specifically, ABA interventions, social approaches, toilet training, functional assessment, and communication training were successful for individuals with Angelman syndrome. Both behavioral and cognitive-behavioral treatments, informant-based measures, social communication questionnaires, and neuropsychological strategies were positively adopted for children with Cornelia de Lange syndrome. Assistive technology, experimental and visual paradigm, cognitive batteries, communication and parent trainings beneficially involved participants with fragile X syndrome. Cognitive tasks and trainings, functional analysis of challenging behavior, longitudinal investigations, rating scale assessment, and technological aids were used for Rett syndrome [65-69]. Second, the programs' success seemed to be higher for early, intensive and individualized interventions (i.e., single-subject designs), rather than between groups studies. One may argue that by planning a customer tailored treatment the learning process is significantly improved. On the other hand, between groups investigations with large samples enabled to establishing specific genotype-phenotype connections. Different syndromes' sub-types were adequately observed. The scale assessments allowed to characterize each syndrome. Longitudinal studies were crucial for measuring the participants' history variable. Neuropsychological and electrophysiological measures provided critical information between the brain activity (i.e., neural substrates) and the behaviors directly observed. Parent training ensured families' involvement. Assistive technology-based were essential for reducing caregivers' burden [70-73]. Third, challenging behaviors were significantly reduced during intervention periods, whenever such dependent variable was examined. Two basic assumptions could be emphasized. Participants no more exhibited the challenging behaviors because they were constructively engaged and positively occupied. Consequently, they did no more need to produce the stimulation by them-selves. Alternatively, one may argue that

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the participants correctly re-directed their stereotyped behaviors into the functional activities proposed by the rehabilitative programs to which they were exposed. Functional analysis/assessment was the main experimental, reliable, and solid method to determine whether the challenging behavior could be maintained by one or another function (e.g., social attention, tangible items, task escape). Cognitive trainings relevantly empowered the brain activity, with positive outcomes on both adaptive (i.e., by increasing it) and challenging (i.e., by reducing it) behaviors observed during the interventions [74-77]. Fourth, once recorded, intervals with indices of happiness significantly augmented during the rehabilitative programs. One may argue that the participants enjoyed the sessions and their quality of life was relevantly improved. Thus, their social desirability, image, and status progressed. Beside the independent access to positive stimulation, the participants appreciated the interventions with beneficial effects on their positive mood. In other words, the indices of happiness seemed to be very closely connected to the sessions, and allowed to emphasize the treatments' effectiveness and suitability [78-80]. Fifth, follow-up, post-intervention checks, maintenance, and generalization phases revealed the consolidation of the learning process. Once the participants improved their performances, they transferred their learning skills in other daily contexts (e.g., home, school, medical centers, community settings). Furthermore, they were capable to consolidating their learning abilities, even if the intervention was suspended. One can argue that children with rare genetic syndromes and severe to profound intellectual or developmental disabilities could acquire awareness of their own behavior and use it purposefully, through learning principles (i.e., causal association between behavioral responses and environmental consequences) [81-82]. Sixth, external expert raters involved in the social validation assessments (e.g., caregivers, parents, and practitioners) formally endorsed the adoption of such intervention strategies. In fact, they systematically scored higher the intervention sessions if compared to the baselines. That is, raters who should be expected to be familiar and sensitive to the matter

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(i.e., cognitive-behavioral rehabilitative interventions for individuals with rare genetic syndromes and developmental disabilities), consolidated the programs' clinical validity. Both parents and caregivers of the participants involved in the reviewed studies were preliminarily excluded because they could produced biased scores [83-85].

5. FUTURE DIRECTIONS In light of the above, future research perspective should consider few basic points within this topic. First of all, further extensions are warranted. That is, an enlargement of the reviewed investigations to new participants with the examined syndromes should be essential. Moreover, other rare genetic syndromes (e.g., cri du chat or Williams) could be analyzed. New cognitive-behavioral strategies with further experimental paradigm should be adopted. Both neuropsychological and behavioral assessment should be carried out. New EEG patterns associated to specific functional behaviors should be recorded. Secondly, new technological solutions should be planned for guaranteeing the best options for the recruited participants. With this regard, one should select a plausible behavioral response. Subsequently, a suitable technological device should be adopted. Finally, highly motivating and rewarding environmental events in order to efficiently compensate the response cost should be screened. Both economic/financial and human resources should be constantly examined. New groups of external raters (e.g., students and teachers) should be considered. Extended indices of participation and/or preference check assessments should be analyzed. Essentially, one could integrate both single subjects designs and between groups designs on one hand, and assistive technology-based interventions on the other, with both cognitive and parent trainings and scale rating assessments or both electrophysiological and neuropsychological measures to provide clinicians, parents, and caregivers with a complete and exhaustive framework.

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[41] Curie A, Brun A, Cheylus A, Reboul A, Nazir T, Bussy G, Delange K, Paulignan Y, Mercier S, David A, Marignier S, Merle L, De Fréminville B, Prieur F, Till M, Mortemousque I, Toutain A, Bieth E, Touraine R, Sanlaville D, Chelly J, Kong J, Ott D, Kassai B, Hadjikhani N, Gollub RL, Des Portes V. A novel analog reasoning paradigm: New insights in intellectually disabled patients. PLoS ONE. 2016;11(2). [42] Kurtz PF, Chin MD, Robinson AN, O'Connor JT, Hagopian LP. Functional analysis and treatment of problem behavior exhibited by children with fragile X syndrome. Res Dev Disabil. 2015;43-44:15066. [43] Tonnsen BL, Grefer ML, Hatton DD, Roberts JE. Developmental trajectories of attentional control in preschool males with fragile X syndrome. Res Dev Disabil. 2015;36:62-71. [44] Stasolla F, Damiani R, Perilli V, Di Leone A, Albano V, Stella A, Damato C. Technological supports to promote choice opportunities by two children with fragile X syndrome and severe to profound developmental disabilities. Res Dev Disabil. 2014;35:2993-3000. [45] Stasolla F, Perilli V, Damiani R, Albano V. Assistive technology to promote occupation and reduce mouthing by three boys with fragile X syndrome. Dev Neurorehabilitation. 2017;20:185-93. [46] Stasolla F, Perilli V. Assistive technology to promote communication, leisure and occupation skills for children with Rett syndrome and severe to profound developmental disabilities: A literature overview In: Rett Syndrome and Other Communication Disorders: Symptoms, Treatment and Prognosis. 2015 p. 59-80. [47] Stearns NA, Schaevitz LR, Bowling H, Nag N, Berger UV, BergerSweeney J. Behavioral and anatomical abnormalities in Mecp2 mutant mice: A model for Rett syndrome. Neuroscience. 2007;146:907-21. [48] Chapleau CA, Lane J, Pozzo-Miller L, Percy AK. Evaluation of current pharmacological treatment options in the management of Rett syndrome: From the present to future therapeutic alternatives. Curr Clin Pharmacol. 2013;8:358-69.

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[49] Neul JL, Lane JB, Lee H-, Geerts S, Barrish JO, Annese F, Baggett LM, Barnes K, Skinner SA, Motil KJ, Glaze DG, Kaufmann WE, Percy AK. Developmental delay in Rett syndrome: Data from the natural history study. J Neurodevelopmental Disord. 2014;6(1). [50] Quest KM, Byiers BJ, Payen A, Symons FJ. Rett syndrome: A preliminary analysis of stereotypy, stress, and negative affect. Res Dev Disabil. 2014;35:1191-7. [51] Fabio RA, Billeci L, Crifaci G, Troise E, Tortorella G, Pioggia G. Cognitive training modifies frequency EEG bands and neuropsychological measures in Rett syndrome. Res Dev Disabil. 2016;53-54:73-85. [52] Fabio RA, Colombo B, Russo S, Cogliati F, Masciadri M, Foglia S, Antonietti A, Tavian D. Recent insights into genotype-phenotype relationships in patients with Rett syndrome using a fine grain scale. Res Dev Disabil. 2014;35:2976-86. [53] Fabio RA, Castelli I, Marchetti A, Antonietti A. Training communication abilities in Rett syndrome through reading and writing. Front Psychol [Internet]. 2013;4(DEC). [54] Fabio RA, Antonietti A, Castelli I, Marchetti A. Attention and communication in Rett syndrome. Res Autism Spectr Disord. 2009;3:329-35. [55] Fabio RA, Giannatiempo S, Oliva P, Murdaca AM. The increase of attention in Rett syndrome: A pre-Test/Post-test research design. J Dev Phys Disabil. 2011;23:99-111. [56] Stasolla F, Caffò AO. Promoting adaptive behaviors by two girls with Rett syndrome through a microswitch-based program. Res Autism Spectr Disord. 2013;7:1265-72. [57] Stasolla F, De Pace C, Damiani R, Di Leone A, Albano V, Perilli V. Comparing PECS and VOCA to promote communication opportunities and to reduce stereotyped behaviors by three girls with Rett syndrome. Res Autism Spectr Disord. 2014;8:1269-78. [58] Stasolla F, Perilli V, Di Leone A, Damiani R, Albano V, Stella A, Damato C. Technological aids to support choice strategies by three girls with Rett syndrome. Res Dev Disabil. 2015;36:36-44.

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[59] Stasolla F, Perilli V. Microswitch-based programs (MBP) to promote communication, occupation, and leisure skills for children with multiple disabilities: A literature overview In: Recent Advances in Assistive Technologies to Support Children with Developmental Disorders. 2015 p. 195-216. [60] Lancioni GE, Singh NN, O'Reilly MF, Sigafoos J, Boccasini A, La Martire ML, Buonocunto F, Biancardi E, Sacco V. Microswitchaided programs for a woman with Rett syndrome and a boy with extensive neuro-motor and intellectual disabilities. J Dev Phys Disabil. 2014;26:135-43. [61] Didden R, Sigafoos J, Korzilius H, Baas A, Lancioni GE, O'Reilly MF, Curfs LMG. Form and function of communicative behaviours in individuals with Angelman syndrome. J Appl Res Intellect Disabil. 2009;22:526-37. [62] O'Reilly MF, Lancioni GE, King L, Lally G, Dhomhnaill ON. Using brief assessments to evaluate aberrant behavior maintained by attention. J Appl Behav Anal. 2000;33:109-12. [63] Wachter LE, Hagopian LP. Psychopharmacology and applied behavioral analysis: Tandem treatment of severe problem behaviors in intellectual disability and a case series. Isr J Psychiatry Relat Sci. 2006;43:265-74. [64] Rivard M, Terroux A, Mercier C. Effectiveness of early behavioral intervention in public and mainstream settings: The case of preschool-age children with autism spectrum disorders. Res Autism Spectr Disord. 2014;8:1031-43. [65] Stasolla F, Perilli V, Caffò AO, Boccasini A, Stella A, Damiani R, Albano V, D’Amico F, Damato C, Albano A. Extending microswitch-cluster programs to promote occupation activities and reduce mouthing by six children with autism spectrum disorders and intellectual disabilities. J Dev Phys Disabil. 2017;29:307-24. [66] Chiapparino C, Stasolla F, de Pace C, Lancioni GE. A touch pad and a scanning keyboard emulator to facilitate writing by a woman with extensive motor disability. Life Span Disabil. 2011;14:45-54.

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[67] Lancioni GE, Belardinelli MO, Chiapparino C, Angelillo MT, Stasolla F, Singh NN, O'Reilly MF, Sigafoos J, Oliva D. Learning in post-coma persons with profound multiple disabilities: Two case evaluations. J Dev Phys Disabil. 2008;20:209-16. [68] Lancioni GE, Comes ML, Stasolla F, Manfredi F, O'Reilly MF, Singh NN. A microswitch cluster to enhance arm-lifting responses without dystonic head tilting by a child with multiple disabilities. Percept Mot Skills. 2005;100:892-4. [69] Stasolla F, Caffò AO, Perilli V, Boccasini A, Stella A, Damiani R, Albano V, Damato C. A microswitch-based program for promoting initial ambulation responses: An evaluation with two girls with multiple disabilities. J Appl Behav Anal. 2017;50:345-56. [70] Trabacca A, Vespino T, Di Liddo A, Russo L. Multidisciplinary rehabilitation for patients with cerebral palsy: Improving long-term care. J Multidiscip Healthc. 2016;9:455-62. [71] Lancioni GE, O'Reilly MF, Singh NN, Stasolla F, Manfredi F, Oliva D. Adapting a grid into a microswitch to suit simple hand movements of a child with profound multiple disabilities. Percept Mot Skills. 2004;99:724-8. [72] Nazareth T, Li N, Marynchenko M, Zhou Z, Chopra P, Signorovitch J, Wu E, Ahmed S, Marvel J, Sasane R. Burden of illness among patients with fragile X syndrome (FXS): A medicaid perspective. Curr Med Res Opin. 2016;32:405-16. [73] Vekeman F, Gauthier-Loiselle M, Faust E, Lefebvre P, Lahoz R, Duh MS, Sacco P. Patient and caregiver burden associated with fragile X syndrome in the united states. Am J Intellect Dev Disabil. 2015;120:444-59. [74] Stasolla F, Perilli V, Damiani R, Caffò AO, Di Leone A, Albano V, Stella A, Damato C. A microswitch-cluster program to enhance object manipulation and to reduce hand mouthing by three boys with autism spectrum disorders and intellectual disabilities. Res Autism Spectr Disord. 2014;8:1071-8. [75] Stasolla F, Damiani R, Caffò AO. Promoting constructive engagement by two boys with autism spectrum disorders and high

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[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

Fabrizio Stasolla, Viviana Perilli, Alessandro O. Caffò et al. functioning through behavioral interventions. Res Autism Spectr Disord. 2014;8:376-80. Hyman P, Oliver C. Causal explanations, concern and optimism regarding self-injurious behavior displayed by individuals with Cornelia de Lange syndrome: The parents' perspective. J Intellect Disabil Res. 2001;45:326-34. Hardiman RL, McGill P. The topographies and operant functions of challenging behaviours in fragile X syndrome: A systematic review and analysis of existing data. J Intellect Dev Disabil. 2017;42:190203. Stasolla F, Perilli V, Damiani R. Self monitoring to promote on-task behavior by two high functioning boys with autism spectrum disorders and symptoms of ADHD. Res Autism Spectr Disord. 2014;8:472-9. Lancioni GE, Singh NN, O'reilly MF, Oliva D, Smaldone A, Tota A, Martielli G, Stasolla F, Pontiggia G, Groeneweg J. Assessing the effects of stimulation versus microswitch-based programmes on indices of happiness of students with multiple disabilities. J Intellect Disabil Res. 2006;50:739-47. Lancioni GE, Singh NN, O'Reilly MF, Oliva D, Basili G. An overview of research on increasing indices of happiness of people with severe/profound intellectual and multiple disabilities. Disabil Rehabil. 2005;27:83-93. Stasolla F, Caffò AO, Damiani R, Perilli V, Di Leone A, Albano V. Assistive technology-based programs to promote communication and leisure activities by three children emerged from a minimal conscious state. Cogn Process. 2015;16:69-78. Stasolla F, Damiani R, Perilli V, D'Amico F, Caffò AO, Stella A, Albano V, Damato C, Leone AD. Computer and microswitch-based programs to improve academic activities by six children with cerebral palsy. Res Dev Disabil. 2015;45-46:1-13. Caffò AO, Hoogeveen F, Groenendaal M, Perilli VA, Damen M, Stasolla F, Lancioni GE, Bosco A. Comparing two different

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orientation strategies for promoting indoor traveling in people with Alzheimer's disease. Res Dev Disabil. 2014;3:572-80. [84] Stasolla F, De Pace C. Assistive technology to promote leisure and constructive engagement by two boys emerged from a minimal conscious state. NeuroRehabilitation. 2014;35:253-9. [85] Lancioni GE, Singh NN, O'Reilly MF, Sigafoos J, Renna C, Pinto K, De Vanna F, Caffò AO, Stasolla F. Persons with moderate Alzheimer's disease use simple technology aids to manage daily activities and leisure occupation. Res Dev Disabil. 2014;35:2117-28.

BIOGRAPHICAL SKETCHES Fabrizio Stasolla, PhD, has a post-doctoral degree. He is assistant professor at University of Bari. His topic concerns the assistive technologies for children with multiple disabilities, developmental disabilities, autism spectrum disorders, ADHD, Rett and Down syndromes, cerebral palsy, congenital encephalopathy, fragile X syndrome, post-coma patients who are in a vegetative state either in a minimally conscious state or are emerging/emerged from it. His interest deals with cognitivebehavioral interventions and alternative augmentative communication strategies for non verbal individuals, and/or for persons who are estimated within a normal intellectual functioning but who present pervasive motor disabilities. He teaches psychology of disabilities and rehabilitation to educational sciences students. Furthermore, he works on technological supports, PECS, VOCA, SGD, literacy process, ambulation responses, self-monitoring and self management of instruction cues to promote ontask behavior by students with learning disabilities, behavioral strategies for promoting adaptive responses and reducing challenge behaviors by children with severe to profound developmental disabilities. From 2013 up to present, he is ad-hoc reviewer for 20 peer-reviewed journals, he serves on the editorial board of 4 more peer-reviewed journals and he is an associate editor of the International Journal of Behavioral Research & Psychology.

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Viviana Perilli, psychologist and PhD in psychology of cognitive, emotional and communicative processes, is a research assistant at the NoProfit Organization Lega del filo d’Oro, site in Molfetta, Italy. She graduated in Clinical Psychology of development and relationships (2008) and earned her PhD (2013) at the University of Bari, Italy. During the PhD she started the first researches on cognitive rehabilitation of dementia, in particular on the process of intervention aimed at supporting the residual abilities in patients with Alzheimer's disease by the use of Assistive Technologies. Currently she is involved in research projects focus on cognitive-behavioral interventions for persons affected by psycho-sensorial disabilities, extensive motor disabilities and developmental disabilities. The author works with assistive technologies for promoting communication opportunities, adequate physical exercise or ambulation, self management of instruction cues, leisure activities. Alessandro O. Caffò, PhD, is a researcher in psychometrics at the Department of Educational Sciences, Psychology, Communication, University of Studies of Bari, Apulia, Italy. His main research interests include: spatial cognition in normal aging, mild cognitive impairment and Alzheimer's disease, assistive technology and rehabilitation strategies in persons with severe to profound developmental and multiple disabilities, data analysis and methodology in psychological research. He is author and co-author of several publications on international peer-reviewed journals and books. He also acts as a referee for several international journals. He teaches psychometrics and data analysis in psychology to undergraduate and postgraduate students. Fiora D'Amico, MA and clinical psychologist, is a research assistant at San Raffaele Medical Center (Modugno, Italy). She works on rehabilitative programs and assistive technology-based interventions for promoting selfdetermination and independence of individuals with severe and multiple disabilities. Specifically, she is interested to enhancing occupation, physical, and leisure activities by patients with Alzheimer Disease and amyotrophic lateral sclerosis. Furthermore, her topics are focused on

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assessing signs of awareness on post-coma persons who are diagnosed either in a vegetative state or in a minimally conscious state through technological supports and learning principles. Within this framework, she co-authored several papers published in different indexed and international peer- reviewed journals.

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In: Horizons in Neuroscience Research. Vol. 31 ISBN: 978-1-53612-375-3 Editors: A. Costa and E. Villalba © 2017 Nova Science Publishers, Inc.

Chapter 2

THE EFFECTS OF VALPROATE AND LEVETIRACETAM AS A MONOTHERAPY ON VITAMIN D STATUS IN EPILEPTIC CHILDREN Teodoro Durá-Travé1,2,, MD, Fidel Gallinas-Victoriano2, MD, María Urretavizcaya-García2, MD, Lotfi Ahmed-Mohamed2, MD, Sergio Aguilera-Albesa2, MD and María Eugenia Yoldi-Petri2, MD 1

Department of Paediatrics, School of Medicine, University of Navarra, Pamplona, Spain 2 Department of Paediatrics, Navarra Hospital Complex, Pamplona, Spain



Address correspondence: T. Durá-Travé, Navarra Hospital Complex. Avenue Irunlarrea, 4, 31008 Pamplona, Spain. E-mail: [email protected] Fax: +34-848- 429-924; Tel. +34848-422-563.

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ABSTRACT Introduction. Many classic antiepileptic drugs (AEDs) may cause vitamin D deficiency (e.g., valproate). Levetiracetam (LEV) is a more recent AED widely used in paediatric epilepsy. Adult studies suggest no vitamin D-lowering effect of LEV treatment, but there are few studies in children. Objectives. The aim of this study is to evaluate the influence of VPA and LEV as monotherapy on vitamin D status among children with epilepsy. Material & Methods. A cross-sectional clinical (seizure types, aetiology of epilepsy, dosage, drug levels, and duration of AEDs) and blood testing (calcium, phosphorous, 25-OHD and PTH) study was accomplished in 90 epileptic children (AEDs group: 59 receiving VPA, and 31 receiving LEV) and a control group (244 healthy subjects). Serum 25-OHD levels were categorized as low (>20 ng/ml), borderline (20-29 ng/ml), or normal (>30 ng/ml). Results. The aetiology of epilepsy was idiopathic in 69 patients (76.7%), cryptogenic in 12 patients (13.3%), and symptomatic in 9 patients (10%). The average dosage of VPA and LEV was 20.7 ± 4.7 mg/kg/d and 24.1 ± 7.9 mg/kg/d, respectively. The mean duration of VPA therapy was 2.5 ± 1.4 years, and for LEV was 2.3 ± 1.6 years. Drug levels of VPA and LEV were 72.1 ± 25.9 mcg/ml and 7.7 ± 4.0 mcg/ml, respectively. Calcium and 25-OHD levels were significantly higher (p < 0.05) in the control group. There was a negative correlation (p < 0.01) between 25-OHD and VPA levels (r = -0.442). There was not any correlation between 25-OHD and LEV levels and length of AEDs therapy (VPA or LEV). Vitamin D deficiency was significantly higher (p < 0.05) in VPA (24.1%) and LEV (35,5%) groups than in control group (14%). The multiple logistic regression analysis showed that VPA monotherapy (OR: 1.9, CI 95%: 1.1-3.8) and specially LEV monotherapy (OR: 3.3, CI 95%: 1.5-7.5) were associated with an increased risk of vitamin D deficiency. Conclusion. The prevalence of vitamin D deficiency is common in children with epilepsy taking VPA or LEV. Hence, vitamin D status of children treated with VPA and LEV should be regularly monitored, and vitamin D supplements on an individual basis should be considered.

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The Effects of Valproate and Levetiracetam as a Monotherapy … 39

INTRODUCTION Vitamin D plays several roles in modulation of cell proliferation, differentiation, neurotransmission and immune response in the central nervous system [1]. In addition, vitamin D plays an important role in the regulation of calcium homeostasis and nerve excitability [2]. In fact, an anticonvulsant effect of vitamin D was initially reported in 1974 in patients with pharmacoresistant epilepsy and low serum 25-OH D levels [3]. Moreover, hypovitaminosis D is a global health problem. Gender, pubertal age, skin pigmentation, season of the year in which serum is collected, urban residence, geographical conditions (degree of latitude, cloud cover, etc.), obesity, chronic diseases (skin disease, malabsorption, cholestasis, renal insufficiency, disability) and chronic medications (antiepileptic drugs and glucocorticoids) have been associated with hypovitaminosis D [4-15]. Epilepsy is one of the most prevalent neurological disorders of childhood and most of the children with epilepsy require long-term therapy with antiepileptic drugs (AEDs). Many “classical” AEDs are inducers of hepatic P450 system and may cause vitamin D deficiency [16-22]. However, non-enzyme-inducing AEDs may also cause hypovitaminosis D. For example, lower 25-hydroxyvitamin D levels (25-OHD) and lower bone mineral density have been documented in children with epilepsy under treatment with valproate [16, 17, 20-22]. There is little literature regarding ‘newer’ AEDs and vitamin D status in epileptic children (gabapentin, lamotrigine, oxcarbazepine, levetiracetam, lacosamide, topiramate, vigabatrin, stiripentol, etc.). Levetiracetam is a widely used drug in paediatric epilepsy with favourable tolerability and efficacy profile. Adult studies suggest no vitamin Dlowering effect of levetiracetam treatment, but there are only a few studies in children on this matter [11, 21-23]. The aim of this study is to evaluate the influence of valproate and levetiracetam as monotherapy on vitamin D status and parathormone among children with epilepsy.

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METHODS Participants Ninety patients with epilepsy (39 boys and 51 girls) and a control group (made up with 118 boys and 126 girls) were included in a crosssectional study. All of the participants were Caucasian children and underwent a clinical examination and blood testing in the Paediatric Neurology Unit of the Navarra Hospital Complex in Pamplona, Spain, in the period October 2013 - June 2014. Participants were divided into three groups: VPA group (patients with epilepsy receiving valproate, n = 59), LEV group (patients with epilepsy receiving levetiracetam, n = 31) and control group. All individuals were outpatients with no motor deficits who had received valproate or levetiracetam as monotherapy for at least twelve months. They received no additional vitamin D or calcium supplements, and none of the patients had mental retardation or cerebral palsy, hepatic, skeletal, renal, endocrine, or metabolic disorders. Additionally, the patients included in the study did not receive any other AED previously (other than their current drug). The control group consisted of 359 healthy children with normal nutritional status: BMI Z-score between -1.0 (15th percentile) and + 1.0 (85th percentile). They came from external consultations of the different paediatric subspecialities and neither one had any illness affecting bone health or chronic pathologies that might interfere growth, body composition, food ingestion or physical activity, nor had received any medication (antiepileptic drugs or glucocorticoids) and vitamin D or calcium supplements.

Clinical Information and Anthropometry Information recorded from every patient included epidemiologic and clinical data: sex, age, BMI Z-score, season of study visit, residence,

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The Effects of Valproate and Levetiracetam as a Monotherapy … 41 seizure types (generalized, focal or undetermined), aetiology of epilepsy (idiopathic, cryptogenic or symptomatic), antiepileptic drugs (valproate or levetiracetam), dosage, drug levels, and duration of therapy. The International League Against Epilepsy criteria for epileptic seizures and epileptic syndromes and guidelines for epidemiologic studies were applied for diagnosis and classification [24, 25]. Pubertal stage was determined in each participant according to Tanner’s criteria, and patients were classified in two different groups: prepubertal or school group (Tanner stage I) and pubertal or adolescent group (Tanner stages II–V). Residence was categorized as urban or rural (more or less than 10.000 inhabitants, respectively). The Z-score values for the BMI were calculated using the epidemiologic data contained within the program Aplicación Nutricional, from the Spanish Society of paediatric gastroenterology, hepatology and nutrition (Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica, available at http://www.gastroinf.es/nutritional/). The graphics from Ferrández et al. (Centro Andrea Prader, Zaragoza 2002) were used as reference charts [26].

Biochemical Analysis Calcium, phosphorous and alkaline phosphatase plasma levels were measured during fasting by standardized methodologies. 25-OHD and PTH were measured by chemilumenescence. The United States Endocrine Society criteria for classification of vitamin D status were applied. Vitamin D deficiency was defined as 25OHD lower than 20 ng/mL (75 nmol/L) [27, 28]. Secondary hyperparathyroidism was defined when PTH serum levels exceed 65 pg/ml [4, 7].

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Statystical Analysis Results are displayed as percentages (%) and means (M) with corresponding standard deviations (SD). The statistical analysis (descriptive statistics, Student’s t, ANOVA, Chi-square test, Pearson correlation and multiple logistic regression) was performed using the program Statistical Packages for the Social Sciences version 20.0 (Chicago, Illinois, USA). Statistical significance was assumed when p was lower than 0.05. Parents and/or legal guardians were informed and provided verbal consent for the participation in this study in all cases. This study was approved by the Ethics Committee for Human Investigation at our institution (in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and later amendments).

RESULTS The number of patients with focal, generalized and undetermined epilepsy was 53 (58.9%), 35 (38.9%) and 2 (2.2%), respectively. The aetiology of epilepsy was believed to be idiopathic in 69 patients (76.7%), cryptogenic in 12 patients (13.3%), and symptomatic in 9 patients (10%). The dosage of VPA and LEV was 20.7 ± 4.7 mg/kg/d (range: 12.337.7) and 24.1 ± 7.9 mg/kg/d (range: 13.9-43.9), respectively. Drug levels of VPA and LEV was 72.1 ± 25.9 mcg/ml (range: 17.3-144.7) and 7.7 ± 4.0 mcg/ml (range: 2.3-21.1), respectively. The duration of antiepileptic therapy with VPA was 2.5 ± 1.4 years (range: 1.3-4.5), and with LEV was 2.3 ± 1.6 years (range: 1.2-5.1). There are no significant differences among both groups. Table 1 shows and compares the distribution of the presumed risk factors for hypovitaminosis D between AED groups and control group. The percentage of girls was significantly higher in VPA group, whereas the percentage of boys was significantly higher in LEV group. There were no

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The Effects of Valproate and Levetiracetam as a Monotherapy … 43 significant differences between the distribution in relation to age group, season of blood sample and place of residence. Table 2 shows and compares the mean values for the clinical characteristics and biochemical determination between AED groups and control group. Calcium and 25-OHD levels were significantly higher in control group, whereas phosphorous levels were significantly higher in AED groups. There were not any significant differences in age, BMI (Zscore), alkaline phosphatase and PTH among different groups. Table 1. Distribution of presumed risk factors for hypovitaminosis D in AEDs groups and control group Items Sex Boys Girls Age Group School Adolescent Season of study visit Autumn Winter Spring Residence Urban Rural

VPA group (n = 59)

LEV group (n = 31)

Control group (n = 244)

p

18 (30.5%) 41 (69.5%)

21 (67.7%) 10 (32.3%)

118 (48.4%) 126 (51.6%)

0.003

30 (50.8%) 29 (49.2%)

17 (54.8%) 14 (45.2%)

135 (55.3%) 109 (44.7%)

0.825

20 (33.8%) 19 (32.2%) 20 (33.8%)

10 (32.3%) 9 (29.0%) 12 (38.7%)

93 (38.1%) 82 (33.6%) 69 (28.3%)

0.283

36 (61%) 23 (39%)

18 (58.1%) 13 (41.1%)

170 (69.7%) 74 (30.3%)

0,251

Table 2. Clinical and biochemical characteristics of the AED groups and control group Items Age (yr) BMI (Z-score) Calcium (mg/dL) Phosphorous(mg/dL) ALP (IU/L) PTH (pg/mL) 25-OHD (ng/mL)

VPA group (n = 59) 10.15 ± 3.02 0.02 ± 0.59 9.88 ± 0.33 4.91 ± 0.54 217.44 ± 81.23 26.94 ± 9.41 23.37 ± 9.11

LEV group (n = 31) 9.38 ± 3.83 0.17 ± 0.54 9.87 ± 0.55 4.99 ± 0.69 246.30 ± 81.27 28.21 ± 11.25 22.64 ± 9.08

Control group (n = 244) 9.64 ± 3.40 -0.05 ± 0.50 9.98 ± 0.35 4.54 ± 0.55 233.43 ± 77.99 31.05 ± 16.18 26.97 ± 7.09

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p 0.208 0.226 0.041 0.001 0.261 0.093 0.037

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Figure 1 depicts and compares the prevalence of hypovitaminosis D between AED groups and control group. Vitamin D deficiency was significantly higher in VPA group (24.1%) and LEV group (35.5%), whereas vitamin D deficiency was lower in control group (14%) (p = 0.004). In control group, parathyroid hormone levels over 65 pg/mL (hyperparathyroidism) were found in 8 cases (4.7%), whereas no patient with hyperparathyroidism was detected in AED group.

Figure 1. Prevalence of hypovitaminosis D in AED groups and control group.

There was a statistically significant correlation (p < 0.01) between 25OHD and VPA levels (r = -0.442). There was not any correlation between 25-OHD and LEV levels and length of anticonvulsive therapy (VPA or/and LEV). The multiple logistic regression models (Table 3) demonstrated significant values for the odds of vitamin D deficiency associated with adolescent age, urban residence and AEDs (VPA and LEV). The remaining variables (sex, seizure types, aetiology of epilepsy, and duration of therapy) did not contribute significantly to the models and have been omitted.

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The Effects of Valproate and Levetiracetam as a Monotherapy … 45 Table 3. Multiple logistic regressions: factors associated with vitamin D deficiency Items OR (CI 95% Age group Children Adolescents Residence Rural Urbana AEDs Control Group VPA LEV

Vitamin D deficiency (p)

1 (referent) 1.9 (1.1-3.1)

0.013

1 (referent) 1.6 (1.1-2.2)

0.010

1 (referent) 1.9 (1.1-3.8) 3.3 (1.5-7.5)

0.029 0.003

DISCUSSION There are few studies evaluating vitamin D status in epileptic children medicated with “newer” antiepileptic drugs [13, 18, 21, 22], and this is the first report to estimate the effect of LEV monotherapy on vitamin D status in Spanish children. The patients enrolled in this study constituted a group of children with focal or generalized epilepsy, being idiopathic aetiology predominant (brain magnetic resonance imaging normal) and receiving valproate or levetiracetam as monotherapy. It has been intended to make both groups (AEDs groups and control Group) as similar as possible in order to avoid confounding factors that may lead to misinterpretation of results. In fact, none of the patients had motor deficits, mental retardation or cerebral palsy, and neither had any pathology that might affect growth, body composition, food ingestion or physical activity. In addition, the distribution of several factors related to hypovitaminosis D, such as gender, pubertal age, skin pigmentation (all of the participants were white

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children), season of the year in which serum is collected, residence, and nutritional status were similar among AED groups and control group. Enzyme-inducing AED therapy (e.g., phenobarbital, phenytoin, carbamazepine and primidone), particularly long-term antiepileptic drug therapy and polytherapy, is known to be associated with vitamin D deficiency and, consequently, with impaired bone health [17, 18, 20, 22, 29]. It is assumed that cytochrome 450-inducing AEDs upregulate the enzymes that catalyse the conversion of 25-OHD into polar inactive metabolites [12]. The resulting decrease in 1,25(OH)2 vitamin D leads to reduced calcium absorption, with consecutive secondary hyperparathyroidism, increased bone resorption and accelerated bone loss; this would explain why people suffering from epilepsy have higher risk of fractures than general population [12, 14, 22, 30]. However, some studies have shown that enzyme-inducing AEDs can also have a negative impact on skeletal integrity in the absence of vitamin D deficiency. Possible mechanisms suggested are decreased intestinal absorption of calcium, resistance to PTH, calcitonin deficiency and a direct drug effect on bone cell functions [12, 14]. Although several researchers concluded that non-enzyme-inducing AED monotherapy did not lead to vitamin D deficiency [31], all the patients included in this study had received non-enzyme-inducing AEDs (valproate or levetiracetam) and had a higher prevalence of vitamin D deficiency compared with healthy individuals (controls). Valproate is a widely used AED in paediatrics patients and is an inhibitor of the cytochrome P450 system. There are very different data related to adverse effects of valproate therapy on vitamin D status and biochemical markers of bone turnover in children with epilepsy [15, 21, 29]. The results obtained in this study would support that VPA treatment as monotherapy for at least twelve months is associated with significantly lower serum calcium and 25-OHD levels and high prevalence of deficiency vitamin D compared to controls (24.1% of the children in the VPA group were deficient in vitamin D vs. 14% in control group); there were not any significant differences in PTH levels among both groups. In addition, a negative association between 25-OHD and VPA levels is observed, and the

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The Effects of Valproate and Levetiracetam as a Monotherapy … 47 analysis of the different factors associated to hypovitaminosis D (multiple logistic regressions) confirms that patients with epilepsy receiving valproate showed a higher tendency towards vitamin D deficiency compared to controls. At this moment, no sufficient clinical data are available concerning the vitamin D status with the use of ‘newer’ AEDs, especially in the paediatric population (gabapentin, tiagabine, lamotrigine, oxcarbazepine, levetiracetam, lacosamide, topiramate, vigabatrin, stiripentol, zonisamide, etc.). Levetiracetam is a broad spectrum AED with favourable efficacy and safety in severe types of epilepsies [32, 33]. It is not metabolized, and it does not cause induction or inhibition of the P450 enzyme system or other enzyme systems. Clinical data on the effects of LEV on vitamin D status and skeletal integrity are scarce. An experimental study in rats observed that LEV treatment would cause microstructural changes in bone matrix without affecting bone mineral density [34], but other researchers reported that long term levetiracetam treatment significantly reduced bone mineral content in rat models [35]. Some authors had examined the relationship between vitamin D status and LEV monotherapy in children, but do not observe any difference in 25-OHD levels in comparison to a control group after 1 or 2 years of treatment [36, 37]. In the same way, the results obtained in this study would support that LEV treatment as monotherapy for at least twelve months is associated with significantly lower serum calcium and 25-OHD levels, and a high prevalence of deficiency vitamin D compared to controls (35.5% of the children in the LEV group were deficient in vitamin D vs. 14% in control group); there were not any significant differences in PTH levels among both groups. In this case, no association between 25-OHD and LEV levels is observed, but multiple logistic regressions confirms that patients with epilepsy receiving levetiracetam showed a higher tendency towards vitamin D deficiency compared to controls. The exact mechanism of action of non-enzyme-inducing AEDs, and particularly valproate and levetiracetam therapy, on vitamin D and parathormone in epileptic children is still unclear. Several hypothesis has been postulated, such as renal tubular dysfunction leading to increased loss

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of urinary calcium, a direct effect of the drug on bone cell function by inhibiting osteocalcin secretion and the proliferation of osteoblasts, a reduced intestinal calcium transport, or an abnormal parathyroid gland response caused by AEDs [12. 14 17, 18]. In addition, some authors speculated that genetic variations related to vitamin D receptor polymorphism may influence vitamin D status in patients with epilepsy on AEDs treatment [14, 38]. However, additional studies are needed to evaluate the underlying mechanisms. The Endocrine Society’s Guidelines recommend evaluation of vitamin D status in epileptic children under treatment with AEDs, which includes patients under valproate or levetiracetam therapy. Although there is some controversy regarding the definition of vitamin D deficiency, the Endocrine Society defines vitamin D deficiency as a 25-OHD level 2.35, P < 0.01, cluster size = 10) for the whole sample group in a, PiB- sub-group in b and PiB+ sub-group in c.

LME modeling was performed to predict CBF by baseline age and sex effects, adding modulation factors by PiB A uptake level (measured as mean DVR cortical values) and APOE4+ status as well as longitudinal rate of CBF change. Significantly lower CBF with age were found in all brain regions, especially at cortical and sub-cortical gray matter regions (P < 0.01, cluster corrected) (Figure 5). Regionally higher CBF (orange) was observed in the subcortical putamen, thalamus and posterior cingulate regions in women than in men. Longitudinal interval effects showed CBF decrement in frontal, temporal, posterior cingulate, and caudate regions, accompanied with CBF increment change in subcortical putamen and pallidum as well as cerebellar regions at follow-up times. Mild APOE and PiB as well as with age interaction effects based on CBF were observed.

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Figure 3. Non-negative matrix factorization to the CBF data showed PiB+ group (a) and APOE4+ (b) group have different CBF spatial distribution: with higher visual CBF in PiB+ group in contrast to higher frontal and visual CBF in APOE4+ group.

Figure 4. Mild positive correlations (indicated as red color) between CBF and BOLDbased default mode network functional connectivity found from clusters in posterior cingulate, left frontal and premotor regions, and subcortical thalamus with uncorrected P < 0.05 based on whole-brain voxel-wise correlations (a), as well as voxel-wise correlation between CBF and RS-fMRI functional activity with fALFF (b).

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Figure 5. LME modeling of CBF predicted by baseline age and sex effects, and modulated by PiB and APOE status as well as longitudinal change of CBF. Interval by age, PiB by age, and APOE by age interaction effects were shown as well. Significantly lower CBF with age were found in all brain regions, especially at cortical and sub-cortical gray matter regions (statistical T-map, |T| > 2.35, P < 0.01, cluster size = 10). Regionally higher CBF (orange) was observed in the subcortical putamen, thalamus and posterior cingulate regions in women. Longitudinal interval effects showed longitudinal CBF change decreases in frontal, temporal, posterior cingulate, and caudate regions, accompanied with increases of CBF longitudinal change in subcortical putamen and pallidum as well as cerebellum regions. Mild APOE4 and PiB and interactions with age effects (mean cortical DVR values) based on CBF were observed as well as modulation by age effects.

LME modeling of PiB R1 (rCBF) transport rate showed significantly lower R1 with age in all brain regions as well, especially at cerebellum, cortical and sub-cortical gray matter regions (P < 0.01, cluster corrected) (Figure 6). Longitudinal interval effects showed pseudo-CBF decreases in small clusters from frontal including superior and anterior cingulate,

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precentral and inferior frontal portions, post-central and temporal regions. Very mild APOE, PiB and with age interaction effects based on R1 were observed as well.

Figure 6. LME modeling of PiB R1 transport rate predicted by baseline age and sex effects, and modulated by PiB and APOE status as well as longitudinal change of R1. Interval by age, PiB by age, and APOE by age interaction effects were shown as well. Significantly lower R1 with age were found in all brain regions, especially at cerebellum, cortical and sub-cortical gray matter regions (statistical T-map, |T| > 2.35, P < 0.01, cluster size = 10). Longitudinal interval effects showed longitudinal rCBF decreases in small clusters from frontal including superior and anterior cingulate, precentral and inferior frontal portions, post-central and temporal regions. Very mild APOE and PiB (mean DVR cortical values) and interactions with age effects based on R1 were observed as well as modulation by age effects.

In addition, regional CBF increase in especially posterior visual and superior parietal regions after glucose energy drink uptake compared to baseline (Figure 7). And CBF was globally lower in whole brain after coffee drinking compared to baseline (Figure 8). Lower OEF and CMRO2

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after coffee ingestion compared to baseline, but relatively small OEF change and regional CMRO2 increase after glucose uptake with SAGA sequence for the same subject measured in the same imaging session had been observed as well.

Figure 7. Global CBF reduction after coffee ingestion (b) compared to baseline (a). Lower OEF and CMRO2 after coffee were observed with SAGA sequence as well (results not shown).

Figure 8. Regional CBF increase in especially posterior visual and superior parietal regions after glucose energy drink uptake (b: white arrows) compared to baseline (a).

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Discussion and Conclusion Our results demonstrated slightly different age, sex and genetic effects to the standard CBF and pseudo-CBF (R1) measures, although two measures were significantly correlated in majority of brain regions, including especially the frontal cortex. Accounting for all mixed effects from age, sex, APOE and PiB, age is the predominate factor contributing to baseline CBF change with remarkably lower CBF with age. As expected, regionally higher CBF (but not R1) was observed in the subcortical putamen, thalamus and posterior cingulate regions in women than in men. Longitudinal interval effect also demonstrated CBF changes including mostly frontal, subcortical (e.g., caudate and thalamus) and posterior cingulate reductions, together with regional increment in subcortical putamen and pallidum as well as cerebellar regions at followups. On the other hand, longitudinal interval effect also showed R1 (rCBF) decreases at follow-ups in small clusters from frontal including superior and anterior cingulate, precentral and inferior frontal portions, post-central and temporal regions. Similar to longitudinal effects, age by interval effect was observed on CBF or R1(rCBF). Very mild APOE4 or PiB effects had found on CBF and R1(rCBF). Expected voxel-wise CBF, OEF and CMRO2 changes induced by caffeine challenge or glucose uptake had been observed, for instance, regional CBF increases after glucose energy drink uptake and globally CBF decreases after caffeine ingestion. Mild correlations between CBF and BOLD indicates BOLD signal measures the combined effects from OEF, CMRO2 and blood volume besides CBF. This work suggests distinct and independent voxel-wise brain CBF changes identified from different methods, and prominent effects of age and longitudinal changes (in relatively old participants) compared to other factors including gender, APOE, amyloid load and physiological challenges.

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SECTION II: CBF-BASED RAPID VASCULAR REACTIVITY MEASURE Introduction Cerebrovascular reactivity (CVR) describes the compensatory dilatory capacity of cerebral vasculature in upregulating perfusion (Zhou et al., 2015). Reliability and reproducibility of CVR based on cerebral blood flow (CBF) and BOLD with breathing protocols and other techniques had been reported recently (Totaro et al., 1999; Kassner et al., 2010; McDonnell et al., 2013; Sousa et al., 2014). Previous reports based on either magnitude or phase of BOLD signals have found reduced brain CVRs in sickle cell disease, as well as lower static CVR (in comparison to dynamic latencybased fitting) in regions of white matter hyperintensities (Leung et al., 2016; Sam et al., 2016). Studies with breath-holding tasks observed lower CVRs in stroke patients at acute phase (Raut et al., 2016), decreased CVRs and cortical thinning in diabetes and hypertension patients (Tchistiakova et al., 2014). Breath-holds paradigm (usually breath holding period of 20-30 secs and interleaved with normal breathing, for about 3-6 cycles) is a simple and efficient way to measure brain vascular response (especially blood flow rate) with good test-retest reliability (Bright et al., 2009) (Bright et al., NI, 2013). The time delay between the breathing hold protocol and time curve of the MRI signal (either velocimetry or magnitude) indicates quantitative temporal information of the relative response time of the vasculature, and have been found to be informative of brain vascular reactivity (Blockley et al., 2011). The delay parameter is also associated with regions of high bolus delays (Christen et al., 2015). A rapid velocimetry method incorporating non-gated phase-contrast magnetic resonance imaging to quantify total CBF (tCBF) with motion-sensitizing gradient waveforms to encode information about velocity into the phase of the MR signal had been previously reported to measure global response to apnea (Rodgers et al, 2013). Magnitude-based fluctuations contain mixed

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information of blood flow and oxygenation, and might provide extra information besides the velocimetry methods. Endothelial cells produce a variety of vasodilators, chief among which is nitric oxide (Davignon and Ganz), but also vasoconstrictors such as endothelia. Reactive oxygen species (ROS) (Boms et al., 2010) such as the superoxide radical anion (O2), occurring in cigarette smoke, are well known to dysregulate the normal vasodilatory response of the endothelium to increased demand for blood flow (Church and Pryor, 1985). Endothelial dysfunction is believed to be the earliest initiator of atherogenesis followed by the well-known sequelae leading to neurovascular and heart disease (Davignon and Ganz, 2004). Reduced cardiac output, peripheral vasoconstriction, and cerebral vasodilation (Ainslie and Ogoh, 2010) represent the normal physiologic response to apnea. To measure the change in superior sagittal sinus blood flow at high (2second) temporal resolution during breath-hold (a predominantly hypercapnic stimulus), breath-hold index (BHI) is used as the slope of the flow velocity-time curve. Decreased BHI should reflect deterioration of vasomotor reactivity from chronic smoking, a trend that is expected to reverse following smoking cessation (Boms et al., 2010). The standard deviation of BHI across feeding arteries and draining veins including superior sagittal sinus (SSS) was found to be about 5% over N=20 healthy subjects (de Boorder et al., 2004). Thus the relative change in SSS blood flow velocity is a valid measure of BHI, which is in agreement with the tight coupling between arterial and venous flow (Symon et al., 1973). A single examination protocol includes dynamic venous oximetry that makes use of venous oxygen saturation as an endogenous tracer monitored during hyperemia along with arterial velocity had been developed recently (Langham et al., 2015). Lower limb ischemia was induced by applying a blood pressure cuff (i.e., cuff paradigm) to the upper right thigh imaged with a multi-echo gradient-recalled echo (GRE) sequence to measure central and peripheral vascular reactivity. Using this advanced cuff paradigm, lower peripheral VR in smokers and elderly subjects were found in a large cohort of subjects (about 200 subjects at baseline and follow-up visits) (Langham et al., 2015).

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In this work, both velocimetry and magnitude-based breath holding index quantifications including slope and delay parameters were explored with individual and average fitting algorithms, and to further demonstrate brain vascular reactivity changes in response to apnea in smokers and elderly population. And finally the neurovascular reactivity parameters were linked to peripheral vascular parameters that have previously been reported and incorporated into the same MRI session.

Methods Subjects Vascular reactivity was assessed in a subset of patients (18 nonsmokers and 17 smokers) drawn from a larger study designed to evaluate the effects of smoking and age on a variety of vascular measures in 169 subjects without symptomatic cardiovascular disease conducted at 3T field strength (Langham et al., 2015). Eight young non-smokers (YNS; age: 28.9 ± 2.8 years), 7 young smokers (YS; 35.6 ± 4.5 years), 10 old nonsmokers (ONS; 58.2 ± 3.9 years) and 10 old smokers (OS; 57.3 ± 4.1 years) were recruited. Magnetic Resonance Imaging and Data Analysis All MR procedures were performed on a 3T Siemens TIM Trio scanner (Siemens Medical Solutions) using an 8-channel extremity coil for studies at the location of the femoral/popliteal artery and vein (Part I), and a combination of two body matrix and spine coils for peripheral VR assessments including pulse wave velocity (PWV) of the aorta, iliac and femoral circulation (Part II) (Langham et al., 2015). All customdesigned pulse sequences were implemented in SequenceTree (http://wisdmhub.org/dev2/apps/sequencetree/). Each part of the MRI protocol, including scout scans, lasted approximately 20 mins and the patients were scanned in feet-first supine position. Measures of peripheral VR and endothelial dysfunction methods were incorporated into a single examination protocol for dynamic venous oximetry that makes use of

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venous oxygen saturation as an endogenous tracer (Langham et al., 2010) monitored during hyperemia, along with arterial velocity (Langham et al., 2013). PWV is measured in the central and peripheral arteries using new projection imaging techniques (Langham et al., 2011; Langham and Wehrli, 2011). All peripheral VR methods were evaluated in a large cohort including elderly and smokers reported previously (Langham et al., 2015). The 6-min breathing protocol was implemented in the end of the scan with 12-channel head coil and a headphone set. A brain scout and axial T1 images were obtained for positioning the slice that was perpendicular to the orientation of superior sagittal sinus (SSS) venous flow prior to the breathing protocol with approximately 1-min. The subjects were coached to hold their breath at normal end expiration before the scan. During the BH experiment, subject was asked to breath in or out with normal pace for three breath-holding cycles. Subjects underwent an apnea paradigm consisting of a single 30-second normal breathing baseline period followed by three repeated blocks of a 30-second breath-holds, each separated by a 90-second normal breathing recovery period. Blood flow velocity in the SSS during the 6-min apnea paradigm was quantified using a non-gated phase-contrast BRISK acquisition scheme with BRISK k-space sampling and view sharing (Rodgers et al., 2013) achieving a temporal resolution of 2s or 3s. In general, patient motion is a concern due to the length of the scan and the nature of the paradigm, but the BRISK acquisition scheme alleviates this concern given the high temporal resolution (3s) achievable. Sequence parameters were: flip angle = 15°, bandwidth = 347 Hz/pixel, TE/TR = 6.5/31.25 ms, VENC = 50 cm/s, FOV = 220 × 220 × 5 mm3, resolution = 1.15 × 1.15 × 5 mm3. The data were evaluated in terms of the slope of the velocity versus time curve, expressed as cm/s2, referred to as BHI slope. Similar magnitude-based BHI and delay parameter estimated from Gaussian linear fitting using individual and average fitting algorithms were implemented with in-house developed scripts. Correlations among various VR parameters and statistical analyses of age and smoking effects were performed in MATLAB (www.mathworks.com, R2015b).

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Results The enlargement of SSS area and higher velocity during the breath holding period compared to baseline measured with phase image can be appreciated with rapid 3-sec phase-based velocimetry method (Figure 1). Preliminary data of SSS blood flow velocity time-course during an apneic challenge is shown in Figure 2a for three successive BH cycles using velocimetry. The slope-based BHI relies on multiple data points rather than just a single maximum velocity, thereby ensuring superior precision. Acceleration of blood flow (slope of dashed line, BHI) during the three apneic periods were 0.28, 0.22 and 0.20 cm/s2 respectively. Similar method for magnitude-based BHI quantification is shown in Figure 2b with the same mean as the velocimetry. Individual BHI fittings based on velocimetry, oximetry and susceptometry in a representative subject of young non-smoker and an old smoker are shown in Figure 3a and b respectively. Lower BHI as well as disruption of temporal pattern of the blood flow rate in the old smoker compared to young non-smoker can be appreciated.

Figure 1. The enlargement of SSS area (blue arrow on magnitude image in a) and higher velocity in the SSS during the breath holding period (c) compared to baseline (b) on phase image can be appreciated.

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Figure 2. Individual fitting based on velocimetry (a) and magnitude (b). BHI slope (slope of dashed line) during the three apneic periods was 0.28, 0.22 and 0.20 cm/s 2 per cycle respectively (mean of 0.23 cm/s2) with velocimetry. Magnitude-based BHI slope was 0.25, 0.21, 0.24 cm/s2 per cycle respectively (same mean of 0.23 cm/s2). Magenta box regions correspond to the three cycles of 30s breath-hold periods. Rise and fall before beginning of actual BH starts reflects the breath-in and breath-out preparation.

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Figure 3. Individual BHI fitting based on velocimetry (top panel), oximetry and susceptometry (bottom panel) in a representative subject of young non-smoker (a) and an old smoker (b) with three BH cycles. Yv=venous oxygenation, OEF=oxygen extraction function, rCMRO2=relative cerebral metabolic rate of oxygen.

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Figure 4. GLM fitting to estimate latency and slope (i.e., optimal fitting of three cycles).

Figure 5. Histogram of the General linear model (GLM) fitting to estimate slope (a, peak around 0.4 cm/s2) and latency (b, peak around 20sec).

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Figure 6. Significant smoking effects observed between smokers and non-smokers (P = 0.013 for slope in a and P = 0.032 for BHI in b) based on velocimetry, especially in elderly smokers (OS) and non-smokers (ONS) (P = 0.0002 for slope in c and P = 0.002 for BHI in d).

Automatic Gaussian-fitting algorithm with delay and slope parameters as dependent variable to the velocity curve of all the three cycle (average fitting BHI) is illustrated in Figure 4. Histogram of the General linear model (GLM) fitting to estimate slope (a, peak around 0.4 cm/s 2) and latency (b, peak around 20sec) is shown in Figure 5. Significant smoking effects were observed between smokers and non-smokers (P = 0.013 for slope and P = 0.032 for BHI) based on velocimetry, especially in elderly

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Figure 7. Marginally smoking effects observed between smokers and non-smokers (P = 0.05 for slope and P = 0.05 for BHI) based on magnitude method.

smokers (OS) and non-smokers (ONS) (P = 0.0002 for slope and P = 0.002 for BHI) (Figure 6). Marginal smoking effects were observed between smokers and non-smokers (P = 0.05 for slope and P=0.05 for BHI) based on magnitude method (Figure 7). Furthermore, Table 1 listed significant correlations (P < 0.05) within BHI metrics (i.e., slope, BHI and delays) using velocimetry, magnitude and delay with different fitting algorithms from the breathing protocol. Correlations with peripheral vascular compliance parameters were also listed. BHI and slope correlated significantly (P=0.009 for velocimetry and P