Curr Sleep Medicine Rep (2015) 1:131–140DOI 10.1007/s40675-015-0012-1SLEEP AND PSYCHOLOGICAL DISORDERS (DT PLANTE, SECTION EDITOR)Sleep in Autism Spectrum DisordersOlivia J. Veatch 1 & Angela C. Maxwell-Horn 2 & Beth A. Malow 1Published online: 24 April 2015# Springer International Publishing AG 2015Abstract Autism spectrum disorders (ASD) are common neurodevelopmental conditions, affecting 1 in 68children. Sleep disturbance, particularly insomnia, isvery common in children diagnosed with ASD, withevidence supporting overlapping neurobiological andgenetic underpinnings. Disturbed sleep exacerbates coreand related ASD symptoms and has a substantial negative impact on the entire family. Treatment of sleepdisturbance holds promise for ameliorating many of thechallenging behavioral symptoms that children withASD and their families face. Behavioral and pharmacological studies indicate promising approaches totreating sleep disturbances in this population. Awareness of treatment options is particularly important asparents and clinicians may believe that sleep disturbance is part of autism and refractory to therapy. Inaddition, autism symptoms refractory to treatment withconventional psychiatric medications may improvewhen sleep is addressed. Additional evidence-basedstudies are needed, including those that address theunderlying biology of this condition.This article is part of the Topical Collection on Sleep and PsychologicalDisorders* Beth A. [email protected] J. [email protected] C. leep Disorders Division, Department of Neurology, VanderbiltUniversity Medical Center, 1161 21st Avenue South, Room A-0116,Nashville, TN 37232-2551, USA2Department of Developmental Medicine, Vanderbilt UniversityMedical Center, Monroe Carell Children’s Hospital, 11101 DOT,Nashville, TN 37232, USAKeywords Pediatric sleep disorders . Autism .Neurodevelopmental disorders . Diagnosis . Behavioraltherapy . Pharmacotherapy . Genetics . BiochemistryIntroductionAutism spectrum disorders (ASD), whose core features areimpairments in social communication and the presence ofrestricted and repetitive behaviors , are common with aprevalence of 1 in 68 children . In children with ASD,approximately 50–80 % have disturbed sleep, primarilyrelated to sleep onset or sleep maintenance insomnia[3–5]. This high prevalence is in contrast to 11–37 % inchildren of typical development [6, 7]. While the relationship of sleep disturbance to challenging daytime behaviors(e.g., attention deficit hyperactivity disorder symptomatology) has been established in typically developingchildren , those with ASD may be even more vulnerable to the detrimental effects of sleep disruption ondaytime behavior given their neurodevelopmental condition. Sleep problems in children with ASD have beenassociated with more internalizing and externalizing behavior problems and poorer adaptive skill development. In our work, poor sleepers with ASD (defined byparent report, polysomnography, and actigraphy) hadmore inattention, hyperactivity, and restricted/repetitivebehaviors .In this review, we evaluate the current literature related tosleep problems in children with ASD and their treatment, withreference to the biological mechanisms underlying expressionof both of these neurological conditions.Causes and Categories of Sleep Problems in Individualswith ASDSleep problems in ASD have a broad differential, and areoften multifactorial. Table 1 provides an overview of thedifferent causes, as well as the categories. In this section,
132Curr Sleep Medicine Rep (2015) 1:131–140Table 1 Causes and categories of sleep problems common in childrenwith ASDCategories of Sleep Problems in ASDCauses of sleep problems–Neurobiological–Medical, including psychiatric and medications–BehavioralCategories of sleep problems–Insomnia–Sleep disordered breathing–Sleep-related movement disorders–Parasomnias-Sleepwalking, sleep terrors, confusional arousals-NightmaresInsomnia—Parent Report and Objective Measures-REM sleep behavior disorder-Bruxismwe discuss first the broad causes of sleep problems inASD. We then discuss the categories of sleep problemsin this population, including insomnia, circadian rhythmdisorders, sleep disordered breathing, sleep-related movement disorders, and parasomnias.Causes of Sleep Problems in ASDWhile there is natural overlap among these causes, it ishelpful to consider sleep problems in ASD as beingneurobiological, medical, or behavioral in origin. Theneurobiological causes can be thought of as relating togenetic or neurotransmitter abnormalities shared bysleep and autism (e.g., abnormalities in the melatoninpathway) and are discussed in the subsequent sectionBOverlapping Mechanisms between Sleep and ASD .The medical causes include a variety of conditionscommon in ASD, including epilepsy and gastrointestinal disturbances that disrupt sleep. Psychiatric conditions, including depression, anxiety, and attention deficit hyperactivity disorder, which are also more common in ASD, can be included with these causes, although we acknowledge they have clear neurobiological underpinnings. Medications used to treat medicaland psychiatric conditions can also be included withthese causes, as many of these medications (e.g., fluoxetine) tend to be stimulating and disrupt sleep. Finally, the behavioral category includes behaviors thatare related to the ASD phenotype, such as resistancetransitioning from daytime activities to nighttime activities, difficulty understanding what is expected at bedtime, and preferences for using electronic devices(which inhibit sleep).Insomnia, defined as difficulty falling asleep or staying asleep,is the most common sleep problem reported by parents instudies employing questionnaire data [4, 11]. While the literature has focused on children with ASD, reports in adults havefound similar findings . Only a few studies have looked atobjective polysomnographic or actigraphic data to evaluatethe sleep of individuals with ASD. For the most part, thesestudies have confirmed parent report, although there havebeen some discrepancies, which may reflect differences inmethodology related to collection of data, or clinical heterogeneity in the sample studied. Souders et al. found that theprevalence of sleep problems by actigraphy was comparableto that of parent report . Malow et al., examiningpolysomnography results, found longer sleep latencies andlower sleep efficiency in children with ASD who were reported by their parents to be Bpoor sleepers compared to theBgood sleepers, these results were comparable to childrenof typical development without sleep problems . Alliket al. also found concordance between actigraphy and parentreport in children with ASD .In contrast, Wiggs and Stores  did not find anyactigraphic differences in children with ASD with and withoutparent-reported sleep problems. However, when they pooledthe data and compared them to a control group of typicallydeveloping children whose actigraphy data was available in adatabase, they did find some notable differences. The childrenwith ASD often fell asleep later, woke up more during thenight, and awakened either very early or very late .Rapid Eye Movement DifferencesThe amount of time spent in rapid eye movement (REM) sleephas also received attention, especially given the role of REMsleep in memory consolidation . As noted above, fewstudies have performed polysomnography in ASD. Buckleyet al. conducted a one-night polysomnographic study andcompared PSG data between children with ASD, developmental delay, and typical development. Their study found that,as compared to typically developing children, those with ASDhad a lower percentage of REM sleep .Conversely, Malow et al. found no significant difference inREM sleep in children with ASD versus typically developingchildren on night two of polysomnography . Anotherstudy evaluating adults with high functioning ASD also foundno difference in REM sleep versus controls . It is possiblethat the Buckley et al. finding of decreased REM sleep following only one-night of polysomnography was confoundedby sleep being more disrupted on the first night of alaboratory-based study as many children with ASD have
Curr Sleep Medicine Rep (2015) 1:131–140difficulty sleeping in an unfamiliar environment. However, asubsequent study from this group evaluating the first nighteffect in children with ASD found no difference betweenPSG recordings measured on night one compared to nighttwo . Further study of REM sleep in ASD appearswarranted.Circadian Rhythm DisordersIt is difficult to differentiate whether delayed sleep is due toinsomnia, or a delayed sleep phase circadian rhythm disorder(or potentially both disorders) as circadian rhythm disorders inchildren with ASD often do not fit traditional ICSD3 diagnostic criteria . For example, a child may have delayed sleeponset but also wake early and have multiple wakings throughout the night. These features are atypical for classic delayedsleep phase disorder which is characterized by delayed waketime and normal sleep continuity. Social cues, to which children with ASD may be less attuned because of their decreasedawareness of social cues, are important synchronizers of circadian rhythms. Children with ASD have been postulated tobe vulnerable to circadian rhythm disturbances (see review by) . Distinguishing between circadian factors and insomnia can be quite challenging, especially given the biological and environmental factors that contribute to bothdisorders.Another challenge is related to sleep duration. Importantly,there are no finite amounts of sleep that are considered idealfor individuals with ASD. While guidelines have beenestablished for children with typical development [21, 22], itis still unclear whether children with ASD require more, less,or similar amounts of sleep compared to typically developingpeers. In fact, what are considered adequate sleep durations inchildren with ASD is an important area of controversy. Manystudies have indicated that children with ASD on averagesleep less during the night compared to children of typicaldevelopment. The largest prospective, longitudinal study todate indicates that total sleep duration in children with ASDis reduced compared to typically developing peers from30 months of age, persisting into adolescence . However,the fact that these children slept less does not give any indication into what should be considered an adequate amount ofsleep, which likely varies from child to child.Sleep Disordered BreathingWhether or not children with ASD are more prone to sleepdisordered breathing (SDB) is unclear. One study found nopolysomnographic differences in sleep apnea indices for individuals with or without autism  and another study identified sleep apnea in only 1 of 21 children with ASD ,comparable with prevalence rates in general pediatrics of 1–5 % .133However, even if SDB is equally common in children withASD than in those of typical development, children with ASDmay still stand to benefit from improvement in their sleeppatterns. This is an area where more research is warranted,especially given evidence of improvements in behavior andquality of life when SDB is treated in children of typical development . Malow et al.  observed that for the childwith ASD who also had SDB, symptoms of social communication, attention, and repetitive behaviors improved afteradenotonsillectomy . However, we have also encounteredin our clinical experience children with ASD whose problematic behaviors (e.g., irritability, aggression) worsened afteradenotonsillectomy, likely reflecting removal of the sedatingeffects of SDB.Sleep-Related Movement DisordersMovement disorders during sleep relevant to ASD include thefollowing: rhythmic movement disorder and restless legs syndrome (RLS) along with periodic limb movements in sleep(PLMS) and periodic limb movement disorder . Rhythmicmovement disorder is characterized by repetitive movementsof the extremities, trunk, or head that often occurs during thetransition from wake to sleep . These sleep-related movements may resemble self-stimulatory behaviors during wakefulness, and there is likely overlap among these behaviors.The differential diagnosis for sleep-related movement disorders (SRMDs) includes epileptic seizures. Clinicians observing these events may also confuse them with psychogenicevents.RLS is characterized by an uncomfortable feeling in thelegs which is worse at night or when lying down, and relievedby movement. A related condition, periodic limb movementsin sleep, is characterized by repetitive movements of the extremities during sleep. Periodic limb movement disorder,which is rarer than periodic limb movements in sleep, is characterized by these movements but has accompanying sequelae, such as sleepiness during the day.RLS is already difficult to diagnose in children of typicaldevelopment who have great difficulties in describing theirsymptoms . This diagnostic complexity is compoundedwhen one is trying to diagnose these conditions in a child withASD and communication challenges. In our experience, evena highly verbal child will often have difficulty trying tocommunicate an Buncomfortable feeling . We are dependent on observant parents and astute physicians to unravel exactly what the child is experiencing and howtheir symptoms are manifesting, and to combine othersupportive data to assist with the diagnosis, such asbehavioral observations, as well as family history, lownormal ferritin levels ( 50 ng/ml), and periodic limbmovements on an overnight PSG .
134ParasomniasParasomnias are undesired events that happen during sleep.Events encompass sleep walking, sleep terrors, confusionalarousals, nightmares, REM sleep behavior disorder, and bruxism . Several studies have found that parasomnias may bemore common in children with ASD versus controls [29–31].In fact, parental questionnaires have a very high positive predictive value in diagnosing parasomnias in children . Oneof the shortcomings of parent questionnaires in diagnosingparasomnias is that night wakings related to insomnia maynot be easily differentiated from parasomnias. Therefore, itis important to follow-up questionnaire findings with a thorough sleep history that assesses the level of consciousness andresponsiveness of the child during a night waking. REM sleepbehavior disorder was reported to be common in ASD in onecase series , although the REM sleep without atonia thatcharacterizes REM sleep behavior disorder was not noted inother PSG studies in ASD [13, 17, 18].Overlapping Mechanisms Between Sleep and ASDIn this section, we will review genetic and biological mechanisms implicated in sleep traits, and in the sleep disorders thatare most commonly observed in individuals with ASD. Further, we compare these with the mechanisms that have alsobeen implicated in risk for ASD. Evidence suggests stronggenetic susceptibility factors underlying ASD. The sibling recurrence risk is estimated at 45–90 times greater than the population risk. Current estimates from twin studies indicate 58–60 % of monozygotic twins are concordant for the full syndrome and 50–90 % are concordant for related social or cognitive abnormalities [33, 34]. Interestingly, the known biological functions for recurrently implicated ASD candidate genessuggest involvement of shared molecular pathways with sleepregulation.Biology and Genetics of Sleep and Sleep Disorders Relatedto ASDNormal SleepThe molecular genetics of sleep timing as a function of circadian rhythm oscillations is well established  and will notbe discussed outside of the relevance to ASD. The involvement of the circadian system in ASD was first proposed in2002, when it was suggested that anomalies in genes operating as Btiming genes in this high frequency oscillator systemmay underlie the timing and social deficits that are fundamental to ASD . Significant allelic associations with ASDhave been detected for variation in the PER1 and NPAS2 genes, which are involved in regulation of the circadian system.Curr Sleep Medicine Rep (2015) 1:131–140Since these initial studies, numerous overlapping biological mechanisms involved in sleep regulation and ASD havebeen identified. Multiple neurotransmitters including serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid (GABA) are involved in homeostatic regulation of sleep and implicated in the etiology of ASD [39–41]. The dopamine transporter has been implicated in regulation of sleephomeostasis , with recent work showing that the presenceof a de novo mutation in the dopamine transporter gene DAT1,identified in one child with ASD, causes hyperactive behaviorin model organisms . Furthermore, some of the most consistently replicated genes harboring common variants relatedto ASD include the SLC6A4 gene encoding the serotonintransporter and the GABRB3 gene encoding a ligand-gatedgamma-aminobutyric acid receptor . The involvement ofthese neurotransmitter systems in expression of specific sleepdisorders is detailed further below.InsomniaBasic science studies have implicated effects on risk for insomnia from numerous molecular mechanisms that overlapwith mechanisms predicted to contribute to risk for ASD(Table 2). In addition, the current heritability estimates forinsomnia range between 21–64 %, evidence that genetic factors are involved . For example, the GABAergic systemhas been strongly implicated in ASD and insomnia. TheGABAergic system is critical to cortical development, suggesting that the neurodevelopmental defects observed inASD may be partially attributed to abnormalities in theGABAergic system . A region of chromosome 15 at theGABRB3 locus, 15q11-13, was observed to have recurrentcopy number variations in a substantial proportion of individuals with ASD [46, 55], and variations in the GABA-Rγ3gene were also found to be associated with ASD risk . Amutation in the gene encoding the GABA-A beta 3 subunitwas identified in patients with chronic insomnia, supportingthe hypothesis that a decrease in GABAergic inhibition maycontribute to insomnia . In addition, functional protonmagnetic resonance spectroscopy data has indicated that children with ASD have lower levels of GABA in multiple cortical regions compared to typically developing children. Regions include the frontal lobes , auditory cortex ,and other motor and auditory regions of interest . Similarfindings reporting globally reduced levels of GABA in thebrain were observed in individuals with chronic insomnia[58, 59], further support for a biological connection betweeninsomnia and ASD.Serotonin is another neurotransmitter involved in bothASD and sleep. Evidence supporting an involvement of theserotonergic signaling system in ASD includes increasedlevels of whole-blood serotonin , altered serotonin synthesis , variation in the serotonin transporter gene (SLC6A4)
Curr Sleep Medicine Rep (2015) 1:131–140135Table 2 Overview of sleep disorders having overlapping mechanismswith ASD. Listed for each sleep disorder are the implicated biologicalmechanisms that are also thought to be involved in ASD. If there arespecific genes that have been identified for both disorders, these areincluded with corresponding referencesSleep disorderBiological mechanismInsomniaGABAergic inhibitionGABA3 Buhr et al. , Shao et al. Serotonergic transmissionSLC6A4 Deuschle et al. , Prasad et al. Melatonergic systemAANAT Wang et al. , Hu et al. Sleep-related movement disordersGeneDopaminergic transmissionDRD2 Connor et al. , Comings et al. Iron metabolismNo specific shared risk genes, and variation in the monoamine oxidase A gene (MAOA)which is responsible for serotonin degradation . Serotoninis thought to be involved in promoting wakefulness andinhibiting REM sleep . More recently, a connection between genetic variation in the serotonin transporter and insomnia was identified .Serotonin is also a precursor for melatonin. Melatonin issynthesized in the pineal gland and its secretion is observed tohave sedative effects that contribute to sleep onset . Melatonin is also involved in many functional processes otherthan regulating the sleep-wake cycle in humans, includingneurodevelopment . Interestingly, the most consistent results reporting abnormal circadian rhythms in ASD concernthe melatonin synthesis pathway . Dysregulation ofthe melatonin pathway has been observed in some individuals with ASD, compared to normally developingcontrols. These individuals have exhibited lower levelsof the major metabolite of melatonin, 6sulfoxymelatonin , and decreased nocturnal [68,69] and daytime  blood melatonin levels. However,a more recent report documented normal overnightblood melatonin profiles in children with ASD andsleep onset delay responsive to supplemental melatonin. Variation in numerous melatonin pathway geneshas been predicted to increase risk for ASD. These include the gene encoding the rate-limiting melatoninpathway enzyme responsible for N-acetylation of serotonin, arylalkylamine (AANAT) [49, 50], and the geneencoding the enzyme which subsequently converts serot o n i n t o m e l a t o n i n [ 7 1 ] , a c e t y l s e ro t o n i n O methyltransferase (ASMT) [70, 72, 73]. Melatonin isprimarily metabolized by the liver enzyme, cytochromeP450 1A2 (CYP1A2) . A potential relationship hasalso been implicated between presence of predictedslow-metabolizing alleles in CYP1A2 and susceptibilityto ASD with comorbid sleep problems [75, 76]. In particular, we observed that expression of insomnia inASD, and response to supplemental melatonin treatment,is potentially related to dysfunctional variation in bothof these melatonin pathway genes. A mechanism wasimplicated connecting lower levels of ASMT transcriptproduction with reduced CYP1A2 metabolic activity inchildren with ASD and comorbid sleep onset delay ;the net result may be normal nocturnal blood melatoninlevels in these children.Sleep-Related Movement DisordersRestless leg syndrome (RLS) is a movement disorder havingstrong evidence for contributions from genetic factors .Furthermore, it is well-established that there is a connectionbetween iron and RLS, and more recently, a connectionbetween dopamine and RLS has been indicated [28, 78].Brain iron levels have been observed to be lower inindividuals with RLS compared to controls . Interestingly, iron deficiency and iron deficiency anemiahave been observed to be more common in childrenwith global developmental delay and/or ASD than inthe general population . A connection between lowserum ferritin and sleep disturbance in children withASD was also suggested based on a treatment trialshowing that for a majority of children with ASD andrestless sleep, iron therapy was effective at improvingsleep .In addition, neuropathological studies of patients withRLS have shown significant decreases in dopamine(DA) D2 receptors in the putamen. This tissue-specificdecrease in dopamine receptors was also shown to becorrelated with severity of RLS symptoms . An abnormally activated dopaminergic system was also observed in both in vivo and in vitro models of ironinsufficiency suggesting that for some RLS patients,there may be a connection between iron and dopaminethat is central to the pathophysiology [28, 82].Disrupted DA function is implicated in a number ofneuropsychiatric disorders, including ASD, and it isthought that alterations in DA homeostasis may conferrisk for ASD and related neuropsychiatric conditions.Specifically, the gene encoding the DAD2 receptors(DRD2) has been implicated in a number of behavioraldisorders (Table 2) .
136Treating Sleep Problems in Individuals with AutismSpectrum DisordersGiven the high prevalence of ASD and of dysregulated sleepin children with ASD, the need for effective treatments iscritical for the health and well-being of the child and family.Furthermore, disrupted sleep may exacerbate core impairments of ASD.Many of the behaviors that are associated with ASD (e.g.,hypersensitivity to environmental stimuli, repetitive behaviorsand/or thoughts, difficulty understanding social and/or communication cues) likely contribute to a child with ASD alsohaving disturbed sleep. Therefore, implementing sleep education and behavioral strategies should be the first-line treatmentfor sleep problems in children with ASD once other medicaland psychiatric issues have been addressed.A practice pathway  emphasized that pharmaceuticalinterventions should be considered only after treatment withbehavioral strategies is either unsuccessful, or when the strategies are not possible to implement without the short-term aid ofa medication. Prior to use of pharmaceutical agents for treatment of a sleep disturbance in a child with ASD, it is also veryimportant to conduct a thorough sleep history and comprehensively address all possible comorbid medical and psychiatricconditions. Many conditions that are associated with ASD(e.g., ADHD, obsessive compulsive disorder, depression,biopolar disorder, epilepsy) are known to affect sleep .In addition, many medications that are prescribed to treatASD symptoms and comorbid psychiatric conditions also affect sleep; some of the most commonly reported adverseevents are insomnia or hypersomnolence . For example,atypical antipsychotics have been evaluated and approved fortreating aggressive or self-injurious behavior, severe moodswings, tantrums, and irritability in individuals with ASD. Acommonly prescribed, and well-studied, atypical antipsychotic in ASD is risperidone . The primary action of this molecule is serotonin 5-HT2 receptor blockade. It is also a potentdopamine D2 receptor antagonist . One of the most commonly reported side effects for treatment with risperidone isdaytime sleepiness; insomnia may also occur. In addition, uncontrolled weight gain may contribute to sleep apnea .Selective serotonin reuptake inhibitors (SSRIs) are also oftenused for treating repetitive behaviors in ASD, and are knownto regulate peripheral and central nervous system serotoninlevels . SSRI use has also been shown to have negativeeffects on sleep including insomnia .Behavioral Sleep InterventionsBehavioral approaches to improving sleep start with properbedtime practices, referred to as sleep hygiene. Proper sleephygiene is composed of activities that make it easier to fallasleep and stay asleep. This includes having a cool, darkCurr Sleep Medicine Rep (2015) 1:131–140environment for sleep and eliminating caffeine ingestion. Asoothing, Bwind-down routine before bed often helps relaxthe body and prepare for bed .It is important to note that what might be relaxing for onechild and therefore part of their Bwind-down routine, mightactually be activating for another child. For example, onechild might relax and calm down when placed in a warm bath.Another child, however, may be stimulated by bath time.Therefore, each child’s bedtime routine should be individualized with activities that are calming and promote sleep for thatparticular child.The use of electronic devices before bed should be discouraged if at all possible. Electronic devices such as televisions,cell phones, and video gaming devices emit background light.The light emitted from such devices suppresses endogenousmelatonin production, which is critical for sleep initiation.Furthermore, the content provided by videos and other devices is often stimulating. It should be noted that in our experience, some children find that playing a game on a parent’sphone or watching a video is actually calming before bed. Insuch cases, the brightness on the screen of the device shouldbe adjusted so that the minimal amount of background lightthat is necessary for viewing is emitted.Pharmacological and Other InterventionsInsomniaMelatonin supplementation is an emerging approach totreating comorbid insomnia in children with ASD. This treatment strategy has been shown to be effective at improvingsleep initiation with minimal reports of adverse events[92–96]. Melatonin is primarily used as a sedative at lowdoses (1 to 3 mgs) given approximately 30 min prior to bedtime. However, exogenous melatonin supplementation has also been observed to effectively treat circadian rhythm sleepdisorders (i.e., abnormal sleep timing). In this case, melatoninis given at specific time-points based on the goal of shifting oradvancing the timing of sleep onset (e.g., 3–5 h before bedtime for delayed sleep onset). Given that the half-life of melatonin is rather short ( 1 h), it is less effective for night wakings ; controlled-release melatonin preparations are sometimes effective for night wakings .When behavioral therapies and melatonin are ineffective,additional pharmacologic treatment may be considered. A fewpsychotropic medications have been evaluated for treatinginsomnia in children with ASD in retrospective, or smallopen-label trials . These include clonidine ,mirtazapine , and gabapentin . Risperidone wasalso shown in another study to improve sleep-onset latency,but not sleep duration ; however, the side effects andother sleep-related health risks mentioned previously that relate to risperidone treatment indicate this medication should
Curr Sleep Medicine Rep (2015) 1:131–140not be recommended solely for insomnia. Some medicationsthat are prescribed to treat coexisting neurological conditionsin children with ASD have sedating effects that promote sleep.When possible, it may be beneficial to choose a medication forthe coexisting condition that will concurrently assist withsleep onset and maintenance . For example, in a child wit
[email protected] Olivia J. Veatch [email protected] Angela C. Maxwell-Horn [email protected] 1 Sleep Disorders Division, Department of Neurology, Vanderbilt UniversityMedical Center, 116121stAvenue South,RoomA-0116, Nashville, TN 37232-2551, USA 2 Department of Devel