Progress in the Neurolobiology of Autism

Abstract

To date, research regarding the neurobiological basis of autism has produced only the most preliminary of data. Although some advances have been made, the need for more definitive knowledge is crucial to more fully understand and treat this disorder. In this review, the autistic spectrum is discussed in terms of its defining symptoms. These symptoms are explained based on current understanding, and the need for more information regarding the bases of these abnormalities is noted. The critical needs of research are discussed, with an emphasis on areas in urgent need of analysis.

1- Introduction

Autism is a lifelong behaviorally defined syndrome usually manifest from very early childhood. Its defining symptoms in preschoolers are impaired social skills, inadequate or virtually absent language and communication, and a narrow range of interests and activities with perseveration and stereotypies. Diagnosing autism reliably poses little difficulty for experienced clinicians. For research purposes, diagnosis of the variants on the autistic or pervasive developmental disorder (PDD) spectrum is made on the basis of one of several questionnaires or observation schedules.1-7

Autism has many biologic etiologies and varies greatly in severity. The term autistic spectrum is used in this review, rather than PDD (the term used in both the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV]1 and the International Classification of Diseases, tenth edition [ICD 10]2), because the term PDD is often a source of confusion for the public, who equates it, erroneously, with the less severe autistic variants. In this review, the terms autism or autistic are used to refer to the entire behaviorally defined autistic (ie, PDD) spectrum, whereas autistic disorder refers specifically to individuals who fulfill prescribed DSM-IV or ICD 10 criteria.

Other conditions on the PDD spectrum are disintegrative disorder (appearance between the ages of 2 and 10 years of autistic symptomatology after fully normal early development of language, cognition, and personality); Asperger's syndrome (autistic symptoms with normal language acquisition, lack of mental deficiency, and, often, associated clumsiness); Rett syndrome (a specific, perhaps genetic, etiology of autism in girls whose brains fail to develop normally postnatally); and PDD-not-otherwise-specified (PDD-NOS), (a residual category for individuals with autistic symptomatology who do not fit the definitions of the other conditions on the spectrum).

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2- Autism and documented brain conditions

Autism is not biologically defined. In the majority of cases, two thirds or more, there is no currently definable brain lesion or detectable biochemical abnormality.8 In the remainder, autistic symptomatology arises in the context of a variety of conditions that affect the brain. Therefore, what seems to matter most is what brain systems are impaired, not the cause of their impairment.

Gillberg and Coleman9 coined the term PARMD (possibly autism-related medical disorder), which stresses the variety of possible biologic conditions that may or may not be associated with autistic behavioral symptomatology, or be its direct cause. Some of these brain conditions include malformations such as hydrocephalus,10 and chromosome abnormalities that include fragile-X,11 Angelman syndrome,2 or, occasionally, Down syndrome13 and other chromosome anomalies.14 Single gene defects such as untreated phenylketonuria15 and genetic neurocutaneous syndromes, tuberous sclerosis,16,17 incontinentia pigmenti, and hypomelanosis of Ito18 may give rise to autism. Congenital infection with the rubella virus19 and temporal lobe destruction as a result of congenital or acquired herpes simplex encephalitis20-23 or tumor,24 and any number of other traumatic, metabolic, or infectious encephalopathies may be associated with the autistic behavioral syndrome.

Judging from twin and family studies, genetics probably plays an important role in individuals without a diagnosable medical association.25-28 More than 90% of monozygotic twins are concordant for diagnosis, although not necessarily severity, whereas concordance in dizygotic twins and siblings is less than 5%. Genetic influence seems particularly strong in Asperger's syndrome, perhaps because it has a better prognosis than autistic disorder and is more often compatible with an independent existence and procreation.29 A recent review suggests that inheritance is likely to be polygenic.30 What is inherited is not clear as the pattern of inheritance rarely follows classic mendelian genetics. Perhaps inheritance, in at least some individuals with autism, consists of undue susceptibility to some infectious, immunologic, or stressful environmental influence.31,32

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3- Epilepsy and autistic regression

By the late 1960s, the realization that by adulthood some 30% of individuals on the autistic spectrum would have epilepsy (at least two unprovoked seizures of any type) was persuasive evidence that autism was a disorder of the immature brain rather than a response to inadequate parenting. All types of seizures can occur,33 including partial complex seizures associated with temporal epileptiform discharges, which are particularly frequent.34,35 Autism may follow infantile spasms36-38 and Lennox-Gastaut syndrome, which are two malignant epileptic encephalopathies of early childhood.39 Autism and epilepsyassociated or not with mental deficiencymay be the joint consequences of the dominant gene for tuberous sclerosis.16,17,40 Rett syndrome,41 which affects girls who have postnatal failure of brain growth, is characterized by autism, seizures, mental deficiency, and other neurological signs.

How often unsuspected epilepsy is responsible for the developmental plateau or regression reported by at least one third of parents is not known. Autistic regression takes place very early, between 18 and 24 months on average,42 when there is a strong possibility that it will be brushed off as a developmental fluctuation in early language development. Consequently, it is the rare toddler who is studied as regression takes place. Usually, the most salient feature of autistic regression is loss of language; however, questioning of parents will bring out reports of their child's of lessened alertness, interest in the surroundings, sociability, and interest in playing, as well as the emergence of undesirable behaviors like temper tantrums, affective lability, and stereotypies, which usually make their appearance during this time. More often insidious, regression may be sudden and occur in the wake of some trivial intercurrent illness or environmental stress that another child would weather without permanent consequence. No one knows how often regression or developmental plateau is the consequence of an untoward event or epilepsy, or represents failed maturation of a late-developing brain network.43

If prolonged electroencephalograms (EEGs) are recorded during slow-wave sleep, frequent unilateral or bilateral centro-temporal spikes will be found in an occasional child with autism who has not had clinical seizures. These discharges are similar to those in children with acquired epileptic aphasia or Landau-Kleffner syndrome,44,45 whose seizures are readily controlled with antiepileptic drugs, but whose language rarely improves apace. In individuals with autistic regression without an epileptiform EEG or clinical epilepsy, there is still no consensus on how often the administration of anticonvulsants such as valproate or vigabatrin, or of adrenocorticotropic hormone/steroids, is likely to be helpful. Therapeutic indications are even more tenuous in children who regressed without seizures or an epileptiform EEG. EEGs months or years after autistic regression are abnormal in only a small minority of children,42 but until a prospective study of autistic regression is performed, the role of potentially treatable subclinical epilepsy in autistic regression remains entirely speculative.

Disintegrative disorder,46,47 in which acquired autistic symptomatology includes language loss and dementia, occurs particularly frequently in the context of continuous spikes and waves in slow-wave sleep, again with or without clinical seizures.45,48 Prognosis in disintegrative disorder is gloomier than in early autistic regression, in which the expected course is a prolonged plateau lasting many weeks or months, usually followed by
improvement but not complete recovery.

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4- Sensorimotor abnormalities

The motor disorders of children with autism have barely been investigated from a neurologic standpoint, and their pathophysiology is unknown. In a large study of preschool children with autism,49 three motor deficits dyspraxia, stereotypies, and oromotor deficitswere more prevalent than in children with isolated language disorders or mental deficiency without autistic features. In another study, clinically referred children with autism50 were more likely to have increased joint laxity or hypotonia than language-disordered children. Hypotonia in autism is widely assumed to index pathology in central motor circuits, particularly in those involving the cerebellum. The possibility that joint laxity might point to a linked systemic deficit such as a disorder of collagen does not seem to have been considered. Toe walking is also common,51 as well as other postural and gait abnormalities that occur in some children,52,53 again, without any information regarding their neurological basis. Dyspraxiadifficulty imitating or carrying out complex movements and motor tasks on verbal commandis prevalent in autism.54,55 Landgren and colleagues56 emphasize frequent clumsiness in high functioning children of the Asperger type, but whether it is the end result of cerebellar abnormalities found at autopsy43,57 or of dyspraxia, is not known. It is not clear how often dyspraxia rather than lack of motivation should be blamed for failure to carry out motor tasks.58 There is evidence to suggest that dyspraxia in autism may have more to do with deficient planning59 than with the defective retrieval of memories for complex motor acts that characterizes apraxia in adults with acquired brain lesions.60

Stereotypies, which are repetitive, apparently purposeless movements such as hand flapping, finger twisting, and running in circles, are ubiquitous in autism.61 Rather than being viewed as the consequence of a neurologically based movement disorder, they are widely attributed to self-stimulation to increase arousal62 (hence, the newly coined expression "stimming"), or they are ascribed to a need to decrease over-arousal and excessive anxiety.63 There are families in which autism and Tourette's syndrome seem to be genetically linked,64,65 and, in fact, it is not always easy to tell the difference between tics and stereotypies in children who are unable to describe an urge to perform their movement, a defining feature of Tourette's syndrome. Stereotypies suggest the possible involvement of dopaminergic, noradrenergic, or other neurotransmitter or neuromodulator pathways, based on animal studies,66,67 and on the beneficial effect of dopamine inhibitors such as haloperidol68 and of the endorphin antagonist, naltrexone,69 reported in some individuals with autism.

Atypical responses of children with autism to sensory stimuli are legion, yet their neurologic basis has barely been investigated.70 In her autobiographical book, Temple Grandin, an adult with autism, provides many insights into her atypical subjective perceptual experiences.71 Among the atypical responses most prominent in young children is a failure to respond to loud sounds, often coupled with intolerance to particular sounds, for instance, hair dryers, rain, or movies, judging from their ear covering and tantrums. Blunted response to vestibular stimulation may explain why some children do a lot of spinning.72 Some atypical visual behaviors include fascination with rotating stimuli, gaze aversion from faces, staring at visual targets out of the corner of the eye, and finger-waving in front of the eyes; again, the basis of these abnormalities is not yet understood.73,74 Intolerance to being touched, a craving for being squeezed, and relative insensitivity to pain may be prominent symptoms. It is not clear whether self-injury, which, for example, may consist of biting, picking at sores, or head banging, should be ascribed to stereotypy or to an increased threshold for pain accounted for by raised levels of endogenous endorphins, or whether it is an attention-getting ploy.75-77 Many children on the spectrum who sniff their food and refuse to eat all but very few foods may have strong aversions to the texture, taste, or odor of certain foods.

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5- Cognitive and language disorders

A majority of children on the autistic spectrum are mentally deficient, but characteristically, their cognitive profile is irregular, with some preserved competencies in the face of other often severely deficient skills.78-80 In a Swedish sample, one-quarter of the children had IQs below 50, nearly half had IQs between 50 and 70, and one-third had IQs above 70, findings consistent with those in other studies.81 The typical cognitive profile is one of subtest scatter, generally with better nonverbal visual-perceptual skills than verbal skills, although the opposite pattern is frequent in Asperger's syndrome.79, 80

There are many reports of autistic individuals with astounding abilities to develop particular skills without formal training, often in the face of restricted overall cognitive competence.82,83 The neurologic basis of so-called "savant" skills is not understood. Much of this learning is rote and is associated with hyperfocused, prolonged attention to a narrow subject or activity. At least in early childhood, ability to generalize or abstract is rarely commensurate with these exceptional abilities. Nonverbal memory tends to be superior to verbal memory, although visual memory may also be impaired.78 The paradox in some children with autism is hyperfocused attention on some activity in the face of severely deficient attention span and total lack of organized activities in other contexts. Deficiency is often most severe when attempting to have the child focus with another person on a joint activity.84 These characteristics have been variously ascribed to the following underlying deficits: lack of motivation, negativism, blunted experience of pleasure in achievement, and impaired executive skills or "theory of mind."85 Dysfunction has been ascribed to dorsolateral frontolimbic networks, in particular the cingulate gyrus,86 amygdala, hippocampus, and other diencephalic structures in which microscopic abnormalities have been described.57 Sleep disorders are frequent, extremely troublesome, and poorly studied.87,88 They suggest brainstem, diencephalic, or pineal dysfunction.

With the exception of those with Asperger's syndrome, children with autism tend to have very delayed language development and some remain completely nonverbal.89-91 Early on, at least, all children have deficits in verbal comprehension and in the conversational use of language (pragmatics). Their language deficits are of two main types: those that affect phonology and syntax, and those limited to higher linguistic processing (semantics and pragmatics).92 The phonologic decoding deficit of some children in the first group may be so profound that it amounts to verbal auditory agnosia (VAA) or word deafness, and their comprehension may be so limited that they are mute or virtually mute. Not surprisingly, autistic children with VAA tend to be severely handicapped with very impaired cognitive and social skills. Children with this language subtype are particularly likely to have an epileptiform EEG with centro-temporal spikes, as mentioned earlier.33 Children with less severe phonologic decoding deficits have better comprehension than expression. Their speech tends to be poorly articulated, sparse, and agrammatical.

Children with deficient higher-order linguistic processing may speak later and go through a phase of jargon, but when their phonology clears, they often progress rapidly to full grammatical sentences. Prominent immediate echolalia may be replaced later by the frequent production of memorized scripts (delayed echolalia). Inadequate comprehension of questions and connected speech, aberrant melody and rhythm (prosody) of speech, unusual word choices, and their difficulty retrieving words and organizing coherent discourse are characteristic of the language of many of these verbal children.92-94

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6- Electrophysiology

There is no EEG pattern characteristic of autism. As one might expect, epileptic children on the spectrum, especially if they have mental deficiency or underwent language regression, are likely to have epileptiform EEGs.95 However, there are also some children with neither epilepsy nor regression who have epileptiform or nonspecifically abnormal EEGs of unknown significance.42

Brainstem auditory-evoked responses are generally normal96 unless the child has hearing loss97 or a brainstem malformation such as Möbius' syndrome.98 The auditory mismatch negativity, which is thought to originate in the auditory thalamocortical pathway and indexes automatic auditory discrimination, seems to be normal in children with autism.99 Klein and colleagues100 found that at least some adults with autism and a history of severe receptive language impairment have delayed N1 waves of the early cortical event-related potentials (ERPs). In contrast to normal controls, in whom the peak of N1 occurred earlier over the left hemisphere than the right during a phonemic discrimination task, asymmetry was reversed in autistic individuals with poor language ability,101 and differences in N1 were related to the level of receptive vocabulary and the mean length of utterance. The N4 component, which in normal adults and children is sensitive to semantic incongruity in linguistic context, is greatly diminished in both autistic adults102 and children.103 These electrophysiologic findings highlight abnormal language processing in autism, which may be specific to the auditory channel.

ERP studies in autism have focused on components that are correlated with orienting to novelty, sustained, and selective attention, and the ability to shift attention.104-106 Early negative ERP components associated with sustained or selective attention are absent or small in both the auditory and the visual modalities.107 Attentionally related negativities are not modulated by task difficulty as in normal individuals. The later positive (eg, P3) components to target auditory stimuli are reduced in amplitude, even in high functioning children and adolescents with autism,108 much more so than in dyslexia, attention deficit disorder, and Down syndrome.106 In contrast, normal detection of visual targets elicits normal or near normal responses,105,109,110 supporting the preeminent role of atypical auditory processing in autism.

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7- Neuropathology and imaging

Lack of postmortem tissue donations by families of individuals with autism has had catastrophic consequences for research and has greatly slowed progress toward understanding the neurologic basis of this disorder. Conflicts between the scant anatomic findings in autopsied brains and the considerable number of different abnormalities reported in a series of imaging studies must be resolved. These conflicts may be due in part to heterogeneity among individuals on the autistic spectrum, even when subjects are selected according to rigorous criteria.

Fewer than 35 postmortem examinations of brains of persons with autism have been published, none of which applied modern immunocytopathologic tools. All pathologic findings to date are therefore quite preliminary. A paucity of Purkinje's cells in the cerebellar hemispheres and deep cerebellar nuclei, with relative preservation of neurons in the dentate nucleus and inferior olive, were interpreted as evidence of curtailed development before 30 weeks of gestation.43,57 The distribution of pathologic findings is somewhat at variance with magnetic resonance imaging (MRI) reports of selective smallness of lobules VI and VII of the cerebellar vermis.111 These MRI findings have been extended and replicated in some,112 but not all studies,113,114 partly because autistic and normal brains overlap in size, and because of a subsample of autistic brains with large lobules VI and VII.115

The report of smallness of the brainstem in some studies,116 but not in others,117 suggests brainstem involvement in autism. Depletion of cells in the facial nucleus and abnormalities of the hypoglossal nucleus and superior olive were described in the brainstem of a 21-year-old woman with autism in whom the complement of neurons in the neocortex was normal.118 It is unfortunate that a detailed neurologic examination was not available, since an occasional individual with Mbius' syndrome, characterized by dysgenesis of multiple cranial nerve nuclei, most often the VIth and VIIth, has autistic behaviors.98 As most children with Möbius' syndrome are not autistic, the relevance of these findings in the cranial nerve nuclei remains unclear.

The neurons in the medial amygdala, the hippocampus, and some other diencephalic and cingulate areas are said to be smaller, to have less complex dendritic arbors, and to be more tightly packed in autistic brains than in control brains, again suggesting inadequate maturation or differentiation.43,57,119 These findings may be correlated with some of the attentional, motivational, affective, and learning abnormalities in autism. Infant monkeys who underwent temporal lobectomies may provide an animal model for autism.120 The relevance of this animal model is enhanced by the description of severe autism and language disability in four infants with medial temporal sclerosis121 and in four children, three with tumors and one with acquired epileptic aphasia, whose autism improved following unilateral temporal lobe surgery.24,122,123

Thus far, no consistent histological changes have been found in the neocortex, except for a report of widened parietal sulci and thinness of the interparietal corpus callosum on MRI,124,125 and another MRI report of minor neuronal migration defects.126 Most routine clinical MRIs are normal.127

On average, the head circumferences128-130 and brain volumes of individuals with autism tend to be somewhat larger,127,131 and brain weights heavier132 than in control subjects. If it is confirmed that head circumferences were generally not larger than expected at birth in school-age children and adults with macrocephaly, this would raise the possibility of an ongoing process in at least some children, a suggestion also brought up by Bauman and Kemper.57 These findings would suggest brain maldevelopment, rather than damage, as a cause of autism in the majority of cases unassociated with a known condition, a speculation that requires further investigation.

Hypometabolism in temporal regions found in a few individuals with single photon emission tomography and photon emission tomography (PET) scans133,134 are consonant with electrophysiological data and the high prevalence of receptive language disorders. PET scanning of 18 children with autism and prior infantile spasms being considered for epilepsy surgery revealed bitemporal interictal hypometabolism, with ictal hypermetabolism, and in some children crossed cerebellar hypermetabolism.38 Functional imaging studies, including magnetic resonance spectroscopy135, 136 carried out in alert cooperative subjects performing cognitively relevant tasks, rather than in sedated subjects, clearly need to be pursued. The behavioral handicaps of autistic subjects make such studies very difficult; however, they may provide a more coherent picture than is currently available of the atypical cortical/subcortical brain organization that characterizes autism.136-139

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8- Neurochemistry and neuroimmunology

Findings in these areas are quite preliminary and have yet to be woven into a unifying theory of autism.140,141 Empirically determined responses to behavior-modifying drugs have influenced the direction of investigations, but better neurochemical insights are needed to devise a more rational psychopharmacology of the most troublesome behaviors of autism. Favorable responses to dopamine receptor antagonists such as haloperidol and the phenothiazines suggest involvement of mesolimbic dopamine systems. Unfortunately, measures of dopamine metabolites in body fluids are inconsistent. There is only weak evidence for a contribution of norepinephrine, even though in high doses, the alpha-receptor-blocker propranolol may reduce unprovoked behavioral explosions,142 and noradrenergic drugs like amphetamine may produce stereotypies. Focus on serotonin metabolism arises from several observations. Some autistic individuals have elevated levels of serotonin in platelets,143 although raised levels of serotonin metabolites in blood, urine, and cerebrospinal fluid are inconstant and are not correlated with the severity of the disease. More recently, reports of hyperserotoninemia with serotonin receptor antibodies in autism but not in mental deficiency,144 and of linkage between the serotonin transporter and autism145 have appeared. Chugani and colleagues146 describe unilaterally decreased serotonin synthesis in thalamic and frontal areas and increased synthesis in the contralateral cerebellar dentate nucleus in seven boys with autism. Observations of the efficacy of specific serotonin reuptake inhibitor drugs like fluoxetine, fluvoxamine, and sertraline for reducing stereotypies and perseveration in patients with obsessive-compulsive disorder have prompted their use in autism.147

Increased levels of endogenous endorphins and frequent self-injurious behaviors have led to trials of naltrexone, resulting in modest success.148 Panksepp149 and Herman76 have articulated an overarching theory that would encompass most of the many biochemical abnormalities, as well as hormonal changes such as the low oxytocin levels implicated in blunted social behaviors.150,151 A single report of increased levels of glial fibrillary acidic protein in the spinal fluid of children with autism152 and one of decreased levels of neuronal cell adhesion molecules in serum153 remain to be duplicated.

The idea that autoimmune mechanisms affecting the brain may play a role in autism was prompted in part by reports that, in some children, autistic regression occurred in the wake of a nonspecific infectious illness. Also, some parents are convinced that their children do better when they are put on restricted diets, although empirical evidence is lacking. In addition, there are reports of abnormalities of complement linked with human leukocyte antigen.154,155 Reports of autoimmune abnormalities against whole brain,156 myelin,157 and serotonin receptors158 are conflicting and generally unconfirmed, yet more sophisticated studies seem to be warranted.159

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9- Final remarks

This review makes it excruciatingly clear that only the most preliminary data are currently available on the neurological basis of autism and that no coherent theory is at hand, although progress has begun. The cerebellar findings have contributed to a revival of interest in the role of the cerebellum in attention,160 cognition, and language, as well as in the learning of automatized tasks.161,162 Sophisticated neurophysiologic and imaging tools are now available, but they need to be used in the context of clever behavioral paradigms if they are to provide meaningful brain/behavior insights.

Applying these tools to clinically referred series of patients no longer suffices. One urgent need is the donation of autopsy tissue for the study of neurons, synapses, and channels with modern molecular techniques such as immunohistochemistry of receptor ligands and markers for apoptosis. Another area in need of investigation is autistic regression and the possible contribution of epilepsy. This will require vigorous efforts to alert pediatricians and other professionals to refer toddlers at the first sign of regression, especially of language, rather than months or years later. Enhanced evidence for cerebral plasticity, and awareness that intensive and appropriate early educational intervention influences the outcome both dictate rigorous studies of the many interventions that are being offered today without definitive evidence of which of these may be efficacious and which are a colossal waste of time, energy, and money. All these biologic and technical investigations must proceed apace, given the lifelong handicap infantile autism portends.

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