Edward M. Ornitz

The early development of autistic children.

A sample of 74 young autistic children was selected and defined by direct observation of specific behaviors and clinical assessment of the presence or absence of associated pathological conditions. Retrospective developmental data on these children and 38 age-matched normal children were gathered by means of a written inventory completed by the parents when the children were relatively young (mean age less than 4 years). The autistic children were reported to have had significant delays in the development of motor abilities, speech, communication, comprehension, and, to a lesser extent, perception during their 1st and 2nd years.

The Modulation of Sensory Input and Motor Output in Autistic Children

This paper explores the possible pathophysiologic mechanisms which might underlie the unusual motility disturbances which occur in autistic children. These motor behaviors are in some way related to the faulty modulation of sensory input which is also a significant feature of the autistic syndrome. Psychologic experiments have revealed that autistic children learn through manipulation and position cues rather than through normal perceptual processes. It is therefore suggested that their spontaneous abnormal motility may be the autistic childrens way of making sense out of both exogenous and endogenous sensations through kinesthetic (sensorimotor) feedback. Experimental demonstrations of a deficient oculomotor response to vestibular and visual stimulation parallel clinical observations of the hypomotility also seen in response to sensory stimulation. Review of the neurophysiology of the vestibular system reveals that the vestibular nuclei modulate motor output at the time of sensory input and sensory input at the time of motor output. It is suggested that a dysfunction of the central connections of the vestibular system with the cerebellum and the brain stem may be responsible for the strange sensorimotor behavior observed in autistic children and may also have implications for understanding the manner in which autistic children learn, since clinical studies point toward a strong motor component to their perceptual processes.

The Functional Neuroanatomy Of Infantile Autism

Infantile autism is a behavioral syndrome consisting of specific disturbances of social relating and communication, language, response to objects, sensory sensitivity and motility. The uniqueness of this syndrome suggests one underlying pathophysiologic mechanism, although multiple etiologies, which could activate or replicate such a mechanism, have been demonstrated. Review of considerable experimental evidence and clinical observation suggests that the symptomatology of autism, including the disturbances of social relating and communication, can best be explained as a disorder of sensory modulation. This in turn suggests a neurophysiologic mechanism consisting of dysfunction of a cascading series of neurophysiologic levels or interacting neuronal loops in the brainstem and diencephalon which subserve modulation of sensory input. Some of those same systems modulate motor output in response to sensory input, and their dysfunction may release the abnormal perseverative motility of infantile autism. Other experimental evidence and clinical observations stress the language deficits of autism and implicate dysfunction of cortical structures. Brainstem and diencephalic centers project rostrally to telencephalic structures and these, in turn, modify brainstem and diencephalic function. Theories of rostrally and caudally directed sequences of pathoneurophysiologic contributions to the system dysfunction in autism are compared. It is concluded that the symptoms of autism can best be explained in terms of dysfunction of brainstem and related diencephalic behavioral systems and their elaboration and refinement by selected higher neural structures.

Neurophysiology of Infantile Autism

Neurophysiologic hypotheses of infantile autism fall into two broad categories. One is a caudally directed sequence of pathophysiologic influence originating in telencephalic structures. The other is a rostrally directed sequence of pathophysiologic influence originating in brainstem and diencephalic structures. This paper relates each hypothesis to relevant aspects of autistic behavior, reviews neurophysiologic research relevant to each hypothesis, and describes recently completed studies of vestibular nystagmus, relating these new findings to the brainstem-diencephalic hypothesis. Those studies that delineate subgroups of autistic children are distinguished from those that characterize the entire group of autistic children. Those results that point toward maturational delays are distinguished from those that characterize deviant neurophysiologic abnormalities.

Vestibular dysfunction in schizophrenia and childhood autism.

Abstract Clinical and experimental studies of responses to vestibular stimulation in schizophrenia and childhood autism suggest that central vestibular mechanisms play a fundamental role in the pathogenesis of these conditions. It is suggested that the vestibular system normally regulates the mutual interaction of sensory input and motor output during both REM sleep and waking. The disturbances of perception and motility which occur in schizophrenic adults and autistic children are attributed to vestibular dysfunction during these states of consciousness. This failure of adequate vestibular modulation of perception and motility appears to be maturationally determined.

Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis

BACKGROUND Children with primary nocturnal enuresis (PNE) wet the bed during all stages of sleep and irrespective of state of arousal, suggesting that during sleep, when voluntary, i.e., cortical control, is not available, the signal from the distended bladder is not registered in the subcortical centers inhibiting micturition. Deficient prepulse inhibition (PPI) of startle has been reported in PNE. This study evaluates the association of this PPI deficit in PNE with comorbidity with attention-deficit hyperactivity disorder (ADHD) and with intelligence. METHODS Prepulse modulation of startle was studied in 96 boys with PNE and 105 nonenuretic boys using intervals of 60, 120, and 4000 msec between the onset of a 75-dB 1000-Hz tone and a 104-dB noise burst. Thirty-one percent of the enuretic and 36% of the nonenuretic boys were diagnosed with ADHD. RESULTS After adjustment for presence or absence of ADHD, lower or higher IQ, age, and unmodulated startle amplitude, there was a significant association between PNE and deficient PPI of startle following the 120-msec prepulse interval. Those enuretic boys who also were ADHD or had higher performance IQs (> or = 110) showed the greatest PPI deficit. CONCLUSIONS A common deficiency of inhibitory signal processing in the brain stem may underlie both deficient PPI and the inability to inhibit micturition in PNE. Strong familiarity for PNE, ADHD, and intelligence suggests a possible genetic mediation of these effects.

Decreased postrotatory nystagmus in early infantile autism

IN 1943 Kanner’ described the syndrome of early infantile autism and defined four features he considered pathognomonic of the disease: [l] inability to relate to people, [2] failure to use language for communication, [3] apparent desire to be alone and to preserve sameness in the environment, and [4] preoccupation with certain objects. During the ensuing twenty-five years other investigators have described similar children, using different theoretical perspectives and with differing notions of etiology. Thus, children with many symptoms in common are diagnosed today as having schizophrenic reaction of childhood,2 atypical ego development,s symbiotic psychosis,4 or “unusual sensitivities.”s We have recently reviewed637 our clinical experience with more than 150 such children, as well as the relevant psychiatric, neurologic, and neurophysiologic literature. From this perspective, it appears that most of the children referred to by the above diagnostic labels are suffering from a unitary disease process. Their symptoms can be grouped into five subclusters involving disturbances of [ 11 perception, [2] motility, [ 31 developmental rate, [4] relating, and [ 5 ] language. We have suggested that the disturbances of perception, motility, and developmental rate are primarily expressive of organic dysfunction and underlie the disturbances of relating and language. For example, such children fail to respond completely to sounds which at other times evoke screaming and panic-like reactions. At an early age, they may be referred for audiologic evaluation because of questioned deafness,8 yet careful examination will reveal that they respond to such sounds as a distant door slamming. A child who is reported to avoid eye contact, look through people, and ignore objects placed in front of him will spend hours staring at tops, record players, or cracks in a wall. These children are usually panicked by riding in elevators and being tossed in the air; yet they will spin themselves uninterruptedly for hours. These apparently paradoxical responses give the clinical impression that normal homeostatic regulation of perception cannot be maintained within the central nervous system of such children and that they experience perceptual inconstancy.6 Based on these clinical observations, experiments have been designed which indicate vestibular dysfunction during certain stages of sleep. It was found that the vestibularly mediated phasic inhibition of auditory-evoked responses seen in normal children during the eye movement bursts of rapid eye movement (REM) sleep was not present in a group of young autistic children.* Instead there was a relative enhancement of the amplitude of the late component of the auditory-evoked response during the eye movement bursts. Furthermore, there was a decreased duration of individual eye movement bursts during REM sleep in the youngest autistic children.10 As the eye movement bursts of REM sleep were mediated by the vestibular nuclei,’lJ‘ these

The auditory evoked response in normal and autistic children during sleep

Abstract 1. 1. The auditory averaged evoked response (AER) was measured at the vertex in age-matched groups of normal and autistic children during Stage 2 and REM sleep and during the ocular quiescent and eye movement burst phases of REM sleep. Amplitudes and latencies of wave N2 of the auditory AER were compared during these different sleep stages. 2. 2. In a group of sixteen autistic children under 5 years 1 month old, the relative amplitude of wave N2 during REM sleep (relative to Stage 2 sleep) was significantly greater than in a group of sixteen normal children. 3. 3. In a group of seventeen autistic children under 61 months old, the relative amplitude of wave N2 during the eye movement bursts (relative to ocular quiescence) was greater than that measured in a group of eighteen normal children. 4. 4. In a group of ten normal children under 61 months old, there was no appreciable difference between amplitudes of wave N2 obtained during the ocular quiescent phase of REM sleep and Stage 2 sleep. In contrast, amplitudes of wave N2 obtained during the eye movement burst phase of REM sleep were significantly smaller than during Stage 2. 5. 5. A group of eleven autistic children showed significantly larger relative amplitudes of wave N2 during both the ocular quiescent and the eye movement burst phases of REM sleep (relative to Stage 2 sleep) than did the group of ten normal children. The relative reduction of response amplitude during the eye movement bursts in normals was markedly overridden in these autistic subjects. 6. 6. The finding that relative reduction of response amplitude during REM sleep in normals is confined to the eye movement burst phase was related to the concept of phasic inhibition distinct from tonic inhibition during REM sleep. The phasic inhibition has been shown to be mediated by vestibular nuclei. The overriding of phasic inhibition in the autistic children was related to clinical observations suggesting vestibular dysfunction and faulty registration of the significance of sensory input.

Is aversive learning a marker of risk for anxiety disorders in children

Aversive conditioning and extinction were evaluated in children with anxiety disorders (n=23), at-risk for anxiety disorders (n=15), and controls (n=11). Participants underwent 16 trials of discriminative conditioning of two geometric figures, with (CS+) or without (CS-) an aversive tone (US), followed by 8 extinction trials (4 CS+, 4 CS-), and 8 extinction re-test trials averaging 2 weeks later. Skin conductance responses and verbal ratings of valence and arousal to the CS+/CS- stimuli were measured. Anxiety disordered children showed larger anticipatory and unconditional skin conductance responses across conditioning, and larger orienting and anticipatory skin conductance responses across extinction and extinction re-test, all to the CS+ and CS-, relative to controls. At-risk children showed larger unconditional responses during conditioning, larger orienting responses during the first block of extinction, and larger anticipatory responses during extinction re-test, all to the CS+ and CS-, relative to controls. Also, anxiety disordered children rated the CS+ as more unpleasant than the other groups. Elevated skin conductance responses to signals of threat (CS+) and signals of safety (CS-; CS+ during extinction) are discussed as features of manifestation of and risk for anxiety in children, compared to the specificity of valence judgments to the manifestation of anxiety.

Disorders of perception common to early infantile autism and schizophrenia.

Abstract The results of clinical, psychological, psychophysiological, and neurophysiological investigations have suggested that a break-down of the homeostatic regulation of sensory input occurs in early infantile autism and in schizophrenia. These investigations are reviewed and evaluated. It is concluded that a profound disturbance of perception is found in both autistic children and schizophrenic adults, and that this perceptual dysfunction may be common to and underlie the divergent clinical pathology present in these conditions.