Indices of Neural Function in Autism: Clinical and Biologic Implications

(1)

Reprint requests to (N.J.M.)3811 O’Hana St, Iroquois Bldg, Suite 208, Pittsburgh, PA 15213.

Indices

of Neural

Function

in Autism:

Clinical

and Biologic

Implications

Nancy J. Minshew, MD

From the Western Psychiatric Institute and Clinic, UnWersity of Pittsburgh, Pennsylvania

ABBREVIATIONS. PET, positron emission tomography; NMR, nuclear magnetic resonance; EEG, electroencephalography; ERP, event-related potential; NC, negative component.

In contrast to neunoanatomic and neuroimaging studies, which have identified abnormalities in the limbic system and cerebellum in autism, physiologic studies have revealed abnormalities of the cerebral cortex and, in particular, of association cortex. Electroencephalognaphic studies in the autistic population have reported a significant incidence of abnormalities involving the cerebral cortex. More specific studies of neural function using evoked potentials, positron emission tomography (PET), and 31P nuclear magnetic resonance (NMR) spec-troscopy have identified abnormalities involving association cortex.

ELECTROENCEPHALOGRAPHY

Electroencephalography (EEG) was one of the earliest techniques used to investigate the neuro-biology of autism. The recognition of a high mci-dence of EEG abnormalities and of seizure disor-ders in the autistic population was among the ear-liest evidence of a biologic basis for this disorder. One of the first of these studies appeared in 1964’ and reported EEG abnormalities in 58% and epi-lepsy in 19% of the 58 young autistic children in their series. The EEG abnormalities consisted of generalized paroxysmal spike and wave activity in the majority of cases, with the remainder having a spike or slow wave focus. In the ensuing decade, the incidence of abnormal EEGs in various series ranged from 10% to 83%, depending on the method

of subject selection and the criteria for interpreta-tion of the EEGs.’ The seizure frequency ranged from 19% to 25% in these studies.

(2)

these studies” found EEG abnormalities in 43% of 100 autistic children who had a single EEG. The abnormalities included diffuse or focal spikes on slow waves, and paroxysmal spike and wave activ-ity, with a mixed discharge being the most common abnormality (38% of the abnormalities). The ab-normalities tended to be bilateral and even when unilateral did not show a predilection for a specific region of the cortex.

EPILEPSY

The development of epilepsy has also been found to be a relatively common occurrence in autism. Epilepsy is estimated to be present in 20% to 35% of autistic individuals; of the seizure types, major motor seizures are the most easily recognized and account for the majority of cases documented. As with EEG abnormalities, the occurrence of epilepsy is more common in the more severely impaired individuals. Onset of seizures is most commonly in early childhood, with a second peak of onset during adolescence.’6”7 However, epilepsy may begin at any age in autism and, hence, estimates of preva-lence depend on the age as well as the IQ compo-sition of the autistic population surveyed. The best available estimates are therefore provided by the longitudinal study of Lockyer and Rutter,’8 which followed 64 autistic individuals from early child-hood through the age of 22 years and the popula-tion-based study of Gillberg and Steffenburg,’9 which followed 46 autistic children into adulthood. The cumulative incidence of seizures in these co-horts was 25% and 33%, respectively. The Lockyer and Rutter study also reported serious neurologic deterioration during adolescence in 12% of their subjects, often associated with the onset of major motor seizures. “The deterioration usually began with a loss of language skills associated with inertia and intellectual decline. In half of these cases, the deterioration was accompanied by the development of fits.” The deterioration in such cases is unex-plained, but the association with the onset of sei-zures and the recent reports of difficult-to-recog-nize complex partial seizures raises concerns about the contribution of seizures to such cases.

Two recent papers have emphasized the occur-rence of complex partial seizures in autistic chil-dren. The first report was prompted by the seren-dipitous discovery of an epileptifonm focus in two autistic children under evaluation for behavior dif-ficulties.2#{176} With the guidance of telemetric EEG monitoring of the epileptiform focus, clinical sei-zures were identified. Successful treatment of these clinical seizures resulted in major clinical improve-ment in behavior, with a dramatic lessening in the

severity of the autistic symptoms. The authors em-phasized the difficulty in recognition of this type of seizure in the autistic population, inasmuch as many of the clinical manifestations of seizures in these cases are routinely attributed to autism. The actual prevalence of complex partial seizures in the autistic population is unknown, but a follow-up study by Olsson, Steffenbung, and Gillberg1 in their population suggests that they may be more common than is recognized. This study also emphasized that the association between epilepsy and autism was with the autism and not with the concomitant mental retardation. This is an important point, inasmuch as epilepsy has often been erroneously interpreted as evidence of an underlying etiology that was different from nonepilepsy cases. This interpretation is not feasible from an epidemiologic perspective, inasmuch as the common association between epilepsy and autism cannot be explained by the chance occurrence of two separate disorders, one of which is uncommon.

In summary, EEG abnormalities are present in about 40% of autistic children assessed with a single EEG of good quality and in about 65% when mul-tiple EEGs are obtained. The most common abnor-malities are diffuse or focal spikes or slowing and paroxysmal spike and wave activity. The EEG ab-normalities have involved all regions of the cortex without predilection for any one region on hemi-sphere. A number of studies have suggested that an abnormal EEG is associated with a poorer long-term prognosis, but in the vast majority of instances this association is related to the greater frequency of abnormal EEGs among more severely affected individuals. The cumulative incidence of major mo-ton seizures in autism is estimated to be 25% to 35% by early adulthood. The reports of deteriora-tion on regression in function in autistic children and the recent report of complex partial seizures in

two such autistic children raise the possibility that such seizures may be an unrecognized but signifi-cant problem in some individuals with autism.

(3)

epi-lepsy in the autistic population is dependent on a clinician’s sophistication in the clinical assessment of autistic individuals and of clinical seizures; din-ical skills in these two areas are typically segregated between psychiatrists and neurologists, with little overlap. The general practice of excluding epilepsy in autistic individuals with a single scalp recording and the extreme deviance ofthe autistic individual’s behavior has further hindered neunologic interven-tion in this area. Any significant progress in the recognition and treatment of epilepsy in this pop-ulation awaits a collaboration between neurologists and psychiatrists with excellent clinical diagnostic skills in relation to autism.

EVOKED POTENTIALS

Brainstem Auditory Evoked Potentials

During the 1970s and early 1980s, many studies reported abnormalities in auditory brainstem evoked potentials in autistic individuals.2225 Typi-cally these studies reported moderate to severe de-lays in wave I (auditory nerve) in some autistic patients and prolonged brainstem transmission times in others, resulting in abnormalities in 20% to 60% of autistic subjects. The earliest of these studies,24 for example, reported the absence of re-sponses in 5 of 15 of their autistic subjects, indicat-ing profound sensorineural hearing loss; in the re-maining group, abnormalities of brainstem trans-mission were initially reported for all parameters but this report was later retracted when these ab-normalities were found to be due to equipment malfunction.24 (The high incidence of deafness in this and other series most probably reflects the incidence of fetal rubella and the frequency of post-meningitis complications in earlier years. This eti-ologic heterogeneity was typical in studies prior to the 1980s when no attempts were made to exclude individuals with obvious neurologic, genetic, and metabolic disorders. The current incidence of iden-tifiable etiologies in the autistic population is prob-ably less than 5%.) Subsequent studies reported various delays in waves I through V (prolonged brainstem transmission), resulting in considerable speculation on the importance of brainstem dys-function in the pathophysiology of autism. How-ever, these fmdings were not to be replicated in later studies.

In 1982, Tanguay et al26 reported that there were no differences in the brainstem auditory evoked potentials between autistic children with normal hearing and without underlying neurologic disor-ders and control subjects, when control subjects were matched for age and gender, important van-ables for evoked potentials. Rumsey et al27

subse-quently reported normal auditory brainstem evoked potentials in 24 of 25 autistic children and adults and 24 of 25 age- and sex-matched normal control subjects. The autistic subjects were between the ages of 6 and 21 and ranged in IQ from the pro-foundly mentally retarded to above-average intel-ligence. Important elements in this study were the exclusion of autistic subjects with diagnosable in-fectious, metabolic, or neunologic disease and seni-ous sensory impairment; the matching of control and autistic subjects for gender; and the reliability of measurements between subjects. Rumsey et al commented that the differences in brainstem laten-dies between autistic and control subjects reported in earlier studies were often in both directions (increased and decreased latencies) and were insig-nificant in the context ofestablished clinical norms. These findings were confirmed by Counchesne et al,m who reported normal brainstem auditory evoked potentials in all of the 10 non-mentally retarded autistic adolescents and young adults in their series; these investigators emphasized, in ad-dition, the importance of controlling for the effects of temperature on latency values.

In summary, it appears that auditory brainstem evoked potentials are normal in autistic individuals, if subject selection excludes cases with obvious neu-rologic disease and controls for gender and if relia-ble methods and clinical normative values are used.

Middle Latency Responses

A single study has reported on auditory middle latency responses in autistic individuals. Middle latency potentials appear 10 to 50 msec after the stimulus, compared to the brainstem auditory po-tentials, which occur in the first 10 msec, and the event-related long latency potentials, which occur between 300 and 600 msec. Middle latency re-sponses were found to be normal in the 13 non-mentally retarded autistic adolescents and young adults studied by Courchesne et al. In addition to documenting the integrity ofthese subcortical path-ways, studies of auditory brainstem evoked poten-tials and middle latency responses documented that the abnormalities observed in the long latency po-tentials are not the downstream effect of abnor-malities in early or middle latency potentials.

Event-Related Potentials: P300s and Negative

Components

(4)

cortical origin. Two ERPs have been explored in autism so far-the P300 and negative component (Nc). P300s are thought to originate from modality-nonspecific association cortex in the panietal lobes and to be dependent on the integrity of pathways between this region and hippocampus and related limbic structures.3#{176} Nc is thought to originate from frontal cortex.

In 1979, Novick et al3’ reported small on absent auditory P300s and visual P400s in three autistic individuals. These potentials were studied using a paradigm that required the subjects to detect ran-dom missing stimuli from a regular train of auditory or visual stimuli. Inasmuch as the autistic subjects were able to accurately detect the missing stimuli, the abnormalities in their ERPs were not attributed to deficits in attention or motivation. The investi-gators proposed instead that the ERP attenuation reflected defective information storage as a result of dysfunction in the pathways linking entorhinal cortex and hippocampus and inferior parietal con-tex, a hypothesis that was to be modified by their next study. The following year Novick et al32 re-ported that auditory P200 and P300 potentials to pitch changes and deleted stimuli were significantly smaller in their sample of five autistic boys com-pared with control subjects. The generators for the P200 potential are controversial but are thought to arise from within the auditory cortex near the su-penior temporal plane. Because the depression in the late potentials was “not limited to experimental conditions in which a temporal interval must be registered but also occurs in tasks that require direct sequential comparison of auditory stimuli” the authors proposed that auditory information processing rather than information storage was de-fective in autism, localizing this ERP abnormality to panietal association cortex.

These ERP abnormalities were replicated by Counchesne et al in their 1984 and 1985m studies in which they also observed attenuation of the auditory P300 despite normal task performance, ie, the ability to attend to and correctly identify novel

stimuli. Visual P300s were found to be less affected but also differently affected than auditory P300s. These investigators went on to report the absence in these same autistic individuals of frontally dis-tnibuted Nc (400 to 700 msec after stimulus pres-entation) to surprising or novel visual on auditory

stimuli under conditions of sustained attention” once again despite normal task performance.

In summary, neurophysiologic studies in autism in the last decade have documented intact brain-stem auditory evoked potentials and midlatency potentials and have traced abnormalities reported by earlier studies to methodologic errors. Recent

studies have consistently reported abnormalities in auditory P300 and auditory and visual Nc poten-tials, providing evidence of bilaterally symmetric neurophysiologic abnormalities in panietal and frontal association cortex. These neurophysiologic abnormalities have been present despite normal task performance, ie, the ability to perceive, attend to, and correctly classify the stimuli. These electro-physiologic abnormalities have been variously pro-posed to be the result of less efficient, alternative strategies for cortical auditory information process-ing or of deficits in the cortical mechanisms for selective attention.

PET AND NMR SPECTROSCOPY

Data from other functional methods are limited to preliminary findings because ofthe small number of studies to date and the inconsistency in the findings. One PET study of 10 high-functioning autistic adult males by Rumsey et al35 reported an increase in 2-fluoro-2-deoxy-D-glucose uptake and, by inference, in the metabolic rate for glucose in frontal, panietal, temporal, and occipital cortex; hippocampus; basal ganglia; and thalamus. There was, however, a large degree of overlap in the data between the autistic and control groups in this study. Further analysis of the data from 18 autistic adults by Horwitz et al’6 with an exploratory statis-tical technique for assessing correlations between regional cerebral metabolic rates revealed fewer interhemisphenic correlations between homologous regions in the frontal and panietal lobes and de-creased intrahemisphenic correlations between the frontal and panietal lobes and the stniatum and thalamus in the autistic group compared with the normal control group. Similar trends were noted in a subsequent PET study of 18 autistic children by De Volden et al37 but were not statistically signifi-cant. A third PET study by Herold et al of 6 young autistic men and 6 normal control subjects did not find any abnormalities of cerebral blood flow or oxygen or glucose consumption in the autistic sub-ject group. These PET studies were all performed under nesting conditions. The discrepancies in these findings may be resolved with the use of cortical activation procedures. A larger sample size and uniformity of age and IQ may also aid in the devel-opment of a consensus in PET studies in autism.

(5)

cortex of high-functioning autistic adolescents and young adults, providing preliminary confirmation of the alteration in energy metabolism seen with 2-fluoro-2-deoxy-D-glucose PET as well as tentative evidence of a neuronal membrane alteration in frontal cortex. Clarification of the membrane phos-pholipid alterations is dependent on a larger sample size in which the effects of age and brain maturation can be distinguished from the consequences of au-tism. If, as neunopathologic studies suggest, the neuronal cytoarchitectune in autism is character-ized by developmental curtailment, then a large scale study of 3’P NMR spectroscopy may provide in vivo neurochemical confirmation of the histoan-atomic observations.

The increase in cerebral glucose metabolism seen in the PET and NMR spectroscopy studies is par-ticularly intriguing, inasmuch as greater cerebral electrical activity has been reported to follow errors in judgment than correct decisions during cognitive evoked potentials. Hence, the increase in glucose metabolism and the decrease in functional linkages with association cortex observed in the PET and

np NMR spectroscopy studies may be additional manifestations of less efficient information

proc-essing in autism, as has been proposed for the evoked potential abnormalities. Alternatively, other investigators have noted that the PET ab-normalities involve the neural circuitry for selective attention and have proposed primary dysfunction

in the cortical mechanisms for selected attention.

DISCUSSION

Studies of neural function in autism have re-vealed abnormalities of the cerebral cortex and, in particular, of association cortex. Electroencepha-lographic abnormalities involving all areas of the cerebral cortex provided the first biologic evidence of central nervous system involvement in autism. Epilepsy has since come to be recognized as an integral part of the clinical manifestations of the brain dysfunction underlying autism, rather than the co-occurrence of two separate disorders or a priori evidence of a different etiology. Neurophysi-ologic studies have delineated bilateral and sym-metric abnormalities in parietal and frontal asso-ciation cortex during decision-making tasks, de-spite the ability of the autistic subjects to attend to and correctly classify stimuli. Preliminary PET data have revealed increased glucose metabolism in all areas of association cortex and in related sub-cortical structures; further analysis of these data has suggested abnormalities in the functional link-ages within and between frontal and panietal asso-ciation cortex. Abnormalities in cerebral cortical

energy metabolism have also been found in a pre-liminary 31P NMR spectroscopy study of dorsal prefrontal cortex. There is, therefore, substantial evidence that the cerebral cortex, and particularly

association cortex, is involved in the pathophysi-ology of autism. At issue is the nature of its role in the neurobiology-is the deficit in information processing in the association cortex a primary def-icit or is it secondary to abnormalities in input to the association cortex from the brainstem or the limbic system?

At the present time, three very different

localiza-tions and mechanisms are being proposed for the neurobiology of autism: dysfunction in the cortical

mechanisms for selective attention secondary to

abnormal ascending projections from the cerebel-lum and brainstem’40; dysfunction in the limbic

mechanisms for information acquisition, ie, memory4144; and dysfunction in information proc-essing by association cortex and its distributed net-work of connections.4547 These three regions and neunologic functions of the brain are quite different and, hence, insights into their respective contnibu-tions to the neurobiology of autism are likely to become apparent from clinical neunologic and neu-nopsychologic studies.

Sensory input to the cerebral cortex has been assessed by neurophysiologic and neunopsychologic studies. Auditory, visual, and somatosensory evoked potentials have shown normal conduction through subcortical pathways. There was no evi-dence in these studies of abnormal or erratic

trans-mission of sensory input to the cerebral cortex.

Furthermore, the autistic subjects were able to ac-curately perceive and attend to the sensory stimuli during neunophysiologic studies. Similarly, neuro-psychologic assessment has failed to reveal

abnor-malities in sensory perception by autistic subjects

or in basic attention.47’48 Basic memory function has been explored by several research groups479 and has also been found to be intact; deficits have been identified instead in complex memory proc-esses dependent on cortical function. Hence, it

ap-pears from studies so fan that sensory input, basic attentional mechanisms, and basic memory func-tion are intact in testable autistic individuals. (High-functioning autistic individuals have been the focus of much of the recent neurophysiologic and neunopsychologic studies because they possess

the requisite abilities for this testing. Such

individ-uals constitute approximately 30% of the autistic population.)

(6)

function: deficits in complex social behavior; in prosodic, pragmatic, and nonverbal language; and in abstraction. These deficits are classically asso-ciated with dysfunction of the cerebral cortex. Al-though some types of deficits in higher cortical function can result from subcortical lesions, certain of the deficits seen in autism are exclusive to cere-bral cortex and, hence, provide strong evidence that higher cortical function deficits in autism are the result of intrinsic dysfunction of the association cortex. Deficits seen in autism which are specific to the cerebral cortex include deficits in abstract rea-soning which are likely responsible for many of the deficits in behavior associated with autism; deficits in the comprehension and use of prosodic language, nonverbal language, and pragmatic language; and the pattern of propositional language development which evolves through a global aphasia, mixed transcortical aphasia, and transcortical motor aphasia to fluency.45 (Prosodic language is the meaning imparted to speech by variations in pitch, cadence, and rhythm. Nonverbal language refers to the use of eye contact, facial expression, and ges-tunes for communication. Propositional language refers to vocabulary and their incorporation in sen-tences according to the rules of grammar. A global aphasia refers to the absence of comprehension, repetition, and spontaneous expression of language. A mixed transcortical aphasia refers to the absence of comprehension and spontaneous expression in the face of intact repetition. A transcortical motor aphasia is intact comprehension and repetition but absent spontaneous expression.)

Hence, all ofthe clinical manifestations of autism can be accounted for by dysfunction of association cortex and certain of the deficits can be explained only by a cortical localization. Studies of sensory input and information input into the cortex have documented the integrity ofthese functions. Hence, it appears that the deficits in higher cortical func-tion characteristic of autism are most likely the result of intrinsic dysfunction of association cortex and are not attributable to dysfunction at the hip-pocampal on subcortical levels. The discrepancy between this hypothesis and the histoanatomic ab-normalities observed in autism is more apparent than real. The decrease in neural connectivity ob-served in the hippocampus may be a reflection of deficits in the larger neural network of association cortex involved in complex information organiza-tion and processing. The compactness of the hip-pocampus relative to association cortex may ex-plain why dendritic abnormalities have been iden-tified in the hippocampus but not in the larger and more complex dendritic structure of association cortex. Inasmuch as the function of the association

cortex is dependent not only on intrinsic processing of information but also on feedback loops with limbic system and subcortical structures, it is not surprising that these structures are also found to be involved on neunopathologic and PET studies.

ACKNOWLEDGMENT

This work was supported by National Institute of

Mental Health grant MH40858.

REFERENCES

1. White PT, DeMeyer W, DeMeyer M. EEG abnormalities in early childhood schizophrenia. Am J Psychiatry.

1964;120:950-958

2. Fish B, Shapnio T. A typology of children’s psychiatric disorders. J Am Acad Child Psychiatry. 1965;4:32-52 3. Hutt SJ, Hutt C, Lee D, Ounsted C. A behavioral and

electroencephalographic study of autistic children. J Psy-chiatr Res. 1965;3:181-197

4. Small JG. Epileptiform electroencephalographic abnormal-ities in mentally ill children. J Neru Ment Dis. 1968;147:341-348

5. Creak M, Pampiglione G. Clinical and EEG studies on a group of 35 psychotic children. Dev Med Child Neurol.

1969;11:218-227

6. Stevens JR, Milstein V. Severe psychiatric disorders of childhood. AJDC. 1970;120:182

7. Ritvo ER, Onnitz EM, Walter RD, Hanley J. Correlation of psychiatric diagnoses and EEG findings: a double-blind study of 184 hospitalized children. Am J Psychiatry.

1970;126:112-120

8. Gubbay 55, Lobascher M, Kingerlee P. A neurological ap-praisal of autistic children: results of a western Australian survey. Dev Med Child NeuraL 1970;12:422-429

9. Small JG. EEG and neurophysiological studies of early infantile autism. Biol Psychiatry. 1975;10:355-397

10. Brown JL. Follow-up of children with atypical development (infantile psychosis). Am J Orthopsychiatry. 1963;33:855 11. Lotter V. Factors related to outcome in autistic children. J

Autism Child Schizophr. 1974;4:263-277

12. DeMyer MK. Research in infantile autism: a strategy and its results. Biol Psychiatry. 1975;10:433-452

13. Tsai LY, Tsai MC, August GJ. Brief report: implications of EEG diagnoses in the subclassification of infantile autism.

J Autism Deu Disord. 1985;15:339-344

14. Waldo MC, Cohen DJ, Caparulo BK, Young G, Pnichand JW, Shaywitz BA. EEG profiles of neuropsychiatrically disturbed children. Am Acad Child Psychiatry.

1978;17:656-670

15. Tsai LY, Stewart MA. Handedness and EEG correlation in autistic children. Biol Psychiatry. 1982;17:595-598

16. Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry. 1990;l:127-129

17. Rutter M. Autistic children growing up. Deu Med Child

NeuraL 1984;26:122-129

18. Lockyer L, Rutter M. A five to fifteen year follow-up study of infantile psychosis: patterns of cognitive ability. Br J Soc Clin Psychol. 1970;9:152-163

19. Gillberg C, Steffenburg S. Outcome and prognostic factors in infantile autism and similar conditions: a population-based study of 46 cases followed through puberty. J Autism Deu Disord. 1987;17:273-287

20. Gilberg C, Schaumann H. Epilepsy presenting as infantile autism? Two case studies. Neuropediatrics. 1983;14:206-212 21. Olsson I, Steffenburg 5, Gillberg C. Epilepsy in autism and

autisticlike conditions. Arch Neurol. 1988;45:666-668 22. Rosenblum SM, Arick JR, Knug DA, et al. Auditory

(7)

Disord. 1980;10:215-225

23. SkoffBF, Minsky AF, Turner D. Prolonged brainstem trans-mission time in autism. Psychiatry Res. 1980;2:157-166 24. Student M, Sohmer H. Evidence from auditory nerve and

brainstem evoked responses for an organic brain lesion in children with autistic traits. J Autism Child Schizophr.

1978;8:13-20

25. Taylor MJ, Rosenblatt B, Linschoten L. Auditory brainstem response abnormalities in autistic children. J Can Sci Neu-roL 1982;9:429-433

26. Tanguay PE, Edwards RM, Buchwald J, Schwafel J, Vi-vienne A. Auditory brainstem evoked responses in autistic children. Arch Gen Psychiatry. 1982;39:174-180

27. Rumsey JM, Grimes AM, Pikus AM, Ranjan D, Ismond DR. Auditory brainstem responses in pervasive developmental disorders. Biol Psychiatry. 1984;19:1403-1417

28. Courchesne E, Courchesne RY, Hicks G, Lincoln A. Func-tioning of the brainstem auditory pathway in non-retarded autistic individuals. Electroencephalogr Clin Neurophysiol.

1987;61:491-501

29. Courchesne E, Lincoln AJ, Yeung-Courchesne R, Elmasian

R, Grillon C. Pathophysiologic findings in non-retarded autism and receptive developmental language disorders. J Autism Dev Disord. 1989;19:1-17

30. Wood CC, McCarthy G, Squires NK, Vaughan HG, Woods

DL, McCallum WC. Anatomical and physiological sub-strates of event-related potentials: two case studies. Ann NY Acad Sci. 1984;425:681-721

31. Novick B, Kurtzberg D, Vaughn HG Jr. An electrophysio-logic indication of defective information storage in child-hood autism. Psychiatry Res. 1979;1:101-108

32. Novick B, Kurtzberg D, Vaughn, HG Jr, Simpson R. An electrophysiologic indication of auditory processing defects in autism. Psychiatry Res. 1980;3:107-114

33. Courchesne E, Kilman BA, Galambos R, Lincoln AJ. Au-tism: processing of novel auditory information assessed by event-related brain potentials. Electroencephalogr Clin Neu-rophysioL 1984;59:238-248

34. Courchesne E, Lincoln AJ. Event-related brain potential correlates of the processing of novel visual and auditory

information in autism. J Autism Deu Disord. 1985;15:55-76 35. Rumsey JM, Duara R, Grady C, et al. Brain metabolism in

autism. Arch Gen Psychiatry. 1985;42:448-455

36. Horwitz B, Rumsey JM, Grady C, et a!. Interregional cor-relations of glucose utilization among brain regions in autis-tic adults. Ann NeuroL 1987;22:118

37. De Volder A, Bol A, Michel C, Congneau M, Goffinet A. Brain glucose metabolism in children with the autistic syn-drome: positron tomography analysis. Brain Dev.

1987;9:581-587

38. Herold 5, Frackowiak RSJ, LeCouteur A, Rutter M, Howlin

P. Cerebral blood flow and metabolism of oxygen and glucose in young autistic adults. Psychol Med. 1988;18:823-831 39. Minshew NJ, Pettegrew JW, Payton JB, et al. Metabolic

alterations in the dorsal prefrontal cortex ofautistic patients with normal IQ. Ann NeuraL 1989;26:438

40. Courchesne E, Yeung-Courchesne R, Press GA, Hesselink

JR, Jernigan TL. Hypoplasia of cerebellar vermal lobules

VI & VII in autism. N Engl J Med. 1988;318:1349-1354 41. Bauman ML, Kemper TL. Histoanatomic observations of

the brain in early infantile autism. Neurology

1985;35:866-874

42. Bauman ML, Kemper TL. Abnormal cerebellar circuitry in autism. Neurology. 1989;39:186

43. Raymond G, Bauman M, Kemper T. The hippocampus in autism: Golgi analysis. Ann NeuraL 1989;26:483-484

44. Bachevalier J. Memory loss and socio-emotional disturb-ances following neonatal damage of the limbic system in monkeys: an animal model for childhood autism. In: Tam-minga CA, Schulz SC, eds. Advances in Psychiatry and Psychopharmacology. New York, NY: Raven Press;

1991;1:129-140

45. Minshew NJ, Payton JB. Part 1: the clinical spectrum of infantile autism. Curr Probi Pediatr. 1988;18:561-610

46. Minshew NJ, Payton JB. Part 2: the differential diagnosis and neurobiology of autism. Curr Probi Pediatr.

1988;19:615-694

47. Minshew NJ, Payton JB, Goldstein G. Abstraction and memory deficits in non-retarded autistics: a fundamental deficit? Neurology. 1989;39(suppl 1):136

48. Rumsey JM, Hamburger SD. Neuropsychological findings in high-functioning men with infantile autism, residual state. J Clin Exp Neuropsychol. 1988;10:201-221

(8)

1991;87;774

Pediatrics

Nancy J. Minshew