C

AD

Aatc(eascht

sfdhcfpe“taciacstt(1(1ltct

H

bcatcf

F

A

R

0d

OMMENTARIES

utism: Searching for Coherence

aniel Geschwind

wareness of autism as a significant public health problem,propelled largely by parent advocacy and recent preva-lence estimates of 1 in 150 and 1 in 200 (1), has moved

utism research into the mainstream of neuroscience. Analogouso other broadly defined and heterogeneous neurobehavioralonditions, such as mental retardation, autism spectrum disorderASD) likely represents many distinct conditions with numeroustiologies (2). Autism spectrum disorder is also highly heritable,nd recent genetic findings, including linkage and associationtudies and studies of rare genetic variation due to chromosomeopy number variation (CNV), further emphasized its etiologiceterogeneity (3,4). This etiological and clinical diversity has ledo the formulation of the term “the autisms” to describe ASD (2).

The extent of this initially unforeseen heterogeneity presentsignificant challenges to those working in the field at all levels,rom identification of its underlying neurobiological bases toevelopment and evaluation of more effective treatments. Thiseterogeneity makes it difficult to conceive of models, whetherognitive, behavioral, or physiological, that capture commoneatures of the autisms under one conceptual umbrella. The mostopular models (e.g., 5,6), ranging from “weak central coher-nce,” deficits in “theory of mind,” “local hyperconnectivity” orlong-range underconnectivity,” “developmental dysconnec-ion,” to the “male brain,” also reflect divergent levels of analysisnd different disciplines, from anatomical, physiological, orognitive, to more popular psychology—not easily amenable tontegration. Nonetheless, these diverse approaches and syntheticttempts represent true progress and highlight several points ofonvergence in the current literature. It is in this context that theeven studies in this special issue of Biological Psychiatry areimely. Here, I briefly focus on two topics in common to a few ofhese articles: 1) the issue of enlarged heads (brains) in autismHobbs et al., pages 1048–1055, and Sacco et al., pages 1038–047, both in this issue), and 2) physiological phenotypesOrhekhova et al., pages 1022–1029, and McCleery et al., pages007–1014, both in this issue). Both share the common theme ofooking for quantifiable features of autism (7), endophenotypeshat are closer to underlying biological processes than the broadognitive and behavioral features that currently define the au-isms.

ead Size

Large heads and atypical head growth trajectory (e.g., 8) haveeen observed in ASD in several studies. Nearly half of thehildren originally described by Leo Kanner had large heads (9),nd macrocephaly, defined as head circumference (HC) greaterhan the 97th percentile is observed in about 20% of autistichildren. Recent studies have also shown that macrocephaly isamilial in ASD and thus likely inherited in this subset of

rom the Neurogenetics Program, Department of Neurology and Center forAutism Research and Treatment, Department of Psychiatry and Biobe-havioral Sciences, Semel Institute, and Department of Human Genetics,Geffen School of Medicine at UCLA, Los Angeles, California.

ddress reprint requests to Daniel Geschwind, M.D., Ph.D., NeurogeneticsProgram, David Geffen School of Medicine at UCLA, 710 WestwoodPlaza, Los Angeles, CA 90095-1769; E-mail: dhg@ucla.edu.

eceived August 31, 2007; accepted September 3, 2007.

006-3223/07/$32.00oi:10.1016/j.biopsych.2007.09.001

approximately 20% of ASD cases (Spence and Geschwind,unpublished data, 2007). Because autism is thought to ariseduring prenatal development, Hobbs et al. studied head andbody size during fetal development. They analyzed midgestationfetuses using retrospective assessment of ultrasound data in 45autistic children and compared this with 222 typical children,finding no evidence of enlarged fetal HC in children with ASD,parallel with previous studies that have reported normal HC atbirth. This agrees with the observations of Courchesne et al. (8)who initially described normal HC followed by an increased rateof postnatal head growth in children with ASD. The current studyby Hobbs et al. provides the first study of fetal HC in ASD andprovides another tier of evidence that abnormal brain size isprimarily related to postnatal developmental processes.

This is not to imply that fetal development is entirely normalin ASD. It certainly is plausible that early processes, such asneurogenesis or process growth, are involved but manifest lateras the brain matures. Additionally, Hobbs et al. did find amarginally significant increase in biparietal diameter (BPD) rel-ative to HC in ASD subjects, as well as soft signs of developmen-tal abnormalities of the renal system, the latter of which isconsidered a marker for increased risk of genetic disorders.These may be important clues and it will be important toreplicate in larger samples of patients, understand their distribu-tion in the population, and study the subset of potentially higherrisk patients for specific genetic anomalies or mechanisms, suchas CNV or chromosomal abnormalities.

Neurophysiological Phenotypes and Local VersusGlobal Processing

Although the core deficits of autism involve higher cognitivefunctions, such as social cognition, language, and repetitive andrestrictive behaviors, alterations in the function of primary sen-sory systems have also been observed, consistent with decadesof patient and parent reports of abnormal sensitivity to sensorystimuli (review, 10). Children with ASD may perform better atdetection of local details relative to global properties of astimulus, supporting the notion that integration of primary orderperceptions into higher order concepts is altered (11). Whetherthis is a top-down deficit, as proposed by the theory of weakcentral coherence or due to heightened primary processingremains to be convincingly demonstrated (11).

Based on the idea that first-degree relatives of ASD probandswill share aspects of heritable quantitative endophenotypes,albeit in a less severe form than their siblings with ASD, McCleeryet al. studied the early developing magnocellular visual pathwayin a small cohort of 6-month-old infants with autistic siblings.These infants are also at a more than twentyfold risk fordeveloping ASD over those without autistic siblings, so that 10%are expected to develop a diagnosis of ASD by 2 to 3 years ofage. The investigators used observation of the infants’ visualpreference to measure luminance sensitivity (magnocellular [M])and chromatic sensitivity (parvocellular [P]) and found an earlyenhancement in luminance sensitivity, consistent with a geneti-cally based alteration in visual system development in the ASDinfant siblings. Rather than identifying a deficit, these dataindicate an enhancement at the level of this surrogate measure of

the M pathway.

BIOL PSYCHIATRY 2007;62:949–950© 2007 Society of Biological Psychiatry

suaetoascosdriuad

caetsiCadwi

(iodgovcpHAfiAigihttp

S

f

950 BIOL PSYCHIATRY 2007;62:949–950 Commentary

w

The authors suggest that this enhancement of a sensorytimulus could have negative consequences for the furtherpstream areas, negatively impacting higher order processes. Anlternative interpretation is that this reflects a true functionalnhancement for processing of local detail and primary perceptshat alone is not sufficient to cause autism, because the majorityf these children will develop typically; hence, its adaptive valuend propagation within the normal population. From this per-pective, the elements that lead to M pathway changes must beompounded by other factors, genetic or otherwise, that co-ccur in the autistic sibling, leading to true central nervousystem (CNS) dysfunction, resulting in ASD. Still, this does notiminish the potential value of M pathway alterations as aelevant endophenotype for genetic studies. It will be verynteresting to determine the generalizability of these findingssing other measures of M pathway function and across theutism spectrum, as well as the relationship to other areas ofysfunction along the life span in ASD.

There is a growing literature reporting primary sensory defi-its in ASD subjects, not only in visual processing but in auditorynd other modalities as well (11). As with the M pathwaynhancements described by Hobbs et al., it remains possible thathese other sensory abnormalities may not be due to primaryensory processing but be the result of more upstream process-ng dysfunction that feeds back to more primary visual processes.onversely, when global or local deficits in neuronal synchronyre ascribed to processes such as weak central coherence orisrupted connectivity (e.g., 12,13), the question arises as tohether these are causal or due to more elemental disturbances

n sensory processing (11).In this issue, Orekhova et al. studied electroencephalogram

EEG) at rest in two different populations of boys with ASD anddentified increased gamma band (high frequency, “global”)scillations in both groups of ASD subjects, providing indepen-ent validation of their findings. Importantly, the extent ofamma band increase was positively correlated with the extentf global developmental delay (mental age) as measured byarious intelligence quotient (IQ) measures. This observationertainly suggests relevance of this quantifiable, physiologicalhenotype to the cognitive functioning of the subjects studied.owever, IQ deficits are not core deficits or strongly heritable inSD, and IQ measures do not measure the severity of the specific

eatures of ASD, such as social communication, which is amongts core features. Rather than solidifying a clear connection toSD, this correlation to mental age more likely signifies that

ncreased resting high-frequency activity is reflective of morelobal brain dysfunction. Although ASD has overlap with generalntellectual disability (mental retardation [MR]), a key issue isow ASD is distinct from MR and other neuropsychiatric diseaseshought to have a significant developmental component, a pointhat will be critical to understanding the relationship of thishenotype to ASD and ASD pathobiology in general.

ome Conclusions

From a neurobiological perspective, autism research is in its

etal stage. The studies in this issue add to rapidly growing

ww.sobp.org/journal

literature showing that the tools are in hand to understand therelationships between different levels of analysis, from molecularand physiological to behavioral and different levels of thenervous system, from pathways to regions to circuits, to demys-tify the neural bases of the autisms.

It is now critical to distinguish the factors in autism thatdifferentiate it from other related neurodevelopmental disorders,in addition to quantifying etiologically relevant phenotypesacross diagnostic boundaries. Furthermore, when any specificphysiological deficits are identified in a primary sensory system,their potential roles in causing ASD need careful scrutiny; suchdeficits, although providing significant clues from an etiologicalstandpoint, may be peripheral to the core features. Additionally,primary and integrative disturbances need not be mutuallyexclusive; from a cellular neurobiological perspective, both maycoexist (13). Because elements of human cognition and behav-ior, such as language or social relatedness, are based on theintegrated activity of specific brain regions, including higherorder association cortices, it remains likely that specific deficits inregional functioning or connectivity will be involved.

I thank Judith Piggott, Ph.D., for her critical reading of themanuscript and Li Hong for her editorial assistance.

Dr. Geschwind receives funding from National Institutes ofHealth (NIH) and Autism Speaks for his own group’s research onautism.

1. ADDM Network Principal Investigators (2007): Prevalence of autismspectrum disorders–Autism and Developmental Disabilities MonitoringNetwork, 14 sites, United States, 2002. MMWR Surveill Summ 56:12–28.

2. Geschwind DH, Levitt P (2007): Autism spectrum disorders: Develop-mental disconnection syndromes. Curr Opin Neurobiol 17:103–111.

3. Autism Genome Project Consortium (2007): Mapping autism risk lociusing genetic linkage and chromosomal rearrangements. Nat Genet39:319 –328.

4. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, et al.(2007): Strong association of de novo copy number mutations withautism. Science 316:445– 449.

5. Baron-Cohen S, Belmonte MK (2005): Autism: A window onto the devel-opment of the social and the analytic brain. Annu Rev Neurosci 28:109 –126.

6. Hill EL, Frith U (2003): Understanding autism: Insights from mind andbrain. Philos Trans R Soc Lond B Biol Sci 358:281–289.

7. Gottesman II, Gould TD (2003): The endophenotype concept in psychi-atry: Etymology and strategic intentions. Am J Psychiatry 160:636 – 645.

8. Courchesne E, Carper R, Akshoomoff N (2003): Evidence of brain over-growth in the first year of life in autism. JAMA 290:337–344.

9. Kanner L (1943): Autistic disturbances of affective contact. Nerv Child2:217–250.

10. Rogers SJ, Ozonoff S (2005): Annotation: What do we know about sen-sory dysfunction in autism? A critical review of the empirical evidence.J Child Psychol Psychiatry 46:1255–1268.

11. Dakin S, Frith U (2005): Vagaries of visual perception in autism. Neuron48:497–507.

12. Uhlhaas PJ, Singer W (2007): What do disturbances in neural synchronytell us about autism? Biol Psychiatry 62:190 –191.

13. Wilson TW, Rojas DC, Reite ML, Teale PD, Rogers SJ (2007): Children and

adolescents with autism exhibit reduced MEG steady-state gamma re-sponses. Biol Psychiatry 62:192–197.