Autism at the Beginning: Microstructural and Growth Abnormalities Underlying the Cognitive and Behavioral Phenotype of Autism

Autism at the beginning: Microstructural and growth abnormalities underlying the cognitive and behavioral phenotype of autism

ERIC COURCHESNE,a,b ELIZABETH REDCAY,a JOHN T. MORGAN,a and DANIEL P. KENNEDYa aUniversity of California, San Diego; and bChildren’s Hospital Research Center, San Diego

Abstract Autistic symptoms begin in the first years of life, and recent magnetic resonance imaging studies have discovered brain growth abnormalities that precede and overlap with the onset of these symptoms. Recent postmortem studies of the autistic brain provide evidence of cellular abnormalities and processes that may underlie the recently discovered early brain overgrowth and arrest of growth that marks the first years of life in autism. Alternative origins and time tables for these cellular defects and processes are discussed. These cellular and growth abnormalities are most pronounced in frontal, cerebellar, and temporal structures that normally mediate the development of those same higher order social, emotional, speech, language, speech, attention, and cognitive functions that characterize autism. Cellular and growth pathologies are milder and perhaps nonexistent in other structures ~e.g., occipital cortex!, which are known to mediate functions that are often either mildly affected or entirely unaffected in autistic patients. It is argued that in autism, higher order functions largely fail to develop normally in the first place because frontal, cerebellar, and temporal cellular and growth pathologies occur prior to and during the critical period when these higher order neural systems first begin to form their circuitry. It is hypothesized that microstructural maldevelopment results in local and short distance overconnectivity in frontal cortex that is largely ineffective and in a failure of long-distance cortical–cortical coupling, and thus a reduction in frontal–posterior reciprocal connectivity. This altered circuitry impairs the essential role of frontal cortex in integrating information from diverse functional systems ~emotional, sensory, autonomic, memory, etc.! and providing context-based and goal-directed feedback to lower level systems.

Autism begins in many ways. In the first weeks months go by, he appears to have good visual of life, a mother notices something is not right attention, perhaps too good, because some- about her newborn baby boy: he has marked times his attention seems stuck. He is also difficulty coordinating his sucking and swal- unexpectedly sensitive to touch or sounds at lowing and sometimes he seems floppy and one moment, but at others he seems almost then at other times strangely rigid. As the first completely oblivious to them. However, he is cuddly and he smiles and coos and seems to The authors were supported by funds from the National be socially connected. Then, during the sec- Institute of Mental Health ~2-ROI-MH36840! and Na- ond half of his first year of life, his vocaliza- tional Institute of Neurological Disorders and Stroke ~2- tions do not continue to develop and mother ROI-NS19855! awarded to Eric Courchesne. becomes truly concerned because now it is Address correspondence and reprint requests to: Eric Courchesne, Center for Autism Research, 8110 La Jolla not just his motor, attention, and sensory re- Shores Dr., Suite 201, San Diego, CA 92037; E-mail: sponses that are awry; he takes a reduced in- [email protected]. terest in her and rarely smiles or looks at her

577 578 E. Courchesne et al. or anyone else. Instead, he seems to regard Table 1. Nine red flags for autism objects with as much interest as people, whom he regards with disinterest or even avoidance. 1. Lack of appropriate eye gaze By his first birthday, a frightening and sad 2. Lack of warm, joyful expressions with gaze 3. Lack of sharing enjoyment or interest thought occurs to the mother: perhaps my baby 4. Lack of response to name has autism. 5. Lack of coordination of gaze, facial expression, Another mother and father swell with joy gesture, and sound because their newborn baby girl is so perfect, 6. Lack of showing and as months come and go, she grows more 7. Unusual prosody 8. Repetitive movements or posturing of the body delightful. Her interest in others grows and 9. Repetitive movements with objects her skills at interacting and engaging others brings a sense of wonder to mother and father, Note: Data adapted from Wetherby et al. ~2004!. and their dreams of what a special person she is to become expand. Each day, the little toddler’s face is filled with different emotions as she expands her social, emotional, speech, and for human togetherness? What could snuff out language skills. She seems as filled with love social drive, a drive that ought to be as strong for her parents as they are for her. In the months as the drive to breath, eat, or survive? What before her second birthday, though, mother goes wrong in how the brain is organized and notices that she has not been herself lately. operates, and how might the impact of these What is it? Perhaps a little quieter, perhaps a processes be mitigated or prevented? little bit less emotional. Worse, as her mother watches, each day she seems to fade a bit Where (and When) to Start Looking for more until there is no doubt: her little girl is the Neurobiological Bases of Social not herself anymore. She has gradually be- Dysfunction in Autism? come more and more remote; her face no longer shows much emotion and she no longer Over the past 40 years, cognitive psycholo- delights in others. In fact, she no longer seeks gists have attempted to identify cognitive def- out mom and dad. She has slowly faded away icits underlying the myriad of behavioral from them. symptoms seen in autism. Contemporary re- Thus, autism begins. In one case described search has identified deficits in complex pro- by Dawson, Osterling, Meltzoff, and Kuhl cessing ~Minshew, Goldstein, & Siegel, 1997!, ~2000!, the beginning was early, rapid, and weak central coherence ~Frith & Happe, 1994!, unmistakable, but in another case described impairment in the dynamic control of orient- by Lord ~C. Lord, personal communication, ing, disengaging, and switching attention NAAR Conference, November 12, 2004!, signs ~Courchesne, Townsend, Akshoomoff, Sai- of autism did not appear until later in the sec- toh, Yeung–Courchesne, Lincoln, James, ond year of life. New research has identified Haas, Schreibman, & Lau, 1994; Townsend, key behavioral red flags for autism during the Courchesne, Covington, Westerfield, Harris, first 2 years of life ~see Table 1; Wetherby, Lyden, Lowry, & Press, 1999!, deficits in ex- Woods, Allen, Cleary, Dickinson, & Lord, ecutive functions ~Rogers & Pennington, 2004!, and many of them involve a lack of 1991!, deficits in theory of mind ~Baron– normal socioemotional behavior and an appar- Cohen, Leslie, & Frith, 1985!, deficits in ent lack of the normal desire to make socio- imitation ~Rogers & Pennington, 1991!, im- emotional contact. pairments in social and affective relations How could the desire for social connection ~Hobson, 1993!, and impairments in joint so- not be there in an infant? Or, even more mys- cial attention ~Mundy, 1995!. However, the teriously, how could that desire appear strongly majority of this research was not aimed at for a time, only to slowly dwindle away, leav- identifying the specific neural bases of this ing a strange void? What could do this to a disorder. With the use of cognitive neurosci- quality so essentially human and so essential ence techniques ~i.e., functional magnetic res- Autism at the beginning 579 onance imaging @fMRI#, positron emission Courchesne, & Elmasian, 1990; Courchesne, tomography @PET#, magnetic encephalogra- Kilman, Galambos, & Lincoln, 1984; Town- phy @MEG#, event-related potential @ERP#, and send, Courchesne, Covington, Westerfield, EEG! the brain bases of these behavioral def- Harris, Lyden, Lowry, & Press, 1999!. Re- icits can be elucidated. By utilizing the grow- duced temporal lobe activity has been re- ing basic and clinical literature of cognitive ported in higher order lateral temporal regions neuroscience, evidence of cognitive and be- during processing of vocal sounds ~Gervais, havioral dysfunctions in autism can point to Belin, Boddaert, Leboyer, Coez, Sfaello, Bar- candidate brain regions of abnormality ~e.g., thelemy, Brunelle, Samson, & Zilbovicius, see Mundy, 2003; Williams, Whiten, Sudden- 2004!, speech sounds ~Boddaert, Belin, Cha- dorf, & Perrett, 2001!. bane, Poline, Barthelemy, Mouren–Simeoni, Cognitive neuroscience studies of autism Brunelle, Samson, & Zilbovicius, 2003; Bod- have identified altered patterns of neurofunc- daert et al., 2004!, and faces ~Pierce, Müller, tional activity, specifically reduced activity in Ambrose, Allen, & Courchesne, 2001!, and higher order frontal, temporal, and cerebellar during a mentalizing task ~Castelli et al., 2002!. regions but normal to increased activity in Further, ERP and MEG studies have identi- lower order posterior visual regions ~for re- fied reduced or abnormal temporal lobe reviews, see Belmonte et al., 2004; Courchesne, sponses to a variety of speech and nonspeech Redcay, & Kennedy, 2004; Frith, 2003!. These sounds ~Bruneau, Bonnet–Brilhault, Gomot, higher order regions are critical to the initia- Adrien, & Barthelemy, 2003; Bruneau, Roux, tion, perception, and interpretation of socio- Adrien, & Barthelemy, 1999; Ceponiene, Lep- emotional and communicative functions, which isto, Shestakova, Vanhala, Alku, Naatanen, & are strikingly impaired in autism, as well as Yaguchi, 2003; Dawson, Finley, Phillips, Galp- other higher order cognitive, attention, and ert, & Lewy, 1988; Gage, Siegel, Callen, & memory functions that are also abnormal in Roberts, 2003! and during spatial tuning of this disorder. Reduced frontal activation has attention to selective auditory sound sources been reported in dorsal or medial frontal cor- ~Teder–Salejarvi, Pierce, Courchesne, & Hill- tices in a theory of mind task ~Castelli, Frith, yard, 2005!. In contrast to these reductions of Happe, & Frith, 2002!, in response to socially activity, recent fMRI studies report normal familiar faces ~Pierce, Haist, Sedaghat, & activation in visual cortex in response to basic Courchesne, 2004!, during a gender or emo- visual stimuli ~Hadjikhani, Chabris, Joseph, tion decision task ~Hubl, Bolte, Feineis– Clark, McGrath, Aharon, Feczko, Tager– Matthews, Lanfermann, Federspiel, Strik, Flusberg, & Harris, 2004!. Furthermore, sev- Poustka, & Dierks, 2003!, in working mem- eral of the above-mentioned fMRI studies that ory tasks ~Luna, Minshew, Garver, Lazar, Thul- show reductions in frontal and0or temporal born, Eddy, & Sweeney, 2002!, in an embedded regions show increased activity in occipital figures task ~Ring, Baron–Cohen, Wheel- regions, including lateral extrastriate regions wright, Williams, Brammer, Andrew, & Bull- ~Ring et al., 1999!, medial occipital cortex more, 1999!, in an emotion Stroop task ~Hubl et al., 2003!, and ventral occipital cor- ~Kennedy, Redcay, & Courchesne, 2004!,in tex ~Belmonte & Yurgelun–Todd, 2003!. These visual spatial attention tasks ~Belmonte & findings suggest that posterior, lower order Yurgelun–Todd, 2003!, and during sentence regions may be relatively spared while ante- comprehension ~Just, Cherkassky, Keller, & rior, higher order regions may be more Minshew, 2004; Muller, Behen, Rothermel, severely affected. Furthermore, functional con- Chugani, Muzik, Mangner, & Chugani, 1999; nectivity studies have revealed reduced func- Muller, Chugani, Behen, Rothermel, Muzik, tional connectivity between lower order and Chakraborty, & Chugani, 1998!. ERP studies higher order brain regions ~e.g., occipital to have consistently found reduced or absent frontal, Castelli et al., 2002; superior temporal physiological responses from frontal cortex to inferior frontal, Just et al., 2004; and pari- during a variety of auditory and visual at- etal to frontal, Horwitz, Rumsey, Grady, & tention and orienting tasks ~Ciesielski, Rapoport, 1988!. 580 E. Courchesne et al.

Findings from the cerebellar cortex in au- the animals of choice for genetic and environ- tism appear to parallel those of the cerebral mental factors research on autism. cortex in that a similar dissociation between Although much data exist to document the higher order and lower order processes and behavioral and cognitive impairments in au- regions is seen. Although only a handful of tism, comparatively little is known about the functional neuroimaging studies of the cerebel- underlying microstructural neural defects. Ex- lum in autism exist, these studies reveal re- istent postmortem neuropathology studies that duced cerebellar activity during higher order have relied on visual qualitative inspection in tasks, including attention ~Allen & Courchesne, autism have shown abnormalities in micro- 2003!, listening to and generating sentences anatomy within frontal, temporal ~Bailey, Luth- ~Muller et al., 1998, 1999!, and judgement of ert, Dean, Harding, Janota, Montgomery, facial expression ~Critchley, Daly, Phillips, Rutter, & Lantos, 1998!, limbic ~Bauman & Brammer, Bullmore, Williams, Van Amels- Kemper, 2005; Kemper & Bauman, 1998!, and voort, Robertson, David, & Murphy, 2000! cerebellar regions ~Bailey et al., 1998; Kemper with normal to increased activity during lower & Bauman, 1998; Ritvo, Freeman, Scheibel, order motor tasks ~Allen & Courchesne, 2003; Duong, Robinson, Guthrie, & Ritvo, 1986!. Allen, Muller, & Courchesne, 2004; Muller, However, these qualitative studies have been Pierce, Ambrose, Allen, & Courchesne, 2001!. few in number, and none of these abnormali- The cerebellum has reciprocal projections to ties have been rigorously quantified. Further, both prefrontal ~Middleton & Strick, 2001! the nature of observed abnormalities revealed and temporal ~Schmahmann & Pandya, 1991! is diverse, from increased cell packing density lobes, and thus, not surprisingly, reductions of to laminar abnormalities to ectopic neurons in activity in the cerebellum during higher order white matter ~Bailey et al., 1998!. Indeed, nu- tasks are often seen with concurrent reduc- merous microstructural abnormalities likely un- tions in prefrontal or temporal lobe activity derlie the diverse behavioral phenotype of ~e.g., Muller et al., 1999!. These functional autism. Systematic and quantitative neuropath- findings suggest a system of neural dysfunc- ological investigations require such an invest- tion including higher order frontal, temporal, ment of time and effort that an uninformed and cerebellar regions may underlie many of search for potentially subtle, but important, the social and speech abnormalities seen in neuropathological differences would be inef- older children and adults with autism. ficient and impractical. Thus, knowledge of An important question is what structural candidate brain regions of abnormality in au- developmental abnormalities lead to these out- tism, as gained through cognitive neurosci- come frontal, temporal, and cerebellar neuro- ence, allows for an efficient hypothesis-driven functional abnormalities. It is argued here that analysis of neurobiological abnormalities in useful models and knowledge of the neural autism. Further, knowledge of regional neuro- developmental biology that precedes and pro- functional abnormalities provides an essential duces the initial autistic behavioral dysfunc- framework for interpreting the potential functions are necessary on three fronts: they can tional significance of postmortem neuronal and provide explanations for outcome neuro- molecular findings. For example, the neuro- behavioral deficits that have been carefully imaging literature would predict neuronal de- documented by behavioral and neuroimaging fects that are more apparent in prefrontal and research. They can provide information that higher order temporal regions but less appar- constrains and directs candidate causes that ent in occipital cortex. In sum, to understand can plausibly lead to these more specific early the emergence of autism, a multilevel analysis neural defects. Last, they can provide specific approach is useful wherein behavior informs neurobiological processes and defects for tar- cognitive neuroscience, which informs basic geting in animal models; autism is a disorder neurobiology, and vice versa. of higher order social, emotional, speech, lan- In the following paper, we will focus on guage, and cognitive functions that are not findings from macroscopic ~e.g., MRI! and convincingly modelable in rodents, which are microscopic structural investigations of au- Autism at the beginning 581

Figure 1. Golgi-stained sections showing the growth of pyramidal neuron soma and dendrites in the middle frontal gyrus. The normal newborn has sparse neural circuitry; then, with increasing age, there is a tremendous increase in the complexity of dendritic arborizations. In this frontal cortical area, the dendrite arbors for layer 3 pyramidal neurons, which are only 3% of mature size in the newborn, are still only about 50% by 2 years of age and do not reach 100% until the end of childhood ~see text!. From The Human Brain ~3rd ed!, by J. Nolte, 1993, St. Louis, MO: Mosby Year Book0Elsevier. Copyright 1993 by Mosby Year Book0Elsevier. Reprinted with permission from Elsevier.

tism, highlighting findings from very young ated by slowly maturing regions such as fron- children with autism. Further, we will attempt tal cortex, while basic sensory and perceptual to relate this new microstructural evidence with functions are mediated by relatively more rap- findings of macroscropic structural and func- idly and earlier maturing systems. tional abnormalities in autism. In the frontal cortex at birth, the length of the pyramidal cell dendritic arbors in layer 3 is only 3% of full mature size, and by 2 years White and Gray Matter Growth of age it is only 48% ~see example in Fig- Pathology in the First Years of Life ure 1!; many additional years will pass before in Autism: MRI Evidence full size is reached. By comparison, in primary visual cortex pyramidal dendritic arbors The first years of life are uniquely are already 33% of full size at birth, and by 2 important for brain development years they have reached mature size ~table 1.3 Figure 1 is an example of the sparse neural in Huttenlocher, 2002!. Myelination follows connections in the frontal cortex of a new- the same functional hierarchical pattern, with born. The circuitry necessary for complex in- basic-level systems developing earlier than formation processing and complex behavior higher order association systems ~Kinney, does not yet exist. Instead, it will be created in Brody, Kloman, & Gilles, 1988!. Compared the first postnatal years by neuronal differ- to more posterior cortices, frontal cortex un- entiation and growth, dendritic and axonal dergoes synapse formation later, and for a lon- growth, axonal myelination, and a tremen- ger period of time, and develops far larger dous increase in synapse numbers. Higher or- pyramidal neurons with far more synapses der social, emotional, cognitive, attention, ~about 100,000 vs. about 20,000! and far larger speech, and language functions are all medi- dendritic ~e.g., in layer 3, 6836 vs. 2900 mm! 582 E. Courchesne et al. and axonal arbors and axonal projections ~Hut- to be abnormally enlarged ~18 and 39%, re- tenlocher, 2002!. spectively!; cerebral gray matter is enlarged It has long been recognized that this unique by 11% ~Courchesne et al., 2001!. Most im- period of neural differentiation and circuit for- portantly, there were striking regional differ- mation is also a time when the brain is partic- ences in this overgrowth pathology: in 2- to ularly vulnerable to abnormal events that 4-year-old autistic toddlers, frontal cortex and disrupt the formation of cortical connectivity, frontal white matter volumes were the most producing aberrant circuits and functions and abnormally enlarged, but the occipital lobes behavioral deficits ~Dobbing, 1981; Hutten- did not differ significantly from normal ~Car- locher, 2002; Kinney et al., 1988!. More slowly per, Moses, Tigue, & Courchesne, 2002!. maturing brain regions such as frontal cortex Within the frontal cortex, dorsolateral and me- have a longer window of vulnerability than sial prefrontal cortices were most abnormal, more rapidly maturing ones, such as the oc- but the precentral gyrus, like the occipital lobe, cipital cortex. was not significantly different from normal ~Carper & Courchesne, 2005!. Temporal gray matter and parietal white matter were also en- Findings in young autistic children larged but not to the magnitude of frontal gray and white volumes ~Carper et al., 2002!;in Recent evidence indicates that autism may in- the limbic system, the amygdala was also en- volve brain growth pathology during this very larged by 4 years of age ~Sparks et al., 2002!. window of vulnerability; it is early, brief, and A PET study of 3- to 4-year-old autistic chil- age delimited ~for reviews, see Courchesne, dren reported hypoperfusion in frontal cortex 2004; Courchesne et al., 2004; Courchesne & in autism which was interpreted as evidence Pierce, 2005a; Dementieva, Vance, Donnelly, of delayed frontal maturation ~Zilbovicius, Elston, Wolpert, Ravan, DeLong, Abramson, Garreau, Samson, Remy, Barthelemy, Syrota, Wright, & Cuccaro, 2005!. At birth, head cir- & Lelord, 1995!. cumference in autism, and therefore brain size An equally striking and important second ~Bartholomeusz, Courchesne, & Karns, 2002!, phase of growth pathology in autism follows were found to be either equivalent to the nor- on the heels of the early overgrowth: abnormal average or slightly smaller than normal mally slow or arrested growth. A recent meta- ~Courchesne, Carper, & Akshoomoff, 2003; analysis of 12 MRI brain volume studies Courchesne et al., 2001; Dementieva et al., showed an autism brain size difference from 2005; Gillberg & de Souza, 2002; Lainhart, normal of about 11% between 1 and 3 years Piven, Wzorek, Landa, Santangelo, Coon, & of age, which declined through childhood Folstein, 1997!.1 During the first year of life ~when the normal, but not autistic, brain con- the autistic brain grows at an abnormally ac- tinues to grow!; by adolescence the autism celerated rate ~Dementieva et al., 2005; Mann brain size difference from normal is only about & Walker, 2003!, such that by the end of this 1–2% ~Redcay & Courchesne, 2005!.Be- critical period at 2–3 years of age, quantita- tween 2–4 and 6–8 years of age, frontal and tive MRI studies show it to be about 10% temporal cortical gray matter increase by 20 larger than normal ~Courchesne et al., 2001; and 17% in normal children but change by Piven, 2004; Sparks et al., 2002!. only 1 and Ϫ1%, respectively, in autism Both cerebral and cerebellar white matter ~Carper et al., 2002!. The dorsolateral sub- volumes in autistic toddlers have been found region of frontal cortex increases by 27% from 2–5 years to 5–9 years of age in normals, but 1. There is excellent agreement among reports of birth by only 7% in autistic children ~Carper & head circumference in autism: it was 34.7 cm in Gill- Courchesne, 2005!. White matter growth is berg and de Souza ~2002!, 34.17 cm in Lainhart et al. likewise retarded; for example, between 2 and ~1997!, and 34.65 cm in Courchesne et al. ~2003!. Normal average birth head circumference is between 4 years and 7 and 11 years of age, frontal 34.5 and 35.9 cm, depending on the clinical norms white matter volume increases by 45% in nor- used for reference ~Bartholomeusz et al., 2002!. mal children, but by only 13% in autistic chil- Autism at the beginning 583 dren ~Carper et al., 2002!, and between 2 and ~2003! reported greater white matter volume 3 years of age and adolescence, cerebellar white in 7- to 11-year-old autistic children and in a matter volume increases by 50% in normal second study found that this deviation from children, but by only 7% in autistic children normal was greatest in frontal white matter ~Courchesne et al., 2001!. Thus, regions that underlying cortex ~so-called “radiate white show the greatest early overgrowth in autism, matter”! and least in occipital lobe ~Herbert, frontal lobe and cerebellar white matter, also Ziegler, Makris, Filipek, Kemper, Normandin, show sharply reduced or arrested growth Sanders, Kennedy, & Caviness, 2004!. Har- thereafter. dan, Jou, Keshavan, Varma, and Minshew Last, in contrast to the cerebellar white ~2004! found abnormally increased gyrifica- matter changes just described, during early tion in frontal cortex in an autistic sample development in autism there appears to be a ranging in age from 8 to 50 years. Levitt, reduction in the size of one or another region Blanton, Smalley, Thompson, Guthrie, Mc- of the cerebellar vermis, which is largely gray Cracken, Sadoun, Heinichen, and Toga ~2003! matter ~review in Courchesne, 2004!.Inone reported that some frontal and temporal sulci MRI study with over 200 autistic and control are abnormally shifted superiorly and posteri- subjects ~making this the largest autism MRI orly in autistic children. Altered serotonin study ever done!, Hashimoto, Tayama, Mura- synthesis in the cerebello–thalamo–frontal kawa, Yoshimoto, Miyazaki, Harada, and pathway has been described in autistic chil- Kuroda ~1995, p. 229! reported underdevelop- dren ~Chugani, Muzik, Rothermel, Behen, ment of the cerebellar vermis in autistic indi- Chakraborty, Mangner, da Silva, & Chugani, viduals ranging from infants to adolescents. 1997! and a theory has been proposed linking In another MRI study of 3- to 9-year-old chil- serotonin abnormality during prenatal devel- dren, reduction in the size of cerebellar ver- opment to minicolumn and other neural abnor- mis lobules VI–VII was found to be specific malities in autism ~Chugani, 2000!. to autistic children compared with normal, fragile X, fragile X with autism, Down syndrome, and Down syndrome with autism children Microstructural Defects in Autism: ~Kaufmann, Cooper, Mostofsky, Capone, Prominent Cerebral and Kates, Newschaffer, Bukelis, Stump, Jann, & Cerebellar Abnormalities Lanham, 2003!. In a third recent MRI study of autistic children, the posterior portion of the According to in vivo MRIs of autistic toddlers cerebellar vermis was found to be signifi- and young children, the frontal lobe, which cantly reduced in size ~Levitt, Blanton, would be predicted to be the most vulnerable Capetillo–Cunliffe, Guthrie, Toga, & Mc- during postnatal neuronal growth, differentia- Cracken, 1999!. These findings are consistent tion, and circuit formation, is indeed the struc- with some previous developmental MRI stud- ture with the greatest early growth pathology ies reporting hypoplasia of the one or another and later functional pathology. Conversely, oc- region of the cerebellar vermis ~e.g., Ciesiel- cipital lobes would be predicted to be the least ski, Harris, Hart, & Pabst, 1997; Courchesne, vulnerable, and in fact, they show a nonsignif- Yeung–Courchesne, Press, Hesselink, & Jerni- icant difference from normal both structurally gan, 1988!. and functionally. Temporal and parietal cortices fall between these two extremes. This raises the hypothesis proposed by Courchesne and Findings in older autistic children Pierce ~2005a, 2005b! that fine quantitative and adults mapping of neural microstructure and white matter in autism will show that the greatest Recent structural imaging results on older au- pathology occurs in cortical association re- tistic children are compatible with this evi- gions that have the latest and most protracted dence of gray and white matter abnormality in neuronal and functional developmental time autistic toddlers. For example, Herbert et al. tables. 584 E. Courchesne et al.

Similarly, the cerebellum is vulnerable dur- lar Purkinje neuron numbers are abnormally ing the first 2 years of postnatal life because reduced in autism ~see reviews in Courchesne, the genesis of cerebellar cells continues well 1997, 2004!. Cerebellar Purkinje neuron loss into the first and perhaps second year of life. may be the single most commonly reported It is unique in this regard because neurogen- neuronal abnormality in the autism literature esis during brain development is prenatal for to date. all other major brain structures; whether this final phase of cytogenesis in the cerebellum Implications of increased cortical neurons generates neurons, glia or both is uncertain. and decreased Purkinje neurons This vulnerable structure also develops abnormally in autism in the first years of life accord- Many fundamental questions remain before ing to the in vivo MRI data reviewed above, the implications of an increase in cortical neu- and of all MRI abnormalities, the most strik- rons and axons can be fully interpreted. Are ing and pronounced is overgrowth of cerebel- there regional increases in neurons and axons lar white matter ~Courchesne et al., 2001!. that parallel regional increases in MRI gray and white matter volume? The only existent stereological count of cerebral neurons was Neuron numbers: Excess in cerebrum, global, not regional ~Schmitz, 2004!.Inour reduction in cerebellum pilot study, we reported what appeared to be In collaborative and as yet unpublished re- an increased number of neurons in layer 3 search projects, neuron numbers in the cere- throughout frontal cortical regions but not in brum, cerebellum, and subcortical structures primary visual cortex. Although this fits the in a set of autistic and control postmortem reports of regional MRI volumetric differ- cases aged 4–67 years were counted ~Schmitz, ences, it was not a stereologically conducted 2004; Wegiel, 2004!. These were among the count. It will be valuable for future studies to first studies to utilize modern stereological pro- perform regional stereological neuron counts. cedures in a study of the autistic brain. There Because cerebral neurons in different layers appeared to be a tendency toward an excess are generated at different but somewhat over- number of cerebral cortical neurons was found lapping developmental times, it will also be in autistic cases as compared to controls important to determine whether or not the in- ~Schmitz, 2004!. Interestingly, the magnitude creases are layer specific. There have been of this excess showed an age-related decline hypotheses that autism involves deficient cor- across child to adult autism cases. It is not yet tical inhibitory control, and so it will be inter- known whether there are regional differences esting to know if there is an imbalance in the in the excess neuron numbers or in the rate numbers of excitatory pyramidal neurons and and magnitude of the age-related decline in inhibitory interneurons such as chandelier cells. numbers. Because roughly 75–80% of cortical neurons In contrast, decreased neuron numbers were are pyramidal cells ~Jones, 1984!, an aberrant reported for the cerebellum and basal ganglia increase in their numbers could have a signif- ~Wegiel, 2004!. Cerebellar Purkinje neuron icant overall effect on both total neuron counts numbers were decreased by about 30% and and gray matter volume even if the number of the volume of the cerebellum was reduced by inhibitory neurons remained constant or even about 19%. This loss of Purkinje neurons was decreased slightly. seen at all ages in the autism sample from 4- An excess number of cerebral neurons could to 67-year-olds. Large decreases in neuron be because of any one of several possibilities: numbers were also reported for the nucleus a failure to correctly regulate the number of accumbens and basal ganglia, but neuron neurons produced during the neurogenesis numbers in the hippocampus were remarkably stage of prenatal development in autism, a similar in autistic and control cases. This quan- deficit or delay in apoptosis so that too many titative and stereological study adds to a large survive into postnatal life, or a compensatory number of observational reports that cerebel- neural genesis during perinatal or postnatal Autism at the beginning 585 life that is triggered by adverse events such as each of which could underlie the arrested or those that ignite the neuroinflammatory reac- slowed growth of gray and white matter that tion reported by Vargas, Nascimbene, Krish- has been observed in MRI studies of older au- nan, Zimmerman, and Pardo ~2005!. tistic children and adults. Already mentioned There is no experimental data as yet that were abnormal age-related declines in cerebral could speak to the abnormal neurogenesis pos- neuron numbers, the presence of abnormal lev- sibility. However, if the excess resulted from els of molecules that might promote apoptosis, an early prenatal failure to regulate genesis, and abnormally narrow minicolumns. Small cell then it might be expected that this early ex- size has been noted in the cingulate cortex cess would cause the brain to appear to be ~Kemper & Bauman, 1998! and in other frontal enlarged at birth as well as after birth, but in regions ~Buxhoeveden, Semendeferi, Schen- fact, in the majority of cases, head circumfer- kar, Switzer, & Courchesne, 2005! in older au- ence at birth in autism is normal to slightly tistic postmortem cases. smaller than normal. On the other hand, if the Increased numbers of cerebral neurons excess in neuron numbers is regionally lim- could underlie the volume increases in cere- ited to only late maturing frontal and other bral gray matter that have been reported in higher order association cortices, then per- MRI studies. In addition, an excess of neurons haps at birth its presence might not be appar- likely means an excess of axons, and this could ent and only becomes so across the first months underlie volume increases in white matter that and years of postnatal life. have also been reported in MRI studies of The second possibility involving abnormal autism. These excesses mean cortical connec- deficits or delays in apoptosis is compatible with tivity must be abnormal. Some have specu- observations of abnormally increased levels of lated that autism involves cerebral anatomical molecules that should promote apoptosis mol- overconnectivity ~Casanova, 2004!, while oth- ecules in frontal and cerebellar cortices in adult ers have argued in favor of cerebral functional autistic postmortem cases ~Araghi–Niknam & underconnectivity ~Belmonte & Yurgelun– Fatemi, 2003! and of an age-related decline in Todd, 2003; Horwitz et al., 1988; Just et al., the magnitude of the excess numbers from child- 2004!. It has also been suggested that the key hood to adult years in autism ~Schmitz, 2004!. is an abnormally increased ratio of excitation The third possibility involving an aberrant to inhibition ~Rubenstein & Merzenich, 2003!. late compensatory genesis could help explain Here it is proposed that each of these defects why the brain at birth in autism is not abnor- underlies autism: there is an abnormal ratio of mally enlarged in the great majority of cases. excitation to inhibition, there is anatomical It is now appreciated that such a “compensa- overconnectivity but primarily within frontal tory” late genesis of neural and glial cells can cortical regions, and there is functional under- occur in response to some adverse conditions connectivity but principally in long-distance ~Vaccarino & Ment, 2004!. frontoposterior reciprocal pathways. More- Abnormally slowed or arrested growth that over, it is proposed that connectivity patterns follows the brief period of overgrowth in the and defects change with development. autistic toddler could be because of a late onset of apoptosis as just discussed above, be- Minicolumns are abnormally narrow cause of the conclusion of the period of late in frontal and temporal cortex compensatory neural and glial genesis also but not occipital cortex just discussed, or because the excess of neurons and connections produces dysfunctional The minicolumn is a fundamental unit of in- neural activity that causes elimination or re- formation processing. Figure 2 shows sche- tarded growth of ineffective neurons, axons, matics of a minicolumn. The minicolumn is a and dendritic and axonal arbors. Certainly there roughly columnar vertical assembly of pyra- are a number of clear microstructural signs of midal neurons and interneurons, their inter- arrest of growth, loss, and insufficient devel- connections, and input and output axons that opment in the older child or adult with autism, extend from layer 6 up to the cortical surface. 586 Autism at the beginning 587

Each is 30–60 mm in diameter with perhaps 21, and 22; Casanova, Buxhoeveden, Switala, 80–100 pyramidal neurons per minicolumn. In & Roy, 2002!. In a pilot study, we aimed to humans, minicolumns in frontal association cor- determine which frontal regions have this mini- tex are nearly twice the diameter and several column abnormality, and whether this abnor- times the volume of those in primary sensory mality is present at the time of clinical onset cortices such as the primary visual cortex ~Bux- of autism. We measured minicolumn size in hoeveden & Casanova, 2002!. These 80–100 layer 3 throughout dorsal, mesial, and orbital pyramidal neurons are thought to have origi- frontal cortex in a postmortem 3-year-old nated from a common precursor cell during autistic case; minicolumn size in primary vi- neurogenesis in the second and third trimes- sual cortex was measured as a contrast site ters. Thus, the number of minicolumns in ce- ~Buxhoeveden et al., 2005!. To test whether rebral cortex reflects the number of precursor there is arrest of minicolumn growth in frontal cells that gave rise to each minicolumn. Ex- cortex in autism, we compared results from pansion of cerebral cortex and increase in its this 3-year-old to those from a postmortem processing power across evolution up to hu- 41-year-old adult with autism. We measured mans is due to an increase in the number of between 1,600 and 2,000 individual minicol- prenatally generated minicolumns. The verti- umns per case, and we also measured con- cal array of pyramidal cells is surrounded by trols. Minicolumn and neuropil sizes were neuropil space; in humans, this neuropil space significantly reduced throughout dorsal, me- that contains synapses and dendrites has ex- sial, and orbital frontal cortices in the 41-year- panded greatly, allowing for more complex mi- old adult with autism, being almost half the crocircuitry and refined and powerful neural volume of normal adults. In addition, minicol- computation within each minicolumn ~Buxho- umns and their surrounding neuropil space in eveden & Casanova, 2002!. These vertical as- the 3-year-old autistic case were nearly the semblies of interconnected pyramidal neurons same size as this 41-year-old autistic adult, have large inhibitory interneurons ~e.g., chan- which suggests the hypothesis that in autism delier cells! that modulate the synchronous out- minicolumn growth is arrested sometime dur- put of clusters of minicolumns. Synchronous ing early childhood. In contrast to findings in processing and signaling locally in minicol- frontal cortices, in both the 3-year-old and umns provide more powerful coherence of out- 41-year-old autistic cases, minicolumn size was put to other cortical regions and cortico–cortical normal in primary visual cortex. In addition, coupling.The function of minicolumns is to pro- in the frontal cortex in these autistic cases, vide fine tuning of information processing and there appeared to be an excess number of neu- learning within a cortical column. rons in each minicolumn, but this was not The first quantitative study of minicolumn stereologically confirmed. The reduction in size in autism examined layer 3 and found frontal minicolumn size in our small pilot study minicolumns to be abnormally narrow in one was greater than that reported for minicol- frontal and two temporal cortical areas ~BA 9, umns in temporal cortex in the Casanova et al.

Figure 2. The minicolumn is a fundamental unit of information processing. ~a! It is a roughly columnar vertical assembly of pyramidal neurons and interneurons, their interconnections, and input and output axons that extend from layer 6 up to the cortical surface. Each is 30–60 mm in diameter with perhaps 80–100 pyramidal neurons per minicolumn. ~b! A schematic closeup of cortical layer 3 within a minicolumn. The shaded area represents the neuropil space that surrounds the vertical assembly of neurons. This area contains mostly synapses, dendrites, and unmyelinated axons. The unshaded section is where the majority of the cell soma reside and it contains myelinated axons. From “Morphological Differences Between Minicolumns in Human and Nonhuman Primate Cortex,” by D. P. Buxhoeveden, A. E. Switala, E. Roy, M. Litaker, and M. F. Casanova, 2001, American Journal of Physical Anthropol- ogy, 115. Copyright 2001 by American Journal of Physical Anthropology. Adapted with permission from Wiley–Liss, a subsidiary of John Wiley & Sons, Inc. 588 E. Courchesne et al.

~2002! study. Together, the Casanova study neurons in the frontal cortex. Migration abnor- and our pilot study reveal regional differences mality could fracture or interrupt the funda- in minicolumn size in autism, with maximum mental vertical integrative feature of the maldevelopment in the dorsal and orbital fron- minicolumn organizational design, cause an tal cortex, somewhat less in the temporal cor- excess of neurons in some minicolumns but tex, and none detectable in the primary visual reduction in others, and0or produce an excess cortex. of neurons settling in certain layers within minicolumns and a deficit in other layers. Such migration-based defects would lead to frac- Implications of underdeveloped tionated and incompletely or aberrantly formed minicolumns minicolumn vertical circuitry, as well as an An interesting question is whether the in- imbalance between excitation and inhibition crease in cerebral neuron numbers indicates within and between minicolumns. This could too many minicolumns or too many neurons explain why minicolumns are “narrow” or “un- per minicolumn. The number of minicolumns derdeveloped” and an excess of neuron num- in cortex in autism has not been quantified. bers could explain why cortical gray matter Certainly, a modest increase in the number of volumes are larger than normal. otherwise normal minicolumns cannot ex- The presence of normal minicolumns in plain the emergence of autistic behavior in the primary sensory cortex may signal that the first 2 years of life. On the contrary, one can autistic brain retains the capacity for detailed imagine the opposite view: a modest increase and refined processing of lower level visual in the number of otherwise normal minicol- information, and in fact, normal visual activa- umns could produce a modest improvement in tion in autism has been found by recent fMRI information processing power. studies ~Hadjikhani et al., 2004!. Thus, corti- In contrast, an excess number of neurons cal areas of impaired and spared minicolumns per minicolumn would likely disrupt the nor- parallel areas of impaired and spared function mal intrinsic microcircuitry and physiological in autism. To our knowledge, this is the first functioning within each minicolumn, espe- evidence of such a regionally specific cere- cially if there is an imbalance between the bral cytoarchitectonic–cerebral function par- number of excitatory pyramidal cells per col- allel in autism. Major strides in understanding umn and the number of inhibitory cells. Be- the fundamental neural bases of autistic because normally more neurons are generated havior may ensue from combined investiga- than are later retained, an excess of neurons tions of regional differences in minicolumns, per minicolumn would be indicative of a fail- MRI volumetric growth patterns, and neuro- ure of the normal neuron selection and prun- functional activity. ing process of apoptosis. The retention of an The double defect of aberrant migration abnormal number of neurons and their connec- and an excess of neurons due to failure of tions would alter minicolumn circuit design normal apoptosis would be devastating to and function. Because minicolumn cell assem- minicolumn circuit formation and function. blies are thought to be the most basic unit of Although a simple increase in minicolumn refined information processing in cortex, their numbers does not by itself explain abnormal defect could be part of the explanation of in- function and behavior in the first 2 years of formation processing deficiencies in autism. life in autism, dysfunctional minicolumn as- A more profound disturbance of minicol- sembly could explain numerous findings of umn circuit design and function would result dysfunctional frontal activity. The underdevel- from migration abnormality. Migration de- opment of minicolumns in frontal cortex likely fects have been observed in several postmor- signals the failure of the normal emergence of tem autism cases ~Bailey et al., 1998!, and a diversity of highly specialized vertical func- Kennedy, Semendeferi, and Courchesne ~un- tional units that are necessary for the refined published! have also seen rafts of cells in ab- processing of and learning about information errant locations and disoriented pyramidal critical to higher order functions. Indeed, ab- Autism at the beginning 589 normalities in a variety of higher order social Implications of neuroinflammation ~Castelli et al., 2002; Pierce et al., 2004!, emo- and glial activation tional ~Kennedy et al., 2004!, and cognitive functions ~Belmonte & Yurgelun–Todd, 2003; Glial activation in cerebellar and frontal white Just et al., 2004; Luna, Minshew, Garver, Lazar, matter reported by Vargas et al. ~2005! might Thulborn, Eddy, & Sweeney, 2002! have been contribute to the significant increases in cer- demonstrated by neuroimaging in many stud- ebellar and frontal lobe white matter volumes ies of older children and adults with autism. documented by in vivo MRI in 2- to 4-year- old autistic children ~Carper et al., 2002; Courchesne et al., 2001!, as well as to the Abnormal glia activation and retarded growth in white matter after this early neuroinflammation are present overgrowth period. The reported glial activa- in frontal lobes and cerebellum tion involved enlargement of glial cell bodies in the autism postmortem cases ~Vargas et al., Vargas et al. ~2005! found evidence of astro- 2005!; although in that study the number of glial and microglial activation and neuroin- glial cells was not counted, it is possible that flammation in both white and gray matter in autism there might also be an increase in samples taken from posterior cerebellar hemi- glial cell numbers as part of the neuroinflam- spheres, the middle frontal gyrus and anterior mation reaction. Glial activation in white mat- cinguate gyrus in 5- to 44-year-old autistic ter that increases glial cell size and number postmortem cases. Macrophage chemoattrac- could be part of the explanation for the vol- tant protein ~MCP-1! and tumor growth factor- ume increases seen in structural MRI of young beta-1 ~TGF-b-1! derived from glia were the autistic children. It might also be speculated most prevalent cytokines. CSF taken from liv- that when glial activation reaches a plateau or ing autistic children also showed a marked steady state, it would no longer drive volume increase in MCP-1. In all three regions, there increases; if so, this might explain the second was enlargement of astroglial cell bodies and phase of growth pathology in autism: abnor- their processes. Microglial activation was mally slow or arrested growth. present in the cerebellum and cerebral cortex In the anterior cingulate gyrus and middle and its underlying white matter; the cerebel- frontal gyrus in the Vargas et al. ~2005! study, lum had the most pronounced microglial acti- microglial activation was prominent at the junc- vation. In the cerebellum, glial activation was tion of cortex and underlying white matter. In associated with degenerating Purkinje neu- vivo diffusion tensor imaging also reports white rons, granule cells and axons, and in nearly all matter abnormality in these same two frontal autistic brain examined, there was Purkinje zones in older autistic children ~Barnea– and granule cell loss. Degenerating Purkinje Goraly, Kwon, Menon, Eliez, Lotspeich, & cells were strongly immunoreactive for TGF- Reiss, 2004! and an in vivo MRI study reports b-1. In the anterior cingulate and middle fron- greater volume in autism in the white matter tal gyrus, microglial activation was prominent underlying cortex, the zone of so-called radi- at the junction of cortex and underlying white ate white matter tracts ~Herbert et al., 2004!. matter. There was no evidence of an adaptive Because brain size is normal to smaller than immune reaction ~e.g., T-cell infiltration or normal at birth in autism and the abnormal deposition of immunoglobulin! in the autistic acceleration of brain size begins in the first brains, but evidence of deposition of comple- postnatal months, if glial activation does play ment membrane attack complexes was ob- a role in the overgrowth then it must begin to served in the cerebellum, apparently associated do so sometime between late in the third tri- with Purkinje cells. Interestingly, compared to mester and the first postnatal months of life. the cerebellum and middle frontal gyrus, the It is uncertain how the neuroinflammation anterior cingulate gyrus had a more complex described by Vargas et al. ~2005! might be array of increased proinflammatory and mod- related to the recent report of an increase in ulatory cytokines. the number of cerebral neurons ~Schmitz, 590 E. Courchesne et al.

2004!, but there are several possibilities. One in autism including migration defects, mini- is that the neuroinflammatory activity signals column abnormality, connectivity defects and compensatory reactions that limit the process abnormal neuron numbers. Further research is of apoptosis in cerebral cortex thus sparing needed to determine whether the glial and mo- too many neurons. Another is that the neuroin- lecular abnormalities described by Vargas et al. flammatory activity signals a late onset, com- ~2005! are fundamentally neuroinflammatory pensatory proliferation of glia and cererbral reactions that begin prenatal or early postnatal cortical neurons ~see review in Vaccarino & or reflect aberrations in genetic mechanisms Ment, 2004!. Still another is that genetic fac- that regulate the normal role of glia during tors lead to overproduction of both neural and neural development and organization. glial cells as in the example of the p27 gene Excess glial production and0or activation knock-out model mentioned below. have the potential to produce any or all of the In either event, the overproduction of neu- previously discussed microstructural find- rons, and probably glial cells, may itself trig- ings, including frontal minicolumn abnormal- ger a still later compensatory response; in the ities and increased neuron counts. Abnormal Schmitz ~2004! study there was an age-related glial activation might also help explain some decline in the amount of excess cerebral neu- macrostructural findings in autism such as cer- ron numbers; another study ~Araghi–Niknam ebellar and frontal white matter overgrowth & Fatemi, 2003! found evidence in postmor- and gray matter reduction in the cerebellum. tem autism tissue of reduced anti-apoptotic In addition to its potential explanatory capac- and increased pro-apoptotic molecules in the ity for micro- and macrostructural findings, cerebral cortex. The age-related decline in ex- the increase in glial activity also could under- cess cerebral neuron numbers is compatible lie theories of autism based on functional im- with the in vivo MRI studies of the young aging studies, such as local overconnectivity autistic brain reviewed earlier. Namely, by 2–4 and long-distance underconnectivity, based on years of age, frontal and temporal gray matter the capacity of glia to alter synaptic strength volumes are abnormally enlarged, but there- ~Ullian, Christopherson, & Barres, 2004!. Ex- after they fail to increase in volume, whereas cess glial activation in the cerebellum is also normal cortex grows by about 20% in size in accord with previously discussed findings across childhood ~Carper et al., 2002; of abnormal cerebellar function ~Allen & Courchesne et al., 2001!. Courchesne, 2003; Allen et al., 2004!. Glial cells play key roles in brain organization during development as well as in neuroin- Summary and Conclusions flammatory reactions. They are involved in neural migration, minicolumn structural for- Evidence now supports the hypothesis that mation, and minicolumn function, as well as growth pathology throughout the first years of in apoptosis, including that of Purkinje cells postnatal life prevents the developmental for- ~Marin–Teva, Dusart, Colin, Gervais, van Roo- mation of neural circuitry in frontal, temporal, ijen, & Mallat, 2004!. For example, they nor- and cerebellar cortices that is essential for mally provide crucial signaling to migrating higher order social, emotional, language, neurons and growing axons, and disruption of speech, and cognitive functions ~Courchesne glial development and activity would disrupt & Pierce, 2005a, 2005b!. In the autistic infant neural development and axon connectivity pat- or toddler, the reason these higher order func- terns. They are hypothesized to play an essen- tions do not appear when they should or ap- tial role in minicolumn structural and functional pear only in a nascent form and then regress, development ~Colombo & Reisin, 2004!. Dis- is that neural maldevelopment in these partic- ruption of this role may prevent the emer- ular cortices precedes and prevents these es- gence of functionally discrete minicolumns. sential circuits from forming in the first place. Glial developmental abnormalities, which ap- The reason that it is not until the second and parently occur in autism, may play a part in more commonly the third year of life before it the genesis of microstructural abnormalities is realized that a toddler has autism, is be- Autism at the beginning 591 cause these frontal, temporal, and cerebellar be too small and too densely packed, signs circuits normally have a late and protracted indicating underdevelopment. Minicolumns in development and do not normally “come on- frontal and temporal association cortices ~but line” until the second and third years of life. not in primary visual cortex! are too narrow, a Thus, in the first year of life, the infant with finding suggestive of deviant development of autism and the normal infant are not easily this fundamental unit of neural microcircuitry. distinguished from each other: that is, both In frontal and cerebellar gray and white mat- the autistic and the normal infant lack many ter, astroglia and microglia are activated and of these higher order functions ~e.g., see molecular signals of a neuroinflammatory re- Table 1; most of the red flags of autism are action are present, both findings suggestive of behaviors that are also undeveloped in the nor- either an on-going but delayed developmental mal infant during the first month of life!. stage of apoptosis or an on-going innate in- At the macroscopic structural level, this flammatory reaction to some yet to be identi- process of neural maldevelopment is signaled fied trigger ~e.g., a chemical or pathogen by an abnormally accelerated rate of brain exposure, a genetic defect, etc.!. Finally, ac- growth after birth that is not sustained beyond cording to visual inspection ~and not yet ver- early childhood. By 2 to 4 years of age, the ified by quantitative experiments!, in some structures most abnormally enlarged are fron- autistic postmortem cases neural migration de- tal and temporal gray and white matter, the fects and abnormally oriented pyramidal cells amygdala, and cerebellar white matter. Struc- are both present in frontal and temporal corti- tural data from older children and adults with ces and migration defects are present in the autism shows an abnormal shift in the relative cerebellum. location of several frontal and temporal sulci These microstructural defects are present and increased folding of frontal cortex; white in autistic cases as young as 3 and 4 years, matter underlying frontal and temporal corti- ages during which in vivo MRI studies find ces may be especially abnormally increased in abnormal enlargement of these same cerebral volume and may have abnormal diffusion pat- and cerebellar structures. Thus, these defects terns that are indicative of either abnormally might play a role in the genesis of enlarge- oriented axons or other white matter pathol- ment of those structures. Certainly an excess ogy. Neurofunctional abnormalities in frontal, of cerebral neurons with its attendant excess temporal, and cerebellar cortices have been of axons and activated glial cells ~with per- demonstrated in children and adults with au- haps an increase in the number of glial cells! tism via a large number of fMRI, PET, and might each contribute to the gray and white ERP experiments ~Belmonte et al., 2004; Bel- matter volume increases seen in the first years monte & Yurgelun–Todd, 2003; Chugani et al., of life in autism. There is no evidence of an 1997; Dawson, Osterling, Rinaldi, Carver, & increase in the number of minicolumns, al- McPartland, 2001; Friedman, Shaw, Artru, though it has been speculated that there must Richards, Gardner, Dawson, Posse, & Dager, be an excess of them because cerebral gray 2003; Hughes, Russell, & Robbins, 1994; Luna matter volumes are increased. However, this et al., 2002; McEvoy, Rogers, & Pennington, is not the only explanation. Gray matter vol- 1993; Minshew et al., 1997; Pennington & umes might be increased because cortex is Ozonoff, 1996; Pierce et al., 2004; Rumsey & thicker due to an excess of neurons and pan- Hamburger, 1990; Townsend et al., 2001; Zil- laminar glial activation. Minicolumns might bovicius et al., 1995!. be thin but taller than normal. Another possi- At the microstructural level, both neuronal bility is that minicolumns are initially gener- and glial abnormalities are present in cerebral ated in normal numbers but become structurally and cerebellar structures. In the cerebrum, neu- and functionally fractionated due to migration ron numbers may be increased, but in the cer- abnormalities ~perhaps because glial guid- ebellum they are significantly decreased. ance signals are abnormal!, the failure of apop- Although cerebral neuron numbers may be in- tosis to establish a normal number of neurons creased, in some frontal regions neurons may within a column, or the pathological glial ac- 592 E. Courchesne et al. tivation, which might disturb the ability of an excess in the frontal cortex and perhaps astroglia to perform its developmental role in other association cortical regions but not in minicolumn functional organization. Together, basic-level systems, and there is concurrent an excess of neurons and fractionated minicol- glial activation. These abnormalities could umns might give the misimpression of an in- set in motion a cascade of maldevelopment crease in the number of columns that were in the frontal cortex via several pathways originally generated in early prenatal life. ~Courchesne & Pierce, 2005b!. First, early de- Brain enlargement is absent at birth in at velopment normally involves not only progres- least 94% or more of autistic infants ~review sive growth processes, but also regressive, in Courchesne & Pierce, 2005a!. This means selection, and elimination processes ~Hutten- either that the environmental and0or genetic locher, 2002; Quartz & Sejnowski, 1997!. defects and processes that generate acceler- Thus, abnormal cellular processes that create ated growth during the first years of life begin the overgrowth and then arrested growth dur- in perinatal or early postnatal periods, or that ing this vulnerable developmental time could they remain occult in some way until then. in turn accelerate, retard, or disrupt selection Several scenarios can be conceptualized that and regressive processes that would normally would produce the observed microstructural be occurring. Second, the activation of astro- and macrostructural outcomes. Adverse events glia might disrupt the ability of astroglia to ~e.g., Glasson, Bower, Petterson, de Klerk, play their normal postnatal role in frontal mini- Chaney, & Hallmayer, 2004! during late pre- column functional development. Third, the ex- natal, perinatal, or early postnatal life might cess of frontal cortical neurons after the normal trigger a neuroinflammatory reaction in fron- stage of apoptosis ~which is normally largely tal cortex including glial activation and gen- completed prenatal! might impede the refine- esis of new neural cells. Alternately, the number ment of within-minicolumn circuits, tip the of cortical neurons generated might be nor- excitatory–inhibitory balance in minicolumns mal, but for some reason there is a delay or towards excess excitation, and abnormally in- failure in apoptosis in frontal and possibly crease the target size for long-distance axons other association cortices. In that event, glial from posterior lower level systems which activation reflects a delayed, deviant, or in- would effectively dilute their impact on fron- effective apoptotic process. Another possibil- tal neural functioning. Further, following the ity is that perhaps the number of cortical simple principle that neurons that fire to- neurons generated far exceeds normal, and gether wire together, the abnormal excess of this triggers a prolonged, on-going “correc- frontal neurons, in the absence of normal lo- tive” apoptotic process that abnormally ex- cal inhibitory modulation, might be predicted tends into postnatal life. In addition to scenarios to create local and very short distance eddies in which an inflammation-inducing insult or of excitation that develop into excessively over- proliferative error causes multiple further disconnected but dysfunctional local and short- ruptions, neuronal overproliferation and glial distance circuits. Conversely, long-distance activation could share a common genetic root. cortical–cortical connectivity would be de- One example of a potential genetic base for creased because its development depends on many of the observed micro and macrostruc- spatiotemporally coherent bursts of activity. tural changes is the p27 gene. Its loss causes The net functional result is diminished impact dysregulation of cell proliferation cycles, re- of low-level information on frontal activity sulting in a 250% increase in glia cell num- and diminished impact of frontal activity on bers in the cerebellum and a 30% increase in posterior systems. In effect, then, frontal cor- hippocampal neurons ~Casaccia–Bonnefil, tex is, relative to normal, “disconnected” from Tikoo, Kiyokawa, Friedrich, Chao, & Koff, other cortical and subcortical structures, and 1997!. instead frontal cortex mainly “talks with it- A common theme across these and other self” ~Courchesne & Pierce, 2005b!. The cen- plausible scenarios is that in autism at birth, tral function of frontal cortex, to integrate there is an imbalance of neuron numbers with diverse information from multiple systems and Autism at the beginning 593 provide directive and adaptive feedback, does and reduced functional connectivity are mostly not develop in autism. from older children and adults. Cognitive In the beginning in autism, we hypothesize neuroscience studies of the younger autistic that frontal functions fail to develop normally child are needed to determine if similar neuroin the first years of life and so the first signs of functional findings are present during the early autism are absent or deviant frontal-mediated period of deviant brain development. As seen behaviors. Underlying frontal dysfunction from the anatomical evidence outlined in this may be defective minicolumn microcir- paper, there are macro- and microstructural cuitry, excessive but disorganized local and differences between young children with au- short-distance connectivity, and deficient long- tism and adults with autism, including mea- distance reciprocal cortical–cortical connec- sures of total brain size, gray and white matter tivity. Low-level, basic information processing volumes, and neuron numbers. Thus, it is un- may be relatively spared but it may fail to be likely that neurofunctional findings from the utilized in the serve of high-order context- older autistic child or adult will be generaliz- based, goal-directed behavior. Thus, aberrant able to the infant or toddler in whom autism is cortical long-distance and local circuitry would just emerging. Unfortunately, the new field of impair the essential role of frontal cortex in developmental cognitive neuroscience has been integrating information from diverse and dis- severely slowed by the difficulty in adapting tant functional systems ~emotional, sensory, cognitive neuroscience technologies used in autonomic, memory, etc.! and in providing adults to infants and children. The first docu- context-based and goal-directed feedback to mentation of cognitive ERP components in lower level systems. infants ~Courchesne, Ganz, & Norcia, 1981! This hypothesis of neural information pro- came nearly 2 decades after they were first cessing is corroborated by neurofunctional documented in adults. The first fMRI study of findings of reduced activity in higher order healthy, typically developing infants was car- frontal and temporal regions but normal to ried out in 2001 ~Anderson, Marois, Colson, increased activity in lower order posterior re- Peterson, Duncan, Ehrenkranz, Schneider, gions, as well as reduced functional connec- Gore, & Ment, 2001!, following almost a de- tivity between regions as described above. A cade with scores of fMRI studies of healthy lack of input from higher order association adults. Clearly, there is an enormous gap in regions would lead to a cognitive processing our understanding of the neural development style that is fragmented and incomplete. Rather, of cognitive processes in humans. Such work sensory cortices may receive input normally is of vital importance to link early structural but fail to send and receive inputs from higher findings ~i.e., microscopic postmortem and order association regions, due to deficient long macroscopic MRI! with the emergence of the distance connectivity. This may account for autistic cognitive and behavioral phenotype. the behavioral findings of decreased contex- Significant gains in our understanding of tual and social processing but enhanced pitch the neuroscience of autism will likely be made and visual–perceptual processing. by embracing a combined neurobiological and It is important that these findings of re- cognitive neuroscience approach directed to- duced neural activity in higher order regions ward the early development of autism.

References

Allen, G., & Courchesne, E. ~2003!. Differential effects Anderson,A. W., Marois, R., Colson, E. R., Peterson, B. S., of developmental cerebellar abnormality on cognitive Duncan, C. C., Ehrenkranz, R. A., Schneider, K. C., and motor functions in the cerebellum: An fMRI study Gore, J. C., & Ment, L. R. ~2001!. Neonatal auditory of autism. American Journal of Psychiatry, 160, activation detected by functional magnetic resonance 262–273. imaging. Magnetic Resonance Imaging, 19, 1–5. Allen, G., Muller, R. A., & Courchesne, E. ~2004!. Cer- Araghi–Niknam, M., & Fatemi, S. H. ~2003!. Levels of ebellar function in autism: Functional magnetic reso- Bcl-2 and P53 are altered in superior frontal and cer- nance image activation during a simple motor task. ebellar cortices of autistic subjects. Celullar and Mo- Biological Psychiatry, 56, 269–278. lecular Neurobiology, 23, 945–952. 594 E. Courchesne et al.

Bailey, A., Luthert, P., Dean, A., Harding, B., Janota, I., Carper, R. A., Moses, P., Tigue, Z. D., & Courchesne, E. Montgomery, M., Rutter, M., & Lantos, P. ~1998!.A ~2002!. Cerebral lobes in autism: Early hyperplasia clinicopathological study of autism. Brain, 121, and abnormal age effects. NeuroImage, 16, 1038–1051. 889–905. Casaccia–Bonnefil, P., Tikoo, R., Kiyokawa, H., Friedrich, Barnea–Goraly, N., Kwon, H., Menon, V., Eliez, S., J., Chao, M., & Koff, A. ~1997!. Oligodendrocite pre- Lotspeich, L., & Reiss, A. L. ~2004!. White matter curser differentiation is perturbed in the absence of structure in autism: Preliminary evidence from diffu- the cylin-dependent kinase inhibitor p27kip1. Genes siontensorimaging.BiologicalPsychiatry,55,323–326. and Development, 11, 2335–2346. Baron–Cohen, S., Leslie, A. M., & Frith, U. ~1985!. Does Casanova, M. F. ~2004!. White matter volume increase the autistic child have a “theory of mind”? Cognition, and minicolumns in autism. Annals of Neurology, 56, 21, 37–46. 453; author reply 454. Bartholomeusz, H. H., Courchesne, E., & Karns, C. ~2002!. Casanova, M. F., Buxhoeveden, D. P., Switala, A. E., & Relationship between head circumference and brain Roy, E. ~2002!. Minicolumnar pathology in autism. volume in healthy normal toddlers, children, and adults. Neurology, 58, 428–432. Neuropediatrics, 33, 239–241. Castelli, F., Frith, C., Happe, F., & Frith, U. ~2002!. Au- Bauman, M. L., & Kemper, T. L. ~2005!. Neuroanatomic tism, Asperger syndrome and brain mechanisms for observations of the brain in autism: A review and the attribution of mental states to animated shapes. future directions. International Journal of Develop- Brain, 125, 1839–1849. mental Neuroscience, 23, 183–187. Ceponiene, R., Lepisto, T., Shestakova, A., Vanhala, R., Belmonte, M. K., Cook, E. H., Jr., Anderson, G. M., Alku, P., Naatanen, R., & Yaguchi, K. ~2003!. Speech- Rubenstein, J. L., Greenough, W. T., Beckel–Mitchener, sound-selective auditory impairment in children with A., Courchesne, E., Boulanger, L. M., Powell, S. B., autism: They can perceive but do not attend. Proceed- Levitt, P. R., Perry, E. K., Jiang, Y. H., DeLorey, ings of the National Academy of Sciences USA, 100, T. M., & Tierney, E. ~2004!. Autism as a disorder of 5567–5572. neural information processing: Directions for re- Chugani, D. ~2000!. Autism. In M. Ernst & J. Rumsey search and targets for therapy ~1!. Molecular Psychi- ~Eds.!, The foundation and future of functional neuro- atry, 9, 646–663. imaging in child psychiatry ~pp. 171–188!. New York: Belmonte, M. K., & Yurgelun–Todd, D. A. ~2003!. Func- Cambridge University Press. tional anatomy of impaired selective attention and Chugani, D. C., Muzik, O., Rothermel, R. D., Behen, compensatory processing in autism. Cognitive Brain M. E., Chakraborty, P. K., Mangner, T. J., da Silva, Research, 17, 651–664. E. A., & Chugani, H. T. ~1997!. Altered serotonin Boddaert, N., Belin, P., Chabane, N., Poline, J. B., Bar- synthesis in the dentato–thalamo–cortical pathway in thelemy, C., Mouren–Simeoni, M. C., Brunelle, F., autistic boys. Annals of Neurology, 14, 666–669. Samson, Y., & Zilbovicius, M. ~2003!. Perception of Ciesielski, K.T, Harris, R., Hart, B., & Pabst, H. ~1997!. complex sounds: Abnormal pattern of cortical activa- Cerebellar hypoplasia and frontal lobe cognitive def- tion in autism. American Journal of Psychiatry, 160, icits in disorders of early childhood. Neuropsycholo- 2057–2060. gia, 35, 643–655. Boddaert, N., Chabane, N., Belin, P., Bourgeois, M., Royer, Ciesielski, K. T., Courchesne, E., & Elmasian, R. ~1990!. V., Barthelemy, C., Mouren–Simeoni, M. C., Phil- Effects of focused selective attention tasks on event- ippe, A., Brunelle, F., Samson, Y., & Zilbovicius, M. related potentials in autistic and normal individuals. ~2004!. Perception of complex sounds in autism: Ab- Electroencephalography and Clinical Neurophysiol- normal auditory cortical processing in children. Amer- ogy, 75, 207–220. ican Journal of Psychiatry, 161, 2117–2120. Colombo, J., & Reisin, H. ~2004!. Interlaminar astroglia Bruneau, N., Roux, S., Adrien, J. L., Barthelemy, C. ~1999!. of the cerebral cortex: A marker of the primate brain. Auditory associative cortex dysfunction in children Brain Research, 1006, 126–131. with autism: Evidence from late autitory evoked po- Courchesne, E. ~1997!. Brainstem, cerebellar and limbic tentials ~N1 wave-T complex!. Clinical Neurophysi- neuroanatomical abnormalities in autism. Current ology, 110, 1927–1924. Opinion in Neurobiology, 7, 269–278. Bruneau, N., Bonnet–Brilhault, F., Gomot, M., Adrien, Courchesne, E. ~2004!. Brain development in autism: Early J. L., & Barthelemy, C. ~2003!. Cortical auditory pro- overgrowth followed by premature arrest of growth. cessing and communication in children with autism: Mental Retardation and Developmental Disabilities Electrophysiological0behavioral relations. Inter- Research Reviews, 10, 106–111. national Journal Psychophysiology, 51, 17–25. Courchesne, E., Carper, R., & Akshoomoff, N. ~2003!. Buxhoeveden, D. P., Semendeferi, K., Schenkar, N., Swit- Evidence of brain overgrowth in the first year of life zer, R., & Courchesne, E. ~2005!. Reduced mini- in autism. Journal of the American Medical Associa- columns in frontal cortex in patients with autism. tion, 290, 337–344. Unpublished manuscript. Courchesne, E., Ganz, L., & Norcia, A. M. ~1981!. Event- Buxhoeveden, D. P., & Casanova, M. F. ~2002!. The mini- related brain potentials to human faces in infants. Child column hypothesis in neuroscience. Brain, 125~Pt 5!, Development, 52~3!. 935–951. Courchesne, E., Karns, C., Davis, H. R., Ziccardi, R., Buxhoeveden, D. P., Switala, A. E., Roy, E., Litaker, M., Carper, R., Tigue, Z., Pierce, K., Moses, P., Chisum, & Casanova, M. F. ~2001!. Morphological differences H. J., Lord, C., Lincoln, A. J., Pizzo, S., Schreibman, between minicolumns in human and nonhuman pri- L., Haas, R. H., Akshoomoff, N., & Courchesne, mate cortex. American Journal of Physical Anthropol- R. Y. ~2001!. Unusual brain growth patterns in early ogy, 115, 361–371. life in patients with autistic disorder: An MRI study. Carper, R. A., & Courchesne, E. ~2005!. Localized en- Neurology, 57, 245–254. largement of the frontal cortex in early autism. Bio- Courchesne, E., Kilman, B. A., Galambos, R., & Lincoln, logical Psychiatry, 57, 126–133. A. J. ~1984!. Autism: Processing of novel auditory Autism at the beginning 595

information assessed by event-related brain poten- ~2003!. Cortical sound processing in children with tials. Electroencephalography and Clinical Neurophys- autism disorder: An MEG investigation. NeuroRe- iology, 59, 238–248. port, 14, 2047–2051. Courchesne, E., & Pierce, K. ~2005a!. Brain overgrowth Gervais, H., Belin, P., Boddaert, N., Leboyer, M., Coez, in autism during a critical time in development: Im- A., Sfaello, I., Barthelemy, C., Brunelle, F., Samson, plications for frontal pyramidal neuron and interneu- Y., & Zilbovicius, M. ~2004!. Abnormal cortical voice ron development and connectivity. International processing in autism. Nature Neuroscience, 7, 801–802. Journal of Developmental Neuroscience, 23, 153–170. Gillberg, C., & de Souza, L. ~2002!. Head circumference Courchesne, E., & Pierce, K. ~2005b!. Why the frontal in autism, Asperger syndome, and ADHD: A compar- cortex in autism might be talking only to itself: Local ative study. Developmental Medicine and Child Neu- overconnectivity but long-distance disconnection. Cur- rology, 44, 296–300. rent Opinion in Neurobiology, 15, 225–230. Glasson, E. J., Bower, C., Petterson, B., de Klerk, N., Courchesne, E., Redcay, E., & Kennedy, D. P. ~2004!. Chaney, G., & Hallmayer, J. F. ~2004!. Perinatal fac- The autistic brain: Birth through adulthood. Current tors and the development of autism: A population Opinion in Neurology, 17, 489–496. study. Archives of General Psychiatry, 61, 618–627. Courchesne, E., Townsend, J., Akshoomoff, N. A., Saitoh, Hadjikhani, N., Chabris, C., Joseph, R., Clark, J., McGrath, O., Yeung–Courchesne, R., Lincoln, A. J., James, L., Aharon, I., Feczko, E., Tager–Flusberg, H., & Har- H. E., Haas, R. H., Schreibman, L., & Lau, L. ~1994!. ris, G. ~2004!. Early visual cortex organization in Impairment in shifting attention in autistic and autism: An fMRI study. NeuroReport, 15, 267–270. cerebellar patients. Behavioral Neuroscience, 108, Hardan, A. Y., Jou, R. J., Keshavan, M. S., Varma, R., & 848–865. Minshew, N. J. ~2004!. Increased frontal cortical fold- Courchesne, E.,Yeung–Courchesne, R., Press, G.A., Hesse- ing in autism: A preliminary MRI study. Psychiatry link, J. R., & Jernigan, T. L. ~1988!. Hypoplasia of Research, 131, 263–268. cerebellar vermal lobules VI and VII in autism. New Hashimoto, T., Tayama, M., Murakawa, K., Yoshimoto, England Journal of Medicine, 318, 1349–1354. T., Miyazaki, M., Harada, M., & Kuroda, Y. ~1995!. Critchley, H., Daly, E., Phillips, M., Brammer, M., Bull- Development of the brainstem and cerebellum in au- more, E., Williams, S., Van Amelsvoort, T., Robert- tistic patients. Journal of Autism and Developmental son, D., David, A., & Murphy, D. ~2000!. Explicit and Disorders, 25, 1–18. implicit neural mechanisms for processing of social Herbert, M. R., Ziegler, D. A., Deutsch, C. K., O’Brien, information from facial expressions: A functional mag- L. M., Lange, N., Bakardjiev, A., Hodgson, J., Adrien, netic resonance imaging study. Human Brain Map- K. T., Steele, S., Makris, N., Kennedy, D., Harris, ping, 9, 93–105. G. J., & Caviness, V. S., Jr. ~2003!. Dissociations of Dawson, G., Finley, C., Phillips, S., Galpert, L., & Lewy, cerebral cortex, subcortical and cerebral white matter A. ~1988!. Reduced P3 amplitude of the event-related volumes in autistic boys. Brain, 126, 1182–1192. brain potential: Its relationship to language ability in Herbert, M. R., Ziegler, D. A., Makris, N., Filipek, P. A., autism. Journal of Autism and Developmental Disor- Kemper, T. L., Normandin, J. J., Sanders, H. A., Ken- ders, 18, 493–504. nedy, D. N., & Caviness, V. S., Jr. ~2004!. Localiza- Dawson, G., Osterling, J., Meltzoff, A. N., & Kuhl, P. tion of white matter volume increase in autism and ~2000!. Case study of the development of an infant developmental language disorder. Annals of Neurol- with autism from birth to two years of age. Journal of ogy, 55, 530–540. Applied Developmental Psychology, 21, 299–313. Hobson, R. P. ~1993!. The emotional origins of social Dawson, G., Osterling, J., Rinaldi, J., Carver, L., & Mc- understanding. Philosophical Psychology, 6, 227–249. Partland, J. ~2001!. Brief report: Recognition memory Horwitz, B., Rumsey, J. M., Grady, C. L., & Rapoport, and stimulus–reward associations: Indirect support S. I. ~1988!. The cerebral metabolic landscape in au- for the role of ventromedial prefrontal dysfunction in tism. Intercorrelations of regional glucose utilization. autism. Journal of Autism and Developmental Dis- Archives of Neurology, 45, 749–755. orders, 31, 337–341. Hubl, D., Bolte, S., Feineis–Matthews, S., Lanfermann, Dementieva, Y. A., Vance, D. D., Donnelly, S. L., Elston, H., Federspiel, A., Strik, W., Poustka, F., & Dierks, T. L. A., Wolpert, C. M., Ravan, S. A., DeLong, G. R., ~2003!. Functional imbalance of visual pathways in- Abramson, R. K., Wright, H. H., & Cuccaro, dicates alternative face processing strategies in au- M. L. ~2005!. Accelerated head growth in early devel- tism. Neurology, 61, 1232–1237. opment of individuals with autism. Pediatric Neurol- Hughes, C., Russell, J., & Robbins, T. W. ~1994!. Evi- ogy, 32, 102–108. dence for executive dysfunction in autism. Neuropsy- Dobbing, J. ~1981!. The later development of the brain chologia, 32, 477–492. and its vulnerability. In J. A. Dobbing ~Ed.!, Scientific Huttenlocher, P. ~2002!. Neural plasticity: The effects of foundations of pediatrics ~2nd ed., pp. 744–759!. Lon- environment on the development of cerebral cortex. don: William Heinemann Medical Books. Cambridge, MA: Harvard University Press. Friedman, S. D., Shaw, D. W., Artru, A. A., Richards, Jones, E. G. ~1984!. Laminar distribution of cortical ef- T. L., Gardner, J., Dawson, G., Posse, S., & Dager, ferent cells. In A. Peters & E. G. Jones ~Eds.!, Cere- S. R. ~2003!. Regional brain chemical alterations in bral cortex: Cellular components of the cerebral cortex young children with autism spectrum disorder. Neu- ~pp. 521–553!. New York: Plenum Press. rology, 60, 100–107. Just, M. A., Cherkassky, V. L., Keller, T. A., & Minshew, Frith, C. ~2003!. What do imaging studies tell us about N. J. ~2004!. Cortical activation and synchronization the neural basis of autism? Novartis Foundation Sym- during sentence comprehension in high-functioning posium, 251, 149–166; discussion 166–176, 281–197. autism: Evidence of underconnectivity. Brain, 127, Frith, U., & Happe, F. ~1994!. Autism: Beyond “theory of 1811–1821. mind.” Cognition, 50, 115–132. Kaufmann, W. E., Cooper, K. L., Mostofsky, S. H., Ca- Gage, N. M., Siegel, B., Callen, M., & Roberts, T. P. pone, G. T., Kates, W. R., Newschaffer, C. J., Bukelis, 596 E. Courchesne et al.

I., Stump, M. H., Jann, A. E., & Lanham, D. C. ~2003!. Courchesne, E. ~2001!. Atypical patterns of cerebral Specificity of cerebellar vermian abnormalities in au- motor activation in autism: A functional magnetic res- tism: A quantitative magnetic resonance imaging study. onance study. Biological Psychiatry, 49, 665–676. Journal of Child Neurology, 18, 463–470. Mundy, P. ~1995!. Joint attention and social–emotional Kemper, T., & Bauman, M. ~1998!. Neuropathology of approach behavior in children with autism. Develop- infantile autism. Journal of Neuropathology and Ex- ment and Psychopathology, 7, 63–82. perimental Neurology, 57, 645–652. Mundy, P. ~2003!. Annotation: The neural basis of social Kennedy, D. P., Redcay, E., & Courchesne, E. ~2004!. impairments in autism: The role of the dorsal medial– Cognition, emotion, and the resting state: An fMRI frontal cortex and anterior cingulate system. Journal study of neurofunctional abnormalities in autism. Pa- of Child Psychology and Psychiatry and Allied Dis- per presented at the IMFAR, Sacramento, CA. ciplines, 44, 793–809. Kinney, H. C., Brody, B. A., Kloman, A. S., & Gilles, Nolte, J. ~1993!. The human brain ~3rd ed.!. St. Louis, F. H. ~1988!. Sequence of central nervous system MO: Mosby Year Book. myelination in human infancy. II. Patterns of myeli- Pennington, B. F., & Ozonoff, S. ~1996!. Executive func- nation in autopsied infants. Journal of Neuropathol- tions and developmental psychopathology. Journal of ogy and Experimental Neurology, 47, 217–234. Child Psychology and Psychiatry and Allied Dis- Lainhart, J. E., Piven, J., Wzorek, M., Landa, R., Santan- ciplines, 37, 51–87. gelo, S. L., Coon, H., & Folstein, S. E. ~1997!. Macro- Pierce, K., Haist, F., Sedaghat, F., & Courchesne, E. ~2004!. cephaly in children and adults with autism. Journal of The brain response to personally familiar faces in the American Academy of Child and Adolescent Psy- autism: Findings of fusiform activity and beyond. chiatry, 36, 282–290. Brain, 127, 2703–2716. Levitt, J. G., Blanton, R., Capetillo–Cunliffe, L., Guthrie, Pierce, K., Müller, R.-A., Ambrose, J., Allen, G., & D., Toga, A., & McCracken, J. T. ~1999!. Cerebellar Courchesne, E. ~2001!. Face processing occurs out- vermis lobules VIII–X in autism. Progress in Neuro- side the fusiform “face area” in autism: Evidence from psychopharmacology and Biological Psychiatry, 23, fMRI. Brain, 124, 2059–2073. 625–633. Piven, J. ~2004, May 7!. Longitudinal MRI study of 18–35 Levitt, J. G., Blanton, R. E., Smalley, S., Thompson, P. M., month olds with autism. Paper presented at the Inter- Guthrie, D., McCracken, J. T., Sadoun, T., Heinichen, national Meeting for Autism Research, Sacramento, L., & Toga, A. W. ~2003!. Cortical sulcal maps in California. autism. Cerebral Cortex, 13, 728–735. Quartz, S. R., & Sejnowski, T. J. ~1997!. The neural basis Luna, B., Minshew, N. J., Garver, K. E., Lazar, N. A., of cognitive development: A constructivist manifesto. Thulborn, K. R., Eddy, W. F., & Sweeney, J.A. ~2002!. Behavioral Brain Science, 20, 537–556; discussion Neocortical system abnormalities in autism: An fMRI 556–596. study of spatial working memory. Neurology, 59, Redcay, E., & Courchesne, E. ~2005!. When is the brain 834–840. enlarged in autism? A meta analysis of all brain size Mann, T. A., & Walker, P. ~2003!. Autism and a deficit in reports. Biological Psychiatry, 58,1–9. broadening the spread of visual attention. Journal of Ring, H. A., Baron–Cohen, S., Wheelwright, S., Wil- Child Psychology and Psychiatry and Allied Disci- liams, S. C., Brammer, M., Andrew, C., & Bullmore, plines, 44, 274–284. E. T. ~1999!. Cerebral correlates of preserved cog- Marin–Teva, J. L., Dusart, I., Colin, C., Gervais, A., van nitive skills in autism: A functional MRI study of Rooijen, N., & Mallat, M. ~2004!. Microglia promote embedded figures task performance. Brain, 122, the death of developing Purkinje cells. Neuron, 41, 1305–1315. 535–547. Ritvo, E. R., Freeman, B. J., Scheibel, A. B., Duong, T., McEvoy, R. E., Rogers, S. J., & Pennington, B. F. ~1993!. Robinson, H., Guthrie, D., & Ritvo, A. ~1986!. Lower Executive function and social communication deficits Purkinje cell counts in the cerebella of four autistic in young autistic children. Journal of Child Psychol- subjects: Initial findings of the UCLA–NSAC au- ogy and Psychiatry andAllied Disciplines, 34, 563–578. topsy research report. American Journal of Psychia- Middleton, F. A., & Strick, P. L. ~2001!. Cerebellar pro- try, 143, 862–866. jections to the prefrontal cortex of the primate. Jour- Rogers, S. J., & Pennington, B. F. ~1991!. A theoretical nal of Neuroscience, 21, 700–712. approach to the deficits in infantile autism. Develop- Minshew, N. J., Goldstein, G., & Siegel, D. J. ~1997!. ment and Psychopathology, 3, 137–162. Neuropsychologic functioning in autism: Profile of a Rubenstein, J. L., & Merzenich, M. M. ~2003!. Model complex information processing disorder. Journal of autism: Increased ratio of excitation0inhibition in of the International Neuropsychological Society, 3, key neural systems. Genes Brain and Behavior, 2, 303–316. 255–267. Muller, R. A., Behen, M. E., Rothermel, R. D., Chugani, Rumsey, J. M., & Hamburger, S. D. ~1990!. Neuropsycho- D. C., Muzik, O., Mangner, T. J., & Chugani, H. T. logical divergence of high-level autism and severe ~1999!. Brain mapping of language and auditory per- dyslexia. Journal of Autism and Developmental Dis- ception in high-functioning autistic adults: A PET study. orders, 20, 155–168. Journal of Autism and Developmental Disorders, 29, Schmahmann, J. D., & Pandya, D. N. ~1991!. Projections 19–31. to the basis pontis from the superior temporal sulcus Muller, R. A., Chugani, D. C., Behen, M. E., Rothermel, and superior temporal region in the rhesus monkey. R. D., Muzik, O., Chakraborty, P. K., & Chugani, Journal of Comparative Neurology, 308, 224–248. H. T. ~1998!. Impairment of dentato–thalamo–cortical Schmitz, C. ~2004, November 13!. New aspects in the pathway in autistic men: Language activation data neuropathology of the forebrain in autism. Paper pre- from positron emission tomography. Neuroscience Let- sented at the Integrating the Clinical and Basic Sci- ters, 245,1–4. ences of Autism: A Developmental Biology Workshop, Muller, R. A., Pierce, K., Ambrose, J. B., Allen, G., & Ft. Lauderdale, FL. Autism at the beginning 597

Sparks, B. F., Friedman, S. D., Shaw, D. W., Aylward, E., Vaccarino, F. M., & Ment, L. R. ~2004!. Injury and repair Echelard, D., Artru, A. A., Maravilla, K. R., Giedd, in developing brain. Archives of Diseases in Child- J. N., Munson, J., Dawson, G., & Dager, S. R. ~2002!. hood. Fetal and Neonatal Edition, 89, F190–F192. Brain sructural abnormalities in young children with Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmer- autism spectrum disorder. Neurology, 59, 184–192. man, A. W., & Pardo, C. A. ~2005!. Neuroglial acti- Teder–Salejarvi, W. A., Pierce, K., Courchesne, E., & vation and neuroinflammation in the brain of patients Hillyard, S. A. ~2005!. Auditory spatial localization with autism. Annals of Neurology, 57, 67–81. and attention deficits in autistic adults. Cognitive Brain Wegiel, J. ~2004, November 13, 2004!. Subcortical neuro- Research, 23, 221–234. pathology. Paper presented at the Integrating the Clin- Townsend, J., Courchesne, E., Covington, J., Westerfield, ical and Basic Sciences of Autism: A Developmental M., Harris, N. S., Lyden, P., Lowry, T. P., & Press, Biology Workshop, Ft. Lauderdale, FL. G. A. ~1999!. Spatial attention deficits in patients with Wetherby, A. M., Woods, J., Allen, L., Cleary, J., Dickin- acquired or developmental cerebellar abnormality. son, H., & Lord, C. ~2004!. Early indicators of autism Journal of Neuroscience, 19, 5632–5643. spectrum disorders in the second year of life. Journal Townsend, J., Westerfield, M., Leaver, E., Makeig, S., of Autism and Developmental Disorders, 34, 473–493. Jung, T.-P., Pierce, K., & Courchesne, E. ~2001!. Event- Williams, J. H., Whiten, A., Suddendorf, T., & Perrett, related brain response abnormalities in autism: Evi- D. I. ~2001!. Imitation, mirror neurons and autism. dence for impaired cerebello–frontal spatial attention Neuroscience and Biobehavioral Reviews, 25, 287–295. networks. Cognitive Brain Research, 11, 127–145. Zilbovicius, M., Garreau, B., Samson, Y., Remy, P., Bar- Ullian, E. M., Christopherson, K. S., & Barres, B. A. thelemy, C., Syrota, A., & Lelord, G. ~1995!. Delayed ~2004!. Role for glia in synaptogenesis. Glia, 47, maturation of the frontal cortex in childhood autism. 209–216. American Journal of Psychiatry, 152, 248–252. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.