Autism: The first firm finding = underconnectivity?

John R. Hughes

Department of Neurology, University of Illinois Medical Center at Chicago, 912 South Wood Street, Chicago, IL 60612, USA

Received 14 December 2006; revised 13 March 2007; accepted 14 March 2007Available online 24 May 2007

Abstract

In January 2005, J.R. Hughes and M. Melyn published an electroencephalographic study on autistic children and found 46% withseizures and also a relatively high prevalence of 20% with epileptiform discharges but

without any clinical seizures

(Clin EEG Neurosci2005;36:15–20). Because the discharges have always been viewed as focal events and the clinical seizures as requiring spread, theconclusion from these data was that children with autism may have a deficiency of corticocortical fibers. Since that time many MRIand functional MRI studies have been published confirming that one of the first findings in this devastating condition is underconnec-tivity. Specific findings are the thinning of the corpus callosum and the reduced connectivity, especially with the frontal areas and also thefusiform face area. Other studies involving positron emission tomography scans, magnetoencephalography, and perception have addedto the evidence of underconnectivity. One final point is the initial overgrowth of white matter in the first 2 years of life in autistic children,followed later by arrested growth, resulting in aberrant connectivity; myelination of white matter will likely be significant in the etiologyof autism.

Keywords:

Cerebral cortex; White matter; Magnetic resonance imaging; Functional magnetic resonance imaging; Fusiform face area; Corpus callosum;Frontal area; Brain circuits; Myelination; Autism

1. Introduction

In January 2005, J.R. Hughes and M. Melyn[1]pub-lished an EEG study on autism, reporting seizures in46%, as well as a relatively high prevalence of epileptiformdischarges (20%) in others who did not have a history of clinical seizures. Although 20% may not seem high, thisvalue was signiﬁcantly di

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erent from that of the controlgroup of matched children without autism. Because dis-charges are usually regarded as an exquisitely focal findingand the seizures require some spread from the focus, thefinal conclusion from these data was that a clue to oneproblem in autistic children may be a deficiency of cortico-cortical fibers to account for this presumed lack of spreadfrom a focus. After that study, 19 studies—mainly MRIand functional MRI (fMRI) studies—have been publishedon autism and autistic spectrum disorders that are consis-tent with the original conclusions from the EEG study.The evidence is now clear that one major finding in autismis the underconnectivity within the brain. This finding isconsistent with the behavior of these children, who tendto concentrate on some object, rather than on any person,but without any significant relationship to other sensorymodalities, as may be expected from disconnected cerebralcircuits.

2. Theoretical considerations and methods

2.1. Other theories

Some general conclusions relevant to autism are thatgrowth dysregulation[2]is likely involved and also thatmechanical factors from cortical folding inﬂuencing thelamina[3]may also be implicated. A separate and di

ﬀ

erentview of this disorder is that females are better than males as

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Epilepsy & Behavior 11 (2007) 20–24

‘‘empathizers,’’ dealing with

people

, and males are better‘‘systemizers,’’ dealing with the rules governing thebehavior of

things

[4]. Autism is then viewed as an‘‘extreme male brain’’[5]. Another theory relates to‘‘mirror neurons,’’ action-coding cells that are activatedboth by passive observation of actions and by active execu-tion of the same movements[6]. These neurons are consid-ered to be reﬂected in mu waves (8–12 Hz) from centralscalp areas, known to appropriately attenuate in childrenwhen either moving themselves or observing movement inothers. The conclusion was that such an observation— execution matching system—exists even in the immaturebrain but that such a circuit in autism may be associatedwith a ‘‘faulty mirror neuron’’ system.

2.2. Methods (fMRI)

The next eight studies that are mentioned deal withfMRI as a method to investigate autism, determining func-tional neural connections. The first study used low-fre-quency oscillations that were temporally correlated infunctionally related brain regions to quantify the degreeof functional connectivity by detecting similarities in theoscillation, called ‘‘patterns with hierarchical clustering’’[7]. The next study used a ‘‘time series to estimate fre-quency-dependent correlational matrices’’[8]. The nextstudy to determine functional connectivity used ‘‘concur-rent spontaneous activity and spatial independent compo-nent analysis’’[9]. Two other studies used the decrease inactivity during various tasks[10], and one referred to a fre-quent finding of decreased cerebral blood flow during agiven task[11]. Other studies used ‘‘network modulationfrom rest to a given task’’[12], measuring ‘‘absolute brainstate maps’’ from rest to a given activity[13]or ‘‘linear cor-relational coe

ﬃ

cients’’[14]as a means of determining func-tional connectivity.Thus, examining the complex multivariate correlationalanalyses in the rise and fall of the BOLD signal can help todetermine connectivity.

3. Decreased connectivity

3.1. MRI studies3.1.1. Corpus callosum

The first group of studies discussed here used MRI todetermine underconnectivity. One of the most commonfindings in autism has been the decrease in the size of the corpus callosum. As early as 1993, Courchesne et al.[15]reported the thinning of the corpus callosum as partof white matter volume loss, in addition to the loss in theparietal lobes. Also, the cortical volume loss in the sameparietal lobes was found to extend into the adjacent supe-rior frontal and occipital lobes. The cortical volume losseither could be secondary to disconnection or could resultin underconnectivity or possibly be unrelated. Elevenyears later, Chung et al.[16]confirmed that white matterdensity is an index of neural connectivity and thatpatients with autism exhibit less density in the genu,rostrum, and splenium of the corpus callosum, as a hypo-plasia, rather than as an atrophy. In 2006, Vidal et al.[17]reported a significant reduction in both the splenium andgenu of the corpus callosum, and in the same year, Boger-Megiddo et al.[18]confirmed that the corpora callosawere disproportionately small, reflecting decreased inter-hemispheric connectivity. Finally, Alexander et al.[19]also reported small corpus callosum volumes, in additionto slow processing speeds. For example, the latter patientswith small corpora callosa had significantly lower IQsthan controls.

3.1.2. Frontal area

Another area of interest often mentioned in autistic chil-dren is the frontal area. Reduced connectivity was indi-cated in the (fMRI) finding that bilateral inferior frontalareas[20]were deficient in BOLD signal correlation withthe time series in the visual area. These findings wereviewed as compatible with the hypothesis of ‘‘mirror neu-ron’’ defects mentioned previously. A general commentwas that a ‘‘dorsal stream connectivity’’ in autism wasnot likely fully functional, based on BOLD signals duringvisuomotor coordination, reporting reduced connectivitywith bilateral frontal areas. Another study demonstratedsignificant localized gray matter reductions within thefrontostriatal circuits and within the parietal networks.One other report on the frontal area, by Courchesne andPierce[21], reviewed di

ﬀ

erent methods. Evidence wasfound that connectivity within the frontal lobe was disorga-nized and inadequately selective, whereas connectivitybetween the frontal cortex and other systems was poorlysynchronized and weakly responsive based on inferencesfrom stimulation data. One ﬁnal conclusion was that thereduced long-distance corticocortical reciprocal activitythat appeared in their studies would impair frontal lobefunction. Also reported were decreases in volume beyondthe frontal area, namely, in ventral and superior temporalgray matter, left internal capsule, fornices, and cerebellarwhite matter[22]. The data were suggestive of abnormalanatomy and connections of the limbic–striatal social brainsystem in autistics.

3.1.3. Other studies

Other MRI studies have shown that minicolumnarwidth and mean neuron and nucleolar cross sections aresmaller in autistic children. The findings suggest a biastoward shorter connectivity fibers[23]. One other studydemonstrated changes in cerebellar gray and white mattervolume[24], and a final MRI study showed a decrease inthe gray matter in the right thalamus[25], although withunexpected increases in the right fusiform gyrus, tempo-ral–occipital region, and left frontal pole. The latterincreases may be explained by an additional finding of increased total gray matter volume, which may reverse inlater years.

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3.2. Functional MRI studies3.2.1. Pre-2006 investigations

It should be made clear that these studies do not directlyassess connectivity, and conclusions are drawn from indi-rect measurements. Most of these studies were publishedin 2005 and 2006. Exceptions include the report from2003[26]involving patients performing ﬁnger movements,which demonstrated abnormal variability and scatter of functional maps, suggesting early-onset disturbances inthe development of cerebello-thalamo-cortical pathwaysin autism. Two other exceptions to very recent publicationswere reported in 2004. One showed less activation inBroca’s left inferior frontal gyrus, but especially less syn-chronization between various cortical areas, related to‘‘neurobiological foundations of underconnectivity in aut-ism’’[27]. The patients were tested during sentence compre-hension. The other study[28]showed reduced activation inresponses to the faces of strangers in the fusiform face area,but also in the medial frontal lobe and the amygdala. Thegeneral conclusion was that autistic children exhibit defectsin the systems that modulate the fusiform face area. How-ever, it is impossible to distinguish whether the major issueis an abnormal area a

ﬀ

ecting other regions or a primarydisorder of connectivity.

3.2.2. 2006 investigations of frontal areas

As in the MRI studies, the 2006 fMRI studies empha-sized the frontal areas. Silk et al.[29]studied patients per-forming a mental rotation task and reported a dysfunctionin frontostriatal networks in autism by showing less activa-tion in the lateral and medial frontal, dorsolateral prefron-tal, and anterior cingulate cortex and also in the caudatenucleus. Turner et al.[30]studied patients during a visuo-motor task and found that the circuits from BOLD signalcross correlation with this task were less pronounced oreven absent in association with the orbitofrontal area andcaudate nuclei, as well as the associative, oculomotor,and motor areas. These ﬁndings indicated an ine

ﬃ

cientlyorganized functional connectivity between these regions.Similar results were reported by Just et al.[31], who studiedpatients performing a Tower of London test to assess exec-utive function. They reported lower synchronizationbetween the frontal and parietal areas, in addition to asmaller corpus callosum, indicating reduced intracorticalconnectivity or underconnectivity. Other reports, usingpatients processing sentences with di

ﬀ

erent imagery con-tent, were that functional connectivity among corticalregions, especially the language and spatial centers, is notwell synchronized, again indicating underconnectivity[32]. Still another study[33]using a cognitive task reported loosely connected anterior–posterior circuits as an indica-tion of cortical underconnectivity. A similar conclusionof ‘‘reduced corticocortical connectivity’’ was reached inanother report[34]of patients performing a visuomotortask, even though the opposite was found for subcorti-cal–cortical connectivity. The di

ﬀ

erent areas implicated inthe latter studies may be a reﬂection of the short periodduring which investigators have studied this problem, butthe emphasis on frontal areas seems to be clear. The pres-ent section indicates that most of these studies were doneafter 2005.

3.3. Other studies

One positron emission tomography (PET) study wasperformed to demonstrate reduced functional connectivityby showing less activation in the medial prefrontal, ante-rior, and superior temporal cortex and the connections tothe extrastriate region[35]. A magnetoencephalography(MEG) study revealed an abnormal left hemispheregamma oscillation (40 Hz), ‘‘augmenting connectivity theo-ries of autism by demonstrating deficiencies in long-rangeneural communication’’[36]. In three studies involving per-ception, similar conclusions were drawn. In one study[37],increased amplitude of intrusive saccades and reducedlatency of target fixation led to the conclusion of faultyfunctional connectivity in corticocerebellar networks. Inanother investigation[38], autistic children were found tobe deficient in identifying complex texture-defined gratings,leading to the conclusion of atypical neural connectivity. Inthe third study[39], autistic children showed a lack of ‘‘attentional modulation,’’ especially for social stimuli,and the conclusion of poor connectivity between extrastri-ate and striate regions was drawn. One final study[40]con-cluded that the developmental process was disrupted inautistic children by showing ‘‘abnormal synthesis capacity’’with respect to brain serotonin. It is clear that the latterstudies were not directly measuring connectivity, but pro-duced data that were only consistent with underconnectivity.

4. Emphasis on facial area

One of the major clinical findings in the autistic spec-trum is the lack of apparent recognition of faces, as thesechildren tend to concentrate on things and not people. Anumber of studies have provided evidence to account forthis phenomenon. In 2003, Frith[41]reported that autis-tic children failed to activate the fusiform face area duringface perception tests, also demonstrating weak activationof medial frontal cortex and the superior temporal gyrus.The conclusion was that this finding was a marker forabnormal connectivity, possibly from lack of neural prun-ing. During the next year, Waiter et al.[25]reported anunexpected increase in gray matter volume in the rightfusiform gyrus, as well as in the right temporal–occipital,left frontal, and medial frontal cortex. The conclusion wasthat this finding may ‘‘reflect an abnormally functioningsocial cognitive neural network.’’ Finally, in 2006 Birdet al.[39]reported a lack of attentional modulation of face-selective regions, concluding abnormal connectivity.Two other studies specifically involved fMRI. One wasa study that autistic children exhibit less fusiform activityin response to strangers than to familiar faces. In general,

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