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Reflection & ReactionIs autism a disconnection disorder?Since Kanner and Asperger firstdescribed autism and Asperger’ssyndrome in the 1940s there has beenan exponential increase in thenumber of studies examining thebiological basis of these disorders.There has similarly been anexponential increase in the number oftheoretical proposals to explain thecause of autistic spectrum disorder(ASD). It is widely acknowledged thatASD has a strong genetic componentand there is much indirect evidencefor brain abnormalities, however,these have yet to be defined precisely.

The increasing number ofneuroimaging studies on autism hasresulted in many new suggestionsabout the underlying brainabnormalities. However, diagnosis isstill made from the observation ofbehaviour. The recent paper by Justand colleagues1 confirms the presenceof brain abnormalities, but will notprovide a new diagnostic test.

Just and his colleagues scannedthe brains of volunteers with ASD andthose of healthy volunteers while theyread simple sentences (eg, the cookthanked the father) and answeredsimple questions (eg, who wasthanked, cook or father?). Bothgroups of volunteers activated theclassic language areas whileperforming this task, but the activitywas greater in Wernicke’s area forthose with ASD and greater in Broca’sarea for the controls. The authorssuggested that this result showed thatvolunteers with ASD wereconcentrating on single words ratherthan on the sentence as a whole. Thisattention to details rather than to thewhole (sometimes called weak centralcoherence) is also observed in peoplewith ASD in many domains otherthan language.2

Apart from showing differences inthe pattern of activity, Just andcolleagues also showed differences inconnectivity between brain regions.Connectivity is assessed in terms ofthe extent to which variations overtime in one brain region arecorrelated with activity in anotherbrain region. High correlationsindicate that the two brain regions are

interacting and are thus connected interms of their function. Volunteerswith ASD had substantially reducedconnectivity between the classiclanguage regions compared withhealthy volunteers. My colleagues andI previously showed reducedconnectivity between a different set ofbrain areas when we used PET to scanthe brains of volunteers with ASDwatching non-verbal, animatedcartoons and detecting intentionalbehaviour3

How reduced connectivity isrealised in brain structure is not yetclear, and there are many possibilities.Reduced interactions between brainregions need not imply that there arefewer anatomical connections.Indeed, the little evidence aboutabnormalities of brain structure inASD4 suggests that there are too manyanatomical connections. Childrenwith ASD show a greater increase inbrain size, particularly of whitematter, during infancy than healthychildren. This could reflect a lack ofpruning during the normal growthspurt, leading to excessive pre-servation of un-needed connections.Such an effect would certainly lead toabnormal functional connectivitybetween brain regions.

Also, it is not clear precisely whichanatomical connections are likely tobe abnormal. There is a notabledistinction between feed-forwardconnections and feedback connec-tions. Forward projections are drivingbecause they trigger vigorous actionpotential discharge. In contrast,feedback projections have indirecteffects by modulating the activity inforward projections. In cognitiveterms, the main roles of feedbackconnections are likely to be top-downprocesses. One such top-downprocess is selective attention, in whichprior knowledge and expectationsmodify neural and behaviouralresponses to stimuli. Integration andcentral coherence depend upon suchtop-down processes. There is someevidence that feed forwardconnections are laid down beforefeedback connections and that thelate stages of synaptogenesis and

pruning are mostly about thefeedback connections. Thus there areseveral reasons to predict that theabnormal connectivity associatedwith ASD may relate to feedbackconnections.4

What is the outlook for abnormalconnectivity as a plausible account ofautism? A problem with explainingASD in terms of abnormalconnectivity is that the sameexplanation has been applied toseveral other disorders. Schizophreniahas been described as a disconnectionsyndrome,5 as has developmentaldyslexia.6 Carl Wernicke7 wasprobably the first to discuss theconsequence of abnormalities inlong-range corticocortical connec-tivity. He suggested that, whereasneurological disorders are associatedwith brain lesions, psychiatricdisorders are associated withdisruptions of connectivity, which hecalled sejunctions. If ASD does turnout to be a disorder of brainconnectivity then much work willneed to be done to delineate theabnormality that leads to thisparticular group of cognitive andbehavioural disorders.

Chris Frith

Wellcome Department of ImagingNeuroscience, Institute of Neurology,University College London, London, UK.

Email cfrith@fil.ion.ucl.ac.uk

Conflict of interestI have no conflict of interest.

References1 Just MA, Cherkassky VL, Keller TA, Minshew NJ.

Cortical activation and synchronization duringsentence comprehension in high-functioningautism: evidence of underconnectivity. Brain 2004;127: 1811–21.

2 Happé F. Autism: cognitive deficit or cognitivestyle? Trends Cogn Sci 1999; 3: 216–22.

3 Castelli F, Frith C, Happe F, Frith U. Autism,Asperger syndrome and brain mechanisms for theattribution of mental states to animated shapes.Brain 2002; 125: 1839–49.

4 Frith C. What do imaging studies tell us about theneural basis of autism? In: Bock G, Goode J, eds.Autism: neural basis and treatment possibilities.London: John Wiley (Novartis FoundationSymposium 251), 2003: 149–66.

5 Friston KJ. Schizophrenia and the disconnectionhypothesis. Acta Psychiatr Scand Suppl; 1999;99: 68–79.

6 Paulesu E, Frith U, Snowling M, et al. Isdevelopmental dyslexia a disconnection syndrome?Evidence from PET scanning. Brain 1996;119: 143–157.

7 Wernicke C. Grundrisse der Psychiatrie. Leipzig:Thieme, 1906.

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