Is Autism a Disconnection Disorder?
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For personal use. Only reproduce with permission from Elsevier Ltd 577 Reflection & Reaction Is autism a disconnection disorder? Since Kanner and Asperger first described autism and Asperger’s syndrome in the 1940s there has been an exponential increase in the number of studies examining the biological basis of these disorders. There has similarly been an exponential increase in the number of theoretical proposals to explain the cause of autistic spectrum disorder (ASD). It is widely acknowledged that ASD has a strong genetic component and there is much indirect evidence for brain abnormalities, however, these have yet to be defined precisely. The increasing number of neuroimaging studies on autism has resulted in many new suggestions about the underlying brain abnormalities. However, diagnosis is still made from the observation of behaviour. The recent paper by Just and colleagues 1 confirms the presence of brain abnormalities, but will not provide a new diagnostic test. Just and his colleagues scanned the brains of volunteers with ASD and those of healthy volunteers while they read simple sentences (eg, the cook thanked the father) and answered simple questions (eg, who was thanked, cook or father?). Both groups of volunteers activated the classic language areas while performing this task, but the activity was greater in Wernicke’s area for those with ASD and greater in Broca’s area for the controls. The authors suggested that this result showed that volunteers with ASD were concentrating on single words rather than on the sentence as a whole. This attention to details rather than to the whole (sometimes called weak central coherence) is also observed in people with ASD in many domains other than language. 2 Apart from showing differences in the pattern of activity, Just and colleagues also showed differences in connectivity between brain regions. Connectivity is assessed in terms of the extent to which variations over time in one brain region are correlated with activity in another brain region. High correlations indicate that the two brain regions are interacting and are thus connected in terms of their function. Volunteers with ASD had substantially reduced connectivity between the classic language regions compared with healthy volunteers. My colleagues and I previously showed reduced connectivity between a different set of brain areas when we used PET to scan the brains of volunteers with ASD watching non-verbal, animated cartoons and detecting intentional behaviour 3 How reduced connectivity is realised in brain structure is not yet clear, and there are many possibilities. Reduced interactions between brain regions need not imply that there are fewer anatomical connections. Indeed, the little evidence about abnormalities of brain structure in ASD 4 suggests that there are too many anatomical connections. Children with ASD show a greater increase in brain size, particularly of white matter, during infancy than healthy children. This could reflect a lack of pruning during the normal growth spurt, leading to excessive pre- servation of un-needed connections. Such an effect would certainly lead to abnormal functional connectivity between brain regions. Also, it is not clear precisely which anatomical connections are likely to be abnormal. There is a notable distinction between feed-forward connections and feedback connec- tions. Forward projections are driving because they trigger vigorous action potential discharge. In contrast, feedback projections have indirect effects by modulating the activity in forward projections. In cognitive terms, the main roles of feedback connections are likely to be top-down processes. One such top-down process is selective attention, in which prior knowledge and expectations modify neural and behavioural responses to stimuli. Integration and central coherence depend upon such top-down processes. There is some evidence that feed forward connections are laid down before feedback connections and that the late stages of synaptogenesis and pruning are mostly about the feedback connections. Thus there are several reasons to predict that the abnormal connectivity associated with ASD may relate to feedback connections. 4 What is the outlook for abnormal connectivity as a plausible account of autism? A problem with explaining ASD in terms of abnormal connectivity is that the same explanation has been applied to several other disorders. Schizophrenia has been described as a disconnection syndrome, 5 as has developmental dyslexia. 6 Carl Wernicke 7 was probably the first to discuss the consequence of abnormalities in long-range corticocortical connec- tivity. He suggested that, whereas neurological disorders are associated with brain lesions, psychiatric disorders are associated with disruptions of connectivity, which he called sejunctions. If ASD does turn out to be a disorder of brain connectivity then much work will need to be done to delineate the abnormality that leads to this particular group of cognitive and behavioural disorders. Chris Frith Wellcome Department of Imaging Neuroscience, Institute of Neurology, University College London, London, UK. Email [email protected] Conflict of interest I have no conflict of interest. References 1 Just MA, Cherkassky VL, Keller TA, Minshew NJ. Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity. Brain 2004; 127: 1811–21. 2 Happé F. Autism: cognitive deficit or cognitive style? Trends Cogn Sci 1999; 3: 216–22. 3 Castelli F, Frith C, Happe F, Frith U. Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes. Brain 2002; 125: 1839–49. 4 Frith C. What do imaging studies tell us about the neural basis of autism? In: Bock G, Goode J, eds. Autism: neural basis and treatment possibilities. London: John Wiley (Novartis Foundation Symposium 251), 2003: 149–66. 5 Friston KJ. Schizophrenia and the disconnection hypothesis. Acta Psychiatr Scand Suppl; 1999; 99: 68–79. 6 Paulesu E, Frith U, Snowling M, et al. Is developmental dyslexia a disconnection syndrome? Evidence from PET scanning. Brain 1996; 119: 143–157. 7 Wernicke C. Grundrisse der Psychiatrie. Leipzig: Thieme, 1906. Neurology Vol 3 October 2004 http://neurology.thelancet.com
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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, as has developmentaldyslexia.
Transcript of Is Autism a Disconnection Disorder?
For personal use. Only reproduce with permission from Elsevier Ltd
577
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 [email protected]
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.
Neurology Vol 3 October 2004 http://neurology.thelancet.com
