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Neuroscience and Biobehavioral Reviews
journal homepage: www.elsevier.com/locate/neubiorev
Autism: A world changing too fast for a mis-wired brain?
´ ¸ois Feron b Bruno Gepner a,*, Franc
`ge, Belgique Service de Psychiatrie de l’Enfant et de l’Adolescent, Centre Hospitalo-Universitaire, Lie ´ ´decine, Universite Aix-Marseille, Marseille, France ´ NICN, CNRS UMR 6184, Institut Jean Roche, Faculte de Me
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 September 2008 Received in revised form 25 May 2009 Accepted 15 June 2009 Keywords: Autism spectrum disorders Temporo-spatial processing Motion Emotion Speech processing Imitation Cognition Rehabilitation Slowing down Connectivity Synchrony Neurotransmission
Disorders in verbal and emotional communication and imitation, social reciprocity and higher order cognition observed in individuals with autism spectrum disorders (ASD) are presented here as phenotypic expressions of temporo-spatial processing disorders (TSPDs). TSPDs include various degrees of disability in (i) processing multi-sensory dynamic stimuli online, (ii) associating them into meaningful and coherent patterns and (iii) producing real-time sensory-motor adjustments and motor outputs. In line with this theory, we found that slowing down the speed of facial and vocal events enhanced imitative, verbal and cognitive abilities in some ASD children, particularly those with low functioning autism. We then argue that TSPDs may result from Multi-system Brain Disconnectivity-Dissynchrony (MBD), deﬁned as an increase or decrease in functional connectivity and neuronal synchronization within/between multiple neurofunctional territories and pathways. Recent functional magnetic resonance imaging (fMRI) and electrophysiological studies supporting MBD are outlined. Finally, we review the suspected underlying neurobiological mechanisms of MBD as evidenced in neuroimaging, genetic, environmental and epigenetic studies. Overall, our TSPD/MBD approach to ASD may open new promising avenues for a better understanding of neuro-physio-psychopathology of ASD and clinical rehabilitation of people affected by these syndromes. ß 2009 Elsevier Ltd. All rights reserved.
Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Temporo-spatial processing disorders (TSPDs) of multi-sensory ﬂows . . 2.1. Neuropsychological ﬁndings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Slowing down sensory stimuli as a tool for rehabilitation? . . . . . 2.3. What does TSPD hypothesis predict for behavior and cognition? 2.4. Clinical arguments for TSPDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Suspected neurobiological correlates of TSPDs . . . . . . . . . . . . . . . Multi-system Brain Disconnectivity-Dissynchrony (MBD) . . . . . . . . . . . . 3.1. Functional magnetic resonance imaging (fMRI) studies . . . . . . . . 3.2. EEG and MEG studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. MBD and other neurobiological theories of ASD . . . . . . . . . . . . . . 3.4. MBD in other developmental and neuro-psychiatric disorders . . Neurobiological correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic and environmental factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Genetic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Genes implicated in cortical organization . . . . . . . . . . . . . . . . . . . 5.3. Genes implicated in synapse formation and synaptic plasticity . . 5.4. Genes implicated in neurotransmission and neuromodulation . . 5.5. Genes implicated in voltage-gated ion channels . . . . . . . . . . . . . . 5.6. Environmental and epigenetic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1228 1228 1228 1229 1229 1230 1231 1232 1232 1233 1234 1234 1234 1235 1235 1235 1235 1236 1236 1236
Abbreviations: ASD, autism spectrum disorders; TSPD, temporo-spatial processing disorders; MBD, Multi-system Brain Disconnectivity-Dissynchrony. * Corresponding author. ´ E-mail addresses: email@example.com (B. Gepner), firstname.lastname@example.org (F. Feron). 0149-7634/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2009.06.006
. . with early onset (before 36 months) (WHO. 2002. . . . . It is also currently accepted that these disorders altogether have a prevalence of about 0. . . This disordered (under. Fe 6. .. 2002). . .1228 ´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B. . . and review the recent fMRI and electrophysiological data supporting MBD. . . . particularly when the speed of movement is high and (ii) children with Asperger syndrome exhibit normal or even over-postural reactivity to the same type of stimuli (Gepner and Mestre. . . . . associating them into meaningful and coherent patterns. . . . Kohen-Raz et al. 1994. . cognitive and motor disturbances observed in people with ASD. disorders of functional connectivity and neural synchrony within/between multiple brain regions.. . . . . . First. . Acknowledgements . 2000. . . In the present paper. . 1974. Leary and Hill. . . and (c) proprioception and motor anticipation in a bimanual load lifting task. . Consistently. 2002) and constitute a major public health problem all over the world. . Interestingly. . dyslexia – and obsessive compulsive disorders (Volkmar and Pauls. . Then.. . . . . such as poor motor coordination. numerous questions concerning the etio-pathology and physiopathogeny of these affections are still unsolved. . 1992. . . . . 2006). . 2000). 1997). Impaired oculomotor reactivity to fast visual-motion. . . led us to propose the rapid visual-motion integration deﬁcit hypothesis of autism (Gepner and Mestre. . . In a second series of studies. Understanding the pathogenesis of ASD at molecular and cellular levels is an even more daunting task as it involves combinations of numerous genetic. . poor or enhanced postural control. . . Lecavalier. attention deﬁcit with/ without hyperactivity. Then. . . . . . . . . 1992. 2003. . . 2002b). . and producing real-time sensory-motor adjustments and motor outputs. We also present results demonstrating that slowing down the speed of facial and vocal events enhance imitative. . . . it was reported that (i) children with low-functioning autism are posturally hypo-reactive to environmental movements. . . especially at high speed and when the direction was less predictable (Gepner. . . as also observed by others (Spencer et al. . . higher motion coherence thresholds. . . . . . . . translational and rotational direction of movement (see also Dakin and Frith. 2005). They represent a constellation (Gepner and Tardif. . . . 2002). epigenetic and environmental risk factors (Gepner and Soulayrol. . Furthermore. we propose that TSPDs are based on Multi-system Brain Disconnectivity-Dissynchrony (MBD). This deﬁcit. . . . . we combine data from clinics. . . (b) speech ﬂow perception and segmentation through categorization of simple and complex phonemes. . . . Noticeably. .. . . . . . . Gepner. . . . Interestingly. . . . 2002) are known as behavioral syndromes including various degrees of verbal. . . . . . . . . . . Synthesis and conclusion. is a strong argument for a degraded temporo-spatial integration in the visual modality. . 2. . . . . . . 2003). language learning impairments – dysphasia. Green et al. (2003) showed that high-functioning autistic subjects exhibit a deﬁcit in the perception of second order radial. that are rendered even more complex by the frequent association to mental delay. . . . . . Neuropsychological ﬁndings It was ﬁrst demonstrated that children with autism display a weak postural reactivity to visually perceived environmental motion (Gepner et al. We ﬁrst propose that temporo-spatial processing disorders (TSPDs) of multisensory ﬂows represent a common neuropsychological basis for the main behavioral. i. . Their treatments are consequently unspeciﬁc and disappointing. . . Temporo-spatial processing disorders (TSPDs) of multi-sensory ﬂows The TSPD hypothesis emerged from recurrent observations indicating that ASD patients exhibit various degrees of disability in (i) perceiving and integrating environmental dynamic multisensory stimuli online and (ii) producing real-time sensory-motor coupling. . . . . Persico and Bourgeron. . . . . . . anxiety and mood disorders often inﬂuence personality and behavior of individuals with ASD (Tardif and Gepner. F. . . . . visuo-postural mis-coupling is a good example of sensory-motor coupling disorders described 40 years ago (Ornitz and Ritvo. . . . . . . for a review). . . . . 2006) of fairly heterogeneous disorders. . the group of ASD subjects showed weak oculo-motor reactivity in response to global motion. Although there is an international consensus for considering these syndromes as phenotypic expressions of impairments affecting the development of the central nervous system (CNS). .. . . References . . . . . .6% (Fombonne. this difﬁculty to integrate single points into a global coherent motion is also an argument for weak central coherence (Mestre et al. neuropsychology. Pellicano et al. . . . . 1995). . . it was demonstrated that ASD children have trouble perceiving the motion of small squares on a computer screen. .e. . along with above-mentioned results demonstrating postural hypo-reactivity to fast environmental movements in children with autism and results suggesting impairments in rapid human movements processing (see below). we list the suspected neurobiological mechanisms underlying TSPDs and MBD. Damasio and Maurer. . . Finally. . . . . . . .1. .. and longlasting handicapping social and/or cognitive consequences. . 1238 1238 1238 1. . 2009 for reviews). . . . .. . Clinically. . . . which supposes a defect in rapid temporal analysis of visual-motion stimuli embedded in noise. . . . Milne et al. APA. . . . . . . ASD remain enigmatic for numerous reasons. . through three types of tasks and measurements: (a) oculo-motor reactivity to global movement of a coherent pattern of lighting points (a random dot kinematogram) through opto-kinetic nystagmus. . . . . . 2005. . . Pellicano et al. .e. Ornitz. . nonverbal and social impairments as well as restricted or stereotyped interests and activities. . . . . 2005 for a review. . . 1968. epilepsy. this weaker oculo-motor reactivity was observed in reaction to high motion velocities (Mestre et al. . . .or over-) visuo-postural coupling in children with ASD may partly explain executive dysfunction in ASD patients (Hill. . . . . . . . 2002. 1996. 1978. . . . neuroimaging. Bertone et al. . .. 2004 for a review) and sensory-motor and motor disturbances. . .. . . . . . . 1974). . . neurophysiology. . . . . .. . . . 2002). . . 2. verbal and cognitive abilities of some ASD children. . . . ASD individuals would present various degrees of disability in processing dynamic multi-sensory stimuli online. . through electromyographic and kinematic index (Gepner & Massion (dir. 2005). . . . . According to this hypothesis. . 2006) that affect different stages of neurodevelopmental and neurofunctional mechanisms. .. . . postural adjustments and adequate verbal and nonverbal outputs. . . Additional evidence supporting TSPD hypothesis stem from observed impairments in children and adolescents with ASD who were tested for their ability to extract online relevant information among noisy stimuli. . . . . by). genetics and epidemiology in a coherent approach to ASD. when compared to control children (Mestre et al. 2002a). . gross or ﬁne motor clumsiness (Ornitz et al. . . . . i. Introduction Autism and other related autism spectrum disorders (ASD) (Rapin. . . . . .
Compared to control children using a feed-forward mode of control to stabilize their forearm while lifting an object placed on it. Gaab et al. verbal comprehension and ﬁnally in verbal and language abilities (Rapin and Dunn. autistic children over-categorized MNA in a NA response. speciﬁc language impairment) failed to do so.e. Hadjikhani et al. 1976). 1996... and was ameliorated by slowing down the speed of speech ﬂow (Tallal et al. In a complementary study.. In other words. As a consequence. What does TSPD hypothesis predict for behavior and cognition? According to our hypothesis. along with visual-proprioceptive processing deﬁcit (i. autistic children are reacting instead of predicting. 2002. 2007. particularly in ´ children with low-functioning autism (Laine et al. which results in slowing down their movement. 2003). Slowing down sensory stimuli as a tool for rehabilitation? If the world is changing too fast for some ASD individuals. found that 80% of individuals with intact language (Asperger syndrome. Tardif et al. decreased visual ﬁxations to the eye region.. This deviant over-categorization speciﬁcally appeared in autistic subjects when speech phonemes were displayed at normal speed. perceptual and cognitive acts.. subjects with ASD exhibit slowed attentional processes such as shifting or orientating spatial attention (Wainwright-Sharp and Bryson. (2008) found that event related . Nishitani et al. lip movements and emotional facial gestures.. Phoneme categorization deﬁcit may partly be due to a difﬁculty in rapid speech ﬂow processing and thus to a temporal integration deﬁcit in the auditory modality (Tardif et al. Townsend et al. The authors concluded that deﬁcient rapid temporal processing may contribute to impaired language development by interfering with the processing of brief acoustic transitions.. McPartland et al. To brieﬂy summarize. Welsh et al... 2002. 1964. 1994.. 1988. inferior parietal lobe and inferior frontal lobe. 2008). may contribute to executive dysfunction in ASD people (Hughes et al. 1996. Davies et al. 2006 for a review). Fe 1229 Second. recognize signiﬁcantly more emotional and non-emotional facial expressions. the environmental world may be changing too fast in one or several sensory modalities for at least some ASD children and adults. 1996). they would inadequately perceive and respond to rapid physical and human movements. 2006).. As a consequence. Given the parallel between language disorders in ASD and developmental language disorders (Rapin and Dunn. whereas such improvement was not seen in healthy children or in ´ mentally retarded ones (Laine et al.. while 65% of patients with impaired language (autism. Wong et al. 2007). see Hutt et al. perform equally as well as typically developing children of the same developmental age in emotional and facial speech recognition tasks when the stimuli are slowly displayed on video (Gepner et al. (ii) code and parse language. 2007.2. whereas their phoneme categorization was normalized when phonemes were slowed down by a factor of 2. These numerous disabilities are likely to disrupt verbal and emotional communication and therefore to be detrimental for social interaction between ASD subjects and their human environment (Gepner and Tardif. normal adults) responded to the second tone. 2008a). For example. (ii) facial imitation (Loveland et al. 2003). Williams et al.... 2000.3. especially facial movements such as eye movements (which are the most rapid ones in humans). Third. Hobson et al. Hobson et al. (2004) observed that adults with Asperger syndrome display a delayed cortical activation from occipital cortex to superior temporal sulcus. M100) to two 40 ms tones passively presented in rapid succession via magnetoencephalography.. autistic children mostly use a feedback mode of control. We observed that slowing down the presentation of facial and body gestures enhanced voluntary imitation of ASD children (especially the more affected ones).. 2009). would it be beneﬁcial to slow it down? It was ﬁrst found that ASD subjects. 1972.. Vivanti et al. 1991. and (iii) anticipate and program postural adjustments. Gepner. This impairment. at least during the learning phase of the task. 2. particularly those having the more severe autistic syndrome. Similarly. 2004 for a review) and particularly to slowed sensory-motor processing speed. 2008b. F.. Dawson et al. Dalton et al. but also body movements. Moreover. our group devised software that slows down simultaneously visual and auditory cues.g. (iii) recognition of facial stimuli involving motion or emotion (e.. 2003). Compared to control children who categorized an ambiguous phoneme such as MNA (made of an algorithmic superimposition of MA and NA) in a MA or a NA random response. Gepner et al.. Pelphrey et al. verbal imitation. 2001). it was found that a subgroup of the same autistic subjects displayed a deﬁcit in motor anticipation in a bimanual load-lifting task (Schmitz et al. Hill. 2005).´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B. Klin et al. it was found that slowing down the visual and auditory presentation of single or double sentences enhance verbal comprehension. De Gelder et al. (2005).g. although they had reacted to the ﬁrst tone. when imitating still pictures of lip forms. 1996). 1994. Oram Cardy et al. 2002). deﬁcit of visuo-postural and visuooculomotor reactivity)... in order to further test how slowing down facial and vocal cues would impact imitative and cognitive performance in autistic children. (2007) strenghtened these results by demonstrating that some children with autism. this deﬁcit may account for the receptive and expressive language and verbal communication impairments observed in individuals with ASD. Tallal and Gaab.. Rogers et al.. 2007). In line with these results. who usually perform poorly in facial recognition tasks involving the processing of facial dynamics (e. (2004) found electrophysiological evidence for slowed neural speed of face processing in autism. Rogers and Pennington. Gepner et al. it is not surprising that the same deﬁcit was found in children with language learning impairments (Tallal. the same group of ASD subjects exhibited a deﬁcit in speech phoneme categorization. Critchley et al. TSPD hypothesis postulates that the environmental world is changing too fast to be processed on time. and therefore also predicts that some ASD individuals would exhibit a slowed processing speed (see. TagerFlusberg and Caronna. in motor (see above Schmitz et al. 2005 for a review. 2002.. 1991. these ﬁndings may be of potential high interest for rehabilitating verbal and emotional communication disorders in at least some individuals with ASD. TSPD-exhibiting ASD individuals would tend to avoid rapid visual. TSPDs would induce impairments in (i) attention to faces (e. As a result. typical development. 2005. the correct use of an internal representation of the weight to be load-lifted and the precise adjustment of the timing of muscular events. 2004 for a review).g. 1994. Next. 2. DeMeyer et al. impairments in rapid auditory processing would induce deﬁcits in phoneme categorization. crucial for speech perception. and exhibit more facial-vocal induced imitation when facial expressions and their corresponding vocal sounds are slowed down in an ecological or artiﬁcial way. e. considered as aversive stimuli..g. and (iv) action imitation (e. The task requires the rapid processing of proprioceptive inputs. 1988. Speer et al. 2007 for reviews).. This deﬁcit of accurate timing of anticipatory control partly results from an impaired processing of proprioceptive inputs. 2003. In addition. 1993. which required rapid temporal processing demands. 1991... measuring evoked neural activity (M50. many ASD individuals display deﬁcits in temporospatial integration of sensory inﬂow which is necessary to (i) detect and integrate visual motion. auditory or proprioceptive ﬂows..g. Overall. 2003. and thus from a temporo-spatial integration deﬁcit in the proprioceptive modality. De Gelder et al.
(ii) visual avoidance or visual attraction for moving.. 2005) of life in ASD children. 2000). Finally. 1988) and prolonged latency to disengage visual attention (Zwaigenbaum et al. 1989. auditory and sensory-motor behaviors (the ‘productive signs of autism’). or in other terms. I want to get off’. Time phenomenon is relative to space. Gepner. autism spectrum): ‘‘Minor sensory processing deﬁcits heightened my attraction to certain stimulation (e. . spinning and rolling objects. some of which probably have an adaptive and/or compensatory value. people behaved like in old frame-by-frame movies. . but they are not integrated together . mentioned that ‘‘she spoke very fast and I found it difﬁcult to follow her . perceive. 2002a). possibly as a consequence of a failure to catch the rapid dynamic aspect of verbal ﬂow. Concerning the behavioral consequences of an excessively rapid environment and the potential usefulness of slowing down the sensory environment for ASD patients. 1994). On the connection between time. Donna Williams (1992) wrote that ‘‘the constant change of most things never seemed to give me any chance to prepare myself for them. During a certain period of time a non-autistic person can digest more percepts than me because I am constrained to digest each object piece by piece . they may also display a lack of interest for moving games and objects and self-stimulating sensory and sensory-motor behaviors. righting. a weak central coherence (Frith. for reviews) and auditory singularities (e. 1993. (1993) and Sauvage (1988) observed that they frequently exhibit deﬁcits of postural adjustment. . at the expense of global or contextual information (Gepner. ´ ´ Happe. in which early temporo-spatial processing disorders of . integrate and interact with. 1998) or Asperger syndrome (Teitelbaum et al.. sometimes leading to high levels of performance and over-abilities in some ﬁelds.. Osterling and Dawson. 39–40). The time course of autistic symptoms during infanthood may then appear as succession and intrication of maldevelopmental cascades. autistic babies may exhibit early atypicalities of gaze contact and ocular pursuit of moving objects or individuals (Adrien et al. 2004b).. 2002b) and support our TSPD approach. 2004 for a review) may be observed. . Between 6 and 12 months. The stress of trying to catch up and keep up often became often too much and I found myself trying to slow everything down and take some time out .and hand-ﬂapping in front of their eyes (Adrien et al. Daniel Tammett (2006). when compared to controls. Van Dalen (1994). 2005). a lack or a delay in anticipating attitudes as well as in oculo-manual coordination. . .e. ‘Stop the world. during both explicit and implicit emotion-processing tasks. speed and movement (i.. 2005). Consequently. 1993... If you blinked really fast. an autistic savant. a nonautistic person sees me as living slowly. 1997. babies who will later be diagnosed as autistic often fail to orient to their name and present a delayed development of expressive and receptive language (Zwaigenbaum et al. observed several peculiarities of visual behavior such as (i) gaze or face avoidance.1230 ´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B. About the auditory modality. rocking and swaying. on the one hand.. as well as mental state decoding (medial prefrontal lobe). and it took me some time to answer her’’. (2007) demonstrated that ASD individuals responded signiﬁcantly more slowly than their controls during a cognitive assessment task. 2006). 2004. (iii) visual attraction for details of objects. Finally. Mottron. 2001). 2001. . and an enhanced static vision. 2005). space. One of the ways of making things seem to slow down was to blink or to turn the lights on and off really fast. While autistic babies generally display a developmental delay (the ‘negative signs of autism’). auditory and sensory-motor mis-behaviors in the ﬁrst (Zwaigenbaum et al. with visual attraction and overfocused attention to details and singularities. . visual attraction for rapidly moving stimuli possibly veils a primary dysfunction in processing such stimuli. These compensatory strategies may mask the primary dysfunctions (Belmonte et al.g. Adrien et al. time seems to ﬂow out rapidly. the rapid succession of questions was intrusive .4. rapid dynamic stimuli and become more and more capable to process them (Gepner.’’. 2004. on the other hand.. Sauvage. sitting. their dynamic versus static environment (Gepner. including lying. (iv) sensory-motor disorders. enhanced abilities in spatial memory and graphism. 2003. Gepner and Mestre. were signiﬁcantly weaker and/or slower in autism. as well as hand. studies using family home movies in the last two decades identiﬁed early speciﬁc visual. 2008). Clinical arguments for TSPDs How do clinical observations support TSPDs? Several reports from ASD adults are in accordance with the rapid visual-motion integration deﬁcit hypothesis of autism (Gepner and Mestre. Since the dynamic environmental world seems difﬁcult to handle for ASD individuals. 1999. Zwaigenbaum et al. and stereotyped behaviors like swinging. habituate themselves and learn to handle and cope with. . 2005. TSPD). Others may also search for. Happe and Frith. 2008). Overall. Long before these self reports by ASD adults. One autistic person reported that looking at people’s eyes was difﬁcult because the eyes did not stay still’’. Concerning motor development. In addition. static patterns and puzzles. Werner and Dawson. and strongly related to the number of distinct entities to be processed. 2005) or second year (Werner and Dawson. Conﬁrming the importance of such a question. such as motor clumsiness.g. an adult with mild autism. stated: ‘‘For me. 2.. they also show atypical self-stimulating visual. Similarly. associated to face detection (visual cortex) and conﬁgural processing of faces (fusiform gyrus).e. possibly aimed at compensating it.. like the effect of strobe lights without the control being taken out of your hands’’ (p.. 2004) show disturbances in some or all of the milestones of development. Mottron. while exhibiting atypical interests for their hands and focusing on particular static objects in the environment (Adrien et al.. TSPD hypothesis predicts that some ASD individuals may develop compensatory mechanisms.. I always loved the saying. 1993. In the domain of visual behavior. F. a fraction of ASD individuals would search to slow down the speed of sensory inﬂow (see Williams’ statement below). For example. and weak central coherence. One should notice that all these symptoms directly or indirectly question the way ASD children attend to. awkwardness. crawling and walking. Mottron et al. In regard to the domain of auditory behavior. Schmitz et al. in the ﬁrst 6 months of life. airport’s doors). like ﬁnger. Another statement by Grandin (1995) accounts for the various visual behavior impairments along the ‘autistic continuum’ (i. . TSPD hypothesis additionally predicts an overfocused attention to static visual stimuli (Burack et al. Because of this I found pleasure and comfort in doing the same things over and over again.g. frequently followed by self-stimulation of dynamic vision. whereas a greater sensory processing defect might cause another child to fear and avoid the same stimulus’’. arm or body stereotypes. Fe potentials (ERP). I like to compare eyes of autistic persons to those faceted eyes of insects: there are numerous different subtile details. Kanner (1943) in the ﬁrst description of autistic children in the literature. via sensory-motor overcoupling (e. and increased pitch sensitivity (Bonnel et al. babies who will later exhibit typical autism (Teitelbaum et al. and that this reduced processing speed was correlated to decreased frontal lobe parenchymal volume. all of these symptoms being possibly due to a distorted proprioceptive and visuo-postural integration. The link between TSPDs and gaze aversion was substantiated by Temple Grandin who declared (1995) that ‘‘some of the problems autistics have with making eye contact may be nothing more than intolerance for the movement of the other person’s eyes. vision in ASD infants appears to be dissociated between a poor or avoided dynamic vision.
and schematized in Fig. (v) Enhanced facial expression recognition. emotional facial and body movements. 2. ASD children display basic sensory and sensory-motor anomalies and. i. Disorders generated by two distinct sensory cascades are represented in a composite colour (e. 2001) and empathizing deﬁcit (Baron-Cohen. 2008. Disorders generated by three distinct sensory pathways are represented in white.5.e. joint attention deﬁcit and mindblindness. F. enhanced spatial memory and sometimes enhanced graphic abilities. E-Motion Mis-sight has been proposed to be an early precursor of mindblindness (Baron-Cohen. 2004b. empathizing deﬁcit and mindblindness. i. eye contact disorders. that may result. postural adjustments and adequate verbal and nonverbal outputs. Each maldevelopmental cascade is represented with a speciﬁc colour (red for visual-motion processing deﬁcit. lip movements. 2004. 1995. we hypothesized they may be based on deﬁcits in temporal encoding of multi-sensory inputs. in conjunction with lip movements processing deﬁcits. 2005). (iii) Dynamic auditory processing deﬁcits that may result in phoneme categorization impairment. motor and cognitive consequences of temporo-spatial processing disorders (TSPDs) of multi-sensory ﬂows. affecting higher order cognitive functions. various degrees of disability in perceiving and integrating motional and emotional stimuli on time (Gepner. in visuo-auditory association disorders. alone or in conjunction with proprioceptive ﬂow processing deﬁcits.g. 1: (i) Impairments in perceiving and integrating physical movements. Gepner. and. resulting in numerous maldevelopmental cascades. that may result in eye direction detection deﬁcit. as well as for slowed perceptual and sensory-motor processing speed. blue for proprioceptive ﬂow processing deﬁcit). In summary. that may account. for executive dysfunction. 1. Belmonte et al. (ii) Impairments in perceiving and integrating biological motion such as: a. 2006). 2001. later in life. 2002). the reader is referred to the web version of the article. 2008. Behavioral. and in language impairments. auditory and proprioceptive stimuli impact secondarily on (i) sensory-motor development. One of these maldevelopmental consequences has been named E-Motion Mis-sight. Gepner and Tardif. the various behavioral. In the ﬁrst or second year of life.e. alone and in conjunction with speech ﬂow processing deﬁcit. (iv) Over-focused attention on static visual stimuli that may explain enhanced local perception and weak central coherence. TSPDs are considered as central early neuropsychological disorders. eye movements. (For interpretation of the references to color in this ﬁgure legend. may account for visuoauditory association deﬁcits.) . including various degrees of disability in perceiving and integrating visual. increased facial and body imitation and improved verbal comprehension when visual and/or auditory stimuli are slowed down. motor and cognitive manifestations seen in ASD subjects. c. auditory and proprioceptive stimuli online and in producing real-time sensory-motor coupling. that may result in EMotion Mis-sight. Gepner et al. Frith.. b. Fe 1231 visual. (ii) verbal and emotional communication and social interactions between a baby and his physical and human environment (Gepner.´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B. Findings by our group revealed the existence of TSPDs of multi-sensory ﬂows in subjects with ASD. yellow for speech ﬂow processing deﬁcit. Suspected neurobiological correlates of TSPDs When in search for the neurobiological bases of TSPDs. These impairments may also consequently account for slowed perceptual and cognitive processing speed and imitative impairments. their disturbances become more complex and intricate. temporal coupling of sensory-motor Fig.. TSPDs of multi-sensory stimuli may account for numerous clinical and neuropsychological ﬁndings in ASD that are synthesized and articulated below. verbal imitation deﬁcits and language impairments. overfocused attention on auditory singularities that may trigger enhanced pitch sensitivity. as well as in facial and body processing deﬁcits and peculiarities. violet for disorders generated by visual and proprioceptive processing deﬁcits).
2004 for epilepsy. 2.. Castelli et al. 2001. rapid sensory information (rapid sensory ﬂows) would arrive too quickly to be processed on time by the autistic brain. 1993) is known to play a crucial role in all these stages. via projections on motor and premotor cortices as well as on prefrontal. among other sensorycerebellar pathways. 1998). 2005. (2006) observed that. Convergent with our proposal. Neural synchrony can therefore be considered as a mechanism of temporal connectivity. First.g. Welsh et al..g. Bailey et al. 2005). a mathematic model simulating brain functioning) of brain connectivity found that the speed of synchronization depends on the dynamical and network parameters. Just et al. 2007. some authors have suspected that the functional connectivity between brain areas could be abnormal in subjects with ASD (Horwitz et al. Visuo-cerebellar pathways. visual inputs.g. travel through mossy ﬁbres via the pontine nuclei before reaching the cerebellum (Glickstein and Stein.. temporal and parietal cortices (Middleton and Strick. Brock et al. 1994.. These anomalies of synchronization would (i) impair the ability of individuals with ASD to process rapid information (e. Appropriately. during either resting state and simple or complex cognitive tasks. the cerebellum exerts a real-time ﬁne tuning of movement (e.or over-connectivity. Fig. 2007 for a review) in subjects with ASD. The Multi-system Brain Disconnectivity-Dissynchrony (MBD) hypothesis includes numerous functional brain anomalies (i. The cerebellum (i. 2007 for reviews). Fe events. Second. the clock of the brain as stated by Massion. 2000). their ability to use rapid sequences of cues for the development of normal language skills). a neuromimetic model (i. Studies using functional magnetic resonance imaging (fMRI) during the past 5 years have conﬁrmed that functional brain connectivity could either be decreased (see Wickelgren. 3. Fourth. Minshew and Williams. Geschwind and Levitt.. 3. 2005 for schizophrenia. neuronal hypo. 2004 for autism) and (iii) neuromimetic models (e. 1984). are therefore highly suspected to be involved in the neurophysio-pathology of ASD (Takarae et al. 2002. Yet.. or sometimes increased (Rippon et al. The main functional and structural brain abnormalities in ASD. 1991). we propose the concept of Multi-system Brain Disconnectivity-Dissynchrony (MBD). (ii) human psychophysiopathology (Babiloni et al. 2003. F. 2002b). evidenced functional interdependence and equivalence between neural synchronization (at the level of neuron assemblies). Functional magnetic resonance imaging (fMRI) studies Functional connectivity is the mechanism allowing the achievement of a cognitive task or perceptual process by coordinating and spatio-temporally correlating activities between different neural assemblies (Fingelkurts et al. 1993.1. Symond et al.. Breakspear. Gepner. Structural brain abnormalities underlie MBD. . 2002).. 2000). 2). 1988. deﬁned as an increase or decrease of functional connectivity and neural synchrony within/ between multiple cortical and subcortical regions of the brain (Fig.g. 2004a). 2002. 1988. Belmonte et al. 2004). brain rythmicity and functional connectivity. Kemper and Bauman. within/between multiple brain areas and pathways). Based on several arguments. although the anterior and posterior midline regions were similar in volume and in organization in ASD subjects and control individuals.. Courchesne et al.e. (2005).g. possibly. Johnson and Ebner. 2004). Multi-system Brain Disconnectivity-Dissynchrony (MBD) In an attempt to further understand the neurophysiological basis of TSPDs in ASD. Under resting state. and (ii) result in slowing their perceptual and cognitive processing speed. The authors surmised that disturbances in the inferior olive structure found in autism (see e. especially dynamic ones.. functional under. some of the most consistent neuroanatomic anomalies affecting people with ASD are likely to affect the cerebellum (e.e. Before reviewing the recent functional brain imaging and electrophysiological studies supporting our MBD approach to ASD. 2004). Cherkassky et al..e. would disrupt the ability of inferior olive neurons to become electrically synchronized and generate coherent rhythmic output. for a review). the cerebellum contributes with the basal ganglia to motor control as well as to learning (Doya. and consequently in olivocerebellar pathways. and is most probably limited by the network connectivity (Timme et al. a functional under-connectivity between these regions was observed in ASD individuals.. Ito.or hyper-synchrony. and temporal production of motor outputs (Gepner & Massion (dir by). see also below). the bizarre cognitive style and higher order cognitive peculiarities observed in this population (Gepner and Mestre.1232 ´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B.. the cerebellum plays a major role in speed and temporal coding and therefore in integrating multi-sensory dynamic inputs (e. 2000). it should be emphasized that numerous data emerging from (i) animal and human physiology (Varela et al. that could explain the unusual visuo-motor reactivity and..g. Borgers and Kopell. Following Welsh et al. (2005) proposed to link neuroanatomic abnormalities of the cerebellum with cognitive impairments in ASD. Third.
ﬁndings from fMRI and EEG coherence studies evidenced modiﬁcations in functional connectivity and neural synchronization in the brain of ASD patients. Brown et al. Fe 1233 During sentence comprehension tasks. Just et al. between amygdala and dorso-medial prefrontal cortex. (2008) found that greater social impairments were correlated to reduced connectivity between fusiform face area (FFA) and amygdala. during another visuo-motor coordination task. on the one hand. orbitofrontal oculomotor and motor circuits in subjects with autism. In an executive function task. What was found in autistic subjects compared to controls was mainly under-connectivity (e. this hyper-functional subcortico-cortical connectivity could potentially compensate a reduced cortico-cortical connectivity. Similarly. suggesting the possibility that this impairment may underlie the deﬁcits in cognition and behavior associated with the disorder. 2007. In order to take into account not only under. As suggested by the authors. Gepner and Tardif. as interactions between and within brain areas occur with a precision in the millisecond range. This ﬁnding is in accordance with the Systemizing-Empathizing and Extreme male brain theories of autism (Baron-Cohen. In the domain of complex visual processing. the same individuals exhibited a diffuse increased connectivity. Assessing functional connectivity with electroencephalographic coherence among adults with ASD and control adults in an eyes-closed resting state. (2005) showed an overall increased gamma-activity in individuals with autism in comparison to healthy individuals whilst identifying the presence or absence of an illusory Kanizsa shape. (2004) found a diminished functional connectivity between Wernicke’s area and Broca’s area in autistic subjects. a time resolution that fMRI cannot provide (Singer. In both samples. in another visuomotor coordination task. between V1/V2 and fusiform gyrus. Coben et al. Kennedy and Courchesne (2008) recently showed that there was an altered functional organization of the network involved in social and emotional processing in autistic subjects but no group difference in the functional organization of the network involved in sustained attention and goal-directed cognition. 3. According to Singer (2007). Just et al. ¨ Buchel and Friston. Finally. 1999). early abnormalities in the neuronal mechanisms generating high frequency EEG rhythms may contribute to the development of the disorder. boys with autism demonstrated a pathological increase of gamma (24. As also stated by Singer (2007). (2007) used magnetoencephalography to examine the integrity of local circuitry by focusing on gamma band activity in auditory cortices of children and adolescents with autism and control subjects. 2006. they present abnormal patterns of effective connectivity (which is deﬁned as the inﬂuence one system exerts over another in respect to a given experimental context. (2005) described a decreased functional connectivity between V1 and bilateral inferior frontal cortex. Wilson et al. although there was a decreased connectivity between associative.and under-connectivity that were apparent at distinct spatial and temporal scales. Altogether. an abnormally strong inﬂuence of right dLPFC on fusiform gyrus could represent the neural instantiation of a compensatory cognitive mechanism that would explain the similar levels of performance in the explicit emotional task in both groups. Findings obtained through these experiments parallel and complete results obtained in fMRI sudies. Mizuno et al. we proposed to name these processes multi-system functional disconnectivity (Gepner et al. (2007) investigated whether beta and gamma range EEG abnormalities are characteristic for young boys with autism. these ﬁndings add crucial evidence that precise timing of neural activity is disturbed in ASD. 2005. Kana et al. These ﬁndings evidence that aberrations in local circuitry could underlie putative deﬁciencies in long-range neural communication. During facial identity processing.´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B. (2006) showed that the language and spatial centres in autistic patients were not as well connected as in controls.. A new generation of experiments on neural synchrony using EEG coherence during both resting conditions and simple or complex cognitive tasks has emerged. (2006) demonstrated a more extensive connectivity between thalamus and cortex (especially left insula. on the other hand. Villalobos et al. However. F. but over-connectivity was also found between right dorsolateral prefrontal cortex (dLPFC) and fusiform gyrus. BaronCohen et al. 2002. these investigations provide only indirect evidence for dysfunctional neural synchrony in ASD. What seems to emerge from the latter studies is that when they have to process dynamic visual (such as facial . However. In regard to auditory processing. Turner et al. (2006) showed that. 2005). (2007) observed that subjects with autism exhibited a decreased connectivity between anterior and middle cingulate gyri. mostly in pericentral regions and visual cortex. Murias et al. the authors suggest that deﬁcits in neural synchrony may not exclusively involve long-range synchronization between cortical regions.g. Transient synchronization of neuronal discharges in the beta (13– 30 Hz) and gamma (30–80 Hz) frequency ranges has been proposed as possible mechanism to dynamically bind widely distributed sets of neurons into functionally coherent ensembles that represent the neural correlates of a cognitive content or an executive program (Singer. (2007) demonstrated an under-connectivity between frontal and parietal regions in autistic subjects. Kleinhans et al. EEG and MEG studies Functional MRI studies are useful to investigate the interaction between brain areas in ASD.. EEG was recorded during sustained visual attention in two independent samples of autistic boys aged 3–8 years. For these authors. Orekhova et al. In an inhibition task. According to the authors. inferior frontal and right inferior parietal regions. Furthermore. Kana et al. and insula. given the important role of high frequency EEG rhythms for perceptual and cognitive processes. memory and attention) and executive functions are based on the coordinated interactions of large numbers of neurons that are distributed within and across different specialized brain areas.0 Hz) activity. Wicker et al. This abnormal gamma activity was interpreted as a decreased ‘‘signal to noise’’ processing due to decreased inhibitory processing in ASD.but also overconnectivity between multiple brain areas in ASD. whereas subjects with ASD perform equally as well as healthy controls when viewing emotional expressions. and in age matched typically developing boys. during resting state and cognitive tasks. Gepner. 2007). Studying sustained visual attention. and increased connectivity between FFA and right inferior frontal cortex in subjects with ASD.4–44. 2000). (2007) found patterns of over. In another sentence comprehension task with imagery content. Gepner. but also local synchronization within cortical areas. In a visuo-motor task. The authors demonstrated that the production and/or maintenance of left hemispheric gamma oscillations appeared abnormal in participants with autism.2. (2008) also found dysfunctional integration of frontal and posterior brain regions in autistic subjects along with a pattern of neural under-connectivity.. Tardif et al. 2008). Speciﬁcally. (2008) demonstrated that. while listening to 500 ms duration monaural click trains with a 25 ms inter-click interval. and the right middle. most of the brain’s cognitive functions (such as perceptual organization. right postcentral and middle frontal regions) in autistic subjects. In another eyes-closed resting condition study. and between ventro-lateral prefrontal cortex and STS).
Spencer et al. and sometimes the brainstem. Among the most studied. cerebellum and related inferior olive. the authors conclude that there is no clear and consistent neuro-pathological signature that has emerged for autism. Neurobiological correlates In this section. due to heterogeneity of both the core and co-morbid features of ASD.. Courchesne et al. 3. 2004. 2000) and temporal (e. rather than the ﬁnal product. Courchesne et al. 3. cognitive and motor anomalies observed in ASD people. thus. 2008) and neurodegenerative disorders. subjects with ASD generally exhibit functional underconnectivity or neuronal hypo-synchronization. Pellicano et al. 2008). i. according to the nature of the tasks to be processed. schizophrenia (Spencer et al. Symond et al.. Van Kooten et al. Also supporting these ﬁndings. 2). Fe movements) and auditory stimuli (such as click trains and verbal speech). basal ganglia. However. However. reviewed by Bauman and Kemper (2005). especially at the neuroanatomical and neurofunctional levels. 2003). dyslexia (Cao et al. the time course of brain development. Hadjikhani et al. 2001). 2006. Schultz et al. hippocampus (Nicolson et al. Baron-Cohen et al. Allen and Courchesne. 1994). and (iii) accounts. 2004).. Deruelle et al. Post mortem studies. responsible for various temporo-spatial processing disorders of visual and auditory stimuli.. MBD and other neurobiological theories of ASD Our MBD hypothesis is in accordance with several other neurobiological theories of ASD. Gepner.. Gervais et al.g. 2007). This mini-columnopathy may therefore account for association and high-order cognitive processes abnormalities seen in ASD (Casanova. amygdala and cerebellum as the most frequent pathological areas in autism.. 2007) underline that recent magnetic resonance imaging studies have revealed brain growth abnormalities involving gray and white matter in the ﬁrst few years of life. (ii) lies on functional disconnectivity involving not only cortical but also subcortical regions. Brain dissynchrony and disconnectivity is therefore likely to constitute a universal signature of mental diseases.. as postulated by Rubenstein and Merzenich (2003). and less compact in their cellular conﬁguration. 1994. for a large spectrum of behavioral. as well as for the high incidence of epilepsy and epileptiform activity that are associated with ASD (Tuchman and Rapin.g. 2006).. Parkinson’s disease and Alzheimer’s disease (Uhlhaas and Singer. Amaral et al.g. Further studies assessing and comparing brain connectivity and/or synchronization within and between various neurodevelopmental and mental disorders will uncover similarities and differences between their underlying neural and neurofunctional mechanisms. a signiﬁcantly reduced number of Purkinje cells were reported. Milne et al..4. 2003. the cerebellum (e.. Courchesne et al. Santangelo ¨ and Tsatsanis. preceding and overlapping with the onset of the symptoms. Courchesne et al. sometimes followed by an arrest or a retardation of growth (e. numerous and abnormally enlarged neurons were observed in the brains of young autistic subjects whereas small. 2002.g.. attention deﬁcit/hyperactivity (Wolf et al. These various aspects of CNS formation found as disrupted in ASD may be at least partly correlated to genetic abnormalities inducing (i) decreased apoptosis and/or increased cell proliferation. when sustaining attention or processing static visual stimuli..e. we review some of the structural brain abnormalities that lie beneath MBD (Fig. 2006). discrepancies were observed: in cerebellar nuclei and inferior olive. Conversely. 2006 for a review). 2002. 1997). posterior superior temporal sulcus and fusiform gyrus by dynamic versus static emotional expressions.. frontal (e. see also Rippon et al. 1988. pale and under-numbered neurons were described in adult autistic brains. 2003) and the neural information processing disorders hypothesis (Belmonte et al. 2008). the mirror neuron system (e.. the fusiform gyrus (e.. ASD are distributed disorders. 2000. 2002b. the theory of imbalance between neuronal excitation and inhibition (Rubenstein and Merzenich. Uhlhaas et al. striatum and thalamus (e.g.. 2006).. with reduced neuropil space in the periphery. i. smaller. 2005). and especially the ‘‘social brain’’.g. but also depression (Vasic et al. F. 1999). 2003. Zilbovicius et al. 2007). see also Belmonte and Bourgeron. (2002) found that cell minicolumns in brains of autistic patients were more numerous. The co-occurrence of a disconnected and dissynchronized brain led us to propose the unifying concept of Multi-system Brain Disconnectivity-Dissynchrony (MBD). 2002). Anatomic neuroimaging studies during the last 20 years have shown that multiple cortical and subcortical areas are altered in adults with ASD. Oberman et al. primarily the cerebellum (e..e.g. strengthening the idea that the neuropathology of autism may represent an on-going process. Likewise. 2005. possibly leading to an imbalance between neuronal excitation and neuronal inhibition. (2007) found a lack of modulation of social brain regions including the amygdala. 2004b. 2007). amygdala (Aylward et al.g. 2006).g. Schumann and Amaral. subjects with ASD generally exhibit over-connectivity or hyper-synchronization. It should ﬁnally be added that numerous areas and pathways involved in motion. we moved a step further since our postulate (i) is based on relevant data accounting for either under. Pelphrey et al. 2006). MBD in other developmental and neuro-psychiatric disorders Brain disconnectivity and dissynchrony is not speciﬁc to ASD and has been found to occur in other neurodevelopmental disorders such as epilepsy (e. Villalobos et al. 2004. and corpus callosum (Piven et al. the amygdala (e.or over-connectivity (and hypoor hyper-synchronization) within/between local and distant networks. which may be a key signature of the developmental and functional brain anomalies observed in ASD patients.. 2000) cortices.. facial and auditory processing in daily life. 2007). whereas the reduced neuropil spaces could induce a diminished lateral inhibition. 2008). via TSPD of multi-sensory stimuli. using a computerized imaging program to measure details of cell column morphologic features in the prefrontal and temporal cortices. and the superior temporal sulcus (e. Dapretto et al.. Casanova et al. 2005.. The authors inferred that increased number of mini-columns might result in a more extensive innervation and heightened activation. 1988. 2005 for reviews). Schevon et al. Hadjikhani et al..1234 ´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B. Finally. Within the cerebellum. Further fMRI studies focusing on these various regions of interest could test this hypothesis in the future. revealed consistent ﬁndings in the limbic system.. the dorsal stream (e.. are functioning or highly suspected to function inadequately in ASD subjects. Carper and Courchesne.’s (2008) review on post mortem and structural magnetic resonance imaging studies highlighted the frontal lobes.. 2000. Cody et al. such as the temporal binding deﬁcit hypothesis (Brock et al.3. Amaral et al. (2005. (ii) altered cell migration with disrupted cortical and subcortical cytoarchitectonics and (iii) abnormal cell differentiation with . emotion... Head circumference studies indicated that this early brain overgrowth might begin as early as the ﬁrst year of life. 2005. we can cite the visual magnocellular system (Gepner and Mestre. 4. 2002. Moreover. It can therefore be surmised that MBD within and/or between these key territories and pathways may be a nodal neurophysiological mechanism of ASD.. As highlighted by Muller (2007).g... However..g. is most disturbed in autism.g.
Genetic and environmental factors Many molecular abnormalities observed in ASD patients impact on the communication between neurons and therefore support MBD hypothesis of ASD (see e. The tumor suppressor genes TSC1 and TSC2 are involved in cell growth regulation. synapse formation. a disorder often associated to mental retardation. 2005). e. As a consequence. Fe 1235 reduced neuronal size. Abnormalities in genes involved in neuronal migration and corticogenesis. Selection of misexpressed genes in ASD brains. Welsh et al. 2008). is known to play a role in the regulation of cell proliferation and neuronal migration as well as in the modulation of axonal and dendritic growth and synapse formation. astroglial and microglial) activation and neuroinﬂammation in the brain of patients with ASD (Vargas et al. 2005).g.3. 2001. including nerve growth factor (NGF). 3). A subset of genetic abnormalities (reelin. Elevated levels of BDNF have been found in the blood of children with ASD in several studies (e.g. communication difﬁculties and rigid and repetitive behaviors. . over 100 positional and/or functional candidate genes for autism were analyzed.g. 5. it is currently accepted that ASD candidate genes encode products known to play a role in brain development and/or neurotransmission (Muhle et al.2. Determining speciﬁc genetic changes that increase the susceptibility to developing ASD is however extraordinarily complex due to the polygenic nature of these disorders and the interactions between genes and environmental inﬂuences through epigenetic ´ processes. brain enlargement can be related to neuroglial (i. they may partly be due to environmental factors: in particular. 2008). interact to predispose to ASD.g. Another subset of genetic anomalies affects synaptogenesis (neuroligins.1. Genes implicated in cortical organization Alterations in the protein Reelin (involved in neuronal migration and cortical layering during development) can affect cortical and cerebellar development. localized postsynaptically at glutamatergic (NLGN1. Mutations have been identiﬁed in TSC1 and TSC2. such as social impairment. The neurotrophin family. Nelson et al. Alternatively. synaptic transmission and neuromodulation have been found to be associated with ASD. 2001) and auto-antibodies against BDNF were also found in serum of children with ASD or other associated syndromes (Connolly et al.e. GABA and glutamate receptors. Copy number variations and mutations affecting genes implicated in cortical organization. may impact on neuronal communication (see. neurotrophin-3 and neurotrophin-4.. 2004). dendrite morphology and glutamatergic neurotransmission (Tavazoie et al. Shank3) and neurotransmission (serotonin transporter. twin data and cognitive studies even suggest that non-overlapping genes act on each of the autistic traits. According to Happe et al.... Genetic factors Data from numerous epidemiological.) impacts on neuronal migration and corticogenesis. neurexins.. NLGN3 and NLGN4X/Y) or Fig. Bacchelli and Maestrini. and Fig. F. 2005). Cytogenetic abnormalities in individuals with autism have been found in virtually every chromosome and new deleterious gene expressions are on the way to be identiﬁed (Abrahams and Geschwind. brain-derived neurotrophic factor (BDNF). 1998). However. 2005).. voltage-gated ion channels). During the last decade. Gepner. neural networks and inter-neuron communication are disrupted.´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B. neurotrophin family. 5. etc. 5. 1988. 2006). Smalley et al. epilepsy and autism (Baker et al. 2005) are consistent with the cell migration defects found in autism and cerebellar neuronal abnormalities which are among the more consistent ﬁndings in ASD (Bauman and Kemper. by their consequences on the construction of neural networks. twin and family studies provided substantial evidence that ASD are amongst the most heritable complex brain disorders (e. 2007. 5. Garber.. Mutations in the RELN gene and impaired Reelin signaling in ASD (Fatemi et al. and altered synaptogenesis. which are responsible for tuberous sclerosis. Genes implicated in synapse formation and synaptic plasticity Neuroligins are cell adhesion molecules.. and probably many more. Whole-genome screens in multiplex families indicate that 29 genes (Sutcliffe. 3. Folstein and Rosen-Sheidley... 2006). (2006).
2004 for a review). Indeed.. excessive glutamatergic activity is associated with epileptiform activity.. Another study showed that mutations in neuroligin 1 abolished neuroligin binding to neurexin 1 beta. which is frequently linked to autism (Tuchman and Rapin... mutations of the 7-dehydrocholesterol reductase gene (DHCR7) cause the Smith–Lemli–Opitz syndrome (SLOS). the association of NLGNs with scaffolding proteins is likely to regulate the glutamate-GABA equilibrium. These include several point mutations in SCN1A and SCN2A. encodes FMRP (fragile-X mental retardation protein). For example. Hughes and Melyn. 2006). induce the formation of fully functional presynaptic terminals in contacting axons.1 and Nav1.. 2003). 2007). mental retardation and autism (Turner et al.g.5. 2004).. which encode the voltage-activated Na+ channels Nav1. The reported decrease in BKCa channel activity. 2007). Deﬁciencies in (i) GABA receptor expression or function and (ii) differentiation and migration of GABAergic neurons into the cortex are likely involved in ASD. mutations have been found in genes encoding other ion channels. leading to hyperexcitability in neural networks and disorders in ﬁltering out excessive stimuli from environmental and intrinsic sources (Rubenstein and Merzenich. 2005) and increased levels of glutamate have been found in adults with autism (Shinohe et al. Gepner. 2001). 2002. for a review). genes involved in the differentiation and migration of GABAergic neurons have also been linked to ASD. expressed post-synaptically. 2003). a neuroligin-binding partner regulating the structural organization of dendritic spines. other teams reported that a long promoter variant of the 5-HTT transporter was inherited more frequently by affected family members (Yirmiya et al. is caused by mutations in the FMR1 gene (Chelly and Mandel. see also Sherr. Genes implicated in voltage-gated ion channels Recent studies reviewed by Krey and Dolmetsch (2007) showed that functional mutations in genes encoding voltage-gated Ca2+ channels can lead to ASD. both associated with childhood epilepsy and autism (Weiss et al. 2002).. 2007). defects in the GABAergic inhibitory system have been found in ASD.. Neurexins (and particularly NRXN1) are localized pre-synaptically and play an important role in glutamatergic and GABAergic synaptogenesis. suggests that some forms of ASD are related to abnormally sustained increases of intracellular Ca2+ levels (Krey and Dolmetsch. steroid production and functioning of oxytocin receptor (Bukelis et al.. Principal abnormalities of SLOS include facial dysmorphy and microcephaly. via a neuroligin-neurexin link (Graf et al. SHANK3 (located in the 22q13 region). which is impaired in the neuronal networks of 30–50% ASD patients with clinical or infra-clinical epilepsy (Hughes and Melyn. localized on chromosome X.. Yet. However. One of the mutations in SCN1A lies in the calmodulin binding site of the channel and reduces its afﬁnity for Ca2+/calmodulin. 2003). The Fragile-X syndrome. One of these studies reports the Timothy syndrome. 2004).. as reviewed above and as indicated by much higher concordance rates among monozygotic twins when compared to dizygotic ones (Folstein and Rosen-Sheidley. 2006). This mutation prevents voltage-dependent channel inactivation and leads to prolonged inward Ca2+ currents.. Moreover. no association between ARX mutation and autism has been found in a study involving 226 patients with ASD and mental retardation (Chaste et al. 2001). respectively. movement disorders. these prolonged inward Ca2+ currents are known for their neurotoxicity. 2006). together with the reduced inactivation of voltage-gated Ca2+ channels in autistic patients. 2003). Mutations in ARX (which encodes a transcription factor thought to regulate the development of GABAergic neurons in the basal ganglia and cortex) have been discovered in patients with epilepsy. usually accompanied by mental retardation. Altered cholesterol metabolism may impact numerous stages of CNS development and functions including myelination. 2001). Given its role in inhibiting excitatory neural pathways and its expression in early development (see below). GABA and glutamate.000 children in the 1960s to the current rate of . it is not surprising that the GABAA receptor gene cluster (which contains genes for 3 of the receptor’s subunits: GABRB3. cortical malformations. Several studies strongly suggest the involvement of glutamate receptors in the physiopathogeny of ASD (Muhle et al. and blocked synapse formation (Chubykin et al. 2003). hypogenitalism. 2006).. Finally. Tuchman and Rapin. neuroligins. has been found to be deleted in two brothers with ASD and delayed expressive speech (Durand et al. The most studied gene involved in neurotransmission is SLC6A4. In parallel. the metabotropic glutamate receptor GRM8 in the chromosome 7q31q33 autism susceptibility locus exhibits Linkage Disequilibrium with autism (Serajee et al.. GABRA5 and GABRG3 in chromosome 15q11-13) could be implicated in ASD (Menold et al. Finally. a new multi-system disorder. Another gene. transport of serotonin. which is due to a recurrent de novo CACNA1C calcium channel mutation (Splawski et al. which encodes the serotonin transporter (5-HTT). they are responsible for atrophy of dendritic spines and decreased synaptic connections. which is involved in mRNA transport and translation at the synapse (Bagni and Greenough. often associated to autism. 5. 2005. it cannot be ignored that prevalence of autism has spectacularly soared from 4 in 10.6. In addition to the GABA receptor genes themselves. Furthermore. Genes implicated in neurotransmission and neuromodulation Several studies revealed that variants of genes encoding neurotransmitter receptors and transporters might be susceptibility factors or modulators of the behavioral phenotype of ASD. 1994). Another study reports a decrease in Ca2+-activated K+ channel (BKCa) activity due to a disruption of the BKCa gene (KCNMA1) in one subject with ASD (Laumonnier et al. Mutations in the coding sequences of X-linked NLGN3 and NLGN4 have been identiﬁed in individuals with ASD and mental retardation (Jamain et al.. Whereas Cook et al. 2005). These ﬁndings are consistent with the idea that ASD can be caused by a reduced activity of GABAergic pathways. Environmental and epigenetic factors Genetic factors are undoubtedly important in the pathogenesis of ASD.. 2001).1236 ´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B. Although these mutations have not been conﬁrmed in other studies and probably explain less than 1% of ASD (Persico and Bourgeron. 2002). which is often accompanied by an autistic syndrome.. 2002. an autosomal recessive malformation syndrome caused by a deﬁciency of the last step of cholesterol biosynthesis (Tint et al.2. An autistic population possessed a single amino acid substitution in GluR6 with a higher frequency than a control population (Jamain et al.4. ´ leading to apoptosis in socially isolated rats (Silva-Gomez et al. 2007). e. However. 2–3 toe syndactyly and a characteristic behavioral proﬁle including autism. The FMR1 gene. Genes encoding neurexins have clearly been implicated in ASD by the Autism Genome Project Consortium (2007) in the largest linkage scan of 1168 families with at least two individuals affected by ASD. 2003.. hypotonia. F.. 2005). they shed light on the potentially crucial role of synapse abnormalities in ASD. 5. (1997) found preferential inheritance of a short promoter variant of SLC6A4 in affected individuals. Fe GABAergic synapses (NLGN2) (Varoqueaux et al. 5.
. see also Parker et al. (iii) Prader-Willi and Angelman syndromes which are often associated to ASD may be due to abnormal methylation of the imprinted region of the UBE3A gene on Fig. 2006). 2005) have also been found to be linked to ASD. 2002. Although highly controversial (see e. Schematic overview of our TSPD and MBD approaches to ASD. on brain development. 1994. Fe 1237 30–60 in 10..g. 4. could be partly responsible for the rising rates of ASD (Bernard et al. . 2005).g. the absence of correlation between autism and exposure to thimerosal in Heron and Golding.000 (Rutter. 2004.. Desoto and Hitlan. prenatal exposures to ¨ thalidomide (Stromland et al. for a review). Pre. To date. such as low birth weight and shorter duration of gestation. In addition.. Recently. We can however cite a few: (i) Rett syndrome.and perinatal infections by viral agents like rubella (Chess et al. 2007). motor and cognitive dysfunctions in ASD individuals. loss of language. probably because of an increased risk for obstetric complications. 2003) have been found to increase the risk for ASD. 2008). 1999).. It is now well established that valproic acid acts as a potent inhibitor of histone deacetylase activities ¨ (Gottlicher.. Rasalam et al.. (ii) children exposed in utero to sodium valproate (a medicine used for decades in the treatment of epilepsy and migraine) present an increased risk for ASD.. advanced maternal age has been identiﬁed as a risk factor for ASD.´ron / Neuroscience and Biobehavioral Reviews 33 (2009) 1227–1242 B. hand wringing and seizures is due to mutation of MeCP2 (Amir et al. 2002) or valproic acid (Christianson et al. Although this increased prevalence in the last 40 years may be partly explained by changes in autism diagnostic criteria and growing awareness of the disorder (e. As a result.. 1994. F. found in increasing number in water and food. environmental and epigenetic anomalies induce structural brain abnormalities that are responsible for Multi-system Brain Disconnectivity-Dissynchrony (MBD). to the pathogenesis of ASD. 2004 for a review). a pervasive developmental disorder characterized by autism. It is also recognized that advanced paternal age is associated to ASD (Reichenberg et al. 1978) and cytomegalovirus (Yamashita et al. either per se or via epigenetic mechanisms. and intrapartum hypoxia (Kolevzon et al. These environmental factors are suspected to disrupt the normal encephalogenesis by perturbing neurodevelopmental pathways and/or interacting with the neuroimmune system. 2007.. the autistic brain is affected by various temporo-spatial processing disorders (TSPDs) of multi-sensory dynamic stimuli that in turn generate numerous behavioral. It has also been suggested that thimerosal. Genetic. Waterhouse. a ﬁnding that might be related to de novo copy number variation in this population (Sebat et al. there is also strong evidence to suggest that several environmental factors contribute. 2007). this proposal raises the question of the detrimental role of threatening chemicals. an ethylmercury derivative added in vaccines. a limited number of studies have investigated the role of epigenetic misregulation in ASD.. Gepner. 2004).
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