6.1.1. Brain size, birth weight, growth, and placentation

Whole brain size is reduced in schizophrenia from birth onwards (Cannon et al. Reference Cannon, Jones and Murray2002; Gur et al. Reference Gur, Keshavan and Lawrie2007; McIntosh et al. Reference McIntosh, Job, Moorhead, Harrison, Whalley, Johnstone and Lawrie2006; Tamminga & Holcomb Reference Tamminga and Holcomb2005), due to reductions in grey matter (neuronal tissue) (e.g., Narr et al. Reference Narr, Bilder, Toga, Woods, Rex, Szeszko, Robinson, Sevy, Gunduz-Bruce, Wang, DeLuca and Thompson2005; Woods et al. Reference Woods, Ward and Johnson2005), reduced and altered white matter (mainly brain fatty acids) (e.g., Kieseppä et al. Reference Kieseppä, van Erp, Haukka, Partonen, Cannon, Poutanen, Kaprio and Lönnqvist2003; McDonald et al. Reference McDonald, Bullmore, Sham, Chitnis, Wickham, Bramon and Murray2004; Reference McDonald, Bullmore, Sham, Chitnis, Suckling, MacCabe, Walshe and Murray2005), and lower cortical thickness (Goghari et al. Reference Goghari, Rehm, Carter and Macdonald2007; Kuperberg et al. Reference Kuperberg, Broome, McGuire, David, Eddy, Ozawa, Goff, West, Williams, van der Kouwe, Salat, Dale and Fischl2003). Moises et al. (Reference Moises, Zoega and Gottesman2002) also noted that a considerable range of growth deficiencies, including low birth weight, late maturation, and small brain size, are found in schizophrenia. Reduced brain size may be due in part to slow brain maturation in individuals who develop psychosis (Crow Reference Crow1995; Crow et al. Reference Crow, Done and Sacker1996; James et al. Reference James, Crow, Renowden, Wardell, Smith and Anslow1999; Saugstad Reference Saugstad1998; Reference Saugstad1999).

In autism, cortical thickness is increased (Hardan et al. Reference Hardan, Muddasani, Vemulapalli, Keshavan and Minshew2006), and increased head and brain size is one of the most consistent anatomical findings across studies (DiCicco-Bloom et al. Reference DiCicco-Bloom, Lord, Zwaigenbaum, Courchesne, Dager, Schmitz, Schultz, Crawley and Young2006; Dissanayake et al. Reference Dissanayake, Bui, Huggins and Loesch2006; Lainhart et al. Reference Lainhart, Bigler, Bocian, Coon, Dinh, Dawson, Deutsch, Dunn, Estes, Tager-Flusberg, Folstein, Hepburn, Hyman, McMahon, Minshew, Munson, Osann, Ozonoff, Rodier, Rogers, Sigman, Spence, Stodgell and Volkmar2006; Stanfield et al., in press). In autism, brain size undergoes a striking growth spurt between birth and age four (Cody et al. Reference Cody, Pelphrey and Piven2002; Courchesne & Pierce Reference Courchesne and Pierce2005a; Reference Courchesne and Pierce2005b; Courchesne et al. Reference Courchesne, Redcay and Kennedy2004; Herbert Reference Herbert2005; Lainhart et al. Reference Lainhart, Bigler, Bocian, Coon, Dinh, Dawson, Deutsch, Dunn, Estes, Tager-Flusberg, Folstein, Hepburn, Hyman, McMahon, Minshew, Munson, Osann, Ozonoff, Rodier, Rogers, Sigman, Spence, Stodgell and Volkmar2006; Penn Reference Penn2006; Redcay & Courchesne Reference Redcay and Courchesne2005), an acceleration driven differentially by increases in (metabolically expensive) white matter volume (Herbert et al. Reference Herbert, Ziegler, Makris, Filipek, Kemper, Normandin, Sanders, Kennedy and Caviness2004; Lainhart Reference Lainhart2006; see also McAlonan et al. Reference McAlonan, Daly, Kumari, Critchley, van Amelsvoort, Suckling, Simmons, Sigmundsson, Greenwood, Russell, Schmitz, Happé, Howlin and Murphy2002). Remarkably, a recent study of Asperger syndrome showed that grey matter volume did not decrease with age (from 15 to 50), as it does substantially in normal individuals (McAlonan et al. Reference McAlonan, Daly, Kumari, Critchley, van Amelsvoort, Suckling, Simmons, Sigmundsson, Greenwood, Russell, Schmitz, Happé, Howlin and Murphy2002; see also Ge et al. Reference Ge, Grossman, Babb, Rabin, Mannon and Kolson2002; Woods et al. Reference Woods, Ward and Johnson2005); these data suggest that autism and schizophrenia exhibit divergent patterns of grey matter loss, with little to no loss in autism, moderate loss in normal development, and high rates of loss in schizophrenia.

These differences in brain size and development between autistic and schizophrenic individuals are broadly paralleled by differences in birth weight and growth. Thus, autism can involve higher birth weight compared to controls (Mraz et al. Reference Mraz, Green, Dumont-Mathieu, Makin and Fein2007; Sacco et al. Reference Sacco, Militerni, Frolli, Bravaccio, Gritti, Elia, Curatolo, Manzi, Trillo, Lenti, Saccani, Schneider, Melmed, Reichelt, Pascucci, Puglisi-Allegra and Persico2007; Sugie et al. Reference Sugie, Sugie, Fukuda and Ito2005) and faster body growth (Dissanayake et al. Reference Dissanayake, Bui, Huggins and Loesch2006; Fukumoto et al. Reference Fukumoto, Hashimoto, Ito, Nishimura, Tsuda, Miyazaki, Mori, Arisawa and Kagami2008; Mraz et al. Reference Mraz, Green, Dumont-Mathieu, Makin and Fein2007), although some studies report a lack of birth weight difference (Cederlund & Gillberg Reference Cederlund and Gillberg2004; Juul-Dam et al. Reference Juul-Dam, Townsend and Courchesne2001; Larsson et al. Reference Larsson, Eaton, Madsen, Vestergaard, Olesen, Agerbo, Schendel, Thorsen and Mortensen2005) or lower birth weight in autism (Kolevzon et al. Reference Kolevzon, Gross and Reichenberg2007). By contrast, schizophrenia and major depression entail lower weight at birth with considerable consistency across studies (Cannon et al. Reference Cannon, Jones and Murray2002; Costello et al. Reference Costello, Worthman, Erkanli and Angold2007; Gale & Martyn Reference Gale and Martyn2004; Gunnell & Holly Reference Gunnell and Holly2004; Niemi et al. Reference Niemi, Suvisaari, Haukka and Lönnqvist2005; Nilsson et al. Reference Nilsson, Stålberg, Lichtenstein, Cnattingius, Olausson and Hultman2005; Wahlbeck et al. Reference Wahlbeck, Forsén, Osmond, Barker and Eriksson2001a). Imprinted genes are known to exert strong effects on birth weight and childhood weight in humans (Gorlova et al. Reference Gorlova, Amos, Wang, Shete, Turner and Boerwinkle2003; Lindsay et al. Reference Lindsay, Kobes, Knowler and Hanson2002), and Svensson et al. (Reference Svensson, Pawitan, Cnattingius, Reilly and Lichtenstein2006) have demonstrated familial aggregation of low birth weight, with effects from maternal, paternal, and fetal genes. The clearest evidence for enhanced growth in autism comes from Mills et al. (Reference Mills, Hediger, Molloy, Chrousos, Manning-Courtney, Yu, Brasington and England2007), who reported significantly increased head size, body weight, body mass index, and levels of growth hormones (including the key, paternally expressed growth factor IGF2) in autistic children compared to normal controls. Diametric patterns of growth can also help to explain the higher incidence of schizophrenia than autism, given that there should be many more genetic, epigenetic, and environmental ways to disrupt and reduce growth than to increase it. We also note that genomic conflicts and strong selection may contribute to the high heritabilities of autism and schizophrenia via such processes as antagonistic pleiotropy, evolutionary disequilibrium, and increased scope for mutation-selection balance via disruption of developmental tugs-of-war (Crespi Reference Crespi2006; Crespi et al. Reference Crespi, Summers and Dorus2007).

Fetal development is critically dependent upon placentation, which in humans is highly invasive and has evolved in the context of constrained maternal–fetal conflict (Haig Reference Haig1993). Anderson et al. (Reference Anderson, Jacobs-Stannard, Chawarska, Volkmar and Kliman2007) recently described a highly significant, three-fold increase in placental inclusions in autism. Such inclusions are caused by increased proliferative growth of cytotrophoblast, the stem-cell-like component of the placenta. Placental inclusions are also found disproportionately in Beckwith-Wiedemann syndrome and hydatiform moles (molar pregnancies involving placental overgrowth), both of which represent disorders of genomic imprinting that involve excessive effects from paternal gene expression (Devriendt Reference Devriendt2005; Fisher et al. Reference Fisher, Hodges, Rees, Sebire, Seckl, Newlands, Genest and Castrillon2002; Ohama et al. Reference Ohama, Ueda, Okamoto, Takenaka and Fujiwara1986; Saxena et al. Reference Saxena, Frank, Panichkul, Van den Veyver, Tycko and Thaker2003). Placental development in general is strongly regulated by imprinted genes, with paternally expressed genes favoring increased placental growth (Dunger et al. Reference Dunger, Petry and Ong2006; Fowden et al. Reference Fowden, Sibley, Reik and Constancia2006; McMinn et al. Reference McMinn, Wei, Schupf, Cusmai, Johnson, Smith, Weksberg, Thaker and Tycko2006; Reik et al. Reference Reik, Constancia, Fowden, Anderson, Dean, Ferguson-Smith, Tycko and Sibley2003).

Risk of schizophrenia decreases with increased placental weight (Wahlbeck et al. Reference Wahlbeck, Forsén, Osmond, Barker and Eriksson2001a). Intrauterine growth restriction, which is caused predominantly by placental underdevelopment and engenders increased fetal hypoxia (Gagnon Reference Gagnon2003), is also a strong risk factor for schizophrenia (Abel & Allin Reference Abel, Allin, Baker and Sibley2006; Cannon et al. Reference Cannon, Rosso, Hollister, Bearden, Sanchez and Hadley2000; Rees & Inder Reference Rees and Inder2005). Effects of fetal hypoxia on brain development are also indicated by experiments in rats that link hypoxia with altered lateralization of the dopaminergic system (Brake et al. Reference Brake, Sullivan and Gratton2000). Finally, in humans, monozygotic twin concordance for schizophrenia is much higher when the twins share a placenta (60%), than when they do not (11%) (Davis et al. Reference Davis, Phelps and Bracha1995). Abel (Reference Abel2004) describes additional evidence that fetal growth restriction, mediated by imprinting effects, contributes to the development of schizophrenia.

Placentation is crucial to brain development, and it represents a key arena for imprinted-gene conflict, because fetal brain growth, especially deposition of fatty acids, is one of the most metabolically costly processes during pregnancy, as well as exerting severe energetic costs in early postnatal development (Foley & Lee Reference Foley and Lee1991; Herrera Reference Herrera2002; Kuzawa Reference Kuzawa1998). Mothers bear virtually all of these costs, and indeed, during the late stages of pregnancy mothers metabolize their own brain fat for transfer to the fetus. We hypothesize that the contrasting patterns of brain size, growth, composition, and birth weight in psychosis and autism are mediated by effects of maternal versus paternal genes, with paternal genes driving the acquisition of increased brain fatty acids in particular. Directly parallel arguments have been made concerning intragenomic conflict over body fat in human babies (Haig Reference Haig and Stearns1999b): Human neonates exhibit by far the highest average body fat content of any mammal, which may represent an adaptation to sequester resources to fuel sustained brain growth in early childhood (Badcock Reference Badcock2000, pp. 208–212; Cunnane & Crawford Reference Cunnane and Crawford2003; Kuzawa Reference Kuzawa1998). A role for imprinted genes in human fat metabolism is suggested by Silver-Russell syndrome, which is caused by a bias towards relative maternal gene expression and involves a striking lack of subcutaneous fat (Monk & Moore Reference Monk and Moore2004).

Patterns and predictions regarding early brain growth in autism and schizophrenia are critically important to the theory proposed here, because altered early brain growth rates are expected to strongly influence patterns of brain connectivity and cerebral lateralization, as described in detail in the next sections.

6.1.2. Hippocampus and amygdala size

The hippocampus is centrally involved in learning and the consolidation of memory, with the right side more involved in spatial cognition, and the left side dedicated more to aspects of memory (Burgess et al. Reference Burgess, Maguire and O'Keefe2002; Piefke & Fink Reference Piefke and Fink2005). By contrast, the amygdala provides social and emotional valence to sensory perceptions, such as the recognition of fearful stimuli, providing input on emotional content to brain structures such as the hippocampus and neocortex (Adolphs et al. Reference Adolphs, Baron-Cohen and Tranel2002; Sander et al. Reference Sander, Grafman and Zalla2003; Skuse et al. Reference Skuse, Morris and Lawrence2003). Integrated activity of the amygdala, hippocampus, and social-brain components of the neocortex has been hypothesized as a core aspect of the social brain system, that processes the rapid, complex information flow involved in human interaction, especially interactions involving emotion, language, and facial expression.

Autism and schizophrenia both involve alterations in structure and function of the interacting amygdala, hippocampus, and prefrontal cortex (Baron-Cohen et al. Reference Cohen, Pichard, Tordjman, Baumann, Burglen, Excoffier, Lazar, Mazet, Pinquier, Verloes and Héron2005; Berretta et al. Reference Berretta, Munno and Benes2001; Burns Reference Burns2004; Reference Burns2006a; Gisabella et al. Reference Gisabella, Bolshakov and Benes2005; J. D. Johnson Reference Johnson2005). The available evidence indicates that relative to brain size, the hippocampus and amygdala are larger in autism than in controls (at least during early development) (Schumann et al. Reference Schumann, Hamstra, Goodlin-Jones, Lotspeich, Kwon, Buonocore, Lammers, Reiss and Amaral2004; Stanfield et al., in press), and (in most studies, and in adults) smaller in schizophrenia and schizotypy (Aleman & Kahn Reference Aleman and Kahn2005; Geuze et al. Reference Geuze, Vermetten and Bremner2005; Gur et al. Reference Gur, Kohler, Turetsky, Siegel, Kanes, Bilker, Brennan and Gur2004; Reference Gur, Keshavan and Lawrie2007; Kuroki et al. Reference Kuroki, Kubicki, Nestor, Salisbury, Park, Levitt, Woolston, Frumin, Niznikiewicz, Westin, Maier, McCarley and Shenton2006; Lawrie et al. Reference Lawrie, Whalley, Job and Johnstone2003; Narr et al. Reference Narr, van Erp, Cannon, Woods, Thompson, Jang, Blanton, Poutanen, Huttunen, Lönnqvist, Standerksjold-Nordenstam, Kaprio, Mazziotta and Toga2002; Reference Narr, Thompson, Szeszko, Robinson, Jang, Woods, Kim, Hayashi, Asunction, Toga and Bilder2004; Suzuki et al. Reference Suzuki, Zhou, Takahashi, Hagino, Kawasaki, Niu, Matsui, Seto and Kurachi2005; Tamminga & Holcomb Reference Tamminga and Holcomb2005; van Elst & Trimble Reference van Elst and Trimble2003). In schizophrenia, smaller size and altered shape of the hippocampus may be functionally related to positive symptoms such as paranoia and delusions, in that the hippocampus mediates the creation, maintenance, and updating of contextual social and spatial “worldviews” and beliefs, via interactions with the neocortex and amygdala (e.g., Gray Reference Gray1998; J. D. Johnson Reference Johnson2005). In autism, increased hippocampus size may be related to enhanced visual-spatial, mathematical, and mechanistic aspects of cognition (Baron-Cohen et al. Reference Baron-Cohen, Wheelwright, Skinner, Martin and Clubley2001; Minshew et al. Reference Minshew, Goldstein and Siegel1997), as best seen in Asperger syndrome mechanistic skills, and the abilities of autistic savants at calculation and memory (Heaton & Wallace Reference Heaton and Wallace2004; Pring Reference Pring2005; see also Young et al. Reference Young, Ridding and Morrell2004). Individuals with schizophrenia, and schizotypal individuals, exhibit cognitive profiles of impaired visual-spatial and arithmetic abilities, relative to verbal abilities, as described in more detail in the section on sex difference further on.

6.1.3. Cerebral lateralization

Schizophrenia involves reduced structural and functional brain asymmetry, as indicated by an increased incidence of mixed or inconsistent handedness, imaging studies of neuroanatomy with a focus on language-related regions such as the planum temporale, asymmetries in neurotransmitter activity, and higher impairments in verbal ability for individuals less lateralized for handedness (Chance et al. Reference Chance, Esiri and Crow2005; Collinson et al. Reference Collinson, Mackay, James, Quested, Phillips, Roberts and Crow2003; Crow Reference Crow1997; Reference Crow1998; Reference Crow2000; Crow et al. Reference Crow, Crow, Done and Leask1998; DeLisi et al. Reference DeLisi, Svetina, Razi, Shields, Wellman and Crow2002; Honea et al. Reference Honea, Crow, Passingham and Mackay2005; Leask & Crow Reference Leask and Crow2005; Mitchell & Crow Reference Mitchell and Crow2005; Schiffman et al. Reference Schiffman, Pestle, Mednick, Ekstrom, Sorensen and Mednick2005; Shirakawa et al. Reference Shirakawa, Kitamura, Lin, Hashimoto and Maeda2001; Sommer et al. Reference Sommer, Ramsey and Kahn2001; Weiss et al. Reference Weiss, Hofer, Golaszewski, Siedentopf, Felber and Fleischhacker2006). This reduced brain lateralization and lower degree of torque in schizophrenia is apparently associated with slower brain development (Crow et al. Reference Crow, Done and Sacker1996; Reference Crow, Crow, Done and Leask1998; Saugstad Reference Saugstad1998; Reference Saugstad1999), relatively increased dysfunction of components of the left hemisphere compared to the right (e.g., Honea et al. Reference Honea, Crow, Passingham and Mackay2005; Kasai et al. Reference Kasai, Shenton, Salisbury, Hirayasu, Lee, Ciszewski, Yurgelun-Todd, Kikinis, Jolesz and McCarley2003a; Reference Kasai, Shenton, Salisbury, Hirayasu, Onitsuka, Spencer, Yurgelun-Todd, Kikinis, Jolesz and McCarley2003b; Mucci et al. Reference Mucci, Galderisi, Bucci, Tresca, Forte, Koenig and Maj2005) with diminished left-hemisphere specialization for language (Dollfus et al. Reference Dollfus, Razafimandimby, Delamillieure, Brazo, Joliot, Mazoyer and Tzourio-Mazoyer2005; Mitchell & Crow Reference Mitchell and Crow2005), and an increase in the extent of positive symptoms such as delusions (Verdoux et al. Reference Verdoux, Liraud, Droulout, Theillay, Parrot and Franck2004). Similar patterns have been detected in healthy individuals, in whom the degree of schizotypal cognition is positively associated with mixed handedness and other evidence of reduced cerebral lateralization (Barnett & Corballis Reference Barnett and Corballis2002; Jaspers-Fayer & Peters Reference Jaspers-Fayer and Peters2005; Preti et al. Reference Preti, Sardu and Piga2007; Shaw et al. Reference Shaw, Claridge and Clark2001).

Impaired or reduced left-hemisphere language function in schizophrenia and schizotypy may result in greater reliance on right-hemisphere processing of some components of thought and language (Fisher et al. Reference Fisher, Mohanty, Herrington, Koven, Miller and Heller2004; Mohr et al. Reference Mohr, Krummenacher, Landis, Sandor, Fathi and Brugger2005; Taylor et al. Reference Taylor, Zäch and Brugger2002). A crucial result of such a shift may be more “coarse” semantic processing; generation of “loose,” more-distant associations between events and thoughts (Pizzagalli et al. Reference Pizzagalli, Lehmann, Gianotti, Koenig, Tanaka, Wackermann and Brugger2000); overestimation of meaningfulness of naturally occurring coincidences; increased paranormal ideation; and at the extreme, delusion, paranoia, and other positive symptoms of schizophrenia (Brugger Reference Brugger, Houran and Lange2001; Brugger & Graves Reference Brugger and Graves1997a; Reference Brugger and Graves1997b; Leonhard & Brugger Reference Leonhard and Brugger1998). This hypothesis is supported by a diverse range of additional evidence, from modelling of neural networks (Hoffman et al. Reference Hoffman, Hampson, Varanko and McGlashan2004), to neurocognitive and psychological analyses of schizotypy (Claridge Reference Claridge1997), and the use of dopamine agonists to restore left-hemisphere language dominance (Mohr et al. Reference Mohr, Krummenacher, Landis, Sandor, Fathi and Brugger2005). The hypothesis also provides a relatively simple neuroanatomical and neurophysiological explanation for the links between creativity and psychosis as a cognitive style that involves more-distant and more-novel associations between components of thought (Barrantes-Vidal Reference Barrantes-Vidal2004; Brugger Reference Brugger, Houran and Lange2001; Gianotti et al. Reference Gianotti, Mohr, Pizzagalli, Lehmann and Brugger2001). The general links of imagination and creativity with psychosis (Claridge et al. Reference Claridge, Pryor and Watkins1990; Nettle Reference Nettle2001; Sack et al. Reference Sack, van de Ven Vincent, Etschenberg, Schatz and Linden2005) strongly contrast with the lower levels of pretend play and symbolic creativity, as well as increased repetitive and compulsive behavior, in autism (Atlas & Lapidus Reference Atlas and Lapidus1987; Blanc et al. Reference Blanc, Adrien, Roux and Barthélémy2005; Boucher Reference Boucher2007; U. Frith Reference Frith2004; Honey et al. Reference Honey, Leekam, Turner and McConachie2006; Turner Reference Turner1999).

Whereas schizophrenia is associated with reduced asymmetry, autism tends to involve increased size of some right-hemisphere cortical structures (i.e., reversed asymmetry compared to normal), and reversed lateralization of language (Bigler et al. Reference Bigler, Mortensen, Neeley, Ozonoff, Krasny, Johnson, Lu, Provencal, McMahon and Lainhart2007; De Fossé et al. Reference De Fossé, Hodge, Makris, Kennedy, Caviness, McGrath, Steele, Ziegler, Herbert, Frazier, Tager-Flusberg and Harris2004; Escalante-Mead et al. Reference Escalante-Mead, Minshew and Sweeney2003; Flagg et al. Reference Flagg, Cardy, Roberts and Roberts2005; Herbert et al. Reference Herbert, Harris, Adrien, Ziegler, Makris, Kennedy, Lange, Chabris, Bakardjiev, Hodgson, Takeoka, Tager-Flusberg and Caviness2002; Reference Herbert, Ziegler, Deutsch, O'Brien, Kennedy, Filipek, Bakardjiev, Hodgson, Takeoka, Makris and Caviness2005; see also Rinehart et al. Reference Rinehart, Bradshaw, Brereton and Tonge2002b; Sutton et al. Reference Sutton, Burnette, Mundy, Meyer, Vaughan, Sanders and Yale2005). As the right hemisphere develops earlier than the left hemisphere in the fetal and neonatal stages (Chiron et al. Reference Chiron, Leboyer, Leon, Jambaqué, Nuttin and Syrota1995; see also Rinehart et al. Reference Rinehart, Bradshaw, Brereton and Tonge2002b), a pattern of rightward asymmetry in autism may be due simply to a faster, earlier pattern of brain development – a heterochronic shift opposite to a slower developmental profile in schizophrenia (Saugstad Reference Saugstad1999). Accelerated early brain development in autism, and relatively slow brain development in schizophrenia, may thus both lead to anomalous lateralization of cognitive functions.

6.1.4. Corpus callosum size and brain connectivity

In autism, the corpus callosum is relatively small (for brain size) compared to control individuals (Cody et al. Reference Cody, Pelphrey and Piven2002; Egaas et al. Reference Egaas, Courchesne and Saitoh1995; Nydén et al. Reference Nydén, Carlsson, Carlsson and Gillberg2004; Piven et al. Reference Piven, Bailey, Ranson and Arndt1997; Sherr et al. Reference Sherr, Owen, Albertson, Pinkel, Cotter, Slavotinek, Hetts, Jeremy, Schilmoeller, Schilmoeller, Wakahiro and Barkovich2005; Stanfield et al., in press; Waiter et al. Reference Waiter, Williams, Murray, Gilchrist, Perrett and Whiten2005). A pattern of reduced interhemispheric brain connectivity in autistic individuals (Belmonte et al. Reference Belmonte, Allen, Beckel-Mitchener, Boulanger, Carper and Webb2004a; Reference Belmonte, Cook, Anderson, Rubenstein, Greenough, Beckel-Mitchener, Courchesne, Boulanger, Powell, Levitt, Perry, Jiang, DeLorey and Tierney2004b; Nydén et al. Reference Nydén, Carlsson, Carlsson and Gillberg2004) fits with one of the central hypotheses for the cognitive architecture of autism: that it involves increased local and decreased global information processing, reduced “central coherence,” increased “bottom-up” relative to “top-down” processing, and decreased overall brain connectivity (Baron-Cohen & Belmonte Reference Baron-Cohen and Belmonte2005; Belmonte et al. Reference Belmonte, Allen, Beckel-Mitchener, Boulanger, Carper and Webb2004a; Reference Belmonte, Cook, Anderson, Rubenstein, Greenough, Beckel-Mitchener, Courchesne, Boulanger, Powell, Levitt, Perry, Jiang, DeLorey and Tierney2004b; Happé & Frith Reference Happé and Frith2006; Just et al. Reference Just, Cherkassky, Keller and Minshew2004). Courchesne and Pierce (Reference Courchesne and Pierce2005b) have referred to autistic neurocognition as the frontal cortex unconsciously “talking to itself,” concomitant with loss of language and other elements of social cognition.

Findings regarding corpus callosum size in schizophrenia are mixed and inconsistent, apparently due to marked variation with age, sex, handedness, and clinical profile (Bachmann et al. Reference Bachmann, Pantel, Flender, Bottmer, Essig and Schroder2003; Brambilla et al. Reference Brambilla, Cerini, Gasparini, Versace, Andreone, Vittorini, Barbui, Pelizza, Nosè, Barlocco, Marrella, Gregis, Tournikioti, David, Keshavan and Tansella2005; Downhill et al. Reference Downhill, Buchsbaum, Wei, Spiegel-Cohen, Hazlett, Haznedar, Silverman and Siever2000; Highley et al. Reference Highley, DeLisi, Roberts, Webb, Relja, Razi and Crow2003; Luders et al. Reference Luders, Rex, Narr, Woods, Jancke, Thompson, Mazziotta and Toga2003; Tuncer et al. Reference Tuncer, Hatipoglu and Ozates2005). The issue of brain connectivity in schizophrenia has yet to reach a consensus among researchers, as it has for autism, perhaps due to the high clinical heterogeneity in schizophrenia. A considerable body of evidence suggests that schizophrenia involves altered intrahemispheric and interhemispheric connectivity, but such changes take particular forms, such as altered transfer of verbal information between hemispheres (Barnett & Kirk Reference Barnett and Kirk2005; Barnett et al. Reference Barnett, Corballis and Kirk2005; Endrass et al. Reference Endrass, Mohr and Rockstroh2002), that are difficult to interpret without a cognitive model for their significance. One possibility suggested by neural network models, and consistent with increased relative corpus callosum size, is that schizophrenia involves reduced local (relative to global) connections (Siekmeier & Hoffman Reference Siekmeier and Hoffman2002), which would provide a contrast with the enhanced local connectivity and processing found in autism (Courchesne & Pierce Reference Courchesne and Pierce2005a; Reference Courchesne and Pierce2005b; Happé & Frith Reference Happé and Frith2006). This hypothesis is supported by several findings, including: (1) the results of Whalley et al. (Reference Whalley, Simonotto, Marshall, Owens, Goddard, Johnstone and Lawrie2005), who recorded increased connectivity of left parietal with left prefrontal regions in individuals at high risk of schizophrenia; (2) hyperconnectivity across brain regions for some (though not other) EEG frequencies in schizophrenia (Sritharan et al. Reference Sritharan, Line, Sergejew, Silberstein, Egan and Copolov2005; Strelets et al. Reference Strelets, Novototsky-Vlasov and Golikova2002; see also McCreery & Claridge Reference McCreery and Claridge1996); and (3) coactivation of inner speech and language regions normally activated in sequence (Hubl et al. Reference Hubl, Koenig, Strik, Federspiel, Kreis, Boesch, Maier, Schroth, Lovblad and Dierks2004) and inferred wider-spreading activation of brain regions in schizophrenia (Chance et al. Reference Chance, Esiri and Crow2005) and schizotypy (Pizzagalli et al. Reference Pizzagalli, Lehmann and Brugger2001; see also Niebauer Reference Niebauer2004). Sumich et al. (Reference Sumich, Chitnis, Fannon, O'Ceallaigh, Doku, Faldrowicz and Sharma2005) provide MRI evidence that unreality symptoms and hallucinations in schizophrenia involve dysfunctions in Heschl's gyrus that impair bottom-up processing, “giving greater perceptual control to ‘top-down’ mechanisms” (p. 947); Seal et al. (Reference Seal, Aleman and McGuire2004) provide evidence for “heightened influence of top-down processing on perception” in auditory hallucinations of schizophrenics; and Carter et al. (Reference Carter, Robertson, Nordahl, Chaderjian and Oshora-Celaya1996), Granholm et al. (Reference Granholm, Perry, Filoteo and Braff1999), and Bellgrove et al. (Reference Bellgrove, Vance and Bradshaw2003) have shown that schizophrenia involves greater impairments in local as opposed to global processing of stimuli, and exaggerated global-processing advantages for some tasks.

Finally, the neuroanatomical and cognitive correlates of dyslexia are notably similar to those found in schizophrenia and schizotypy (Bersani et al. Reference Bersani, Maneschi, Tarolla and Pancheri2006; Bradshaw & Nettleton Reference Bradshaw and Nettleton1983, pp. 242–54; Edgar et al. Reference Edgar, Yeo, Gangestad, Blake, Davis, Lewine and Cañive2006; Heim et al. Reference Heim, Kissler, Elbert and Rockstroh2004; Richardson Reference Richardson1994), and dyslexia has also been linked with “enhanced ability to process visual-spatial information globally (holistically) rather than locally (part by part)” (von Károlyi et al. Reference von Károlyi, Winner, Gray and Sherman2003). By contrast, hyperlexia, the spontaneous and highly precocious mastery of reading in children (Grigorenko et al. Reference Grigorenko, Klin and Volkmar2003; Silberberg & Silberberg Reference Silberberg and Silberberg1967; Reference Silberberg and Silberberg1971), is found almost exclusively in conjunction with autism (Burd & Kerbeshian Reference Burd and Kerbeshian1988; Just et al. Reference Just, Cherkassky, Keller and Minshew2004; Turkeltaub et al. Reference Turkeltaub, Flowers, Verbalis, Miranda, Gareau and Eden2004). The neural basis for hyperlexia was investigated in a single case study using fMRI: Hyperlexic reading was associated with hyperactivation of the left superior temporal cortex, a region that is hypoactivated in dyslexia (Turkeltaub et al. Reference Turkeltaub, Flowers, Verbalis, Miranda, Gareau and Eden2004).

6.3.1. Gaze and intention

Humans are unique among primates in exhibiting a white sclera (the “whites of the eyes”) (Emery Reference Emery2000), which allows direct observation of the form and directionality of gaze (e.g., Whalen et al. Reference Whalen, Kagan, Cook, Davis, Kim, Polis, McLaren, Somerville, McLean, Maxwell and Johnstone2004). Gaze is a fundamental component of social interactions, with most humans exquisitely cognizant of the gaze of others and perceptive of direction and form of gaze, and expressions around the eyes, as conveying a considerable amount of social information concerning mental state and intention (Emery Reference Emery2000). Specific neural regions, in the neocortex and amygdala, are dedicated to perception and interpretation of gaze and facial expression in humans and other primates (Emery Reference Emery2000; M. H. Johnson Reference Johnson2005). The amygdala in particular is highly activated when humans gaze upon one another, as emotional valence of the interaction is inferred from features of the eyes and surrounding face, with especially notable sensitivity to fear (Adolphs et al. Reference Adolphs, Gosselin, Buchanan, Tranel, Schyns and Damasio2005; Castelli Reference Castelli2005; Schwartz et al. Reference Schwartz, Wright, Shin, Kagan and Rauch2003a; Reference Schwartz, Wright, Shin, Kagan, Whalen, McMullin and Rauch2003b; Whalen et al. Reference Whalen, Kagan, Cook, Davis, Kim, Polis, McLaren, Somerville, McLean, Maxwell and Johnstone2004).

Autistic individuals exhibit notable avoidance of gaze, and reduced or absent following of gaze (Asperger Reference Asperger and Frith1991; Emery Reference Emery2000; Frith Reference Frith2003, p. 105; Ristic et al. Reference Ristic, Mottron, Friesen, Iarocci, Burack and Kingstone2005). Such behavior has motivated the development of theories for autism based on impairment of the amygdala (as in cases of amygdala damage), with consequent reduction in ability to detect and assimilate social and emotional information from the eyes and faces of other humans (Adolphs et al. Reference Adolphs, Baron-Cohen and Tranel2002; Baron-Cohen et al. Reference Baron-Cohen, Ring, Bullmore, Wheelwright, Ashwin and Williams2000; Brambilla et al. Reference Brambilla, Hardan, di Nemi, Caverzasi, Soares, Perez and Barale2004; Shaw et al. Reference Shaw, Lawrence, Radbourne, Bramham, Polkey and David2004). First-person accounts by autistic individuals (Lawson Reference Lawson1998, pp. 11–12; O'Neill Reference O'Neill1999, p. 26) suggest that amygdala “impairment” may involve hyperactivation, such that direct gaze is sufficiently uncomfortable, overwhelming, and fear-inspiring to warrant avoidance. This inference is also supported by the larger size of the amygdala in autism (at least during early childhood) (Schumann et al. Reference Schumann, Hamstra, Goodlin-Jones, Lotspeich, Kwon, Buonocore, Lammers, Reiss and Amaral2004), lower levels of the fear-reducing neuropeptide oxytocin in autism (Green et al. Reference Green, Fein, Modahl, Feinstein, Waterhouse and Morris2001; Kirsch et al. Reference Kirsch, Esslinger, Chen, Mier, Lis, Siddhanti, Gruppe, Mattay, Gallhofer and Meyer-Lindenberg2005), the ability of autistic children to recognize basic emotions (though not social, self-conscious emotions) from eyes and facial features (Castelli Reference Castelli2005; see also Adolphs et al. Reference Adolphs, Gosselin, Buchanan, Tranel, Schyns and Damasio2005), reduced inhibition of the amygdala in autism (Rubenstein & Merzenich Reference Rubenstein and Merzenich2003), a functional-imaging study that shows heightened amygdala activation in response to gaze fixation in autism (Dalton et al. Reference Dalton, Nacewicz, Johnstone, Schaefer, Gernsbacher, Goldsmith, Alexander and Davidson2005a), and relatively strong neurological links between the amygdala and the right hemisphere in normal subjects compared to autistics (Noesselt et al. Reference Noesselt, Driver, Heinze and Dolan2005). Long-term avoidance of gaze and faces presumably reduces opportunities for autistic children to develop skills related to this core component of social behavior, via cognitive appraisal of eye and facial features during interactions (Gläscher & Adolphs Reference Gläscher and Adolphs2003; M. H. Johnson Reference Johnson2005; Skuse et al. Reference Skuse, Morris and Dolan2005; see also Adolphs et al. Reference Adolphs, Gosselin, Buchanan, Tranel, Schyns and Damasio2005). Such deficits, as well as other components of the social brain, may be involved in the underdeveloped theory of mind found in Kanner autism and to a lesser extent in Asperger syndrome (Baron-Cohen Reference Baron-Cohen2002; Reference Baron-Cohen2003; Bowler Reference Bowler1992; Downs & Smith Reference Downs and Smith2004).

Langdon et al. (Reference Langdon, Corner, McLaren, Coltheart and Ward2006b) demonstrated that schizophrenia involves abnormal over-responsiveness in attentional orienting to gaze (see also Emery Reference Emery2000; Franck et al. Reference Franck, Daprati, Michel, Saoud, Daléry, Marie-Cardine and Georgieff1998), which is the opposite pattern to that observed in autism. Although impairments in tests of recognizing expression from eyes and faces have been described in schizophrenia (e.g., Kington et al. Reference Kington, Jones, Watt, Hopkin and Williams2000) as for autism, such deficits appear to be a function of inaccurate inferences concerning gaze of others as directed towards them (Hooker & Park Reference Hooker and Park2005), and mistaken inference of mental states from gaze (Langdon et al. Reference Langdon, Coltheart and Ward2006a; Reference Langdon, Corner, McLaren, Coltheart and Ward2006b), rather than the underdevelopment or absence of mental-state attribution ascribed to autistic cognition (Baron-Cohen Reference Baron-Cohen2002; Craig et al. Reference Craig, Hatton, Craig and Bentall2004; Frith Reference Frith2003). Paranoia, a prominent feature in the positive symptoms of psychosis, also commonly involves obsession with the gaze of others as directed towards one's self, often concomitant to delusions of persecution and conspiracy (e.g., Badcock Reference Badcock, Crawford and Salmon2004; Franck et al. Reference Franck, Daprati, Michel, Saoud, Daléry, Marie-Cardine and Georgieff1998; Green & Phillips Reference Green and Phillips2004; LaRusso Reference LaRusso1978; McKay et al. Reference McKay, Langdon and Coltheart2005).

We interpret these features of psychosis as forms of hyper-mentalizing, such that theory of mind is dysregulated via impaired, inflexible, or extreme inferences regarding social cues and over-attribution of mental states and intentions (Abu-Akel Reference Abu-Akel1999; Abu-Akel & Bailey Reference Abu-Akel and Bailey2000; Badcock Reference Badcock, Crawford and Salmon2004; Blackwood et al. Reference Blackwood, Howard, Bentall and Murray2001; C. D. Frith Reference Frith2004; Harrington et al. Reference Harrington, Langdon, Siegert and McClure2005a; Reference Harrington, Siegert and McClure2005b; Langdon & Coltheart Reference Langdon and Coltheart1999; Langdon et al. Reference Langdon, Coltheart and Ward2006a; Phillips et al. Reference Phillips, Senior and David2000; Steiner Reference Steiner2004). Indeed, the evolutionary psychiatrist Randolph Nesse noted that “those who have worked with schizophrenics know the eerie feeling of being with someone whose intuitions are acutely tuned to the subtlest unintentional cues, even while the person is incapable of accurate empathic understanding” (Nesse 2004, p. 62), and Claridge et al. (Reference Claridge, Pryor and Watkins1990, p. 221) noted that “anyone who has interacted with psychotics will know of their uncanny capacity to respond to subtle social cues, believed to have been concealed from them.” These patterns contrast with the extreme literal-mindedness found in autistic individuals, in comparison to the common overinterpretation of linguistic and visual input in schizophrenia and to some degree in schizotypy (Langdon & Coltheart Reference Langdon and Coltheart2004; Langdon et al. Reference Langdon, Coltheart, Ward and Catts2002; Russell et al. Reference Russell, Reynaud, Herba, Morris and Corcoran2006), although schizophrenia can also involve deficits that engender impaired processing of figurative language (Thoma & Daum Reference Thoma and Daum2006). Both autistic literal-mindedness and mechanistic cognition, and psychotic-spectrum overinterpretation can lead, though by different mechanisms, to deficits in theory of mind tasks and understanding of pragmatic language such as metaphor and humor (C. D. Frith Reference Frith2004; Frith & Allen Reference Frith, Allen, Bebbington and McGuffin1988; Mitchell & Crow Reference Mitchell and Crow2005). Taken together, this evidence suggests that reaction to gaze, as well as tendency to attribute mental states and intentions to others, exhibit contrasting patterns of hyperdevelopment and underdevelopment in psychosis and autism (Table 1).

The neurophysiological and psychological mechanisms underlying hyperdevelopment of gaze, inference of intention, and theory of mind in schizophrenia require further study. As in autism, the amygdala plays an important role in the interactions that mediate theory of mind skills in schizophrenia (Benes & Berretta Reference Benes and Berretta2001; Brüne Reference Brüne2004; Brüne & Brüne-Cohrs Reference Brüne and Brüne-Cohrs2006). Many (though by no means all) functional-imaging studies demonstrate that schizophrenia engenders underactivation of the amygdala compared to controls in tests of recognizing facial expression and emotional valence (Brunet-Gouet & Decety Reference Brunet-Gouet and Decety2006; Das et al. Reference Das, Kemp, Flynn, Harris, Liddell, Whitford, Peduto, Gordon and Williams2007; Gur et al. Reference Gur, McGrath, Chan, Schroeder, Turner, Turetsky, Kohler, Alsop, Maldjian, Ragland and Gur2002; Holt et al. Reference Holt, Kunkel, Weiss, Goff, Wright, Shin, Rauch, Hootnick and Heckers2006; Kucharska-Pietura et al. Reference Kucharska-Pietura, Russell and Masiak2003; Paradiso et al. Reference Paradiso, Andreasen, Crespo-Facorro, O'Leary, Watkins, Boles Ponto and Hichwa2003; Phillips et al. Reference Phillips, Williams, Senior, Bullmore, Brammer, Andrew, Williams and David1999; Schneider et al. Reference Schneider, Weiss, Kessler, Salloum, Posse, Grodd and Müller-Gärtner1998). These findings are consistent with the emotional dysregulation commonly found in schizophrenia (Aleman & Kahn Reference Aleman and Kahn2005), although the connections between emotion and cognition in this and other psychotic-spectrum conditions remain unclear. Underactivation of the amygdala may also be a manifestation of reduced cognitive effects from the paternal brain (Keverne Reference Keverne2001a; Reference Keverne2001b) in negative-symptom schizophrenia.

Finally, gaze and intentionality are intimately associated with the expression of emotion, which is generally recognized as reduced in schizophrenia and major depression (e.g., Gaebel & Wölwer Reference Gaebel and Wölwer2004; Troisi et al. Reference Troisi, Pompili, Binello and Sterpone2007), although lack of facial expression need not indicate a lack of emotional experience (Trémeau et al. Reference Trémeau, Malaspina, Duval, Corrêa, Hager-Budny, Coin-Bariou, Macher and Gorman2005); indeed, a relatively high level of positive schizotypy appears to be associated with more intense emotionality (Kerns Reference Kerns2005). Parental reports provide evidence that autistic children are highly expressive, especially for negative emotion, although they “communicated feeling states idiosyncratically, in a manner only their mother understood” (Capps et al. Reference Capps, Kasari, Yirmiya and Sigman1993) (p. 475). Losh and Capps (Reference Losh and Capps2006) also report that autistic children are no less emotionally expressive than controls for basic emotions, though not self-conscious ones. In autism, levels of basic emotionality may thus be as high or higher than normal (in keeping with relatively enhanced paternal-brain functions), but emotional reactions lack social context and sensitivity due to reductions in the ability of the neocortical, maternal brain to integrate social-cognitive understanding and control with emotion and behavior.

6.3.2. Agency and self

Monitoring of gaze and inference of intention involve application of theory of mind skills to other individuals (Emery Reference Emery2000; Tomasello et al. Reference Tomasello, Carpenter, Call, Behne and Moll2005). The other domain for theory of mind is reflexive – that is, self-consciousness, mentalized awareness of one's self as an agent acting upon the external world, and exhibiting spontaneous self-directed thought. Several lines of evidence suggest that autism involves a diminished or altered sense of self: (1) selective impairments of episodic and autobiographical memory – the mental constructs that generate and maintain a sense of self (Gardiner Reference Gardiner, Baddeley, Aggleton and Conway2002; Gardiner et al. Reference Gardiner, Bowler and Grice2003) – while rote, factual memory is spared or enhanced (O'Shea et al. Reference O'Shea, Fein, Cillessen, Klin and Schultz2005; Toichi & Kamio Reference Toichi and Kamio2002; Williams et al. Reference Williams, Goldstein and Minshew2006b); (2) a tendency to think in visual pictures (Grandin Reference Grandin1995; Hurlburt et al. Reference Hurlburt, Happé and Frith1994; Kana et al. Reference Kana, Keller, Cherkassky, Minshew and Just2006), suggesting a shift to the right hemisphere for brain regions generating spontaneous thought (Christoff et al. Reference Christoff, Ream and Gabrieli2004); (3) a reduced sense of self-consciousness and personal agency, perhaps due to reduced central coherence at this level (Ben Shalom Reference Ben Shalom2000; Fitzgerald Reference Fitzgerald2005, p. 78; Frith & Happé Reference Frith and Happé2005; Grandin Reference Grandin1995; Reference Grandin2004; Johnson Reference Johnson2003; Lawson Reference Lawson1998, p. i; Lombardo et al. Reference Lombardo, Barnes, Wheelwright and Baron-Cohen2007; Toichi et al. Reference Toichi, Kamio, Okada, Sakihama, Youngstrom, Findling and Yamamoto2002); (4) a less developed imagination, as noted earlier (Craig & Baron-Cohen Reference Craig and Baron-Cohen1999; Happé Reference Happé1994, p. 37; Losh & Capps Reference Losh and Capps2003); and (5) less developed experience of social and self-conscious emotion (Heerey et al. Reference Heerey, Keltner and Capps2003; Losh & Capps Reference Losh and Capps2006). Autism also involves cognition highly focused on few particular non-social aspects of the environment, which is expressed in repetitive behavior, intense preoccupations about specific and narrow topics, and difficulties in shifting attention (Courchesne et al. Reference Courchesne, Townsend, Akshoomoff, Saitoh, Yeung-Courchesne, Lincoln, James, Haas, Schreibman and Lau1994; Goldstein et al. Reference Goldstein, Johnson and Minshew2001a; Happé Reference Happé1994; Landry & Bryson Reference Landry and Bryson2004; Murray et al. Reference Murray, Lesser and Lawson2005). These features may interact via positive feedback to reduce the degree to which these individuals become socially enculturated (Murray et al. Reference Murray, Lesser and Lawson2005), a central process in human development.

In contrast to autism, schizotypy and schizophrenia are characterized by high levels of distractability, reduced filtering of sensory input, and “loose” associations between external stimuli and between components of thought (e.g., Bellgrove et al. Reference Bellgrove, Vance and Bradshaw2003; Brugger & Graves Reference Brugger and Graves1997a; Reference Brugger and Graves1997b; Claridge & Beech Reference Claridge, Beech, Raine, Lencz and Mednick1995; Grossberg Reference Grossberg2000b; Mathes et al. Reference Mathes, Wood, Proffitt, Stuart, Buchanan, Velakoulis, Brewer, McGorry and Pantelis2005; Nakamura et al. Reference Nakamura, Matsushima, Ohta, Ando and Kojima2003; Pizzagalli et al. Reference Pizzagalli, Lehmann, Gianotti, Koenig, Tanaka, Wackermann and Brugger2000). The positive symptoms of schizophrenia often involve delusions, such as persecution and grandiosity, that “reflect individuals' preoccupations about their position in the social universe” (Bentall Reference Bentall, Kircher and David2003b, p. 293) in creating complex and fanciful mental autobiographies (Salazar-Fraile et al. Reference Salazar-Fraile, Tabarés-Seisdedos, Selva-Vera, Balanzá-Martinez, Martínez-Aran, Catalán, Baldeweg, Vilela-Soler, Leal-Cercós, Vieta and Gomez-Beneyto2004), and an increased awareness of self and intentionality is found in schizophrenic delusions of control (Frith Reference Frith2005b). Social and reflexive preoccupations can be described in terms of exaggerated self-consciousness (Sass & Parnas Reference Sass and Parnas2003), and indeed, auditory hallucination, thought insertion, and passivity phenomena (e.g., Behrendt Reference Behrendt2004; Crow Reference Crow2004a; Reference Crow2004b) can be interpreted as functions of a breakdown in cognitive distinction between self and other, as in some spiritual experiences of schizotypal individuals (Brugger Reference Brugger, Houran and Lange2001). Breakdowns in self-monitoring, such as interpreting inner speech as external, or delusions of control of hand movements, have an apparent neurological basis in impaired ability to self-monitor the coordination of intended (premotor) actions (mainly speech and gesture) with one's current and predicted state (Frith et al. Reference Frith, Blakemore and Wolpert2000; Jones & Fernyhough Reference Jones and Fernyhough2007). By contrast, autism appears to involve absent or reduced use of inner speech (Whitehouse et al. Reference Whitehouse, Maybery and Durkin2006).

Finally, auditory hallucinations commonly involve social dialogue, commentary, and commands, with a focus on complex, self-conscious emotions such as shame, contempt, derogation, and embarrassment (e.g., Legg & Gilbert Reference Legg and Gilbert2006); Bentall (Reference Bentall2003a, p. 354) notes how such hallucinations often involve the voices of “significant family members,” and Birchwood et al. (Reference Birchwood, Gilbert, Gilbert, Trower, Meaden, Hay, Murray and Miles2004) describes them as operating “like external social relationships.” These patterns, and the common feelings of guilt, deserved punishment, and worthlessness in major depression (Keller et al. Reference Keller, Schatzberg and Maj2007), suggest that social emotions and interactions are often overdeveloped in psychotic-spectrum disorders, in contrast to their reduction in autism, as described earlier.

6.3.3. Functional imaging of the social brain

The neurological basis for dysregulation of gaze, intention, agency, and theory of mind in autism and psychosis provides a mechanistic level of analysis that should dovetail with psychological descriptions of these processes. Thus, autistic- and psychotic-spectrum disorders may be expected to exhibit contrasting patterns of brain activation in functional-imaging studies that involve analyzing specific components of the social brain, as described earlier for the amygdala. We have found evidence for specific contrasts involving four brain regions or networks, although differences in the tasks utilized limit the strength of inferences in some cases.

First, Greicius et al. (Reference Greicius, Krasnow, Reiss and Menon2003) have described the brain's “default mode” or “resting state” network, which includes the medial prefrontal cortex, posterior cingulate cortex, ventral anterior cingulate cortex, and precuneus. This midline-structure network exhibits high metabolic rate at rest, with functions related to self-referential processing, processing of information related to theory of mind, inner speech, retrieving and manipulating memories, and developing future plans (Garrity et al. Reference Garrity, Pearlson, McKiernan, Lloyd, Kiehl and Calhoun2007; Greicius et al. Reference Greicius, Krasnow, Reiss and Menon2003; Kennedy et al. Reference Kennedy, Redcay and Courchesne2006). This network is then “deactivated” when attention is redirected to a specific cognitive task. Kennedy et al. (Reference Kennedy, Redcay and Courchesne2006) have described a “failure to deactivate” in autistics, which they attribute to a lower level of baseline resting-state activity, and default-mode cognition directed more towards obsessive interests and sensory-environment processing than towards self-reflective, theory-of-mind, and memory-retrieval activities. Moreover, a higher level of social impairment was associated with a lower degree of deactivation among subjects, which suggests a direct link between social cognition and activation of the resting network. Ohnishi et al. (Reference Ohnishi, Matsuda, Hashimoto, Kunihiro, Nishikawa, Uema and Sasaki2000) and Castelli et al. (Reference Castelli, Frith, Happé and Frith2002) also found reduced activation in autism for regions involved in theory of mind, notably the medial prefrontal cortex.

In contrast to these results for autism, Garrity et al. (Reference Garrity, Pearlson, McKiernan, Lloyd, Kiehl and Calhoun2007) and Harrison et al. (Reference Harrison, Yücel, Pujol and Pantelis2007) have described greater task-induced deactivation in schizophrenics than in controls, for some regions. Garrity et al. (Reference Garrity, Pearlson, McKiernan, Lloyd, Kiehl and Calhoun2007) have also reported that stronger positive symptoms are associated with greater deactivation (due to increased activity at rest), and that schizophrenics included a larger area of the parahippocampal gyrus in the default mode than did controls. Higher deactivation has also been reported in anxiety disorder than in controls (Zhao et al. Reference Zhao, Wang, Li, Hu, Xi, Wu and Tang2007); and in major depression, a specific, affect-processing region of the default network, the subgenual cingulate, exhibits increased metabolic rate and higher functional connectivity with the medial prefrontal cortex than in controls (Greicius et al. Reference Greicius, Flores, Menon, Glover, Solvason, Kenna, Reiss and Schatzberg2007), which the authors ascribe to increased self-referential and emotional processing in this condition. This set of studies suggests that psychotic-spectrum conditions may involve alterations in resting-state network activation specific to increased mentalistic functions, and that they also show a pattern of greater deactivation of the default network than in controls or in autism.

Second, one of the primary areas involved in mental attribution and processing of agency is Brodmann's area (BA) 8 in the dorsomedial frontal cortex (Finger et al. Reference Finger, Marsh, Kamel, Mitchell and Blair2006; Fletcher et al. Reference Fletcher, Happé, Frith, Baker, Dolan, Frackowiak and Frith1995; Goel et al. Reference Goel, Grafman, Sadato and Hallett1995; Marjoram et al. Reference Marjoram, Job, Whalley, Gountouna, McIntosh, Simonotto, Cunningham-Owens, Johnstone and Lawrie2006). Increased activity in this region has been associated with increased genetic risk of schizophrenia by Whalley et al. (Reference Whalley, Simonotto, Flett, Marshall, Ebmeier, Owens, Goddard, Johnstone and Lawrie2004), and Frith (Reference Frith1996) describes evidence that this region is involved in auditory hallucinations in schizophrenia. By contrast, Happé et al. (Reference Happé, Ehlers, Fletcher, Frith, Johansson, Gillberg, Dolan, Frackowiak and Frith1996) found normal activity in this area among controls in a theory-of-mind task, but a complete lack of activation in an Asperger syndrome group.

Third, Luna et al. (Reference Luna, Minshew, Garver, Lazar, Thulborn, Eddy and Sweeney2002) and Silk et al. (Reference Silk, Rinehart, Bradshaw, Tonge, Egan, O'Boyle and Cunnington2006) described reduced activation in autism for BA 46 in the dorsolateral prefrontal cortex in a spatial working memory task, which the former authors interpreted in terms of reduced “top-down” executive function. By contrast, significantly increased activation of right-hemisphere BA 46 was found by Seidman et al. (Reference Seidman, Thermenos, Poldrack, Peace, Koch, Faraone and Tsuang2006) in adolescents at high risk for schizophrenia, and these authors describe parallel findings of exaggerated activity in this region from three previous studies. A role for this region in social cognition is indicated by Knoch et al. (Reference Knoch, Pascual-Leone, Meyer, Treyer and Fehr2006), who found activation in this area during implementation of fairness-related behaviors in social-reciprocity tasks.

A final set of core regions of the social brain is the mirror neuron systems. These systems, comprising regions of the superior temporal sulcus, inferior prefrontal cortex, inferior parietal cortex, and other regions, provide neural substrates for inference of intention, theory of mind and empathy, via activation of the same premotor circuitry during observation and execution of specific facial, manual, or other movements (Iacoboni & Dapretto Reference Iacoboni and Dapretto2006). Such matching of premotor to observed motor activations allows for automatic inferences regarding the intention, disposition, and emotional state of another individual, which can generate cognitive and emotional resonance during social interactions. In autism, a key component of this system, BA 44 (the pars opercularis), was hypoactivated in tasks involving imitation or viewing emotional expressions (Dapretto et al. Reference Dapretto, Davies, Pfeifer, Scott, Sigman, Bookheimer and Iacoboni2006); by contrast, Quintana et al. (Reference Quintana, Davidson, Kovalik, Marder and Mazziotta2001) found overactivation of BA 44 in schizophrenia compared to controls for tasks involving affective facial expression, which they described in terms of “increased mirror-like representational mechanisms . . . with cues of obvious social value” (p. 923).

Hadjikhani et al. (Reference Hadjikhani, Joseph, Snyder and Tager-Flusberg2007) and Dapretto et al. (Reference Dapretto, Davies, Pfeifer, Scott, Sigman, Bookheimer and Iacoboni2006) describe evidence that face- and gaze-processing deficits in autism are due to impairments in the integrated activity of the mirror-neuron system use in facial processing. Patterns of hypoactivation in mirror-system regions in autism are paralleled by evidence for cortical thinning of these areas in autism, which is directly related to the severity of autistic symptoms (Hadjikhani et al. Reference Hadjikhani, Joseph, Snyder and Tager-Flusberg2006; Zilbovicius et al. Reference Zilbovicius, Meresse, Chabane, Brunelle, Samson and Boddaert2006). Reduced activation of mirror neuron systems in autistics appears specific to tasks dependent upon mentalistic cognition, rather than representing a more general impairment that also includes conscious, deliberate imitation or inference of intention from functional gestures (Hamilton et al. Reference Hamilton, de, Brindley and Frith2007).

Taken together, these findings indicate that underdevelopment of the integrated social brain in general, and social aspects of the mirror neuron system in particular, are associated with some of the social-behavioral deficits found in autism (Williams et al. Reference Williams, Whiten, Suddendorf and Perrett2001; cf. Dapretto et al. Reference Dapretto, Davies, Pfeifer, Scott, Sigman, Bookheimer and Iacoboni2006; Hadjikhani et al. Reference Hadjikhani, Joseph, Snyder and Tager-Flusberg2006; Reference Hadjikhani, Joseph, Snyder and Tager-Flusberg2007). Schizophrenia also clearly engenders impairments in theory-of-mind skills and mentalizing (Brunet-Gouet & Decety Reference Brunet-Gouet and Decety2006; Harrington et al. Reference Harrington, Langdon, Siegert and McClure2005a; Reference Harrington, Siegert and McClure2005b; Pinkham et al. Reference Pinkham, Penn, Perkins and Lieberman2003), which commonly involve “over-mentalizing,” such as delusional ideation, inferring false intentions, and a general pattern of confabulation of subjective experience in the face of misinterpreted objective reality (C. D. Frith Reference Frith1992; Reference Frith2004; Frith & Frith Reference Frith and Frith1999). Arbib and Mundhenk (Reference Arbib and Mundhenk2005) link such impairments to the mirror neuron system, in suggesting that functional dissociations between action or speech imagination, and enactment of movement or speech, lead to misattribution of agency and consequent confabulation and rationalizing, which manifests as auditory hallucination, delusions, and paranoia. Similar considerations may apply to the mirror-neuron system underlying face perception and emotional resonance, which is also dysregulated in schizophrenia in the context of emotion inappropriate to social context and flat affect (e.g., Aleman & Kahn Reference Aleman and Kahn2005; van Rijn et al. Reference van Rijn, Aleman, Swaab and Kahn2005). A recent review of functional-imaging studies of social brain dysfunction in schizophrenia also suggests that two mirror-neuron regions – the inferior frontal cortex and the inferior parietal lobe (see Arbib & Mundhenk Reference Arbib and Mundhenk2005) – are selectively responsible for some core cognitive manifestations of this disorder, as well as strongly implicating the medial prefrontal cortex, anterior cingulate cortex, and amygdala (Brunet-Gouet & Decety Reference Brunet-Gouet and Decety2006).

These findings indicate that in contrast to autism, where the mirror-neuron system does not develop to full, integrated functional maturity, in schizophrenia this system develops but is subject to diverse forms of selective malfunction. Thus, aspects of theory of mind, and mirror-neuron system skills, are selectively impaired in both autism and schizophrenia (Brüne & Brüne-Cohrs Reference Brüne and Brüne-Cohrs2006; C. D. Frith Reference Frith1992; Reference Frith2004; Lee et al. Reference Lee, Farrow, Spence and Woodruff2004; Mazza et al. Reference Mazza, De Risio, Surian, Roncone and Casacchia2001; Pickup & Frith Reference Pickup and Frith2001; Russell et al. Reference Russell, Reynaud, Herba, Morris and Corcoran2006; Shamay-Tsoory et al. Reference Shamay-Tsoory, Shur, Barcai-Goodman, Medlovich, Harari and Levkovitz2007; see also McCabe et al. Reference McCabe, Leudar and Antaki2004), but, we believe, for different reasons.