Journal of Psychiatric Research 33 (1999) 477±489
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Early cerebro-craniofacial dysmorphogenesis in schizophrenia: a lifetime trajectory model from neurodevelopmental basis to `neuroprogressive' process John L. Waddington a, b,*, Abbie Lane c, Paul Scully b, David Meagher b, John Quinn b, Conall Larkin c, Eadbhard O'Callaghan c a
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin, 2, Ireland b Stanley Foundation Research Unit, St Davnet's Hospital, Monaghan, Ireland c Stanley Foundation Research Unit, St John of God Psychiatric Service, Co. Dublin, Ireland Received 11 June 1999; accepted 14 June 1999
Abstract Understanding the temporal origin(s) of schizophrenia, through specifying the earliest identi®able pathology, might indicate when to look for etiological factor(s), what their nature might be, and how course of illness might evolve from these origins. From this premise, earlier formulations are elaborated to oer a rigorously data-driven model that roots schizophrenia in cerebro-craniofacial dysmorphogenesis, particularly along the mid-line but involving other structures, over weeks 9/10 through 14/15 of gestation. However, a brain that has been compromised very early in fetal life is still subject to the normal endogenous programme of developmental, maturational and involutional processes on which a variety of exogenous biological insults and psychosocial stressors can impact adversely over later pregnancy, through infancy and childhood, to maturation and into old age, to sculpt brain structure and function; it should be emphasised that the eects of such endogenous programmes and exogenous insults on such an already developmentally-compromised brain may be dierent from their eects on a brain whose early fetal origins were unremarkable. From these early origins, a lifetime trajectory model for schizophrenia from developmental basis to `neuroprogressive' process is constructed. Thereafter, consideration is given to what the model can explain, including cerebral asymmetry and homogeneity, what it cannot explain, what empirical ®ndings would challenge or disprove the model, what cellular and molecular mechanisms might underpin the model, and what are its implications. # 1999 Elsevier Science Ltd. All rights reserved. Keywords: Schizophrenia; Cerebro-craniofacial dysmorphogenesis; Neurodevelopment; Neuroprogression; Lifetime trajectory model
1. Introduction As for any disorder of similar complexity to schizophrenia (Schultz and Andreasen, 1999), constructs and model-building can, in general terms, proceed on at least two levels: they can focus on issues of causality, proposing one or more putative etiological factor(s) that might give rise to particular abnormalities in
* Corresponding author. Tel.: +353-1-402-2245; fax: +353-1-4022453. E-mail address:
[email protected] (J.L. Waddington)
patients and the subsequent course of their illness; alternatively, they can focus on issues of evolution, proposing one or more putative core abnormality(ies) that might implicate etiological factor(s) and account for subsequent illness course. The premise of the model oered here is that understanding the temporal origin(s) of schizophrenia, through specifying the earliest identi®able pathology, might indicate when to look for etiological factor(s), what their nature might be, and how course of illness might evolve from these origins (Waddington et al., 1997). It is rigorously data driven. Firstly, we describe in outline the background issues from which the model has emerged. The model
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itself and its empirical basis is then described, in elaboration of our earlier formulations thereof (Waddington et al., 1998a,b, 1999). Thereafter, we consider what it can explain followed by what it does not in itself explain. Importantly, we then point out future empirical ®ndings that would disprove the model. Finally, we consider some of its implications.
2. What is the issue? The background to the model can be stated simply: given what is now a wealth of evidence for abnormalities of brain structure and function in schizophrenia, (i) is there any common denominator among the apparent diversity of regions aected, and (ii) do these abnormalities re¯ect a brain that was once normal but became subject to some later pathological process, or do they re¯ect a brain whose very early development was compromised in some way so as to preclude acquisition of normal cerebral structure and function (Waddington, 1993) In relation to apparent diversity of brain regions aected, overview of neuropathological investigations, structural and functional neuroimaging techniques and neuropsychological studies implicates concerted dysfunction in fronto(prefrontal/cingulate/orbitofrontal)striato-pallido-thalamo-cortical/fronto-temporal/cerebellar network(s) which involve aerents to and eerents from midline systems (Andreasen et al., 1996, 1997; Pearlson et al., 1996; Jones, 1997; Lewis, 1997; Benes, 1998; Waddington et al, 1998a, 1999; Schultz and Andreasen, 1999; Selemon and Goldman-Rakic, 1999). The most recent reports continue to indicate abnormalities that encompass midline systems, including the thalamus (Staal et al., 1998) and cerebellum (Wassink et al., 1999), with even inevitable negative ®ndings for certain previously implicated structures being accompanied by positive ®ndings for third ventricle and temporal horn enlargement (Roy et al., 1998) and for reduced size of the thalamus (Gur et al., 1998). In relation to the origin of these brain abnormalities and hence of the disease process in schizophrenia, the bulk of available evidence clearly implicates a developmental origin. Consideration of a reverse time-line for the disorder, in the manner of a `read-back' analysis, indicates the general presence at the ®rst psychotic episode of many of those abnormalities identi®ed most commonly in patients having an established, chronic illness; it then proceeds through childhood psychosocial impairments to infant neurointegrative de®cits, and hence poses another fundamental question: to how early a stage of development should one continue this `read-back' analysis? The substantial weight of epi-
demiological evidence indicates that this should be continued back to the intrauterine period (Waddington et al., 1998a, 1999; Hultman et al., 1999; Mortensen et al., 1999). It is now well-established that structural brain pathology in schizophrenia lacks the hallmarks of conventional neurodegenerative disease; rather, its characteristics appear more compatible with early neurodevelopmental disturbance(s) of intrauterine origin (Waddington et al., 1998a, 1999). However, clari®cation of these issues would be aided considerably by an index of early developmental disturbance that could be accessed readily and related to aspects of brain structure and function, and which might be more informative biologically as to the nature and timing of the initial developmental event(s). The present model derives from the eorts of ourselves and others to identify such an index, with exploration of its explanatory capacity and refutability.
3. What is the model? An in extensio description of the basic model has been given previously (Waddington et al., 1998a); it can be outlined as follows (Waddington et al., 1999). Cerebral morphogenesis over early fetal life proceeds in such exquisite embryological intimacy with craniofacial morphogenesis that classical neurodevelopmental disorders (e.g. Down's syndrome, velo-cardio-facial syndrome, fetal alcohol syndrome and Apert's syndrome) are well recognised to be characterised also by dysmorphic features which involve other regions of the body in general and of the craniofacies in particular; these can range in severity from major congenital malformations to minor physical anomalies (MPAs), and constitute biological markers of ®rst/early second trimester dysmorphogenesis. Several studies have now indicated MPAs to occur in excess among patients with schizophrenia, with the primary (though by no means exclusive) ®nding being subtle dysmorphogenesis of the craniofacial region (Lane et al., 1996; Trixler et al., 1997; Ismail et al., 1998). Though heightening of the palate, a mid-line anomaly, is one of the most consistent ®ndings (Clouston, 1891; Green et al., 1989; O'Callaghan et al., 1991; Lane et al., 1996; Ismail et al., 1998), the topography of MPAs in schizophrenia is poorly understood due to widespread reliance on a limited qualitative scale for their assessment; yet such information is fundamental to understanding the timing and nature of the dysmorphic event(s). On applying an anthropometric approach, we have recently resolved in patients with schizophrenia multiple quantitative and qualitative dysmorphic features
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in craniofacial structures and of the hands and feet. More speci®cally, there was a core topography of dysmorphology characterised by an overall narrowing and elongation of the mid-and lower anterior facial (fronto-nasal) region, in terms of heightening of the palate and reduced mouth width, with widening of the skull base and extensive abnormalities of the mouth, ears and eyes; within this core topography, midline dysmorphology appeared to have primacy (Lane et al., 1997). Recently, other investigators have identi®ed independently a similar anthropometric pro®le of frontonasal vis-aÁ-vis maxillary vs mandibular craniofacial dysmorphology in schizophrenia (Deutsch et al., 1997). 3.1. Relationship to brain structure and function in schizophrenia Craniofacial dysmorphology is associated in general terms with abnormalities of the skull base and with primary anomalies of the corpus callosum, septum pellucidum and hippocampus, i.e. mid-line and medial temporal lobe structures found in schizophrenia to evidence brain pathology (Waddington et al., 1998a); indeed, the human mid-line constitutes a developmental `®eld' that is particularly vulnerable to dysmorphogenesis (Lubinsky, 1987). In schizophrenia, reduced temporal lobe volume and regional widening of cortical sulci are associated with some enlargement of the sylvian ®ssure; recently, idiopathic enlargement of the sylvian ®ssure has been reported to be associated with craniofacial dysmorphology, among which heightened or cleft palate was common (Bingham et al., 1998). More speci®cally, prominence of MPAs in schizophrenia appears to be associated with increasing size of the third (mid-line) but not of the lateral ventricle, and with prominence of qualitative abnormalities particularly of the temporal lobe on MRI; this latter ®nding was part of a triad of inter-relationships between MPA score, qualitative brain abnormalities on MRI and reductions in frontal lobe creatine, a putative index of energy metabolism, on 1H-MRS. At a symptomatic level, prominence of MPAs was associated with more severe negative (but not positive) symptoms, and with lower premorbid (but not current) intellectual function, particularly in terms of craniofacial anomalies (Alexander et al., 1994; Buckley et al., 1994; O'Callaghan et al., 1995; Waddington et al., 1998a,b); such ®ndings `root' these clinical and biological features of schizophrenia in early cerebro-craniofacial dysmorphogenesis. 3.2. Timing of dysmorphogenesis in schizophrenia As elaborated elsewhere (Waddington et al., 1998a, 1999), palatal morphology originates at 6±9 weeks and has achieved its essential postnatal form by 16±17
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weeks of gestation. Over the early phase of palatal morphogenesis, there is elongation and narrowing of the anterior midface with dissociation of skull base width from anterior facial changes and vertical separation of the brain and face; thus, vertical growth of the midfacial region with narrowing of the frontonasal prominences is among the most evident features of embryonic craniofacial growth during primary palate formation. Therefore, it is apparent that the topography of craniofacial dysmorphology in schizophrenia overlaps substantially with, and thus indicates disturbances in, these aspects of so critical a period of morphogenesis. Embryological considerations implicate the operation in schizophrenia of dysmorphogenic events over a time frame that may have limits of 6±17 weeks, but more likely encompasses 9±16 weeks of gestation; over this interval, neurogenesis, migration from the ventricular zone, early programmed cell death and early myelination are interacting in the development of brain structure and function (Giedd, 1999). 3.3. Mis-interpretations of early dysmorphogenesis in schizophrenia It is important that the present developmental model of schizophrenia is not mis-understood or misinterpreted at each of two unrelated levels. Firstly, the model in no way proposes or requires that dysmorphic features in schizophrenia involve only the craniofacies. Like others (e.g. Ismail et al., 1998), we (Lane et al., 1997) ®nd additional body regions, particularly the hands and feet, to also be dysmorphic; however, within this overall distribution it is the topography of craniofacial (dys)morphogenesis that bears the greatest embryological and, in our hands, statistical intimacy with brain (mal)development. Secondly, the model in no way proposes or requires that an early developmental basis to schizophrenia excludes the operation of later events in determining overall course of illness or is inherently incompatible with any active, progressive process subsequently (Weinberger, 1995); rather, we (Wadington et al., 1997, 1998a, 1999) conceptualise early cerebro-craniofacial dysmorphogenesis in schizophrenia as the developmental underpinnings of a lifetime trajectory of disease, as elaborated further below.
4. What does the model explain? In proposing on a rigorously data-driven as opposed to theoretical basis that schizophrenia is rooted in a characteristic topography of cerebro-craniofacial dysmorphogenesis occurring over weeks 9±16 of gestation, it is critical to consider the extent to which this model can explain other empirical aspects of the disorder.
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4.1. Topographical Ð temporal aspects of cerebral ®ndings Ventricular enlargement endures as the most robust abnormality of brain structure in schizophrenia (Daniel et al., 1991; Waddington et al., 1998a). Anterior and inferior (temporal) horns of the cerebral ventricles ®rst appear well-de®ned from 8 weeks of gestation, overlapping the third ventricle in lateral projection with a narrowing of the interventricular foramen (O'Rahilly and Muller, 1990); the posterior horn appears only considerably later in fetal life (Westergaard, 1971). Pathology of the hippocampal formation (hippocampus-parahippocampal gyrus/ entorhinal cortex) in schizophrenia is sustained by meta-analysis (Nelson et al., 1998) and endures as a major focus for pathophysiological investigations (Velakoulis et al., 1999). As elaborated elsewhere (Waddington et al., 1998a, 1999), the hippocampal formation is one of the ®rst cortical areas to dierentiate at approximately 9±10 weeks, and undergoes substantial growth and dierentiation particularly before and within 15±19 weeks of gestation. Entorhinal and parahippocampal cortices have strong reciprocal connections not only with the hippocampus, which are already established in essentially adult form by 19 weeks, but also with a wide range of association areas in the frontal, parietal and temporal lobes; it is the period of 9.5±13.5 weeks, during which dierentiation of the entorhinal cortex is yet more advanced than that of the hippocampus, which may thus be critical for developmental pathology aecting this area in schizophrenia. Also, there is temporal contiguity with critical developmental periods for mid-line structures reported to be abnormal in schizophrenia, such as the thalamus (10±16 weeks?) and cingulate cortex (13±15 weeks?); speci®c involvement of the frontal lobes is considered separately below. There thus appears to be temporal congruity between craniofacial dysmorphogenesis and critical developmental `windows' for brain regions reported to show structural and/or functional abnormalities in schizophrenia, over a time-frame having limits of 6-19 weeks but within which the strongest common denominators would appear to implicate events acting between weeks 9/10 through 14/15 of gestation. During this period of primary palate formation, the face is growing forward more rapidly than is the brain; this divergence of facial and cerebral growth may be a major mechanism by which the narrowing and vertical elongation of the anterior mid-face occurs by virtue of a relative reduction in anterior brain growth. A modest overall reduction in grey but not white matter volume in schizophrenia appears to derive from more prominent reductions in anterior (prefrontal to temporoparietal, including heteromodal association areas) than in
posterior (parietal to parieto-occipital) cortical regions; abnormalities in synaptic vesicular protein appear to show a similar anterior > posterior gradient, while abnormal cytoarchitecture in the cingulate cortex appears to be accompanied by reduced metabolism in its anterior extent (see Waddington et al., 1998a, 1999); there appears to be a 9% reduction in temporal lobe length which is not simply a manifestation of decreased overall brain size and whose extent considerably exceeds a 3% reduction in temporo-occipital length (Highley et al., 1998a). Recently, investigators have begun to quantitate not only the length/area/volume of a given structure but also its shape, in a manner analogous to craniofacial anthropometrics. In an initial study of the cerebral ventricular system (Buckley et al., 1999), dysmorphology involved primarily the foramen of Monro, around the midline in the region of the third ventricle, and the proximal temporal horn. This ventricular dysmorphology was con®ned essentially to males; while gender dierences are not a primary focus of this presentation of the model, on grounds of space, it should be noted that when present they are usually in the direction of raised vulnerability and earlier onset, greater prominence of psychopathological and biological abnormalities, and poorer outcome among males, in congruence with the well-recognised greater vulnerability of the male brain to developmental disorders. More speci®cally, hippocampal structure in schizophrenia appears to be characterised more by abnormality in shape than in volume (Csernansky et al., 1998); dysmorphology involves primarily the superior and lateral aspects of the head of the hippocampus, which projects to the prefrontal cortex, and the medial aspect of its body. To summarise, the present model for schizophrenia involves a shift towards more prominent narrowing and vertical elongation of the anterior mid-face during embryonic-fetal primary palate formation that would predict a relative impairment in anterior and midline cerebral development and function; the available data indicate such a disproportionate abnormality in anterior and midline regions, with fronto-temporal dysfunction being a nexus of contemporary empirical research and pathophysiological theorising in complementary juxtaposition with fronto-striato-pallido-thalamo-cortical/cerebellar network dysfunction (see Waddington et al., 1998a, 1999). 4.2. Temporal aspects of dermatoglyphic and epidemiological ®ndings Dermatoglyphic (digital and palmar) abnormalities, particularly reduced ridge numbers, have also been described in schizophrenia as an additional index of developmental disturbance. Volar pads exhibit rapid growth between 6.5±10.5 weeks of gestation, and it is
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from this period up to volar pad regression at 15±17 weeks over which (ab)normal number is determined; subsequently, secondary ridges appear with emergence of ridge dissociation and abnormal ridge features as potential indicators of developmental disturbance(s) thereover (Babler, 1991; Gutierrez et al., 1998). Among a variety of classical and contemporary epidemiological ®ndings implicating the intrauterine period in events which in¯uence risk for schizophrenia, the increase in risk associated with winter birth and with urban birth (Torrey et al., 1997a,b; Mortensen et al., 1999) are not otherwise informative in the temporal domain. However, several other associations are of greater temporal import. Maternal dietary insuciency (Susser et al., 1996), maternal rubella (Brown et al., 1998), and maternal stressors (Myhrman et al., 1996; Van Os and Selten, 1998) each appear associated with increased risk for schizophrenia in ospring, with these eects being most prominent for exposure over the ®rst trimester or months 2±4 of gestation relative to unexposed control cohorts; maternal in¯uenza (McGrath and Murray, 1995) also endures as a controversial risk factor for schizophrenia and implicates perhaps a slightly later time-frame centred over the second trimester. When these factors are considered together, particularly the ®rst three exposures, the focus of the present model on events acting over weeks 9/10 through 14/15 of gestation oers an explanation for the periods over which these adverse maternal events are most likely to increase risk for schizophrenia; it is also compatible with dermatoglyphic ®ndings. The diversity of these risk factors, together with what has been interpreted previously as their small eect sizes/population-attributable-risks, fails to indicate any speci®c or substantial mode of disruption to cerebro-craniofacial dysmorphogenesis. However, recent analysis of the eects of season and place of birth suggests a populationattributable-risk considerably larger than has been entertained previously (Mortensen et al., 1999); further studies to clarify these issues are needed. 4.3. Obstetric complications Over recent decades, there has evolved a considerable body of evidence that patients with schizophrenia are more likely than are normal individuals to have been born following a pregnancy and/or delivery that was `complicated' in some manner (Geddes and Laurie, 1995; McNeil, 1996), particularly among males and in relation to psychosis of early onset (O'Callaghan et al., 1992; Hultman et al., 1999). This excess of diverse complications appears most evident over late pregnancy, delivery and the immediate postnatal period, and has served as an attractive candidate for direct developmental insult via perinatal hypoxia.
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However, a number of diculties with this interpretation are apparent; in particular: if a con¯uence of cerebro-craniofacial dysmorphogenesis and epidemiological ®ndings indicate that developmental disturbance in schizophrenia is occurring over weeks 9/ 10 through 14/15 of gestation, how can obstetric vicissitudes that have been reported most commonly to occur to excess some several months later be `causal' for a process that has already taken place? Obstetric complications could be simply an additional, independent source of direct developmental insult, but such a proposition lacks parsimony. An explanation might be found in the diering perspectives of distinct groups of health professionals on such events: schizophrenia researchers have concerned themselves almost exclusively on which/how obstetric complications might impart damage to the nascent nervous system, in the manner of stochastic (random/probabilistic) events, and on what their clinical correlates might be; in contrast to their colleagues in schizophrenia research, obstetricians and neonatologists continue to concern themselves equally with the fundamental issue of why vicissitudes of pregnancy/delivery occur, on the basis that they occur for a reason rather than as stochastic events. Recent studies among the general population indicate that not only inherently `early' obstetric complications such as bleeding in early pregnancy but also `late' complications such as pre-eclampsia, premature delivery, breech birth and cord prolapse are each associated with an excess of diverse congenital anomalies; these ®ndings relate such `late' complications to, and appear to root them in, otherwise unspeci®ed events which have already compromised the fetus over the ®rst or early second trimester (Waddington et al., 1998b, 1999); similarly, low birth weight is associated with reduced growth over the ®rst trimester which can limit fetal growth over the remainder of the pregnancy (Smith et al., 1998). More speci®cally, the pro®le is one of an already neurologically-compromised fetus leading to obstetric complications over later pregnancy and labour (e.g. Rudnik-Schoneborn et al., 1998). On this basis, the presence in schizophrenia of an excess of such diverse `late' obstetric complications among fetuses characterised by cerebro-craniofacial (and other) dysmorphogenesis over weeks 9/10 through 14/ 15 of gestation becomes more compatible if the direction of the putative causal relationship can be at least in part so reversed. Such `late' complications, even when in some part secondary to earlier events, will not be without their own adverse impact on the brain; however, that impact would be on an already compromised brain which may respond dierently to such insult(s) relative to an otherwise `normal' fetus.
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4.4. Cerebral asymmetry There is a long-standing literature to the eect that in schizophrenia the normal pattern of gender-related left-right structural and functional brain asymmetries is disturbed in the direction of reduced asymmetry in a manner that interacts with gender and possibly age at onset (Crow, 1997; Petty, 1999); though not noted in all investigations, recent studies continue to report such ®ndings, particularly in relation to the frontal and temporal lobes, planum temporale and anteriorposterior axis (Maher et al., 1998; Highley et al., 1998b; Kwon et al., 1999; Shapleske et al., 1999). While it is well-recognised in developmental biology that the apparently symmetrical body plans of vertebrates conceal profound asymmetries of the heart, lungs, visceral organs, vascular system and brain, eorts to understand at a cellular level how these asymmetries arise have faced considerable problems; only recently have studies extended our understanding of these processes (Harvey, 1998). Evidence now suggests dorsal mid-line cells to be fundamental in leftright development. Three general models have been oered: the mid-line could (i) serve as a mechanical or physiological barrier to cell signalling or cell migration, (ii) provide a source for signalling molecules that have either inductive or suppressive in¯uences on lateral tissue, or (iii) mechanically elongate the embryo, resulting in altered cell or matrix orientation; it remains possible that the mid-line regulates left-right development through more than one of these mechanisms. Furthermore, while it appears that most cells originating on one side of the embryo remain on that side of origin, some cross the mid-line with the extent of mid-line crossing dependent upon anterior-posterior level; thus any proposal involving the mid-line as a barrier to cell migration must incorporate dierences along the anteroposterior axis (Harvey, 1998; Yost, 1998). Though these phenomena have been studied most extensively in relation to the development of left-right cardiac and visceral asymmetries in non-human species, they appear of potential relevance to cerebral asymmetries in humans (Meno et al., 1998; Cowell et al., 1999), and thus to their putative diminution in schizophrenia; for example asymmetries in language-related areas of the brain such as the planum temporale have been reported in non-human primates (Gannon et al., 1998; Hopkins et al., 1998) as well as in humans. On this basis, the present model of disturbance(s) in schizophrenia of mid-line cerebro-craniofacial development along an anterior±posterior gradient would be expected to result in disturbances of left±right cerebral asymmetry. It should be noted that lateralised behaviour in the human fetus can be noted as early as 10± 12 weeks of gestation and reaches its peak by 15±18
weeks thereof (McCartney and Hepper, 1999); such a period for the emergence of functional asymmetry within the fetal nervous system is congruent with a time-frame of 9/10 through 14/15 weeks for its disturbance in schizophrenia, in a manner that appears to precede detection of typical asymmetries in brain structure (Chi et al., 1977). 4.5. Heterogeneity vs homogeneity Clearly, schizophrenia is a disorder characterised by diversity in phenomenology and long-term course, with no known biological or psychological index pathognomonic of the disease. However, widespread arguments that schizophrenia is therefore a heterogeneous group of disorders (e.g. Tsuang and Faraone, 1995; Buchanan and Carpenter, 1997) require careful evaluation. The proposition that a certain proportion of patients with the disorder but a lesser proportion of controls evidence a given abnormality is not informative: to say that X% of patients manifest a given abnormality in comparison with only Y% of controls (X > Y) cannot be interpreted fully when the presence or absence of that abnormality is de®ned by some arbitrary threshold value along the continuous or categorical scale used in its measure; such an arbitrary de®nition of abnormality arti®cially dichotomises patients (and controls) into two (or more) groups independent of whether the underlying distribution of the measured variable actually indicates the presence of such (sub)groups (Waddington and Scully, 1999). In the present model, on applying an appropriate analytical approach a clear pro®le emerges: a composite score for dysmorphic features in patients with schizophrenia is distributed unimodally in a manner similar to that in normal individuals, the dierence being that in patients the mean of this distribution is shifted signi®cantly to the right (greater dysmorphology) (Lane et al., 1997); this indicates a varying but homogeneous abnormality in patients in the absence of any heterogeneous, sub-group eect. The question then arises as to whether any other biological index in schizophrenia might show what would be regarded in many quarters as such an unexpected pro®le? Proceeding forward temporally from early cerebrocraniofacial dysmorphogenesis: Jones et al. (1994a) have reported frequency distributions for educational test score to be characterised by a shift to the left (reduced educational attainment) in childhood for members of a study population going on to manifest schizophrenia; similarly, David et al. (1997) reported for premorbid IQ a unimodal distributional shift to the left (reduced IQ) among teenage males in whom schizophrenia emerged subsequently. Perhaps the strongest evidence in this regard derives from the most widely replicated and accepted biological ®ndings in
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the brains of adult individuals with schizophrenia, namely ventricular enlargement. There is now a substantial body of evidence to contradict the (widely held) presumption that such enlargement is present in some but not all patients with the disease; on the contrary, ventricular size evidences a unimodal distributional shift to the right (increased ventricular size) in adult schizophrenia (Harvey et al., 1990; Daniel et al., 1991; Jones et al., 1994b). Similarly, laterality coecients for planum temporale asymmetry evidence in schizophrenia a unimodal distributional shift to the right (reduced asymmetry) (Shapleske et al., 1999). More generally, Nopoulous et al. (1998) have described a unimodal distributional shift in height to the left (reduced height) in patients with schizophrenia, suggesting a generic reduction in bodily growth. Several conclusions follow from these analyses (Waddington and Scully, 1999): (i) each of the measures in schizophrenia that have been analysed in this manner appear to indicate population abnormalities evident in essentially `all' patients with schizophrenia; (ii) overlap between the distributions of these abnormalities in patients vs controls, with only a proportion of patients having a measure outside of the control range or 2 SDs above or below the control mean, arm that these measures have limited diagnostic utility but this should not be mis-interpreted as indicating any sub-groups(s) or heterogeneity, for which there is no evidence; (iii) for each patient, even those having measures well within the control range, the measure appears `larger' or `smaller' than would otherwise have been the case had schizophrenia not emerged in that person. Thus, at each of these levels of examination the resultant pro®le is one not of heterogeneity, as is commonly presumed, but of homogeneity of eect in schizophrenia. 5. What molecular and cellular mechanisms might underpin the model? Recent heritability estimates for schizophrenia continue to indicate 82±85% of variance in liability for schizophrenia to be determined genetically (Cardno et al., 1999), with remaining variance accounted for by shared and particularly by unshared environmental eects. We have noted previously (Waddington et al., 1998a, 1999) that it is the transcription and translation of speci®c genes which initiates the sequence of developmental events in cerebro-craniofacial morphogenesis; successful formation of any element requires a cascade of genetically determined local cellular events that are closely timed with spatial changes in association with cerebro-craniofacial growth that must occur within critical periods of development. In addition to genetic abnormalities, environmental factors may
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modulate and disturb the outcome of such processes; indeed, environmental factors may account for a population-attributable-risk in schizophrenia that is larger than estimated previously (Mortensen et al., 1999). A rapidly increasing number of genes and transcription factors are now known to regulate cerebro-craniofacial development. For example, homeobox genes encode homeodomain proteins that are key coordinators during embryogenesis. They achieve their selective control of cerebro-craniofacial patterning not only by temporally but also by spatially well-restricted expression domains, primarily along an anterior±posterior axis. Among these: D1x genes encode homeoproteins required for forebrain and craniofacial development; the Emx gene family displays a nested expression pattern in the forebrain to establish and signal the limits and identity of various embryonic brain regions including cortical, hippocampal, periventricular, and thalamic areas; notably, initial expression of the Barx2 gene is prominent during the development of neural and craniofacial structures, particularly in the telemesencephalon and concentrated in cells along the dorsal midline, followed by less intense expression that encompasses the telencephalon, frontonasal region and limbs; such Bar class and other homeodomain proteins related to Barx2 are all expressed during development of anterior embryonic structures, while development of more posterior regions may be regulated dierently, for example by Pax2 and Pax5 (Vollmer and Clerc, 1998). The family of Wnt genes is expressed at the dorsal mid-line of the developing neural tube, coincident with dorsal patterning; these genes encode intercellular signalling molecules which play important roles in key processes of embryonic development. Recently, components of the Wnt signalling pathway in the hippocampus and subiculum have been reported to show reduced expression in schizophrenia (Cotter et al., 1998) Furthermore, Reelin, the product of the reeler gene that is transacted by the mDab-1 gene product, functions as an extracellular signpost for migrating neurons; there is a preliminary report that the expression of Reelin and reelin mRNA is reduced in the frontal cortex, hippocampus, striatum and cerebellum in schizophrenia (Impagnatiello et al., 1998), while recent developmental studies indicate that Reelin is involved in the regulation of topographical connections, branching and ®bre growth, and synaptogenesis of entorhinal-hippocampal connections (Borrell et al., 1999). In contrast, the gene lefty-1 is normally expressed on the left side of the prospective ¯oorplate of the neural tube, betraying for the ®rst time left-right asymmetry in that structure; by blocking the transfer of laterality information along the mid-line, it is implicated in mid-line barrier function. It appears that one
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Fig. 1. Lifetime trajectory model for schizophrenia (elaborated from Waddington et al., 1998a,b).
important role of lefty-1 is to restrict the expression of the genes lefty-2 and/or nodal to the left side, and that lefty-2 and/or nodal encode for `leftness' (Harvey, 1998; Memo et al., 1998; Yost, 1998). Such mechanisms suggest how mid-line cerebral dysmorphogenesis in schizophrenia could disturb the functional role of lefty-1 and might allow expression of lefty-2 and/or nodal on the right side, thereby attenuating left asymmetry.
6. What does this dimension of the model not explain? These proposed roots in mid-line cerebro-craniofacial dysmorphogenesis over weeks 9/10 through 14/15 of gestation do not in themselves explain directly the subsequent course of illness in schizophrenia: for example, they do not account for the emergence of diagnostic psychotic symptoms only considerably later, typically in the late teens or 20 s, or illuminate the extent to which schizophrenia might `progress' over its subsequent adult course. However, these roots do not constitute the sole element of the model, which encom-
passes a longitudinal dimension to be elaborated below. 7. What evidence would disprove the model? There are at least two lines of evidence that would either disprove the model or else require signi®cant modi®cations thereto. While craniofacial dysmorphology is an element of essentially all known neurodevelopmental disorders, the topography of such dysmorphology is diverse both between and sometimes within these disorders. The model posits a characteristic topography of craniofacial dysmorphology in schizophrenia. Hence were that same topography to be found in a disorder having a clinical phenotype very dierent from that of schizophrenia, several speci®cs of the model would be called into question. However, the topography of any craniofacial dysmorphology among patients having disorders that overlap phenomenologically with schizophrenia may need to be interpreted dierently. In such instances, e.g. bipolar disorder or velocardiofacial syndrome, speci®cation of similarities or dierences in craniofacial dysmorphol-
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ogy vis-aÁ-vis schizophrenia may be particularly informative in relation to `continuum' vs `independent disorder' concepts of psychoses. An increasing body of evidence indicates in `unaffected' (non-psychotic) ®rst-degree relatives of patients with schizophrenia some phenotypic overlap, particularly in areas such as cognition and even aspects of structural brain pathology. If phenotypic overlap in `unaected' ®rst-degree relatives were found to include an identical topography and prominence of craniofacial dysmorphology, this would suggest such dysmorphology to re¯ect the substrate not of the disorder itself but, rather, of some inherited or otherwise acquired schizotypal trait (`schizotaxia') on which one or more additionally imperative event(s) must impact to result in the diagnostic symptoms of schizophrenia.
8. What is the lifetime trajectory dimension of the model? Previous attention has been drawn (see sections 3.3 and 6) to the importance of not mis-interpreting the roots of this model in cerebro-craniofacial dysmorphogenesis as precluding any role for later events in determining overall course of illness or any `progressive' process subsequently. A brain that has been already compromised very early in fetal life is still subject to the normal endogenous programme of developmental, maturational and involutional processes on which a variety of exogenous biological insults and psychosocial stressors can impact adversely over later pregnancy, through infancy and childhood, to maturation and into old age, to sculpt brain structure and function; it should be emphasised that the eects of such endogenous programmes and exogenous insults on such an already developmentally-compromised brain may be dierent from their eects on a brain whose early fetal origins were unremarkable. We have outlined previously a lifetime trajectory dimension consequent to these origins (Waddington et al., 1997, 1998a,b, 1999) and seek here to elaborate a subsequent `neuroprogressive' course through integration of these processes with a `read-forward' analysis of schizophrenia which, when read in the reverse direction (see section 2), argued for a neurodevelopmental basis. More speci®cally (Fig. 1): 1. A characteristic topography of late embryonic-early fetal cerebro-craniofacial dysmorphogenesis, particularly along the mid-line and having an anteriorposterior gradient, is the basis of the biological underpinnings of schizophrenia in neuronal network dysfunction; 2. An already compromised fetus contributes itself to the subsequent emergence of obstetric compli-
3.
4.
5.
6.
7.
8.
485
cations, which impact on an already compromised brain over fetal/neonatal (mal)developmental course. These early brain abnormalities are associated with evolving neurointegrative de®cits over the (mal)developmental course of infancy (Jones et al., 1994a; Walker et al., 1994). Sequentially, this brain pathophysiology is associated with evolving psychosocial abnormalities over the (mal)developmental course of childhood (Done et al., 1994; Jones et al., 1994a; Walker et al., 1994; Malmberg et al., 1998). Thereafter, increasing recognition of neurointegrative and psychosocial de®cits over the later (mal)developmental course towards early adulthood leads to their reconceptualisation as cognitive impairment, and particularly as negative symptoms, which appear to precede and augur the onset of psychosis (Hafner et al., 1998). Florid psychosis emerges only on functional maturation of cerebral systems/processes that result in the underlying neuronal network dysfunction being so expressed, with the threshold for onset appearing to be modulated by exogenous biological factors and psychosocial stressors over the late (mal)developmental course of early adulthood; as craniofacial dysmorphology is evident even in patients who experience the onset of psychosis in late life (Lohr et al., 1997), otherwise unspeci®ed `protective' factors may operate to delay onset in some circumstances. The onset of psychosis appears to re¯ect the crudescence of some active, morbid process that is associated at least in part with increasingly poor outcome (Wyatt, 1991; Loebel et al., 1992; Scully et al., 1997), particularly in the psychomotor poverty domain (Meagher et al., 1998). The subsequent course of illness can be modulated at least in part by the timeliness and eectiveness of intervention with antipsychotics to ameliorate this morbid process (Wyatt, 1991; Loebel et al., 1992; Scully et al., 1997; Birchwood et al., 1997), and of psychosocial interventions to sustain and promote functioning, over what appears to be a critical early phase of psychosis (McGlashen and Fenton, 1993; Birchwood et al., 1997). Thereafter, negative symptoms and cognitive impairment may accrue in severity and adverse prognostic weight (McGlashen and Fenton, 1992). These later phases of the illness may continue to be in¯uenced by the long-term eectiveness of antipsychotic medication and psychosocial interventions, but on a background of interactions with involutional processes.
In summary, the lifetime trajectory dimension of the model posits early cerebro-craniofacial dysmorphogen-
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esis as the origin of the disease process of schizophrenia. Thereafter, the inherently varying `normal' developmental, maturational and involutional programmes impact sequentially on an already compromised brain to give rise to apparent clinical diversity, both prior to and following the emergence of psychosis, on both cross-sectional and longitudinal bases, but rooted in a substantially homogeneous pathophysiological process. This emergence of psychosis appears to have a substrate in some active, morbid process, the biological basis of which is poorly understood but may be evident in longitudinal progression of structural brain pathology, both early (DeLisi et al., 1997; Rapoport et al., 1997) and late (Davis et al., 1998) in the psychotic phase of schizophrenia; that this active, morbid process itself impacts on a developmentallycompromised brain may account in part for why apparent progression in structural pathology has been reported in regions of the brain found to be already abnormal at the ®rst psychotic episode. We have speculated elsewhere (Waddington et al., 1998a) on possible neuronal mechanisms which might subserve such progression; this includes dopamineinduced apoptotic loss of dopaminoceptive cells, which might arise through putative increases in presynaptic dopaminergic activity in schizophrenia (Hietala et al., 1995; Laruelle et al., 1996; Breier et al., 1997), and which might be ameliorated through early and eective intervention with antipsychotics. Yet the putative savings due to such early and eective intervention, even with novel, second-generation antipsychotics, should not be over-estimated; these processes appear to account for only a modest proportion of variance in long-term outcome measures, in juxtaposition with several other determinants of outcome (Waddington and Scully, 1998). Irrespective of these considerations, this evolving lifetime trajectory model (Waddington et al., 1997, 1998a,b, 1999) is complemented by the perspectives of others (DeLisi, 1997; Woods, 1998) in suggesting a way forward beyond the sterile advocacy of either neurodevelopmental or neuroprogressive processes in schizophrenia.
Acknowledgements The authors' studies are supported by the Stanley Foundation.
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