SCHIZOPHRENIA RESEARCH

ELSEVIER Schizophrenia Research 30 (1998) 115-125

The disconnection hypothesis

Karl J. Friston * The Wellcome Department of Cognitive Neurology, Institute of Neurology, Queen Square, London, WCI N 3BG, UK Received 3 June 1997; accepted 4 July 1997

Abstract

This article reviews the disconnection hypothesis of schizophrenia and presents a mechanistic account of how dysfunctional integration among neuronal systems might arise. This neurobiological account is based on the central role played by neuronal plasticity in shaping the connections and the ensuing dynamics that underlie brain function. The particular hypothesis put forward here is that the pathophysiology of schizophrenia is expressed at the level of modulation of associative changes in synaptic efficacy; specifically the modulation of plasticity in those brain systems responsible for emotional learning and memory, in the post-natal period. This modulation is mediated by ascending neurotransmitter systems that: (i) have been implicated in schizophrenia; and (ii) are known to be involved in consolidating synaptic connections during learning. The proposed pathophysiology would translate, in functional terms, into a disruption of the reinforcement of adaptive behaviour that is consistent with the disintegrative aspects of schizophrenic neuropsychology. © 1998 Elsevier Science B.V.

Keywords: Schizophrenia; Functional integration; Plasticity; Disconnection

1. Introduction for a pathology of integration. This paper is divided into three sections. In the first we address This article presents a disconnection hypothesis the two issues above. In the second section a and discusses it in relation to underlying neurobio- mechanistic version of the disconnection hypothe- logical mechanisms. Although disconnectionism sis is presented. The third section reviews evidence provides a compelling framework for understand- in favour of schizophrenia as a functional discon- ing schizophrenia it has to contend with two major nection syndrome. problems: (i) There is little evidence for the ana- tomical interruption of connections in schizo- phrenia. (ii) Many deficits in schizophrenia can be 2. The nature of the disconnection hypothesis explained by regionally specific abnormalities of function or physiology. Although these abnormali- 2.1. What sort of disconnection syndrome? ties could be framed in terms of abnormal connec- tivity, they do not in themselves constitute evidence The disconnection hypothesis considered here states that schizophrenia can be understood in * Tel: 44 171 833 7456; Fax: 44 171 813 1445; cognitive terms, and in terms of pathophysiology, e-mail: [email protected] as a failure of proper functional integration within

0920-9964/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. Pll S0920-9964 ( 97 ) 00140-0 116 K.J. Friston / Schizophrenia Research 30 (1998) 115-125 the brain. Functional integration refers to the important to remember that this sort of evidence integration of functionally specialized systems (i.e., is being used as a 'lesion deficit' model of a populations of neurons, cortical areas and subar- functional disconnection. These observations are eas), that is required for adaptive sensorimotor used to make the point that psychotic symptoms integration and cognition. Functional integration emerge when functional interactions are disrupted is mediated by the influence that the dynamics or by anatomical lesions, not that anatomical lesions activity of one neuronal system exerts over another are aetiologically important. The concern about and is therefore determined by the connections the lack of evidence for abnormal white matter in between them. The pattern of connections is, in schizophrenia could be replaced by the critical turn, a function of epigenetic, activity- and experi- question: 'How many of the neurochemical and ence-dependent plasticity that underlies ontology cytoarchitectonic abnormalities in schizophrenia and the post-natal remodelling of synaptic connec- are a consequence of putative disruptions of experi- tions. This article suggests that the pathophysio- ence-dependent plasticity that is normally responsi- logy of schizophrenia involves the modulation or ble for modelling the cellular and sub-cellular facilitation of long-term changes in connection infrastructure of neuronal circuits?'. strength. This is distinct from an abnormality of plasticity per se and focuses on the aberrant regula- 2.2. Dysfunctional integration or dysfunctional tion of where and when in the brain plasticity specialisation occurs. This dynamic regulation can be attributed, in part, to the ascending modulatory neurotrans- It is worthwhile considering the disconnection mitter systems. This hypothesis is mechanistic. It hypothesis in relation to other formulations. The is not aetiological in that it only specifies the alternative to the disconnection hypothesis would processes that are implicated in a proximate sense. suggest that schizophrenia can be explained by The notion that psychosis can be explained by regionally specific pathophysiology in one or more a pathology of extrinsic connections (cortico-corti- neuronal systems; in other words, impaired func- cal and cortico-subcortical connections that consti- tional specialization as opposed to dysfunctional tute white matter tracts) can be attributed to integration. There is an important distinction here Wernicke. This hypothesis is anatomical and local- between the pathological interaction of two corti- ises the pathology to interruptions of, or abnormal- cal areas and the otherwise normal interaction of ities in, the anatomical connections themselves. two pathological areas. What follows is an attempt This is not the sort of disconnection syndrome to show why this is fundamental. proposed for schizophrenia. In schizophrenia, the The distinction between a regional and an inter- disconnection is explicitly functional, not anatomi- actional pathology begs a related question 'Which cal (Friston and Frith, 1995). More precisely the has ontological primacy, functional specialization disconnection is in terms of effective connectivity or functional integration?'. From the perspective (Gerstein and Perkel, 1969) as opposed to anatom- of the disconnection hypothesis functional integ- ical connectivity. The abnormal interactions ration supervenes: the primary pathology is sup- between neuronal populations will clearly have posed to be enacted at the level of neuronal infrastructural correlates, but these are likely to be interactions and, in particular, the induction and expressed at the level of synaptic specialisations, maintenance of a proper pattern of synaptic con- cellular morphology and cytoarchitectonics. Any nections. A failure to establish this pattern will misconception that the disconnection hypothesis necessarily result in abnormalities of functional pertains to the extrinsic connections themselves is specialisation. The disconnection hypothesis there- understandable given that evidence, cited in sup- fore subsumes both abnormalities of functional port of the disconnection hypothesis, refers explic- integration and specialisation but the latter (i.e., itly to interruptions of cortico-cortical connections abnormalities of local processing, neuronal (e.g., psychotic symptoms in metachromatic leuko- dynamics and infrastructure) are secondary. The dystrophy; Hyde et al., 1992). However, it is distinction between a regionally specific insult to K.J. Friston / Schizophrenia Research 30 (1998) 115-125 117 the brain and aberrant interactions is fundamental. simply a matter of emphasis on the inputs, as A regionally specific pathology, such as stroke or opposed to the changes in the dynamics that they a tumour, is a sufficient explanation for the particu- evoke. It has fundamental implications for empiri- lar cognitive or sensorimotor deficits of some cal observations of brain function: for example, patients. With the exception of psychomotor pov- consider the patterns of neural activity in the erty syndromes these lesion deficit models are not temporal lobe of schizophrenics. Suppose that generally useful in schizophrenia. In terms of neu- these are abnormal relative to control subjects. ropsychology, many of the experiential symptoms The explanation for this abnormality may be of and positive signs of schizophrenia can only be two sorts. Firstly, it could reflect pathology that explained by considering one cognitive process in is entirely intrinsic to the temporal regions, render- relation to another: for example, hallucinations ing them abnormally responsive to inputs from can be construed as a mis-attribution of internally elsewhere or, secondly, they could result from generated speech to an outside agency (Frith, abnormal interactions with the prefrontal cortices. 1992). This speaks to a failure to integrate the These two explanations would lead to very attribution of agency and inner speech. In other different predictions and inferences. The first expla- words, the symptoms and signs of schizophrenia nation would predict that temporal responses do not generally represent a single deficit but can would be abnormal irrespective of the events or be seen as resulting from the abnormal integration tasks used to elicit them. The disconnection expla- of two or more processes. In a similar vein the nation, however, would predict that abnormal disconnection hypothesis suggests that the neuro- temporal responses would only be seen in the nal dynamics underlying these symptoms are not context of tasks that involved interactions within due to a single regionally specific pathophysiology a distributed system that necessarily included the but are expressed when two or more regions prefrontal cortex and temporal regions. It is interact. This is not to say that the regions involved conceivable that both temporal and prefrontal will not show region-specific abnormalities but responses would appear quite normal in situations that these abnormalities are epiphenomena of a that did not typically rely on prefronto-temporal more pervasive problem. The alternative perspec- interactions. In other words, the abnormal tempo- tive, where dysfunctional integration is secondary ral responses are only revealed or expressed in to a regionally specific insult, is a good model for relation to prefrontal dynamics. It should be noted, other organic brain syndromes. For example, a however, that simply demonstrating abnormal middle cerebral artery infarction, resulting in apha- integration between the prefrontal and temporal sia, can be comprehensively understood in terms cortices does not represent sufficient evidence for of a specific insult to the cortical areas functionally a disconnection. Both regions should be demon- specialised for language. Although the damaged strated to have viable responses to inputs from areas will not interact properly with other frontal other areas (e.g., the superior temporal region and temporal regions, the abnormal interactions should still respond to afferent input from the peri- are secondary. auditory or parietal regions). The distinction between dysfunctional integ- ration and dysfunctional regional specialisation is neither specious nor a question of perspective. It 3. The disconnection hypothesis may be thought, given that the dynamics (spatio- temporal patterns of neural activity) in a cortical 3.1. Connections and plasticity area are a function of the intrinsic connectivity (local connections, confined to the grey matter) The key assumption here is that the patho- and input from other areas, that one could not physiology of schizophrenia is expressed in terms meaningfully divorce functional specialisation of abnormal connections. Because synaptic con- from the integration mediated by these inputs. nections are in a continual state of flux, this implies However, the disconnection hypothesis is not an abnormality of time-dependent changes in con- 118 K.J. Friston / Schizophrenia Research 30 (1998) 115-125 nectivity i.e., abnormal plasticity. The disconnec- 1988). It may rely purely on local dynamics or it tion hypothesis is therefore, implicitly, a dysplastic may be influenced by other (modulatory) neuro- hypothesis. The aim of this section is identify the transmitter systems (e.g. Bear and Singer, 1986; particular form of dysplasia that might underlie Kasamatsu, 1991; McGaugh, 1992). schizophrenia (see also Haracz, 1985). To understand functional disconnection, in its 3.2. The plastic processes implicated in broadest sense, one has to appreciate the diversity schizophrenia of mechanisms that are responsible for establishing the complicated and functionally adaptive pattern A first step in identifying the processes that are of connections in the normal brain. These result affected by schizophrenic pathophysiology is to from an interplay between genetic, epigenetic and note that symptoms, reminiscent of those in schizo- activity or experience-dependent mechanisms. The phrenia, can be produced by psychomimetic drugs emphasis in utero is clearly on epigenetic mecha- (e.g. Allen and Young, 1978). This immediately nisms; such as the interaction between the spatio- tells one that the locus of abnormality is likely to temporal topography of the developing cortical be at the modulation of synaptic efficacy (either sheet, cell migration, gene expression and the medi- short- or long-term) in the post-developmental ating role of gene-gene interactions and gene period. Secondly, the fact that schizophrenia is products such as cell adhesion molecules (CAMs). expressed symptomatically in adulthood points to Following birth, the broad schema of connections an abnormal modulation of experience-dependent are progressively refined and remodelled with a plasticity, as distinct from the induction and main- greater emphasis on activity- and use-dependent tenance of synaptic connections through epigenetic plasticity. These changes endure into adulthood mechanisms or indeed activity-dependent plasticity with ongoing reorganisation and experience- in utero: for example, there is no evidence to dependent plasticity that subserves behavioural suggest that the ocular dominance columns in the adaption and learning throughout life. In sum- striate cortex of schizophrenics are abnormal. This mary, there are two basic determinants of connec- does not preclude neurodevelopmental explana- tivity in the brain. (i) Epigenetic: reflecting the tions for schizophrenia (see Weinberger, 1987; and interactions between the molecular biology of gene Murray and Lewis, 1987), but suggests that the expression, cell migration and the slow spatiotem- endpoint of any putative aetiology affects biologi- poral dynamics of morphogenesis and ontology in cal processes that are only expressed in the post- the developing brain. (ii) Activity-dependent mod- developmental period. Thirdly, schizophrenia is a elling of the pattern and strength of synaptic brain syndrome that has a degree of specificity in connections. Activity-dependent plasticity can be terms of the functional, anatomical and neuro- divided into (a) plasticity that depends on inter- transmitter systems that have been implicated: actions between the epigenetically determined pat- given the ubiquitous nature of short- and long- terns of connectivity and neuronal activity intrinsic term potentiation (and depression) of synaptic to the developing nervous system; and (b) experi- efficacy throughout the brain, schizophrenia is ence or use-dependent changes in synaptic efficacy unlikely to be associated with abnormal short or that are elicited by interactions with the environ- long-term plasticity per se but could be associated ment. The latter are associated with learning and with the abnormal control or modulation of plas- memory that subserve adaptive or compensatory ticity; where this control is exerted by systems with changes in emotional, cognitive or sensorimotor a circumscribed anatomy and neurochemistry: integration. This plasticity may be transient (e.g., from the perspective of the disconnection hypothe- short-term potentiation or depression) or enduring sis it is of no surprise that the neurotransmitter (e.g., long-term potentiation). It may or may systems implicated in schizophrenia are exactly not be associated with synaptic remodelling and those that are responsible for modulating short- infrastructural changes in cell processes (e.g., ter- and long-term changes in synaptic plasticity. The minal arbors or dendritic spines; Rotshenker, role of the ascending classical neuromodulatory K.J. Friston/ Schizophrenia Research 30 (1998) 115-125 119 transmitters systems such as dopamine (DA) and over the induction and maintenance of long-term acetylcholine (ACh) in modulating short-term changes in connections that are associated with changes in efficacy at a synaptic and cell assembly learning and memory. From the perspective of level is well known (e.g. Mesulam, 1990; Goldman- theoretical neurobiology (in particular, neuronal Rakic et al., 1989; Mantz et al., 1988; Sawaguchi selection and reinforcement learning) this modula- and Goldman-Rakic, 1991; Williams and tory effect has profound implications for the way Goldman-Rakic, 1995): However, these ascending that adaptive connections can be established. Any systems also have a crucial role in modulating related pathophysiology (e.g., schizophrenia) can long-term associative plasticity that may be even usefully be understood from this perspective. more important in elaborating and maintaining an adaptive pattern of connections. We now consider 3.4. The theoretical importance of modulating this role in some detail. associative plasticity

3.3. Modulation of long-term changes & synaptic The existence of neurotransmitter systems that efficacy can facilitate associative plasticity, has profound implications for the development and maintenance There is considerable evidence to suggest of adaptive connections. The basic idea has two monoaminergic (DA, norepinephrine, NE, and levels: first, if such neurotransmitter systems exist serotonin, 5HT) and cholinergic (ACh) neuro- then any events that lead to a discharge of activity transmission facilitates either the induction or in these systems will consolidate the pattern of maintenance of long-term changes in synaptic synaptic connections extant at that time. This strength. The three most compelling lines of evi- provides a powerful mechanism to select connec- dence are modulation of (i) experience-dependent tions that mediate adaptive sensorimotor integ- changes in synaptic efficacy; (ii) behavioural plas- ration. Clearly, for this selection to work only ticity; and (iii) experimentally induced long-term events that are 'adaptive' or have 'value' should potentiation. One neurodevelopmental example is excite modulatory discharges of this sort (i.e., the the role of ACh in facilitating experience-depen- outcome of any sensorimotor integration should dent organization of connections in striate cortex: be adaptive or valuable for the phenotype). The induction of ocular-dominance shift in cats, and ability of events to elicit activity in ascending its recovery following monocular deprivation modulatory systems will be determined by the depend on the integrity of NE and/or ACh neurot- inputs (afferents) to the cells of origin of these ransmission (Bear and Singer, 1986). ACh and systems (e.g., the VTA for DA or the nucleus NE have both been shown to modulate experience- basalis for ACh). These afferents therefore deter- dependent modification of synaptic connectivity, mine what is valuable (e.g. a reversal of hypogly- possibly in a synergistic way (Brocher et al., 1992). caemia). How that valuable state is achieved Further evidence implicating ACh in the modula- depends on selective consolidation of adaptive tion of plasticity comes from the electrophysiologi- responses to salient stimuli (e.g., conditioned cal correlates of learning. Metherate and responses to appetitive stimuli) mediated by dis- Weinberger (1989) have demonstrated conditioned charges in the ascending systems. The key notion stimulus-specific modification of frequency-recep- here is that the inputs to modulatory systems can tive fields in cat auditory cortex during condition- be specified genetically, therein providing an essen- ing. Pairing of exogenous acetylcholine and a tial link between evolutionary selection (what is single tone resulted in a similar shift, with maximal adaptive about a response to a cue) and neuronal change at the frequency paired with acetylcholine. selection (how that response is acquired or selec- These findings suggest that ACh is necessary for, tively consolidated in relation to other competing and can modulate, associative plasticity in a learn- responses). By embedding neuronal selection in ing-related context. In short, the ascending neuro- evolutionary selection in this way the elaboration transmitter systems can exert a regulatory control of adaptive behaviour (i.e., learning) can be seen 120 K.J. Friston / Schizophrenia Research 30 (1998) 115-125 as a simple emergent phenomenon. The second uncoupling between the sensorimotor and cogni- level considers the fact that the inputs to the tive contingencies encountered in the environment modulatory systems are themselves subject to the and the reinforcement experienced. The disruptive same modulation-dependent selection. A simple effect on adaptive behaviour and underlying pat- consequence of this is that cues or salient stimuli terns of connections is obvious. There would be a can acquire 'value' if, and only if, they are associ- greatly reduced facility to engage in tasks that ated with adaptive responses. These stimuli can involved high-order conditioning and a concomi- themselves now consolidate or reinforce antecedent tant difficulty with developing coherent strategies behavioral responses leading, by recursion, to of adaptive behaviour. If one conjectures that most a succession of adaptive stimulus-contingent of the 'reinforcement' in adult life derives from responses. This sequence must, by the nature of our interactions with other people, then the integ- its construction, arrive at a genetically specified ration of positive or negative feedback from our and valuable endpoint. transactions with others into our repertoire of The above analysis predicts, and relies upon, social responses would become impossible. In transient discharges in ascending modulatory sys- short, there would be a failure of social functioning tems that are associated with the processing of and deterioration; as previously reinforced behavi- salient stimuli that elicit adaptive responses. An ours were 'overwritten' by anomalous facilitation experimental model of this situation is operant of plasticity. An important aspect of the theoretical conditioning, particularly higher-order reinforce- perspective is the recursive consolidation of a ment schedules: experimental evidence for rein- temporal succession of neuronal dynamics, each forcement-specific responses in these systems reinforcing its antecedent. A failure of this 'chain- is clear-cut: for example, the experiments of ing' can be related, in at least a speculative way, Ljungberg et al. (1992) have demonstrated phasic to the disorganized and incoherent language pro- discharges in the cells of origin of the dopaminergic duced by some schizophrenics and the persevera- system that are selective for reinforcing stimuli. tive and 'autistic' aspects of their behaviour. Other models include intracranial self-stimulation and studies of emotional learning in animals (see 3.6. Explanatory power Cador et al., 1989; Metherate and Weinberger, 1989; McGaugh, 1992; White and Milner, 1992). It is proposed that schizophrenia is a functional A full exposition of these ideas will be found in disconnection syndrome mediated by some form Friston et al. (1994) discussed in the context of of dysplasia. We have identified the consolidation the theory of neuronal group selection (Edelman, or modulation of associative changes in synaptic 1993) and reinforcement learning. efficacy (as opposed to the changes themselves) as the process that is most likely to be affected and 3.5. Abnormal modulation in schizophrenia have focused on the ascending neurotransmitter systems in this role. An important aspect of the What would follow from an improper function- disconnection hypothesis is that this sort of patho- ing of these modulatory mechanisms in the light physiology will only be expressed in those systems of the theoretical analysis above? As an example, that: (i) support plastic change; and (ii) are subject consider the ascending mesocortico-limbic dopa- to modulation by the neurotransmitter system or minergic system. The distribution of the terminal systems in question. This allows for entirely normal fields of these ascending neurons shows a regional activity-dependent plasticity in systems that are specificity with a predilection for the prefrontal not subject to such modulation or in those that cortices, and related limbic and paralimbic struc- have already passed through a critical period of tures (Oades and Halliday, 1987). Suppose now plastic organization (e.g., the visual cortex). One that the associative plasticity in these structures might anticipate that by early adulthood only a was modulated or facilitated in an aberrant fash- portion of the brain will be amenable to reinforce- ion. Functionally this would correspond to an ment-dependent changes in synaptic efficacy; K.J. Friston / Schizophrenia Research 30 (1998) 115-125 121 namely, those systems implicated in [emotional] netic signals. These markers of functional learning and memory. A pathophysiology disconnection should be seen in, and only in, restricted to these systems is consistent with many systems that have a high plastic potential, or aspects of schizophrenia: (i) the cardinal deficit equivalently systems that are involved in learning would be a failure to develop or maintain coherent and memory. (ii) Schizophrenics should be and adaptive patterns of reinforced behaviour and impaired on tasks that emphasis temporal succes- is consistent with many of the disintegrative aspects sion, reinforcement and new learning, such as high- of schizophrenic neuropsychology. (ii) The abnor- order reinforcement schedules and reversal learn- mality can be framed in terms of experience or ing. (iii) There should be a demonstrable difference activity-dependent plasticity in systems that are between normal subjects and schizophrenics, in only functionally expressed in the developed brain. terms of how synaptic connections are consoli- This allows for the fact that psychomimetic drugs dated during learning; and (iv) more specifically can induce psychotic symptoms and that schizo- how drugs that manipulate the function of ascend- phrenia is primarily a disorder of adulthood. (iii) ing neurotransmitter systems will modulate asso- The abnormality shows a degree of anatomical ciative plasticity. (v) Discharge rates in ascending and neurochemical specificity; the medial temporal neurotransmitter systems will be abnormal in rela- lobe (amygdala hippocampus, parahippocampal tion to the presentation of stimuli in high-order gyrus and related cortex) and the prefrontal cortex reinforcement schedules. This is not to say that are directly implicated by virtue of their role in the pathophysiology affects these systems directly learning and memory and their high plastic poten- but that the connections to these systems, that tial (Haracz, 1985). The fact that these structures mediate their responses, are likely to be abnormal. have been repeatedly implicated in schizophrenia It is unclear how this could be measured in humans by functional and structural imaging, cytoarchitec- at present; however recent developments in tonic and histochemical studies (e.g., Benes et al., dynamic displacement studies of receptor-specific 1986; Deakin et al., 1989; Bogerts et al., 1991) is radioligands with positron emission tomography entirely consistent with the current formulation. may represent a possible way forward. (vi) A (iv) It directly posits a mechanistic role for the more speculative experimental prediction is that ascending modulatory neurotransmitter systems cytoarchitectonic and biochemical changes seen in that have been implicated in schizophrenia from schizophrenia may be emulated in animal models both a pharmacological perspective (e.g., Dolan where the presentation of stimuli and reinforcers et al., 1995) and in terms of animal models (e.g., in operant paradigms has been disrupted by experi- Sawaguchi and Goldman-Rakic, 1991). (v) It mental design. One could think of many more explicitly brings together molecular biology (con- examples but these serve to illustrate the usefulness solidation of synaptic efficacies) and behaviour of a simple and mechanistic hypothesis. (experience-dependent learning) in a mechanistic way. Bridging between molecular and systems- level descriptions is important, both from a 4. Evidence for the disconnection hypothesis phenomenological point of view (e.g., the stress- diathesis model of schizophrenia) and in terms This section focuses on evidence for schizo- of directed research. phrenia as a functional disconnection syndrome. It should be noted that the notion of disconnection 3. 7. Predictions of the disconnection hypothesis derives not only from neurophysiological data but also from cognitive models of schizophrenia dating The experimental predictions that ensue are back, perhaps, to Bleuler (1911). A more recent fairly straightforward. (i) Schizophrenics should formulation of psychological 'disintegration' is the evidence abnormal functional integration, indexed idea that some experiential symptoms of schizo- by abnormal effective connectivity in neuroimag- phrenia can be explained by a failure to integrate ing, and coherence among electrical and biomag- the intention to act with the perceptual registration 122 K.J. Friston / Schizophrenia Research 30 (1998) 115 125 of the consequences of that action (Feinberg, 1978; like symptoms (Allen and Young, 1978). PCP Frith, 1992). At a neurobiological level this integ- is a potent inhibitor of N-methyl-o-aspartate rative abnormality might correspond to a failure (NMDA) glutamate receptors. Glutamate recep- to integrate signals from the (intentional) prefron- tors are ubiquitous in the brain and glutamate tal regions and the (perceptual) temporal cortices. neurotransmission is the mainstay for the excit- The notion that schizophrenia represents a disin- atory cortico-cortical interactions that integrate tegration or fractionation of the psyche is as old different brain areas. PCP psychosis could then be as its name introduced by Bleuler (1911 ) to convey construed as a transient chemical disconnection a 'splitting' of mental faculties. The lines of evi- syndrome affecting these connections. While a dence reviewed below relate to the neurophysiolog- primary pathology of glutamate receptors is not ical basis of this mentalistic splitting. necessarily an explanation for functional discon- nection, it is likely that a disruption of cortico- 4.1. Anatomical disconnections cortical interactions at any level will be reflected in abnormalities of glutamate function. Although the proposal here is that schizophrenia Schizophrenics have been shown to have abnormal is a functional disconnection syndrome, conditions markers of glutamate function both ex vivo that involve anatomical disconnections may pro- (Deakin et al., 1989; Sherman et al., 1991) and in vide good lesion-deficit models. It is interesting to vivo (Pettegrew et al., 1991). note that Wernicke proposed that psychosis may result from disruption of the 'organs of connection' 4.3. Functional disconnections and neuroimaging (white matter fibre tracts) at about the same time that Bleuler introduced the term schizophrenia. Functional connectivity in neuroimaging is defined as a correlation between remote neuro- However, the evidence for white matter pathology physiological events and effective connectivity as in schizophrenia is not remarkable. Having said the influence that one neuronal system or popula- this, white matter disorders such as metachromatic tion exerts over another (Friston et al., 1993). leukodystrophy do provide compelling models of Measures of functional connectivity are closely schizophrenia, particularly where the pathophysio- related to coherence in multi-channel electrophysi- logy may involve an anatomical deafferentation of ological recordings or correlations in multiunit the prefrontal cortex (Hyde et al., 1992). See also electrode recordings (e.g., Gerstein and Perkel, Bruton et al. (1994). The sequelae of a functional 1969; Aertsen and Preissl, 1991). In positron emis- disconnection syndrome could of course be sion tomography and functional MRI neuroimag- expressed anatomically even at a macroscopic ing studies, functional connectivity is usually level. MRI studies of callosal anatomy suggest a assessed on the basis of the correlations in a time significant reduction in callosal area in schizo- series of brain scans. Our own analyses, of the phrenia although this is not a consistent finding interactions between prefrontal and temporal corti- (Woodruff et al., 1995). There are a number of ces, suggest that schizophrenics have an abnormal cytoarchitectonic studies that could be interpreted pattern of functional connectivity involving both in terms of abnormal cell migration and the forma- an absence of correlations between prefrontal and tion of aberrant connections in neurodevelopment superior temporal regions and the presence of (e.g. Jacob and Beckman, 1986). abnormal positive correlations between prefrontal and more posterior middle temporal cortex 4.2. Neurochemical disconnections (Friston et al., 1996). These observations are pro- visional but replicate. In the same sense that functional disconnections may be modelled by, or have, anatomical corre- 4.4. Theoretical neurobiology lates, neurochemical studies may also provide models. For example phencyclidine (PCP) is a Theoretical neurobiology and, in particular, psychomimetic drug that induces schizophrenia- computational neurobiology can be useful in help- K.J. Fr&ton / Schizophrenia Research 30 (1998) 115-125 123 ing to explain the relationship between emergent phrenia. Hippocampal pathways show the phenomena in mathematical models and those seen strongest and most enduring LTP effects, but LTP in real brains. For example, connectionist models is also seen throughout the limbic forebrain. The have been used to explore the link between cogni- regional specificity of plastic potential has also tive impairment and dopamine neurotransmission. been addressed by looking for the expression of Cohen and Servan-Schreiber (1992) have studied gene products associated with plastic remodelling attention and language processing in relation to of neuronal processes. See Haracz (1985) for a dopaminergic modulation of the sensitivity of pre- review of the experimental evidence relating neural frontal units to input. Hoffman and McGlashan plasticity and schizophrenia. (1993) have related the dynamics of fully intercon- There is considerable histopathological evidence nected Hopfield-type networks to symptoms of for abnormal plasticity in schizophrenia including: schizophrenia by looking at the effect of succes- (i) decreased hippocampal expression of the sively reducing the connections between the inter- embryonic form of the neural cell adhesion mole- acting units. Our own work using synthetic cule (NCAM) in schizophrenia. This form of neuronal models has looked at the relationship NCAM has been proposed to be related to synaptic between the amount of connectivity among neuro- rearrangement and plasticity (Barbeau et al., nal populations and measures of complexity using 1995). (ii) Selective displacement of interstitial nonlinear dynamics (the correlation dimension): white matter neurons in the frontal lobes of schizo- in brief, we see a progressive increase in the phrenics that may reflect an alteration in the correlation dimension when connectivity is reduced migration of subplate neurons or in the pattern of (Friston, 1996). This is consistent with a functional programmed cell death. Both could be associated disconnection in schizophrenia in the sense that at with abnormal neural circuitry and connectivity least some studies show that the correlation dimen- (Akbarian et al., 1996). Electron microscopy of sion is elevated in schizophrenia (e.g. Koukkou synaptic ultrastructure in regions associated with et al., 1993). Again it should be noted that a the dopaminergic system has revealed changes that functional disconnection syndrome does not neces- are consistent with anomalous plasticity: namely, sarily imply a reduced number of anatomical con- anomalous axonal sprouting with an increase in nections but simply an abnormal influence of one axospinous, and decrease in axodendritic, synapses neuronal population over another. Aberrant func- in schizophrenia (Uranova, 1996). tional interactions could, conceivably, be associ- ated with hypertrophic or exuberant connections (see David, 1994). 5. Conclusion

4.5. Neural plasticity in schizophrenia This article has reviewed the disconnection hypothesis of schizophrenia and has presented a Neural plasticity refers to the capacity of the mechanistic account of how dysfunctional integ- nervous system to exhibit structural and functional ration among neuronal systems might arise. The adaptations to impinging stimuli. Long-term- particular hypothesis put forward is that the patho- potentiation (LTP) is considered to be one of the physiology of schizophrenia is expressed at the best models of plasticity that might underlie learn- level of modulation of associative changes in syn- ing. The association between temporal lobe epi- aptic efficacy; specifically the consolidation of asso- lepsy and schizophrenic symptoms (e.g., Ounsted ciative plasticity in those brain systems responsible and Lindsay, 1981 ) can be related to plastic mecha- for emotional learning and memory. This modula- nisms through a predisposition to kindling phen- tion is mediated by ascending neurotransmitter omena (see Cain, 1989 for a comparison of LTP systems that: (i) have been implicated in schizo- and kindling). Mapping studies indicate that LTP phrenia; and (ii) are known to be involved in and kindling phenomena are especially demonstra- consolidating synaptic plasticity. By reference to ble in regions that have been implicated in schizo- theoretical neurobiology this pathophysiology can 124 K.J. Friston / Schizophrenia Research 30 (1998) 115-125 be understood as disrupting the reinforcement of similar are the mechanisms. Trends in Neurosciences 12, adaptive behaviour in a way that is consistent with 6 10. Cohen, J.D., Servan-Schreiber, D., 1992. Context, cortex and the disintegrative aspects of schizophrenic neu- dopamine: a connectionist approach to behavior and biology ropsychology. in schizophrenia. Psychol. Rev. 99, 45-77. David, A.S., 1994. 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