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  If waking and dreaming consciousness became de-differentiated,would schizophrenia result? q Sue Llewellyn Faculty of Humanities, The University of Manchester, Booth Street West, Manchester M15 6PB, UK  a r t i c l e i n f o  Article history: Available online 16 April 2011 Keywords: DreamingWakingConsciousnessSchizophreniaDe-differentiationChaos theoryPhospholipid defects/metabolism a b s t r a c t If both waking and dreaming consciousness are functional, their de-differentiation wouldbe doubly detrimental. Differentiation between waking and dreaming is achieved throughneuromodulation. During dreaming, without external sensory data and with mesolimbicdopaminergic input, hyper-cholinergic input almost totally suppresses the aminergic sys-tem. During waking, with sensory gates open, aminergic modulation inhibits cholinergicand mesocortical dopaminergic suppresses mesolimbic. These neuromodulatory systemsare reciprocally interactive and self-organizing. As a consequence of neuromodulatory rec-iprocity, phenomenologically, the self and the world that appear during dreaming differfrom those that emerge during waking. As a result of self-organizing, the self and the worldin both states are integrated.Some loss of self-organization would precipitate a degree of de-differentiation betweenwaking and dreaming, resulting in a hybrid state which would be expressed heteroge-neously, both neurobiologically and phenomenologically. As a consequence of progressivede-differentiation, certain identifiable psychiatric disorders may emerge. Ultimately,schizophrenia, a disorganized-fragmented self, may result. Ó 2011 Elsevier Inc. All rights reserved. 1. Introduction This paper elucidates the hypothesis that schizophrenia results from the progressive de-differentiation of waking anddreaming consciousness. In support of this, research is synthesized from several domains which have tended to be discrete:the differentiation of conscious states; phenomenological and neurobiological differences in waking and dreaming;phospholipid metabolismin neuronal membranes; dreaming and memory consolidation and workon the neurobiology,phe-nomenology and heterogeneity of schizophrenia. The methodology is hermeneutic in the sense that a more holistic under-standing of schizophrenia may emerge through considering the interrelationships between these areas of work-essentially,iterative steps of ‘what is the significance of this evidence in this domain in the context of that evidence in that domain’.Keshavan, Tandon, Boutros, and Nasrallah (2008)comment that the accumulating ‘fact-base’ on schizophrenia requiresnew integrative approaches that can generate testable predictions, this particular hypothesis is in this spirit.Differentiation is achieved between the conscious states of waking and dreaming (see later). If differentiation has to beachieved, it can fail to be achieved, resulting in de-differentiation and a hybrid waking/dreaming state. The mind-brainprocesses that achieve differentiation are complex and, although reciprocally interactive, can vary independently. Therefore,de-differentiation would be expressed heterogeneously. However, one unifying thread is that conscious experience of theworld and the self would both be disrupted in a de-differentiated state. The integrity of waking and dreaming consciousness 1053-8100/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.concog.2011.03.022 q This article is part of a special issue of this journal on European Science Foundation EMRC Exploratory Workshop: The Dreaming Mind-Brain,Consciousness and Psychosis (Challand Saint Anselme, Italy, 25th – 28th May 2009). E-mail address: sue.llewellyn@mbs.ac.ukConsciousness and Cognition 20 (2011) 1059–1083 Contents lists available atScienceDirect Consciousness and Cognition journal homepage:www.elsevier.com/locate/concog  underlies the differing experience of the self and the world in the two states. De-differentiation would compromise theintegrity of both states (although not necessarily to the same extent at the same time). The progressive de-differentiationof waking and dreaming consciousness and associated loss of self-organization in both states may gradually result inschizophrenia: a fragmented self. It is argued that understanding of both the heterogeneity of schizophrenia and thedisruption to self-experience can be advanced through this de-differentiation hypothesis. 2. Consciousness, conscious experience and the heterogeneity of schizophrenia Schizophrenia is a heterogeneous condition. In classic workBleuler (1911/1950)referred to the ‘group of schizophrenias’.In a recent comment,Carpenter (2008, p. 1003)reiterated that, ‘Schizophrenia has the nosological status of a clinical syn-drome rather than a validated single disease entity. Heterogeneity in clinical presentation and course is routinely observed,and heterogeneity of disease processes is likely’.Tandon, Nasrallah, and Keshavan (2008, p. 1)refer to an ‘ . . . admixture of positive, negative, cognitive, mood and motor symptoms whose severity varies across patients . . . ’. Moreover, there is accep-tance that distinctions between all psychiatric illnesses are fuzzy and symptomatic profiles overlap (Brockington and Leff,1979).Kendall and Jablensky (2003, p. 4)conclude that, ‘ . . . there is little evidence that most currently recognized mentaldisorders are separated by natural boundaries. Researchers are increasingly assuming that variation in symptoms is contin-uous’. For example, obsessive-compulsion disorder (OCD) is not infrequently a co-diagnosis with schizophrenia (Krügeret al., 2000). OCD symptoms have been found in up to 50% of patients with schizophrenia (Berman, Merson, Viegner,et al., 1998). In particular, it appears that schizophrenia and bipolar disorder may be closely related, they share the sameetiology (Craddock, O’Donovan & Owen, 2006; Craddock & Owen, 2005; Lichtenstein et al., 2009; Maier, Zobel & Wagner,2006), exhibit symptomatic overlap (Lake, 2008; Lake & Hurwitz, 2006; Pope & Lipinski, 1978), can follow a similar deteri- orating course (Addlington and Addington, 1997; Zuibieta, Huguelet, O’Neil, & Giordani, 2001), involve sleep disturbances(Benson, 2006; Costa e Silva, 2006), can be difficult to distinguish clinically (Craddock & Owen, 2005; Owen & Craddock, 2009; Walsh, 2009) and partly share genetic determinants (Craddock, O’Donovan & Owen, 2005, 2006; Lichtenstein et al.,2009). Indeed, the diagnosis of schizoaffective disorder recognizes the overlap between schizophrenia and bipolar disorder.Craddock and Owen (2005)comment on the multidimensional space occupied by functional psychiatric pathologies, ‘Therecent findings are compatible with a model of functional psychosis in which. . . . [there is] susceptibility to a spectrum of clinical phenotypes. . . . [or indeed]. . . . a multidimensional space [where] in addition to bipolar disorder and schizophreniathere is genetic overlap between the functional psychoses and major depressive disorder – and, indeed, other disorders –with extension into sub-clinical (or normal) variation’. Reviews of population surveys indicate that attenuated psychoticexperiences are reported by 5–8% of respondents (Polanczyk et al., 2010; van Os, Linscott, Myin-Germeys, Delespaul, & Krab-bendam, 2009). Over 10 years, for a representative sample of adolescents and young adults from the general population,Dominguez, Can Saka, Lieb, Wittchen, and van Os (2010)reported a 12% cumulative prevalence rate for both negative/dis-organized and positive psychotic symptoms.Heterogeneity in presentation and course, overlap with other psychiatric disorders and extension (in attenuated form)into the general population implies difficulty (indeed, most probably, impossibility) in delimiting schizophrenia to a coreconstellation of signs and symptoms. As compared to other illnesses, the diagnosis of schizophrenia has been describedas an art (Eaton, Hall, Macdonald, & McKibben, 2007). One statement that can be definitively made, however, is that schizo-phrenia involves consciousness and disruptsnormal consciousexperience.As consciousness is a notoriously elusive andcon-tested concept (see, for example,Chalmers, 1996), this may not advance matters much unless there is clarification of how‘consciousness’ and ‘conscious experience’ are understood here.In this paper, ‘Consciousness is the appearance of a world’ (Metzinger, 2009. p. 15). A world appears in both waking anddreaming consciousness (but not in deep dreamless sleep), moreover, when a world becomes present, a self also emerges asa part of this world (Metzinger,2009, p. 57). The world andthe self that appear during waking differ, in certainrespects, fromthose that appear during dreaming. (This paper focuses on REM dreaming, rather than the more literal and thought-likeNREM, for a review of the differences see,Nielson, 2003).‘Conscious experience’ is understood in the sense of a ‘cognitive global workspace’ (Baars, 1988, 1997, 2002). At any pointin time consciousexperience focuses on a particular aspect of the world. Conscious experience, ‘ . . . resemblesa bright spot onthe stage of immediate memory, directed there by a spotlight of attention under executive guidance’ (Baars, 2005, p. 46).Again conscious experience differs in waking and dreaming, although there is a ‘spotlight’ of attention in both, during(non-lucid)dreaming‘executiveguidance’ or the intentionalcontrol of that‘spotlight’is lacking.Moreover, asworkingmem-ory is much attenuated in dreaming, the ‘stage of intermediate memory’ dissolves, so, from the perspective of waking con-sciousness, it is unclear why the spotlight is focused where it is in dreaming.In sum, waking and dreaming consciousness are differentiated both with respect to the world that emerges and the self that becomes present. The next section addresses how this differentiation is achieved at the neurobiological level. 3. Achieved differentiation between waking and dreaming consciousness Achieved differentiation between waking and REM dreaming consciousness can be partly understood through the ‘AIMModel’ (Hobson, 1990, 1992, 1997; Hobson & Stickgold, 1994; Kahn, Pace-Schott, & Hobson, 1997). AIM suggests that allconscious states reflect three processes: the level of brain activation (‘A’); the srcin of inputs (‘I’); and dynamic reciprocity 1060 S. Llewellyn/Consciousness and Cognition 20 (2011) 1059–1083  between aminergic and cholinergic neuromodulation (‘M’). Although these processes do tend to vary in concert, they canalso exhibit independent variability (Hobson, Pace-Schott andStickgold, 2003).Activation (‘A’) is a measure of conscious experience (the ‘spotlight’ of attention), ‘ . . . as reflected in the length, intensityand complexity of subjective reports of mental activity . . . ’ (Hobson, Pace-Schott, and Stickgold, 2003, p. 40). Although, phe-nomenologically, reports of conscious experience in dreaming and waking differ in kind (see later), both states are equallyactivated (Hobson, 2002). Indeed,Tononi (2004)argues that during REM dreaming activation may be even higher than in waking. The srcin of inputs (‘I’) reflects the extent to which the brain-mind is making sense either of external sensory dataor internally generated percepts, this difference is driven by both input–output gating of external stimuli and the strength of internal data sources (Hobson, Pace-Schott, & Stickgold, 2003). As would be expected from the reported measures of con-scious experience, thalamocortical activation is at normal (waking) levels during REM dreaming (Behrendt, 2006; Paréand Llinás, 1995), so, to achieve differentiation between the two states, external input must be excluded (Hobson, 1999). When sensory stimuli from the external world are blocked, hallucinatory imagery suffuses consciousness (Behrendt,2003; Behrendt & Young, 2004). In contrast, during waking, internal perceptions are gated by sensory afferents so halluci-natory images do not normally arise (Behrendt, 2003; Llinás & Paré, 1991). Fictive hallucinatory movement in dreams iscompelling. Not only are motor commands issued to motor neurons but they are also copied to the sensory system, motoroutput during dreaming is blocked only through postsynaptic inhibition (Hobson, 1999).Neuromodulation ensures unified, coherent mind/brain responses. In the AIM model, modulation (‘M’) is the ratio of aminergic (noradrenergic and serotonergic) to cholinergic inputs, the predominance of aminergic modulation during wakingsupports directed thought, insight, judgment, abstract thinking, decision-making, working memory and space–time orienta-tion, the almost total lack of aminergic input to dreaming suppresses these executive functions (Hobson, Pace-Schott, &Stickgold, 2003). Process changes in the three AIM parameters go some way to explaining how the differentiation betweenwaking and dreaming is achieved. However, Hobson, Pace-Schott andStickgold (2003)recognize that the three dimensionsof ‘AIM’ do not exhaust the conscious state space; indeed, they propose that more dimensions exist. It is suggested here thatto advance understanding of the achieved differentiation between waking and dreaming and, hence, to grasp the conse-quences of a de-differentiated state, a more comprehensive account of ‘M’ is required (to include mesolimbic–mesocorticaldopaminergic modulation) and a self-organization dimension (‘O’), which is dependent upon ‘I’ and ‘M’, should be included.The reasons for these modifications are discussed, in turn, next.Solms (1999, 2002)argues that the role of dopamine (DA) in directing the dreaming state has been neglected. Indeed heposits that the mesolimbic–mesocortical dopaminergic pathway is crucial for dream generation. Although it is possible thataminergic demodulation may facilitate dopaminergic effects, these DA effects are primary (Solms, 2000). A dynamic recipro-cal relationship between mesocortical and mesolimbic DA projections has been proposed (Davis, Kahn, Ko, & Davidson,1991; Pycock, Kerwin, & Carter, 1980). It has also been shown in rodents that serotonergic systems can modulate the impactof mesolimbic DA (Barr et al., 2004). There is overwhelming evidence that the prefrontal DA inhibits subcortical DA activity(for a review seeGuillin, Abi-Dargham, & Laruelle, 2007). Mesocortical DA enables prefrontal neuronal activity whereas mes-olimbic DA has a critical role in motivation and emotion (Mathé, Nomikos, Blakeman, & Svensson, 1999). As discussed below,on the phenomenological level, dreaming is a hyperemotional state where thinking reaches its nadir. Hence, it is intuitivelyplausible that, during dreaming, mesolimbic DA may predominate over mesocortical DA, with the reverse during waking. Asensitized mesolimbic dopaminergic system is correlated with an increase in cholinergic input (Sarter, Nelson, & Bruno,2005). So, during dreaming, increasing mesolimbic DA is associated with increasing cholinergic neuromodulation. Thus, dy-namic reciprocity characterizes not only aminergic/cholinergic systems but also mesocortical/mesolimbic dopaminergic sys-tems and mesolimbic dopaminergic/cholinergic systems.The combined impact of shifts in ‘I’ and ‘M’ most probably account for the changes in regional activation of the brain thatalso differentiate dreaming and waking (Hobson, Pace-Schott, & Stickgold, 2003). For example, the gating of external stimulialong with the suppression of aminergic and mesocortical DA input may explain the de-activation of the frontal lobe duringREM dreaming. Conversely, the selective activation of the limbic system during REM dreaming may be due to cholinergic andmesolimbic DA stimulation accompanied by strong internally generated percepts. Specifically,Hobson (1999, p. 152)arguesthat dreaming is initiated in the pontine brainstem triggering activation, aminergic demodulation and cholinergic hyperac-tivity which selectively engages the limbic areas. The engagement of the limbic lobe then triggers primary emotions (e.g.fear, elation and rage). These emotions drive dream plot elaboration which is constituted through the visual imagery centresof the associative cortex, the spatial centres of the parietal lobe and the narrative organizing centres of the temporal lobe.Solms (2003) argues that dreaming (unlike REM architecture) is preserved with pontine brain stem lesions whereas a com-plete cessation of dreaming is observed with lesions of the parieto-temporo-occipital (PTO) junction. Despite their differ-ences, both Hobson and Solms agree on certain features of the differential regional activation of the brain during REMdreaming: the dorsolateral prefrontal cortex and the primary visual cortex are deactivated, whereas limbic areas and theoccipitotemporal cortical areas are selectively activated. Normal spatial cognition through the spatial centres of the parietallobe is preserved in both waking and dreaming.Both waking and dreaming are self-organized mind-brain states (Kahn, Pace-Schott, & Hobson, 1997; Tononi, 2004;Tononi, 2008; Tononi & Edelman, 1998). The mind-brain self-organizes through sensory data and neuromodulation (Free-man, 2005; Singer, 1986). As noted above, although external sensory input is largely ignored during dreaming (Mahowald,Woods & Schenck, 1998) self-organization through neuromodulation and internally generated precepts continues (Kahn,Combs, & Krippner 2002). During waking, self-organization generates a brain ‘forward model mechanism’ that enables S. Llewellyn/Consciousness and Cognition 20 (2011) 1059–1083 1061  (across all sensory modalities) automatic distinction between external sensory data and internally generated precepts, with-out this mechanism internally generated precepts may be experienced as having external sources (Ford, Roach, Faustman, &Mathalon, 2007). During REM sleep this mechanism does not operate, internally generated precepts are not recognized assuch and if external data is processed (without causing waking) it is co-opted into the internally generated dream narrative.Self-organization is not stable or fixed but constituted through dynamic processes (Kahn & Hobson, 1993; Kahn, Krippner,& Combs, 2000). These dynamic processes are moulded by ‘attractors’ which enable any self organized state to find its owninherent configurations (Krippner & Combs, 2002). There is a global attractor that leads the mind-brain to settle (albeit,dynamically) at the ‘edge of chaos’ (Goodwin, 1994) or, in other words, in a state of self-organized criticality between orderand disorder (Bak, 1996).Withinevery 24 h, two self-organized, highly activatedstates are achieved:waking and dreaming.Therefore, inthe mind-brain, it is intuitively likely that ‘order’ is represented by an achieved differentiation between waking and dreaming and‘chaos’ (or disorder) results from their de-differentiation.Differentiation between waking and dreaming depends on dynamic reciprocity and is a ‘constantly negotiated compro-mise’ (Hobson, 2002, p. 102). Hence, as is predicted by chaos theory, the achieved differentiation between waking anddreaming is both vulnerable and volatile. Indeed, this is confirmed by the existence of transient dissociated states: luciddreaming; REM sleep disorder; and waking fantasy or ‘daydreaming’ (see Hobson, Pace-Schott andStickgold, 2003, for a re-view). De-differentiation differs from state dissociations in that de-differentiation would impact upon both waking anddreaming consciousness. Also de-differentiation be an enduring (and sometimes progressively deteriorating, see later),rather than a transient condition.Systems, such as the mind-brain, that are poised between order and disorder are optimal for complex tasks (Kauffman,1993). If de-differentiation between waking and dreaming occurred then the ability to undertake complex tasks in bothstates would be effected detrimentally. One of the key tenets of chaos theory is uncertainty over the precise ways in whichthese effects would be manifested. In a state of self-organized criticality, a small perturbation in the mind-brain (in thishypothesis a small shift into de-differentiation) can precipitate fluctuations which are largely unpredictable on the basisof initial conditions (Bak, 1996; Orsucci, 2006). 4. How could de-differentiation occur? The implication of the above arguments is that the heterogeneity associated with schizophrenia (and, possibly, other re-lated psychiatric/neurodevelopmental disorders) may reflect the multifarious possibilities inherent in the process changesthat achieve differentiation between waking and dreaming in the mind-brain. Or, in other words, schizophrenia is a condi-tion of the ‘anomalous dynamics’ (Orsucci, 2006) that can emerge within any system poised at self-organized criticality. Butnot all humans descend into schizophrenia, so the question arises of how these anomalous dynamics are triggered in sus-ceptible individuals.There is evidence of neuronal cell membrane phospholipid abnormalities in patients with schizophrenia (Glen et al.,1994; Horrobin, Manku, Hillman, Iain, & Glen, 1991; Nuss et al., 2009; Yao & Reddy, 2000; Yao, van Kammen, & Welker,1994). These membrane abnormalities are observed prior to treatment, so they may be trait-related ( Jayakumar et al.,2003; Reddy, Keshavan, & Yao, 2004). Schizophrenia may be associated with deficient uptake or excessive breakdown of membrane phospholipids (Fenton, Hibbeln, & Knable, 1999). Excessive breakdown may flow from the over-activity of cal-cium-independent phospholipase A2; such over-activity has been demonstrated in schizophrenia (Horrobin, 1996; Macdon-ald et al., 2004; Smesnya et al., 2005). Evidence of abnormal fatty acid metabolism in schizophrenia includes: reduced fattyacid levels in cell membranes; reduced skin flush response to topical niacin; abnormal electroretinogram; increased levels of calcium-independent phospholipase A2 in blood and brain; and abnormal 31P magnetic resonance spectroscopy of brainphospholipids (Peet, 2002).Essential fatty acids (EFAs) are key components of neuronal cell membranes. Eicosapentaenoic acid (EPA) and docosahex-aenoic acid (DHA) are common essential fatty acids in the brain (see, for example,Horrobin, 1998). Supplementation withEPA has been shown to be effective as an adjunct treatment for already medicated patients with schizophrenia (Emsley, My-burgh, Oosthuizen, & van Rensburg, 2002; Peet, Brind, Ramchand, Shah, & Vankar, 2001; Peet & Horrobin, 2002; Shah, Van-kar, Telang, Ramchand, & Peet, 1998). There is indicative evidence that drug-naïve patients may respond too (Puri et al.,2000; Richardson et al., 2000). EPA has also been shown to reduce the risk of psychosis in high-risk individuals (Ammingeret al., 2007), young people with subthreshold psychotic states (Amminger et al., 2010) and enhance treatment response in patients with a first episode (Berger et al., 2007).Moreover, EPA, along with DHA,has also been found to be efficacious for bipolar disorder (Stoll, Severus& Freeman, 1999;and unipolar and bipolar depression (Frangou, Lewis, & McCrone, 2006; Freeman et al., 2006). In particular, the therapeuticeffects of EPA have been shown to be equal to fluoxetine in treating major depressive disorder ( Jazayeri et al., 2008). Theinclusion of EPA along with other essential fatty acids, vitamins and minerals in the diet of prisoners reduced the incidenceof anti-social behaviour (including violence) by 26.3% (Gesch, Hammond, Hampson, Eves, & Crowder, 2002). The administra-tion of EPA and DHA decreased feelings of anger in substance abusers (Buydens-Branchey & Branchey, 2008). Ultra pureethyl-eicosapentaenoate (E-EPA) diminished aggression and depressive symptoms in women with untreated borderline per-sonality disorder (Zanarini & Frankenburg, 2003). Essential fatty acid deficiencies (with improvements after supplementation) 1062 S. Llewellyn/Consciousness and Cognition 20 (2011) 1059–1083
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