The neuropsychology of delusions

Transcription

1 Ann. N.Y. Acad. Sci. ISSN ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: The Year in Cognitive Neuroscience The neuropsychology of delusions Max Macquarie Centre for Cognitive Science, Macquarie University, Sydney, Australia Address for correspondence: Max, Macquarie Centre for Cognitive Science, Macquarie University, Sydney, NSW 2109, Australia. Work in the field of cognitive neuropsychiatry over the past 20 years has made it plain that various forms of delusional belief are scientifically understandable in the sense that plausible neuropsychological explanations of their nature and genesis have been formulated. A two-factor theory of delusional belief has emerged from this work. According to this theory, explaining the presence of a delusion requires (a) the presence a neuropsychological impairment that initially prompts the delusional belief and (b) the presence of a second neuropsychological impairment that interferes with processes of belief evaluation that would otherwise cause the delusional belief to be rejected. A very similar account of delusion has recently emerged from research on hypothesis evaluation using the associative-learning paradigm with healthy control subjects and people with psychosis. Neuroimaging studies in this context suggest that the region of the brain specifically involved in hypothesis evaluation (and therefore, according to the two-factor theory, impaired in people with delusions) is the right lateral prefrontal cortex. Keywords: delusion; prefrontal cortex; belief; cognitive neuropsychiatry Introduction What could cause a Nobel laureate to believe that he was the left foot of God, and that he would become the Emperor of Antarctica? (I speak here of John Nash 1 ). Delusional beliefs seem so bizarre, and their possible genesis so mysterious, that one of the forefathers of psychiatry declared them to be beyond the ken of science. 2 This counsel of scientific despair has turned out to be exaggerated. Work in the field of cognitive neuropsychiatry over the past 20 years has made it plain that a variety of forms of delusional belief are scientifically understandable in the sense that plausible neuropsychological explanations of their nature and genesis have been formulated. Consider, for example, the mirror sign. 3,4 This is the belief that when you look into a mirror the person you see is not you, but some other person some stranger who looks like you. a There can be a There is an unfortunate ambiguity in the literature on the mirror sign ; this term usually refers to a delusion about the identity of the person in the mirror, but sometimes the term has been used to refer to something quite different: a pathological interest with looking at oneself in mirrors. no doubt that this delusion is neuropsychological in origin, because in one study 4 all seven of the cases described were suffering from dementia, probably Alzheimer s disease. It is also clear that this particular neuropsychological etiology is not necessary for the occurrence of the mirror-sign delusion: one patient with this delusion 5 showed an abrupt onset of the mirror sign immediately following a hypotensive crisis and another 6 was suffering from posterior cortical atrophy regarded as involving Lewy body dementia. Why, exactly, do the specific neuropsychological impairments of these patients lead to their specific belief that the person they see when they look into the mirror is some stranger, not themselves? This has been investigated in two mirror-sign case, TH and FE. 7 9 The authors of this study preferred the more descriptive term mirrored-self misidentification when referring to the mirror-sign delusion, and I will use that term from now on. Detailed neuropsychological investigations of patientth(whoprovedtobesufferingfromthe early stages of a focal-onset dementia) revealed the presence of a second neuropsychological disorder: mirror agnosia. This term refers to an inability to doi: /j x 16 Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences.

2 understand how mirrors work and how to interact with them. So, for example, when TH was looking into a mirror and could see in the mirror an object that was being held behind him above his shoulder, and was asked to touch that object, he repeatedly tried to do so by reaching into, or around and behind, the mirror. For a patient with mirror agnosia, a mirror is not a mirror; it is treated instead as a hole in the wall, or as a window. So when TH looked into a mirror, the person he saw was taken by him to be in a different part of space than TH was, because as far as TH was concerned, this person was being observed by TH through a window, or through a hole in the wall. If the person that TH was observing was occupying a different region of space than TH was, it follows that the person he was looking at in the mirror could not be himself, even though it looked like him. That, argued Breen and colleagues, was what first prompted in TH the idea that the person in the mirror was a stranger. The suggestion that what first made TH think that the person he saw in mirrors was a stranger was his persistent and incorrigible mirror agnosia seems highly plausible as an explanation of what initially gave rise to this belief. However, many patients with mirror agnosia do not exhibit the mirroredself misidentification delusion; they correctly identify themselves in mirrors. 10 If those mirror-agnosic patients were not delusional about the person they saw when they looked in the mirror, why was the mirror-agnosic patient TH delusional about this? We seem to have two choices here. The first is to reject the view that there was any causal connection between the content of TH s delusion and the presence of mirror agnosia in his case: to argue, that is, that the coexistence of these two conditions was simply a coincidence. The second is to propose that TH s mirror agnosia was acausalfactorasfarashis delusion was concerned, but that there was also a second causal factor involved, a factor present in TH s case but not in other (nondelusional) cases of mirror agnosia. 10 Because the nature of mirror agnosia has so plausible a connection to the nature of TH s delusion, I suggest that the first of these choices should be rejected, and that the second choice should be pursued here that is, a two-factor explanation of TH s delusion should be offered. The plausibility of the connection is just this: If I am observing a person through a window (or a hole in the wall; anything other than a mirror), that person is in a different spatial location than I, and so must be a different person than I. The first factor (mirror agnosia) explains the content of his delusion; the second factor is responsible for his failure to reject the belief despite all the evidence against it. TH s family would frequently tell him that the person he saw in the mirror was himself. It was pointed out to him that whenever he saw the person in the mirror, the person s clothing was exactly the same as his. He was asked to perform actions while looking in the mirror such as touching his nose, and it was pointed out to him that every action he executed was also executed in the mirror. He agreed when asked that the person in the mirror looked very like him. But none of this evidence contradicting his belief had any effect: the delusional belief was impervious to the evidence. Thus, the second factor here would seem to be some kind of defect of belief evaluation; more will be said about the nature of this second factor later in this paper. We 11 share with others 12 the view that the processes of inference that are applied by the patient when seeking an explanation of the abnormal data generated by Factor 1 are Bayesian in character. Breen and colleagues 7 9 described a second patient, FE, who was just like TH in that he too believed that the person he saw when he looked into the mirror was not himself but some stranger, and in that this belief was as impervious to the presentation of counter-evidence as TH s was. FE was also, like TH, in the early stages of a focal-onset dementia. But FE differed from TH in that he did not have a mirror agnosia. When a mirror was positioned so that FE could see both himself and his neuropsychological examiner in the mirror, FE correctly identified the examiner s reflection while continuing to assert that his own reflected image was that of a stranger. In contrast, when the same test was performed with TH, he considered that the reflection of the examiner in the mirror was another stranger, not the examiner (a finding which of course is what is predicted by the proposed account of the role of mirror agnosia in TH s delusion). Another case of mirrored-self misidentification 6 also did not have mirror agnosia because, like FE, that patient was able to recognize others in the mirror correctly. What was the factor, then, which suggested to FE that the person he saw in the mirror was not himself, if it was not mirror agnosia? Breen and colleagues Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences. 17

3 found that FE performed poorly on various tests of face recognition. So they suggested that the impairment of face processing ability caused by FE s dementia meant that the representation of his face that his face processing system generated when he looked in the mirror was no longer identical to the long-term mental representation of his own face stored in the face processing system, and that this mismatch between the face he saw in the mirror and his memory for his own face was what suggested to FE that the person he saw in the mirror was not him. The same analysis can be provided for the case of Yoshida and colleagues 6 because that patient also had impaired face processing. But just as one can make the point re TH that not all people with mirror agnosia exhibit mirrored-self misidentification, so one can make the point re FE that not all people with impaired face processing show this delusion. Why was FE like TH in resisting all the evidence presented to him that contradicted his belief about the person in the mirror? It can be argued that this is because the second factor referred to earlier as some kind of defect of belief evaluation was present not only in TH but also in FE. Reasoning of this kind about various forms of delusional belief has led to the development of a general two-factor theory of delusion According to this theory, any form of delusion can be seen as caused by the joint presence of two factors. Factor 1 is what is responsible for the belief having occurred to the person in the first place, as a hypothesis to explain the data generated by the Factor 1 neuropsychological impairment: this factor determines the content of the delusional belief. Factor 2 is responsible for the failure to reject the hypothesis despite the presence of (often overwhelming) evidence against it. This second factor is responsible for the hypothesis being accepted as a belief instead of being rejected: that is, this factor determines the persistence of the delusional belief. Factor 1 varies from delusion to delusion, because different delusional beliefs have different contents. But the imperviousness to counter-evidence that prevents the hypothesis generated by factor 1 from being rejected is constant across all delusions, and so the argument is that Factor 2 is common to all cases of delusional belief. According to this approach, then, what is needed to achieve an understanding of any form of delusion is to determine the answers to just two, separate, questions. The first question is: what suggested the delusional idea to the patient in the first place where did this idea come from? The second question is: what prevented the idea from being rejected after it had occurred why was not the idea dismissed, instead of being adopted as a belief? In its most general formulation, the two-factor theory of delusional belief does not require the two factors to be due to neuropsychological abnormalities. But in practice the theory has so far only been worked out in any detail in relation to forms of delusion that seem clearly neuropsychological in origin (such as mirrored-self misidentification), and so only these kinds of delusion will be considered in any detail here. Capgras delusion is another example of a delusion that seems indisputably neuropsychological in origin. This is the belief that someone emotionally close to you in many cases, this is your spouse, sometimes also other family members has vanished and been replaced by a stranger. Various psychodynamic explanations for this particular delusion have in the past been offered; but it is now clear that the Capgras delusion instead has a neuropsychological explanation. This has been shown by research on autonomic responding to familiar and unfamiliar faces. In control subjects and in nondelusional psychiatric subjects, familiar faces produce much larger responses of the autonomic nervous system (indexed by the skin conductance response [SCR] to the presentation of a face) than unfamiliar faces do. But four different studies of Capgras patients have shown that this differential autonomic responsivity to familiar faces compared to unknown faces is absent in people with Capgras delusion. Thus, when a sufferer from Capgras delusion sees the face of his or her spouse, the expected strong autonomic response will be absent. What could be the cause of this surprising absence of response? Well, if the person being seen were in fact a stranger, no strong autonomic response would occur. So a natural hypothesis to entertain here is that, even though this person looks like the spouse, this is not actually so: the person is actually a stranger. I argued above that the Factor 1 implicated in mirrored-self misidentification (mirror agnosia or impaired face processing) can be present in people who nevertheless are not deluded: hence the 18 Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences.

4 need for a second factor in the explanation of this delusion. The same is true for Capgras delusion. Patients with damage to ventromedial regions of frontal cortex fail to show differential autonomic responsivity to familiar faces compared to unknown faces, in the same way as Capgras patients; but the ventromedial patients are not delusional about the identities of anyone. 20 So once again it seems necessary to postulate the presence of the second factor in cases of Capgras delusion. In people with Capgras delusion, there is evidence to support the stranger hypothesis, namely, the absence of autonomic response when the spouse s face is seen. But much evidence that contradicts the hypothesis will also be present. For example, trusted friends and family will be telling the Capgras sufferer that this person really is his spouse; the suspected stranger may be wearing a wedding ring with the spouse s initials engraved on it; and the suspected stranger may know things about the Capgras sufferer s past life that only the spouse could know. An intact hypothesis evaluation system would therefore not accept the stranger hypothesis and adopt it as a belief, which implies that hypothesis evaluation is impaired in Capgras delusion. In the two delusions discussed so far, mirroredself misidentification and Capgras delusion, neuropsychological impairments that are highly plausible as responsible for the first factor for each delusion have been empirically demonstrated. For some other delusions, a plausible two-factor explanation can also be advanced, but the neuropsychological impairments that are highly plausible as the first factor for the delusion have only been hypothesized and there have not yet been any empirical investigations of them (although how they should be investigated is perfectly clear). Suppose there were a neuropsychological impairment of the face recognition system that had the effect of making that system overresponsive, causing unfamiliar faces to partially activate the representations of various familiar faces in that system (here one might think of these familiar-face representations as having abnormally low thresholds). Now even when a face is unfamiliar there would be a strong autonomic response to it, even though no specific face representation is sufficiently activated to lead to a specific face identification response. The result would be that the affected person would take the faces of many unfamiliar people as familiar (although not being identifiable as the face of any specific familiar person). Exactly this symptom has been reported in a person who had suffered a left lateral temporo-occipital infarction. 21 This study did not measure autonomic responses to faces, but if it had it seems quite possible that the unfamiliar faces that the patient reported as being familiar would have evoked autonomic responses larger than those of unfamiliar faces that the patient reported as unfamiliar. Thus, there would be some faces that the patient could not identify but that evoked autonomic responsesofamagnitudecharacteristicofresponse to faces of people the patient knew. How might a person explain this paradoxical result? One possible hypothesis that might come to the patient s mind is that the individuals who evoked such responses in the patient were in fact people the patient knew (that is why there was an autonomic response) but who were in disguise (that is why they could not be recognized). There are all kinds of reasons why such a hypothesis should be rejected, and the patient reported by Vuilleumier and colleagues 21 wasnotreportedtohaveanysuchbelief.butsuppose there were a patient who had the same lesion as the patient reported by Vuilleumier and colleagues, and in addition had whatever the form of neuropsychological damage is that is responsible for factor 2. This patient might well come to believe that people he knew were following him around but could not be recognized because they were in disguise. This particular delusional belief has been reported; it is known as the Fregoli delusion, and the speculative explanation that it is due to hypersensitivity of the face recognition system has been advanced. 22 No one has studied autonomic responsivity to familiar and unfamiliar faces in sufferers from Fregoli delusion. This needs to be done, because the prediction of this speculative theory is clear: the theory requires that for at least some unfamiliar faces Fregoli patients should show larger autonomic responses than nondelusional controls. When the delusional belief of a patient with Fregoli delusion is challenged by someone making the point that, if this patient were really being followed by acquaintances, the patient should be able to identify these people, one possible response would be for the patient to accept this as strong evidence against the belief, and so abandon the belief. But this is not what happens. Instead, the patient confabulates: invents an explanation for why the followers are not Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences. 19

5 recognized (it is because they are in disguise). This is a very general feature of delusional conditions. 23 For example, one Capgras patient 24 claimed that she could tell the difference between her real son and the imposter because the imposter had different coloured eyes, was not as big and brawny, and that her real son would not kiss her (p. 557). The patient TH described earlier, when asked why, if the person he sees in the mirror is not himself, the mirrored person is always dressed identically to him, simply said He s not changing his clothes, and appeared to be satisfied that this was an adequate response to the challenge. It is a general feature of the kinds of delusions discussed in this paper that when the delusion is challenged by offering evidence that the delusional belief is false, this does not abolish or even weaken the delusion. Instead, patients will try to explain away the evidence by confabulating. As a second example of a kind of delusion where a particular Factor 1 has been proposed but not yet investigated (the Fregoli delusion being the first), consider the neuropsychological disorder known as pure autonomic failure 25,26 in which SCRs to stimuli, which would normally evoke such responses (such as unexpected sudden touches or loud noises), are absent. 26 Presumably this absence of autonomic responsivity would be observed with all kinds of stimuli that would normally arouse autonomic activity. If that is so, what hypotheses might a sufferer from this condition generate to explain this total lack of autonomic response to anything? One hypothesis, which is explanatorily perfectly adequate to explain this lack, although also perfectly bizarre, is the hypothesis I am dead, because it is true that the dead are not autonomically responsive. Patients with pure autonomic failure must be able to reject this hypothesis, because they do not express the belief that they are dead. But if the presence of Factor 2 in any patient with pure autonomic failure prevented this hypothesis from being rejected, the delusional belief I am dead would be expressed. This is a well-attested delusion known as the Cotard delusion, and the speculative explanation that it is due to general nonresponsiveness of the autonomic nervous system has been advanced. 22 No one has studied autonomic responsivity in sufferers from Cotard delusion. This needs to be done, because the prediction of this speculative theory is clear: the theory requires that Cotard patients should show absence of autonomic responses to all stimuli no matter how arousing these stimuli should be. Thus, for both Fregoli and Cotard delusions, speculative but easily testable proposals have been advanced 22 about what the neuropsychological impairments corresponding to Factor 1 could be. But it seems that for both of these impairments there are patients who have the impairment but who are not delusional. Hence if these accounts of the Fregoli and Cotard delusions are to be retained, our Factor 2 must again be invoked. So far I have discussed four forms of delusion for which plausible neuropsychological explanations can be advanced. I will discuss just two more: somatoparaphrenia and the delusion of alien control. Patients with somatoparaphrenia commonly have a paralyzed limb, almost always on the left side of their bodies (the paralysis being due to severe contralateral motor-cortex damage) and they have the belief that the paralyzed limb is not theirs, but belongs to someone else: sometimes the limb owner is the neuropsychological examiner, sometimes a relative of the patient, even a relative not present in the room. Factor 1 here is the paralysis: the patient has to formulate a hypothesis to explain why the limb cannot be voluntarily moved, and an explanatorily adequate hypothesis is that this is because the limb belongs to someone else. But very few patients with unilateral paralysis express such a belief: most will say, when asked why they are unable to move their left arm, that this is because they have suffered brain damage. Acceptance of the bizarre hypothesis about limb ownership as a belief could not occur unless something was very wrong with the hypothesis evaluation system, that is, unless Factor 2 were present in addition to the paralysis that constitutes Factor 1. Patients with the delusion of alien control believe that other people can control the movements of their body: can make a patient s arm rise up, for example, without the patient willing it to rise. It was proposed by Frith 27 that here the Factor 1 (although Frith did not use this particular terminology) is a disorder of body-movement monitoring. When I raise my arm, how do I know that it was I who caused this arm movement? The standard explanation runs as follows. When I form the intention to move my 20 Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences.

6 arm, I create a representation of the sensory feedback that such an arm movement should cause. I then move my arm and of course obtain sensory feedback. I compare the expected and the obtained sensory feedback. If these match, this match generates a feeling of agency and hence the conclusion that it was I who was responsible for the movement. Frith s idea was that this monitoring system is defective in people with alien control delusion, so that even when it is actually they who caused their arms to move, there is no matching of expected to obtained feedback, and hence no generation of a sense of agency: the patient does not feel that he moved his arm and so concludes that some other person was responsible for his arm having moved. Yet again, although, we have to add Factor 2 to this story. There is a condition known as haptic deafferentation in which the patient gets no sensory feedback from any actions performed. 28 This patient cannot experience a sense of agency over any of her movements by comparing expected and obtained sensory feedback. When she sees her arm move yet does not experience an equivalence of expected and obtained feedback, one hypothesis that would explain why this happened is that her arm is under the control of others. But this patient does not believe that other people can cause her limbs to move without her volition. Hence the presence of Factor 2 is needed in addition to the failure of matching of feedback (Factor 1) for the delusion of alien control to occur. The story so far: six different delusions of neuropsychological origin have been discussed in the context of a two-factor theory of delusional belief, where Factor 1 is a neuropsychological impairment responsible for generating a hypothesis, which, if accepted, would constitute a delusional belief, and Factor 2 is what is responsible for the failure to reject the hypothesis generated by Factor 1. This two-factor theory of delusional belief has its roots in seminal work by Ellis and Young 29 and Frith, 27 and is related to ideas about comparator models of belief formation. 30 The theory at present appears promising, and is beginning to attract wide acceptance: Abnormal beliefs in neurological patients: the need for a two-deficit account. Delusional beliefs are not unique to patients with schizophrenia. They can also be found in patients with overt brain damage and are often associated with obvious deficits. For example, patients with paralysis of one arm may believe that the paralyzed arm is not part of them or that they areabletomoveit.thedeficitisclearlynot sufficient to create the false belief, as many patients have paralyzed arms without any such belief. Similarly, a minority of patients with memory loss show confabulation, a false belief about what has happened to them in the past. As has been cogently argued (, 2007;, McKay and Langdon, 2007) two deficits are necessary to explain these delusions: a primary deficit (paralysis or memory loss) and a failure to suppress the implausible responses that result from this deficit. In the case of neurological patients, false beliefs seem to derive from the coincidence of damage in two locations, with the abnormal belief formation associated with damage to the prefrontal cortex. 12 (pp ) A two-deficit account also seems necessary to explain the false beliefs associated with schizophrenia. 12 (p. 56) For all six delusions, something satisfactory, I believe, has been said about Factor 1. It has been specifically characterized in neuropsychological terms for all six delusions. For some of these delusions, direct evidence of the presence of the relevant neuropsychological impairment in the relevant patients exists in the literature. In other cases, it is clear what experiments would provide direct evidence supporting or refuting predictions about what specific neuropsychological impairments should be present to act as Factor1inparticulardelusions. In contrast, very little has yet been said about Factor 2. All that has been said is that it is a defect of a hypothesis evaluation system, a defect claimed to be present in all deluded patients regardless of the form of the delusion and responsible for the deluded person accepting the hypothesis as a belief despite all the evidence available that is consistent with the belief. And almost nothing has been said about the neuropsychology of Factor 2. So I now offer some attempts to flesh out, just a little, a cognitive and neuropsychological account of this second factor. Two immediate problems The claim is that all deluded patients have defective ability to evaluate hypotheses about what the world Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences. 21

7 is like. Because odd ideas of all kinds about what the world is like occur to us all the time, such ideas would occur to people with delusions. Why, then, do not they become more and more deluded about more and more topics over time after their hypothesisevaluation system has become deranged? But this is not what happens. Many delusional patients show no odd beliefs other than the single delusional belief they hold. A possible response to this problem is the omnipresence of Factor 1. Odd ideas come and go, but the failure of autonomic response to the sight of a spouse s face occurs in the Capgras patient every single time that face is seen, and the mismatch between seen and remembered own face occurs for FE every single time he looks in the mirror. So the evidence that supports the delusional belief is unrelentingly present, and so will be much harder to discount than any odd idea that happens to crop up on the odd occasion. If Factor 1 were an impairment a weakening rather than a complete abolition of the hypothesis evaluation system, then hypothesis evaluation might only fail when evidence for the incorrect hypothesis is strong and omnipresent. A second and related problem is that it is often reported that delusions can come and go. For example, family members of some Capgras patients may report that the patient sometimes correctly identifies them and sometimes believes them to be strangers. How could this be, if Factor 1 and Factor 2 are permanent neuropsychological impairments? A possible answer to this question is that if as suggested earlier the hypothesis evaluation system is weak rather than abolished, constant administration of a large amount and variety of evidence of the falsity of the delusional hypothesis might allow the hypothesis evaluation system to make the correct rejection decision. Now the Capgras patient will accept that his spouse is his spouse. So his family, friends, and clinician will cease providing him with evidence that his spouse is his spouse. But his autonomic nervous system will not cease providing him with evidence that his spouse is not his spouse. So the delusion will return. The answers to these two problems may or may not be satisfactory; but I will turn now to a potential source of information about what the putative hypothesis-evaluation system might be like that comes from a different field neuroimaging studies of hypothesis formation and evaluation in healthy control subjects, rather than the study of delusions. The neural basis of hypothesis evaluation Subjects were presented with a task involving hypothesis formation, confirmation, and disconfirmation. 31 The hypotheses in this task concerned associations between syndromes and medications. On each trial, a subject was told that a particular medication was being administered and asked to predict whether the hypothetical patient receiving this medication did or did not have a particular syndrome; feedback was then given as to whether the subject s prediction about the presence or absence of the syndrome was correct or not. This feedback enabled subjects to test and accept or reject hypotheses about what the specific drug syndrome associations were in the structure of the data. On occasional trials, surprising feedback was given that is, feedback that contradicted the hypothesis that was consistent with (i.e., generated correct predictions on) the great majority of relevant trials. Subjects brain activity was imaged using fmri as they performed this task. The imaging data revealed that specific brain regions, dorsolateral prefrontal cortex (DLPFC) and especially right dorsolateral prefrontal cortex (RDLPFC), were specifically associated with performance on this task. Bilateral DLPFC activity was high at the beginning of the experiment and declined as the experiment proceeded. On trials in which feedback contradicted a current hypothesis, RDLPFC activation was high, as compared to trials where the feedback confirmed the prediction from this hypothesis. These findings may be interpreted as follows. Early in learning, no specific hypotheses have yet been adopted, and so subjects will be engaged both in hypothesis generation and hypothesis evaluation, a set of processes that appears to engage DLPFC bilaterally. Later in learning, on contradicting trials a currently-held hypothesis will make a prediction that is inconsistent with feedback, and so this hypothesis will need to be evaluated; the specific process of hypothesis evaluation appears specifically to engage RDLPFC. Hypothesis evaluation is not needed late in learning on those trials when feedback is not contradictory, because there the current hypotheses are generating correct predictions and so do not require evaluation; hence RDLPFC is not activated on such trials. 22 Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences.

8 In a somewhat different hypothesis-formation and hypothesis-evaluation task, subjects were asked 32 to imagine that they were allergists trying to work out what particular foodstuff a hypothetical patient X was allergic to. On each trial the subjects were shown a particular meal containing several different foods, and asked to predict whether X would show an allergic reaction or not, and were then given feedback whether X did or did not show such a reaction to this particular foodstuff combination. Here subjects would generate hypotheses as to what the critical allergenic foodstuff was, hypotheses that would then be confirmed or disconfirmed by the feedback. The composition of the meals and the feedback given were manipulated in such a way that eventually only one hypothesis existed that was consistent with the data from all trials up to this point. Hence the subject could be confident of the correct response on this trial. The subject made this response based on the only hypothesis that could at that point still be true; but was then given feedback that the prediction made on this trial was false. Thus, a prediction error was artificially engendered. As subjects performed this task, their brain activity was recorded using fmri. The imaging data revealed activation of RDLPFC on trials where prediction errors occurred. In a subsequent study using this allergy-detection task, 33 right prefrontal cortex activation on prediction error trials was again observed; however, the authors made the following observation (p. 882): We should point out that, while the main foci of error-dependent activation lie in DLPFC, activations reported here extend more ventrally into inferior frontal sulcus. For the purpose of interpretation, the critical observation is that we have used masking to ascertain that the region overlaps with that identified in our most recent study (Turner et al., 2004). However, in this instance, since the activationsextendventrally,wefeelthatitismoreprudent to refer to the activation as lateral prefrontal. These three studies license the proposal that right lateral prefrontal cortex (RLPFC) is a region of the brain one of whose functions is not just general processes of hypothesis generation, evaluation, and acceptance or rejection, but specific processes of hypothesis evaluation. In the two-factor theory of delusional belief, all patients with delusion, no matter what the form of the delusion is, are hypothesized to have an impairment of hypothesis evaluation: that is Factor 2. This leads to the prediction that there should be RLPFC abnormalities observable in patients with any of the six delusions discussed earlier. The neurology of delusions It is widely accepted that right hemisphere abnormality is very commonly seen in patients with delusions. 34 This was true of the two patients with the delusion of mirrored-self misidentification discussed at the beginning of this paper, TH and FE. Although the CT scans of both patients were clear, extensive neuropsychological examinations showed thatbothperformedpoorlyonanumberofneuropsychological tests of right-hemisphere function while performing well on neuropsychological tests of left-hemisphere function. But the bringing together of the two-factor theory of delusion and the work of Fletcher, Turner, Corlett and colleagues on neuroimaging of performance in hypothesis-evaluation tasks allows us to be much more specific about the particular region of right hemisphere that we might expect to be abnormal in all patients with delusions, at least for delusions that are clearly neuropsychological in origin, such as the six kinds of delusion with which this paper is concerned. This region is right lateral prefrontal cortex. What evidence is there that this specific region is abnormal in people with (neuropsychologically caused) delusion? Areview 14 of some of the relevant neurological evidence concluded that this literature indicates that right frontal damage is commonly reported in cases of Capgras, Cotard, and Fregoli delusion. A more recent review of this literature 35 reaches the same conclusion re right frontal involvement in many different forms of delusion. The allergy-detection task 33 described earlier was used 36 with a group of first-episode psychotic patients and a matched group of healthy controls. As in the earlier studies reviewed earlier, prediction error trials generated RLPFC activations in the control group. This was not observed in the psychiatric group: prediction-error trials and trials where there was no prediction error yielded equivalent activation of RLPFC. An estimate of delusion severity in the patients (rating of the frequency of unusual thought content using the Brief Psychiatric Rating Scale) was significantly correlated with the Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences. 23

9 difference between RLPFC activation on predictionerror trials and RLPFC activation on control trials: the stronger a patient s tendency to delusion, the smaller this difference was. Corlett and colleagues 36 noted (pp ) that those patients in whom there was a relatively preserved link between rpfc activation and prediction error showed lowest delusional scores. This is further evidence that an aberration in this frontally mediated inferential processing relates to delusion formation. We should note that it is perfectly possible that the rpfc is not the site of prediction error per se but may be concerned rather with inferences that are made as a consequence of prediction-error signal. This observation may offer an explanation of why it is possible to have, as we observed here, apparently preserved learning of associations in the face of such frontal perturbation. These observations are entirely consistent with the view that one function of the RLPFC is not hypothesis generation but specifically hypothesis evaluation, as suggested by the two-factor theory of delusion: Corlett and colleagues frontally mediated inferential processing and inferences that are made as a consequence of prediction-error signal correspond to the hypothesis evaluation of the two-factor theory. It is important to consider the specific pattern of results obtained in this study. 36 In the patients, surprising and unsurprising events both evoked responses if RLPFC, and to an equal degree. Hence unsurprising events evoked such activity in the patients when no such activity was evoked in the controls. The implication for the two-factor theory, if one assumes that RLPFC activity is a signature of hypothesis evaluation, is that what is abnormal about the patients is that they are evaluating hypotheses even on those trials where the hypothesis was confirmed and so did not need evaluation. What about putatively nonneuropsychological delusions? It seems clear that the specific content of the beliefs seen in the six kinds of delusion with which this paperhassofarbeenconcernedcanbeplausibly attributed to various kinds of neuropsychological impairments: we can see why a particular kind of neuropsychological impairment might prompt the idea That s not my wife and another kind of neuropsychological impairment might prompt the idea That s not my arm. But what kind of neuropsychological impairment could prompt the specific idea I am the left foot of God or I am going to become Emperor of Antarctica, beliefs held by John Nash? 1 This is in effect a question about the intended scope of the two-factor theory of delusion around which this paper has been organized. Is it just meant to apply to frankly neuropsychological delusions? Or is it meant to apply to all forms of delusion, including delusions such as those of reference, grandeur, and persecution, all of which are much more common than the delusions so far discussed, and for all of which there seems little evidence of neuropsychological involvement? This is a question that I am going to leave open. But I will offer two observations that may be pertinent to it. Consider the delusion known as erotomania (sometimes known as de Clerambault s syndrome). This is the belief, held in the absence of any evidence, that some person of great fame or high social status is in love with you, but refuses to acknowledge that this is so. This seems a clear example of a delusion where there is no plausible neuropsychological explanation to be formulated. And yet there are cases where erotomania arises as a consequence of neuropsychological damage: a review 37 has described 29 cases with varying degrees of evidence of a neuropsychological impairment precipitating an erotomania. This is an example of a delusion where the plausible aprioriassumption that there would not be any neuropsychological impairment that could cause the delusion seems to have turned out to be wrong. There may be other such examples. Consider the belief The weather man on the TV sends me important secret messages, a delusion of reference. What neuropsychological event could possible have prompted such an idea? At first thought, there seems no possible answer. But, on the contrary, possible explanations of delusions of reference in terms of brain neurochemistry have been proposed 38 involving altered salience of environmental stimuli arising from disturbed firing in the mesolimbic dopamine system 39 (p. 619). All that is needed to generate a two-factor interpretation here would be (a) evidence that there are people in whom this mesolimbic dopamine impairment is present but who are 24 Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences.

10 not delusional and (b) evidence that, in any people with this mesolimbic impairment (which is Factor 1) who do have delusions of reference, Factor 2 is also present (signaled by abnormal function in RLPFC). So the distinction between neuropsychological and nonneuropsychological delusions (sometimes referred to as the distinction between organic and functional psychosis) is not at all clear-cut. Can we really be sure that there are any nonneuropsychological delusions? Conclusions As I have shown in this paper, a two-factor theory of delusional belief has emerged from research in cognitive neuropsychiatry over the past 20 years, and especially in the past 10 years. But it has now become apparent that a very similar theory has emerged from research in the tradition of associative learning theory, bolstered by psychopharmacology. This work has recently been reviewed by Corlett and colleagues, 40 who conclude that their views on the explanation of psychotic thought and belief has three concepts at its core. Thefirstisthatmuchofwhatweperceiveisbased in our expectations. That concept is also central to the two-factor theory of delusion because the first factor in most delusions is a violation of expectation (e.g., in Capgras delusion the violation of the expectation of a strong autonomic response upon seeing the face of one s spouse). The second is that perceptual expectations are learned; that is, also consistent with the two-factor theory,becausewelearnhowmirrorswork,welearn that objects and people of value to us will generate strong autonomic responses, etc. The third is that mismatches between what we expect and what we experience drive updating of our expectancies: that too is what the two-factor theory proposes, merely replacing the term updating of our expectancies with the term revision of our belief system. All that is needed to knit together these two strands of work is to make clearer what constitutes the second factor in the associative-learning approach; it is already clear from the quotations given above from Fletcher and Frith 31 that there is no incompatibility between the two approaches as far as this point is concerned. Acknowledgments The authors thank Robyn Langdon, Ryan McKay, Phil Corlett, Paul Fletcher Vince Polito, Emily Connaughton, Nerolie Wise, Michael O Connor, and two anonymous reviewers for valuable criticism of earlier drafts. Conflicts of interest The authors declare no conflicts of interest. References 1. Capps, D John Nash s delusional decade: a case of paranoid schizophrenia. Pastor. Psychol. 52: Jaspers, K. 1913/1963. General Psychopathology, 7th edn. trans. J. Hoenig & M.W. Hamilton. Manchester University Press. Manchester. 3. Foley, J. & L. Breslau A new syndrome of delusional misidentification. Ann. Neurol. 12: Kumakura, T The mirror sign in presenile and senile dementias especially in Alzheimer-type dementias. Seishin Shinkeigaku Zasshi 84: Spangenberg, K.B., M.T. Wagner & D.L. Bachman Neuropsychological analysis of a case of abrupt onset mirror sign following a hypotensive crisis in a patient with vascular dementia. Neurocase 4: Yoshida, T., N. Yuki & M. Nakagawa Complex visual hallucination and mirror sign in posterior cortical atrophy. Acta Psychiatr. Scand. 114: Breen, N, D. Caine & M Models of face recognition and delusional misidentification: a critical review. Cogn. Neuropsychol. 17: Breen, N., D. Caine, M., et al Towards an understanding of delusions of misidentifiication: four case studies. Mind Language 15: Breen, N., D. Caine & M Mirroredself misidentification: two cases of focal-onset dementia. Neurocase 7: Binkofski, F., G. Buccino, C. Dohle, et al Mirror agnosia and mirror ataxia constitute different parietal lobe disorders. Ann. Neurol. 46: , M, P. Menzies & J. Sutton Abductive inference and delusional belief. Cogn. Neuropsychiatry 15: Fletcher, P.C. & C.D. Frith Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia. Nat. Rev. Neurosci. 10: Langdon, R. & M The cognitive neuropsychology of delusions. Mind Language 15: Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences. 25

11 14., M The 33rd Bartlett Lecture: cognitive neuropsychiatry and delusional belief. Q. J. Exp. Psychol. 60: , M., R. Langdon & R. McKay Schizophrenia and monothematic delusions. Schizophr. Bull. 33: Brighetti, G., P. Bonifacci, R. Borlimi & C. Ottaviani Far from the heart far from the eye : evidence from the Capgras delusion. Cogn. Neuropsychiatry 12: Ellis,H.D.,M.B.Lewis,H.F.Moselhy&A.W.Young Automatic without autonomic responses to familiar faces: differential components of covert face recognition in a case of Capgras delusion. Cogn. Neuropsychiatry 5: Ellis,H.D.,A.W.Young,A.H.Quayle&K.W.dePauw Reduced autonomic responses to faces in Capgras delusion. Proc. R. Soc. Lond.: Biol. Sci. B 264: Hirstein, W.S. & V.S. Ramachandran Capgras syndrome: a novel probe for understanding the neural representation of the identity and familiarity of persons. Proc. R. Soc. Lond. B 264: Tranel, D., H. Damasio & A.R. Damasio Double dissociation between overt and covert face recognition. J. Cogn. Neurosci. 7: Vuilleumier, P., C. Mohr, N. Valenza, et al Hyperfamiliarity for unknown faces after left lateral temporooccipital venous infarction: a double dissociation with prosopagnosia. Brain 126: Ramachandran, V.S. & S. Blakeslee Phantoms in the Brain: Probing the Mysteries of the Human Mind. William Morrow. New York. 23. Turner, M. & M Confabulation and delusion: A common monitoring framework. Cogn. Neuropsychiatry 15: Frazer, S.J. & J.M. Roberts Three cases of Capgras syndrome. Br.J.Psychiatry164: Heims, H.C., H.D. Critchley, R. Dolan, et al Social and motivational functioning is not critically dependent on feedback of autonomic responses: neuropsychological evidence from patients with pure autonomic failure. Neuropsychologia 42: Magnifico, F., V.P. Misra, N.M.F. Murray & C.J. Mathias The sympathetic skin response in peripheral autonomic failure evaluation in pure autonomic failure, pure cholinergic failure and dopamine-hydroxylase deficiency. Clin. Auton. Res. 8: Frith, C The Cognitive Neuropsychology of Schizophrenia. Lawrence Erlbaum Associates. Hove, UK. 28. Fourneret, P., J. Paillard, Y. Lamarre, et al Lack of conscious recognition of one s own actions in a haptically deafferented patient. Neuroreport 13: Ellis, H.D. & A.W. Young Accounting for delusional misidentifications. Br.J.Psychiatry157: Gray, J.A The contents of consciousness: a neuropsychological conjecture. Behav. Brain Sci. 18: Fletcher, P.C., J.M. Anderson, D.R. Shanks, et al Responses of human frontal cortex to surprising events are predicted by formal associative learning theory. Nat. Neurosci. 4: Turner, D.C., M.R.F. Aitken, D.R. Shanks, et al The role of the lateral frontal cortex in causal associative learning: exploring preventative and super-learning. Cereb. Cortex 14: Corlett, P.R., M.R. Aitken, A. Dickinson, et al Prediction error during retrospective revaluation of causal associations in humans: fmri evidence in favor of an associative model of learning. Neuron 44: Cutting, J The Right Cerebral Hemisphere and Psychiatric Disorders. Oxford University Press. Oxford. 35. Devinsky, O Delusional misidentifications and duplications: right brain lesions, left brain delusions. Neurology 72: Corlett, P.R., G.K. Murray, G.D. Honey, et al Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions. Brain 130: Anderson, C.A., J. Camp & C.M. Filley Erotomania after aneurysmal subarachnoid hemorrhage: case report and literature review. J. Neuropsychiatry Clin. Neurosci. 10: Kapur, S Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am.J.Psychiatry160: Corlett,P.R.,G.D.Honey,M.R.Aitken, et al Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition, brain activity, and psychosis. Arch. Gen. Psychiatry 63: Corlett, P.R., C.D. Frith & P.C. Fletcher From drugs to deprivation: a Bayesian framework for understanding models of psychosis. Psychopharmacology 206: Ann. N.Y. Acad. Sci (2010) c 2010 New York Academy of Sciences.