Passivity phenomena

Central to the concept of schizophrenia is a breach of physical borders, which we often interpret in mental terms: the dissolution of ego boundaries exemplified by the Schneiderian first-rank symptoms (Reference Schneider, Hirsch and ShepherdSchneider, 1974). The patient with passivity phenomena, ‘made’ thoughts or movements, believes that their autonomy is being usurped by outside forces (Reference Mullins and SpenceMullins & Spence, 2003). A spirit or persecutor controls their movements. Their thoughts are directly accessed by others.

From which brain systems might this sensation arise? Study of patients with neurological damage has suggested that damage to the parietal lobes might produce similar phenomena (Reference SpenceSpence, 2001; Reference Spence and HalliganSpence & Halligan, 2002). One important theoretical account of first-rank symptoms attributes them to a failure in the monitoring of ongoing action; more specifically, to a failure by the brain's motor programming systems to predict the future sensory consequences of action (Reference Frith, Blakemore and WolpertFrith et al, 2000). By ‘forward modelling’, the brain predicts its own outcome states following future acts. If I lift my arm, my brain has already computed the sensory stimuli arising from such an act. A deviation from such predictions alerts the brain to potential errors and the need for correction. However, if there is a fault within the system then my action might feel as if it had come from ‘nowhere’, as if an outside force were responsible.

Although sophisticated cognitive psychological experiments have investigated whether people experiencing first-rank symptoms are aware of their actions (Reference Frith and DoneFrith & Done, 1989), one of the advantages of functional neuroimaging techniques is that they allow investigators to examine the motor system directly and to locate functional abnormality. In one such study, Reference Spence, Brooks and HirschSpence and colleagues (1997) used PET to examine the brain activity associated with moving a joystick in freely chosen directions by people with schizophrenia experiencing passivity (‘made’ thoughts and actions), other people experiencing psychosis but not passivity phenomena, and healthy controls. Patients with passivity exhibited relative hyperactivation of the right inferior parietal cortex, an area implicated in spatial awareness and programming, and the left supplementary motor area, a region of premotor cortex that is also involved in the programming of action. Hence, the findings are consistent with the view that systems engaged in programming action in space are disturbed in people experiencing passivity (their disturbance remitting with symptomatic recovery) (Reference Spence, Brooks and HirschSpence et al, 1997).

Subsequent studies have also found parietal abnormalities in patients with such symptoms (Reference Franck, O'Leary and FlaumFranck et al, 2002). In one recent study hyperactivation of the right parietal cortex was found while such patients performed self-paced finger movements in an MRI scanner (Reference Ganesan, Hunter and SpenceGanesan et al, 2005; Fig. 2). Another study has shown that people with schizophrenia reporting motor passivity phenomena (‘made’ movements) exhibit reductions in right parietal and left prefrontal grey matter volume relative to other people with schizophrenia (Reference Maruff, Wood and VelakoulisMaruff et al, 2005). Moreover, a study of students with high schizotypy scores revealed that those who feared losing control of their thoughts had reduced grey matter volume of the supplementary motor area (Reference Matsui, Yoneyama and SumiyoshiMatsui et al, 2002).

Fig. 2 Aberrant hyperactivation of right parietal (sensory) regions (Brodmann area 40) during action initiation by people experiencing first-rank symptoms of schizophrenia (Talairach coordinates = 57, −29, 36; T = 4.7; P < 0.0001 (uncorrected); family-wise error corrected P = 0.015). Data derived from Reference Ganesan, Hunter and SpenceGanesan et al 2005.

Hence, current studies on passivity phenomena suggest that the parietal cortices (which are concerned with spatial and bodily awareness) and key planning and programming areas within the frontal lobes are implicated in the disturbed sense of agency and bodily awareness.

Somatic hallucinations and delusions

An fMRI study of a 36-year-old man with schizophrenia who was experiencing somatic hallucinations (that he was ‘touched by spirits’) revealed an association with activation of corresponding primary somatosensory and posterior parietal cortices (Reference Shergill, Cameron and BrammerShergill et al, 2001). These findings were consistent with those of an earlier electroencephalographic study of a similar patient (Reference Baldeweg, Spence and HirschBaldeweg et al, 1998). Again, the suggestion is that sensory and association cortices are implicated in the generation of complex abnormalities of bodily experience encountered in schizophrenia. Note that the patient's phenomenology implicated the surface of the body (‘touched by spirits’), which is in line with the primary somatosensory cortex being activated.

There are several interesting case reports from Japan on neuroimaging in patients with delusional parasitosis. Reference Maeda, Yamamoto and YasudaMaeda and colleagues (1998) described an elderly man who felt worms moving around in his mouth. His MRI scan revealed an old infarction of the right putamen (an area receiving parietal afferents); his symptoms resolved with pimozide. Reference Wada, Kawakatsu and KomataniWada et al(1999) performed a SPECT investigation before and after response to clomipramine of an elderly woman who believed ‘something was moving in her abdomen’. At the height of her symptoms she exhibited hypoperfusion of left temporo-parietal cortices.

Similarly, Reference Ota, Mizukami and KatanoOta and colleagues (2003) used SPECT to investigate the brain function of an elderly man before and after modified electroconvulsive therapy for somatic (nihilistic) delusions: ‘Food disappears inside of my oesophagus’, ‘my jaw comes off’. This man exhibited hypoperfusion of left parietal and temporal regions, which improved following treatment. The same regions were implicated in an elderly woman who complained of oral infestation, which responded to paroxetine (Reference Hayashi, Oshino and IshikawaHayashi et al, 2004).

Patients with Cotard's delusion of negation are usually depressed and come to believe that they are dead or decaying. There have been rather disparate accounts of functional anatomical correlates of Cotard's delusion using SPECT. Reference Hashioka, Monji and SasakiHashioka et al(2002) described a patient with bilateral hypofrontality, which resolved on recovery; Reference De Risio, De Rossi and SarchiaponeDe Risio and colleagues (2004) found no focal perfusion deficit in a patient with more classical symptomatology (‘he had no internal organs and was already dead’) but did find a reduction in striatal D₂ receptor binding, which is consistent with excessive endogenous dopamine at the time of psychosis. Reference Gardner-Thorpe and PearnGardner-Thorpe & Pearn (2004) described two further patients: one with associated arteriovenous malformations in the parietal lobes and the other with multiple sclerosis. Despite multiple sclerosis of 20 years’ duration the latter patient described recent onset of transient psychotic episodes. During such episodes she felt as if ‘her flesh were falling off’, ‘as if there were liquid inside her that was draining out’. ‘Whilst experiencing the symptom she believed it was really happening but next morning had gained a somewhat perplexed insight into its hallucinatory nature’ (Reference Gardner-Thorpe and PearnGardner-Thorpe & Pearn, 2004: p. 564). This case report exemplifies the blurring of phenomenological boundaries seen in certain accounts of somatic hallucinations, Cotard's delusion and, indeed, hypochondriacal delusions.

Dysmorphophobia

There is little recent work devoted to the onset of disturbed bodily awareness (dysmorphophobia), where the central feature is preoccupation with slight or non-existent defects in appearance, causing significant distress or impairment in functioning. About half of patients with body dysmorphic disorder experience psychosis, although there is also a phenomenological similarity to OCD, exemplified by repeated checking and ritualised behaviours. Reference Gabbay, Asnis and BelloGabbay and colleagues (2003) described a 24-year-old man who developed a preoccupation with the width of his nose following encephalitis; structural MRI revealed marked left-sided fronto-temporal atrophy.

The emergence of compulsive or ritualistic behaviours has been linked to both temporal lobe and basal ganglia pathology. There is a theory that specific basal ganglia circuits might be involved in OCD-spectrum disorders, with those disorders with cognitive phenomenology (OCD and body dysmorphic disorder) involving the caudate and those characterised by motor abnormalities (Tourette syndrome and trichotillomania) the putamen (Reference Rauch, Phillips and SegalRauch et al, 2003). In this regard it is of interest that an MRI study of eight middle-aged women with body dysmorphic disorder revealed leftward shift of caudate asymmetry and increased white matter volume. However, apart from being a marker of striatal abnormality it is unclear how such an asymmetry might disturb bodily awareness. A SPECT study of brain function in six people with body dysmorphic disorder found a broad range of abnormalities that implicate the parietal lobes (Reference Carey, Seedat and WarwickCarey et al, 2004). This is consistent with the role of the latter in supporting bodily awareness.

Eating disorders

Concern with the body's size and shape is a hallmark of the eating disorders, aspects of which seem to imply a misperception of bodily form. Is there evidence in favour of abnormal cerebral processing of the embodied self? Neuroimaging studies in people with eating disorders are surprisingly few, but already there are some interesting leads.

A study of three people with anorexia nervosa who were confronted with images of their own bodies revealed right amygdala activation, which is consistent with the latter's role in processing negative affect (Reference Seeger, Braus and RufSeeger et al, 2002). Although this finding awaits replication, a later study of a larger sample revealed that people with anorexia and/or bulimia exhibited reduced activation of right temporo-parietal regions (those concerned with bodily awareness and recognition), in comparison with healthy controls, when confronted with images of standard female forms (Reference Uher, Murphy and FriederichUher et al, 2005). The authors concluded that functional abnormalities in specific regions might underlie abnormal self-perception in these disorders. The importance of right-hemisphere abnormalities in eating disorders is also supported by a recent review. Reference Uher and TreasureUher & Treasure (2005) report that although simple changes in appetite and eating behaviour occur with hypothalamic and brain-stem lesions, more complex disturbances, resembling the psychopathology of idiopathic eating disorders, arise more commonly following right frontal and temporal damage.

Recent PET studies of people recovering from anorexia have revealed abnormalities of central serotonergic and dopaminergic function (Reference Frank, Kaye and MeltzerFrank et al, 2002, Reference Frank, Bailer and Henry2005).

Conversion syndromesFootnote ^†

Conversion syndromes are characterised by abnormalities of voluntary movement and subjective report (e.g. hemi-anaesthesia) that cannot be explained by demonstrable cerebral pathology. The onset of the disorder is said to coincide with emotional distress and the symptoms themselves are inconsistent (e.g. paralyses may wax and wane, normal function may be elicited by distraction or sedation; Reference SpenceSpence, 1999). To date, there have been a few neuroimaging studies of single patients or small series of patients with conversion syndromes using SPECT, PET or fMRI. Results may have been influenced by confounding variables such as the presence of comorbid diagnoses (often depression and/or personality disorder) and symptom chronicity (not least since many such studies are from tertiary centres, which attract patients with atypical, chronic disorders). I have reviewed the pros and cons of these approaches elsewhere (Reference SpenceSpence, 1999, Reference Spence, Hallett, Fahn and Jankovic2006).

Nevertheless, a common theme has emerged (Box 2): sensory deficits (e.g. anaesthesia or blindness) are associated with hypoactivation of the relevant sensory cortices and evidence of disturbed function in ‘higher’ frontal regions (Reference Tiihonen, Kuikka and ViinamakiTiihonen et al, 1995; Reference Yazici and KostakogluYazici & Kostakoglu, 1998; Reference Vuilleumier, Chicherio and AssalVuilleumier et al, 2001; Reference Mailis-Gagnon, Giannoylis and DownarMailis-Gagnon et al, 2003; Reference Werring, Weston and BullmoreWerring et al, 2004); whereas motor disturbance is associated with either excessive activation of (inhibitory) orbitofrontal cortices (Reference Marshall, Halligan and FinkMarshall et al, 1997) or suppression of activation in the dorsolateral prefrontal cortex (an area involved in action generation) (Reference Spence, Crimlisk and CopeSpence et al, 2000). A common view is that lower centres are somehow inhibited or suppressed by higher centres. There has been debate as to whether these findings may adequately distinguish conversion syndromes from feigning (Reference Marshall, Halligan and FinkMarshall et al, 1997; Reference SpenceSpence, 1999). Nevertheless, there is the hope that functional neuroimaging techniques may (in the future) help to establish an empirical framework for conversion syndromes.

SomatisationFootnote ^‡

Somatisation refers to recurrent, multiple somatic complaints which cannot be attributed to demonstrable organic pathology. It has been postulated to be a consequence of disturbed attention, so that people with somatisation are unable to filter out irrelevant somatic sensations. There are few neuro-imaging studies of people with somatisation.

Reference Garcia-Campayo, Sanz-Carrillo and BaringoGarcia-Campayo et al(2001) used SPECT to examine a series of people with somatisation who were without comorbid Axis I diagnoses. Visual inspection of the scans (there was no control group) revealed that most of their 11 participants had evidence of focal hypoperfusion, predominantly of the frontal, cerebellar and temporo-parietal regions. Subsequently, Reference Hakala, Karlsson and RuotsalainenHakala and colleagues (2002) used PET to compare brain function of women with chronic somatisation with that of a control group. The women with somatisation exhibited reduced metabolism of specific subcortical regions, including bilateral caudate nuclei. The volume of these caudate nuclei (in the same women) was found to be enlarged by MRI (Reference Hakala, Karlsson and RuotsalainenHakala et al, 2002, Reference Hakala, Karlsson and Kurki2004).

Chronic fatigue syndrome

Fatigue can be defined as difficulty in initiating or sustaining voluntary activities, and may be caused by central or peripheral neurological or systemic factors (Reference Chaudhuri and BehanChaudhuri & Behan, 2004). Chronic fatigue syndrome is characterised by a sense of fatigue that persists for at least 6 months and is unattributable to other physical or psychiatric disorder. It provides another example of a diagnosis of exclusion (similar to conversion and somatisation), resting very much on the patient's subjective account. Nevertheless, it is clinically desirable to perform structural MRI of the brain in patients with chronic fatigue, not least because persistent fatigue may be a presenting symptom of multiple sclerosis (Reference Lange, Wang and DelucaLange et al, 1998).

There have been many neuroimaging studies of people with chronic fatigue over the past decade and in recent years a range of scanning methods and techniques for data analysis have been used. Early studies suggested that structural, white matter defects might be more common in patients with chronic fatigue syndrome, particularly within the frontal lobes (Reference Natelson, Cohen and BrassloffNatelson et al, 1993; Reference Lange, Deluca and MaldjianLange et al, 1999; Reference Cook, Lange and DelucaCook et al, 2001), but this was not demonstrated by others (Reference Cope, Pernet and KendallCope et al, 1995; Reference Greco, Tannock and BrostoffGreco et al, 1997). The defects most often cited were so-called hyperintensities, possibly reflecting vascular pathology; these are often reported to increase with age in healthy people (and also to be over-represented in a number of psychiatric disorders).

Although focal functional deficits were also reported in early studies, a very well-controlled twin study of patients with chronic fatigue syndrome and their discordant (i.e. healthy) co-twins revealed no abnormalities of resting-state regional cerebral blood flow which were specific to the disorder (Reference Lewis, Mayberg and FischerLewis et al, 2001). Hence, there may be no trait resting-state functional abnormalities that adequately characterise all patients with chronic fatigue syndrome. Some investigators have refined their samples to focus on specific features of the disorder, e.g. late-onset syndrome or cognitive impairment. Others have focused on ‘cognitive challenges’: studying functional response while patients perform a cognitive task.

Reference Siessmeier, Nix and HardtSiessmeier and colleagues (2003) conducted the first PET study of cerebral metabolism in chronic fatigue in which the data were analysed using an observer-independent technique (i.e., not a manually determined region-of-interest analysis, which may be subject to observer bias). They found that, despite sample heterogeneity, participants demonstrated reduced activity in the orbitofrontal and anterior cingulate cortex, regions implicated in the control (inhibition and monitoring) of behaviour. However, there was no correlation with fatigue per se.

Reference De Lange, Kalkman and BleijenbergDe Lange et al(2004) used fMRI to study people with chronic fatigue who were attempting motor and visual imagery tasks. Under both conditions participants exhibited hypofunction of the caudate nuclei, whereas on error trials they failed to activate ventral regions of the anterior cingulate cortex (implicated in affect regulation).

In a structural MRI study, Reference Okada, Tanaka and KuratsuneOkada and colleagues (2004) used an automated, data-led approach to reveal bilateral reductions of cortical grey matter in dorsolateral prefrontal regions. The deficit in the right dorsolateral prefrontal cortex correlated with the severity of symptomatic fatigue. This area had also been implicated in an earlier SPECT study of late-onset chronic fatigue (Reference Goldstein, Mena and JouanneGoldstein et al, 1995).

Turning to neurochemistry, Reference Cleare, Messa and RabinerCleare et al(2005) summarised the evidence that fatigue may be associated with excessive serotonergic tone and demonstrated, using a ligand for the 5HT-1A receptor, that untreated patients without comorbid diagnoses had reduced 5HT-1A binding occupancy on PET scans. This finding would be compatible with reduced numbers of receptors or their decreased affinity for the ligand (which would be in accordance with a central disturbance of serotonergic function in chronic fatigue syndrome). There were no correlations with fatigue per se, although the patients studied were at, or close to, ceiling on their fatigue severity ratings. Hence, there may have been insufficient within-group variance to detect such a correlation.

Pain syndromes

Pain is processed within a distributed ‘pain matrix’ involving lateral systems, incorporating the lateral thalamic nuclei, insulae and secondary somatosensory cortices (concerned with pain localisation), and medial systems, incorporating the midline and intralaminar thalamic nuclei, amygdalae and anterior cingulate cortex (which are more concerned with its affective significance) (Reference Ladabaum, Minoshima and OwyangLadabaum et al, 2000; Reference Peyron, Laurent and Garcia-LarreaPeyron et al, 2000; Reference Jones, Kulkarni and DerbyshireJones et al, 2003; Reference VogtVogt, 2005). There is also a distinction between visceral and somatic pain: the former eliciting most response from within the medial system and the latter from the lateral system (Reference Dunckley, Wise and AzizDunckley et al, 2005). In general, visceral pain evokes greater ‘unpleasantness’ than somatic pain, even when ‘pain’ levels are controlled for. These phenomena differ in other respects: visceral pain elicits immobilisation whereas somatic pain is more likely to precipitate a fight/flight response (hence the greater involvement of motor regions) (Reference Ladabaum, Minoshima and OwyangLadabaum et al, 2000; Reference Dunckley, Wise and AzizDunckley et al, 2005, Reference VogtVogt 2005). Visceral pain is likely to be harder to localise (Reference Schnitzler, Volkmann and EnckSchnitzler et al, 1999).