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ORIGINAL ARTICLES |
From the Division of Clinical Neurosciences (J.S., A.Z.), School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK; Division of Psychiatry (E.S., M.S.), School of Molecular and Clinical Medicine, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park, Edinburgh, UK; Department of Neuropsychology (M.M.), Institute for Psychology, University of Zurich, Zurich, Switzerland; Division of Psychological Medicine (R.A.), Institute of Psychological Medicine, Institute of Psychiatry, King’s College, London, UK; Department of Theoretical and Applied Linguistics (S.F.), School of Philosophy, Psychology and Language Sciences, University of Edinburgh, Edinburgh, UK.
Address correspondence and reprint requests to Dr Jon Stone, Dept Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK. E-mail: Jon.Stone{at}ed.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSNOTESREFERENCES |
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Objective: To compare the neural correlates of unilateral functional weakness in conversion disorder with those in healthy controls asked to simulate unilateral weakness.
Methods: Functional magnetic resonance imaging (fMRI) was used to examine whole brain activations during ankle plantarflexion in four patients with unilateral ankle weakness due to conversion disorder and four healthy controls simulating unilateral weakness. Group data were analyzed separately for patients and controls.
Results: Both patients and controls activated the motor cortex (paracentral lobule) contralateral to the "weak" limb less strongly and more diffusely than the motor cortex contralateral to the normally moving leg. Patients with conversion disorder activated a network of areas including the putamen and lingual gyri bilaterally, left inferior frontal gyrus, left insula, and deactivated right middle frontal and orbitofrontal cortices. Controls simulating weakness, but not cases, activated the contralateral supplementary motor area.
Conclusions: Unilateral weakness in established conversion disorder is associated with a distinctive pattern of activation, which overlaps with but is different from the activation pattern associated with simulated weakness. The overall pattern suggests more complex mental activity in patients with conversion disorder than in controls.
Key Words: conversion disorder • fMRI • simulation • paralysis • weakness
Abbreviations: BA = Brodmann area; DLPFC = dorsolateral prefrontal cortex; DSM-IV = Diagnostic and Statistical Manual of Diseases, fourth revision; EPI = echo planar imaging; fMRI = functional magnetic resonance imaging; ICD-10 = International Classification of Diseases, version 10; MNI = Montreal Neurological Institute; MRI = magnetic resonance imaging; NCS = nerve conduction studies; PET = positron emission tomography; SMA = supplementary motor area; SPECT = single photon emission computed tomography; SPM99 = statistical parametric mapping software.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSNOTESREFERENCES |
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Several small studies have used functional brain imaging to examine the neural basis of conversion disorder (6–12) (Table 1). This preliminary evidence is conflicting and has not yet provided clear answers to the following questions: Does conversion disorder have consistent neural correlates? How do these differ from the neural correlates of deliberately feigned or simulated weakness? At what stage in motor execution is the failure to produce movement occurring? Is the process primarily an inhibitory one (8), a failure of initiation (9), or can a number of neural mechanisms give rise to the same clinical phenomenon?
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This is the first study to apply functional magnetic resonance imaging (fMRI) to the problem of motor conversion disorder. We place our findings in the context of the other published studies and explore the implications for theories of symptom generation in conversion disorder and for future research.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSNOTESREFERENCES |
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Selection of Controls
Healthy controls volunteered from hospital secretarial, medical, and paraclinical staff, were right handed, and of comparable age and sex to the patients. Clinical details of the cases and controls are shown in Table 2. The Lothian research ethics committee provided ethical approval for the study.
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Imaging Procedure
In 2002, all cases and controls had an initial normal structural T1 and T2 weighted MRI of their brain. Before functional imaging, all cases and controls were given a single training session lasting approximately 30 minutes on an MRI simulator to familiarize them with the paradigm. Subjects lay supine in the scanner with supportive cushions under their knees and ankles allowing free movement at the ankle but only very limited movement at the hip or knee. Both arms were strapped with cushioned splints to minimize elbow, wrist, and finger movements. Instructions were presented on an LCD (liquid crystal display) monitor reflected in a mirror 50 cm from the patients’ eyes. Subjects could not see their ankles. All subjects wore headphones.
Functional MRI scans were carried out using a combined event-related and block design. During the task, subjects were asked to plantarflex one or the other ankle repetitively. We chose plantarflexion of the ankle in preference to knee extension to minimize movement artifact and also because weakness of plantarflexion is unusual in neurological disease but common in functional weakness. The basic task consisted of 20 blocks of 5 trials. At the beginning of each block the word "PAUSE" was presented (a blank screen for the first block only) in the center of the screen for 4 seconds. This was to indicate the break between the blocks and give the subjects the chance to rest. Each trial started with the presentation of instruction word "LEFT" or "RIGHT" for 2 seconds, immediately replaced by a fixation cross ("+") for 4 seconds, also in the center of the screen. The subjects were instructed to point the ankle down while the fixation cross was on the screen. The blocks of five movements on each side (one movement every 6 seconds) were randomly interleaved over an 11-minute period (e.g., RRRRRLLLLLRRRRRRRRRRLLLL and so on) resulting in balanced numbers of left and right movement.
Healthy controls were asked to carry out the same task but to simulate weakness of one ankle (side matched to cases). To remind them which ankle was supposed to be "too weak and heavy to move," the cue word "(heavy)" was added to the instruction (i.e., (heavy)/LEFT or (heavy)/RIGHT).
All four cases reported (and were observed to be) contracting other leg muscles during attempted ankle plantarflexion with zero or minimal ankle movement. They described a combination of mental effort and of a sensation of movement in the affected leg. We therefore instructed the controls to reproduce this combination of mental and physical effort when trying to move the feigned weak ankle but not to actually make a movement. Cooperation with this instruction was monitored visually and by debriefing.
After brain imaging, all subjects were debriefed to ask how comfortable they had been in the scanner and whether they had understood the instructions. Subjects were asked to describe to what extent they felt they had been moving their ankles.
Brain Imaging
Scanning was performed at the Scottish Higher Education Funding Council Brain Imaging Research Centre for Scotland, Western General Hospital, Edinburgh on a 1.5 T General Electrics (General Electric, Milwaukee, WI) in 2002. fMRI data were acquired with a gradient echo planar imaging (EPI) sequence (Echo Time (TE) = 40 ms, Repetition Time (TR) = 2.5 s, Field of Volume (FOV) = 24 x 24 cm2, matrix = 64 x 64, slice thickness = 5 mm, no slice gap, 30 slices per volume).
Analysis
The data were analyzed with statistical parametric mapping software (SPM99). Images were reconstructed into "Analyze" format, realigned, normalized to the SPM EPI template, and smoothed using a Gaussian filter. Estimates for movement were included. Comparisons were made using a model that combined a transient and steady regressor. The results were displayed on a t-score brain map as either uncorrected (thresholded at p < .001 (two tailed) with a minimum cluster size of 100 to minimize the possibility of type 1 errors) or corrected data (thresholded at p < .05 but corrected for multiple comparisons and with an analysis cluster size of zero). For corrected data, tables of the areas with the highest t score and cluster sizes of greater than 10 were prepared using Tailarach coordinates in Montreal Neurological Institute (MNI) space.
We carried out the following analyses: a) Corrected group analysis of cases and group analysis of controls comparing movement of the weak ankle with that of the normal ankle. For these group analyses data from two patients with left-sided weakness in each group were left-right flipped to correspond with the patients with right-sided weakness; b) Uncorrected group analysis as above provided for the purpose of hypothesis generation; c) Illustrative uncorrected intra-subject single case comparisons of left ankle movement relative to right ankle movement. Images were shown with the left hemisphere on the right side of the picture.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSNOTESREFERENCES |
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Imaging Data
Group Comparisons
Figures 1 and 2, Supplementary Figures 2E to 5E (online) and Tables 3 and 4 show the results of the corrected and uncorrected group analyses. Our principle findings are as follows:
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2) Activation of Basal Ganglia, Insula, Lingual Gyri, and Inferior Frontal Cortex in Cases
Cases, but not controls, activated regions of the basal ganglia, insula, lingual gyri, and inferior frontal cortex.
3) Hypoactivation of Middle Frontal and Orbitofrontal Cortex in Cases
There was relative hypoactivation of the right middle frontal gyrus and orbitofrontal cortex in cases but not in controls on attempted movement of the weak ankle. The uncorrected data in Figure 2 suggests that this hypoactivation is probably bilateral. Our data are also compatible with the alternative interpretation that these areas are relatively hyperactivated on movement of the normal ankle. This ambiguity arises because we compared activations associated with right-limb movements with those associated with left-limb movements in the absence of comparison with rest.
4) Activation of Contralateral Supplementary Motor Area in Controls Feigning Weakness
Controls feigning weakness, but not cases, activated the contralateral (left) supplementary motor area moving the weak ankle compared with moving the normal ankle.
Intrasubject Comparisons
Supplementary Figure 1E with an accompanying description (available as a supplementary Web file) illustrates some of the findings of intrasubject comparisons.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSNOTESREFERENCES |
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1) Reduced and Diffuse Activation of Motor Cortices in Cases and Controls
The extent of activation of the motor cortex, Brodmann area 4, and of the supplementary motor area is known to be proportional to the force generated by the corresponding movement (16). This relationship probably explains the reduced activation of motor cortex contralateral to the "weak" limb in cases and controls. The more diffuse activations noted contralateral to the weak limb, which are particularly apparent in the uncorrected group analyses, may reflect the more widespread recruitment of agonists and antagonists in the "weak" leg. This hypothesis is supported by the verbal reports of the cases and controls who described "tensing their legs with effort" on the weak side while on the normal side only muscles required to move the ankle were recruited.
Two previous studies (8,17) found decreased motor cortex activation contralateral to the paralysis during movement execution but another study by Burgmer et al. did not (18). Burgmer et al. suggest that in their patients, simultaneous agonist and antagonist contraction represented a failure of coordination of movement rather than absence of movement. They put forward their finding of reduced or absent contralateral motor cortex activation in their four patients during movement observation as support for this hypothesis.
2) Activation of Basal Ganglia, Insula, Lingual Gyri, and Inferior Frontal Cortex In Cases
Overall, cases were distinguished from controls by the presence of a more complex set of activations. Cases showed more activation when trying to move their weak ankle compared with their "good" ankle, bilaterally in the putamen and lingual gyri and in the left inferior frontal cortex and left insula. Although we refer to "activations" here, the design of our experiment allows us to be confident only of relative differences between activations associated with movement of the normal and affected limbs. In other words, the "activations" just detailed, associated with movement of the weak limb, could theoretically reflect areas of hypoactivation associated with movement of the normal limb (although this seems less likely).
These regions have been implicated in other work on conversion disorder and hypnosis, a possible model for conversion disorder. Werring et al. (19) have reported findings rather similar to ours in the context of visual loss unexplained by disease: compared with controls, during visual stimulation, patients showed increased activation in the left inferior frontal cortex, left insula-claustrum, and bilaterally in the striatum. Werring et al. (19) draw attention to the comparable activation of these areas in Sahraie’s fMRI study of blindsight (20), associated with the "unaware" mode of visual processing (20). Relating these brain areas to function is fraught with difficulty, but the inferior frontal cortex has an executive role in selecting, comparing, or deciding on information in short-term memory. It is therefore likely to be activated when subjects are especially mindful of their task. Ward et al. (21), studying volunteers with subjectively experienced paralysis (induced by hypnosis), found the strongest activations bilaterally in the putamen. These activations were ascribed to the role of these and other areas in movement preparation. It is interesting in our study that the cases but not controls had activation in these areas. This may be evidence of genuine movement preparation in our patient group. In the same study by Ward et al. (21) left inferior frontal activation was seen in patients with feigned paralysis but not in those with subjectively experienced paralysis. This contrasts with our finding of left inferior frontal activation in cases, but not in controls deliberately feigning weakness.
Vuilleumier et al. (10), using single photon emission computed tomography (SPECT), detected a decrease in regional blood flow in the caudate and putamen contralateral to the weak limb in subjects with recent onset of "hysterical" weakness: this resolved as they recovered. Their "within subject," "before and after" design together with evidence of a correlation between the degree of hypoactivation and the degree of recovery provides the most compelling data yet published in this area.
Other evidence links activation of the insula and lingual gyri to attentional and effortful emotional processing. For example, Critchley et al. found that activity in these areas covaried with the sympathetic skin conductance response induced by rewards and punishments in a decision-making task (22). The insular activation was attributed to its role in mediating cardiovascular sympathetic arousal while the lingual activation was attributed to enhancement of activity in extrastriate visual areas when subjects process visual cues in states of high arousal.
Finally, the finding of activation of the superior parietal region/precuneus in cases may once again reflect increased mental effort or the greater emotional demands of the task in the cases. These brain regions tend to be activated along with frontal regions in working memory and other tasks demanding attention. Their role in imagery and spatial attention could be relevant to patients struggling with movement of a weak limb.
Thus, our findings contribute to the evidence that a network of areas including the insula, inferior frontal cortex, the basal ganglia, and the lingual gyri is implicated in motor conversion disorder, though whether these activations reflect causes, consequences or compensatory mechanisms, and the relative importance of motor, cognitive, and emotional processes, are currently unclear.
3) Hypoactivation of Middle Frontal and Orbitofrontal Cortex in Cases
Figure 2 and Table 3 suggest that regions of the right middle frontal and orbitofrontal cortex were underactive during movement of the weak ankle in the cases with conversion disorder. Inspection of the uncorrected data in Figure 4E suggests that this hypoactivation is probably bilateral. Once again, our design leaves open an alternative interpretation in terms of relative hyperactivation associated with attempted movement of the normal ankle. The initial interpretation is more plausible, however, as these areas are not normally activated by actual or intended movement. The orbitofrontal area we have identified is close to the area identified by Marshall et al. in their study of a patient with hysterical paralysis (8); however, in Marshall’s patient this area was activated on attempted movement of the paralyzed limb. The authors suggested that this area was the locus of "unconscious inhibition" of movement.
4) Activation of Contralateral Supplementary Motor Area (SMA) in Controls Feigning Weakness
The SMA has an important role in the selection, preparation, and sequencing of voluntary real and imagined movements. States of SMA hypoactivity have been associated with impairment in initiation of voluntary movement (for example, Parkinson’s disease). Its contralateral activation in controls feigning weakness suggests an excess of movement-planning activity in comparison to movement of the normal limb. In contrast, the absence of a similar activation in cases with conversion disorder may suggest impairment of voluntary movement planning that is perhaps less emotionally neutral. Interestingly, contralateral SMA was also activated in patients with feigned paralysis, but not hypnotic subjective paralysis, in the study by Ward et al. (21).
Attempting a Synthesis of Previous Studies
The studies summarized in Table 2 have examined the neural correlates of conversion disorder. No wholly consistent findings have yet emerged. The current data are compatible with two competing hypotheses: a) that the primary neural mechanism of conversion disorder is excessive inhibition of normal movement; and b) that there is a failure to activate movement normally.
The first hypothesis, suggested initially by Marshall et al. (8) and supported by their subsequent data from a single patient with hypnotic paralysis (23), suggests that frontal and cingulate activations inhibit movement of the weak limb. Findings suggesting that the underlying problem is increased brain activity are appealing because they are in keeping with clinical observations of transient improvement during sedation (24), hypnosis (25), or sleep (26) repeatedly described in patients with conversion disorder. Activation of these frontal areas might also be in keeping with a resting state of relative thalamic and basal ganglia hypoactivation as seen in the study by Vuilleumier et al. (10). Hypoactivation of the contralateral thalamus during symptomatic states is intriguing because it might explain why so many patients with unilateral conversion symptoms feel "split down the middle." Similar contralateral thalamic hypoperfusion has also been shown in patients with complex regional pain (27) who often have nondermatomal (28) and placebo-responsive sensory abnormalities (29).
In keeping with the second hypothesis, of failure to activate movement normally, Spence et al. (9) found hypoactivation of left dorsolateral prefrontal cortex (DLPFC) in three subjects with hysterical paralysis, while subjects feigning weakness showed right DLPFC deactivation, regardless of the side of the affected limb. These findings were interpreted as evidence of functional pathology in a region known to be active in normal individuals choosing actions and to be dysfunctional in patients with disorders of volition such as schizophrenia.
More recent studies suggest, perhaps unsurprisingly, that things might be more complex than these earlier studies indicated. Mailis-Gagnon et al. (11) studied patients with "functional" sensory loss associated with chronic pain. They found a combination of both activations (notably in the anterior cingulate and prefrontal cortex (Brodmann area 10)) and deactivations (in primary somatosensory cortex, other areas of the prefrontal cortex (Brodmann area 9) and inferior frontal gyrus). A variety of possible plausible explanations were proposed, including functional deafferentation, attention to pain, and artifactual deactivation caused by tonically raised baseline levels of activity. The studies by Werring et al. (19) and Ward et al. (21), summarized in Table 2, have also implicated a network of areas, particularly prefrontal, cingulated, and thalamic, which overlaps with those just mentioned and with those identified in this study. The study by Ghaffar et al. (12) describes the absence of contralateral primary somatosensory cortex activation in three patients with sensory conversion symptoms, even though this was activated normally when a bilateral stimulus is applied. This study also implicates a network of regions including the anterior cingulate, orbitofrontal cortex, thalamus, and striatum, although the results were inconsistent across patients.
Limitations of This Study
Our own study has shortcomings in the number of patients and controls studied, the use of patients with weakness of different sides (creating a need to "flip" images to obtain group data), and the lack of a rest condition. The third limitation implies that although we can implicate certain brain regions in functional weakness, we remain uncertain whether they were hyperactive or hypoactive. The design of our study did not provide for direct statistical comparison of patient and control activations, a desirable analysis in future work.
There was some heterogeneity in the subjects. First, comorbid anxiety or depression are very common in motor conversion disorder: three of our cases had such comorbidity. We felt that exclusion of patients with mild to moderate emotional disorder would lead to the selection of a group of patients unrepresentative of motor conversion disorder. Second, the severity of weakness also varied among our cases: two were able to make reduced but visible movements with their feet whereas two others were not able to move their ankles at all (although all could move their legs to some degree). However, as both cases and controls reported a sensation of tensing their leg while carrying out the task on the affected side, it is unlikely that the differences in imaging findings relate to differences in actual movement. Third, there is always the possibility that the group findings have been influenced by large activations or deactivations within one subject. This does not seem to be the case looking at the base data but cannot be ruled out. Finally, in comparing brain activation of moving the "weak" side with activations of moving the "normal" side in patients with conversion disorder, we are making an assumption that their normal leg is indeed normal.
The Difficulties of Functional Imaging of Motor Conversion Disorder
Further work is clearly required to resolve the conflicting findings from the studies published to date. However, future research on these phenomena must address several challenges. First, the concept of conversion disorder is itself controversial (30). Although patients can be diagnosed with relative reliability as having a symptom such as paralysis that is not explained by disease (15), there is considerable debate about the psychological mechanisms underlying these symptoms. The psychodynamic "conversion" hypothesis remains dominant in DSM-IV, whereas in ICD-10 the hypothesis that the symptoms are a consequence of dissociation is given primacy. Others have considered patients with motor conversion disorder to have a "disorder of action" (17). These are not mutually exclusive hypotheses but one has to consider the possibility that patients who share the same outward symptoms and signs of paralysis could have markedly different psychological mechanisms. This not only makes it difficult to know what the starting point for a functional imaging hypothesis should be but also raises the possibility that individual differences in psychological mechanisms could be obscured in the analysis of group data. Second, patients with paralysis due to conversion disorder may vary from one another in factors including the duration and severity of symptoms, the co-existence of mood disturbance, the use of psychotropic drugs, the presence of pain and other sensory symptoms, the degree of unfitness, and probably their degree of conscious control over the symptom. Third, control subjects, asked to imagine or simulate weakness, may adopt different strategies to achieve this, either attempting to eliminate effort to move altogether ("imagine your leg has become so weak you cannot move a muscle . . .") or attempting to move against insuperable, imaginary, resistance ("imagine that however hard you try you cannot raise your leg . . ."). For either of these strategies, controls may regard their task as being merely to imagine weakness or as a challenge to deceive an observer. The permutations of these differing strategies are likely to give rise to different patterns of activation. It is plausible that the neural mechanisms of weakness in patients with motor conversion disorder are similarly heterogenous. In some patients, the underlying process may be negative, a failure to initiate movement, whereas in others, positive inhibitory processes may be to the fore. Detailed individual case studies comparing patterns of activations on several occasions during the symptomatic state (to establish intrasubject reliability) and after recovery (to control for individual differences) offer one approach to meeting these difficulties.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSNOTESREFERENCES |
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Future work should address the many potential sources of variability in this patient group and explore the likely heterogeneity in the neural mechanisms of motor conversion disorder.
The Chief Scientist’s Office (Scotland) funded this work. The research was conducted at the SHEFC Brain Imaging Research Centre for Scotland, which is supported with a Joint Research Equipment Initiative grant from the UK’s Medical Research Council and the Scottish Higher Education Funding Council with industrial collaboration from GE Medical Systems, Boehringer Ingelheim, Novartis, and Schering. A.Z. was supported by The Health Foundation (previously The PPP Foundation). We thank Charles Warlow, Ian Deary, Steven Laureys, Elvina Goutona, Ian Marshall, and Joanna Wardlaw for contributions.
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NOTES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSNOTESREFERENCES |
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The first two authors contributed equally to the study.
DOI:10.1097/PSY.0b013e31815b6c14
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This article has been cited by other articles:
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  V. Voon, C. Gallea, N. Hattori, M. Bruno, V. Ekanayake, and M. Hallett The involuntary nature of conversion disorder Neurology, January 19, 2010; 74(3): 223 - 228. [Abstract] [Full Text] [PDF]
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