- Email: [email protected]
Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement
RESEARCH LETTERS
Controls Doxycycline p Immunohistology Number of nodules/patients Number of female worms Live, not degenerated Live, degenerated Dead
48/14
50/21
122 96 10 16
112 71 19 22
Number of live females with Numerous* bacteria Few* bacteria Bacteria not detected
92 10 4
0 5 85
Number of live females with intact embryogenesis Number of nodules with living microfilariae
65 44
0† 11
} }
<0·03
<0·0001 <0·0001 <0·0001
endosymbionts in malaria,5 doxycycline targets metabolic pathways unique to endosymbionts and therefore causes little harm to mammalian hosts. This study was approved by the ethical committees of the Medical Board Hamburg, and of the School of Medical Sciences of the University of Science and Technology, Kumasi, Ghana. Study procedures were in accordance with the Helsinki Declaration of 1975 (as revised 1983). Pfizer Inc, Karlsruhe, Germany, provided Vibramycin® tabs. We thank Peter Konadu, Marcelle Büttner, Kerstin Nissen-Pähle, Ingeborg Albrecht, Christel Schmetz, and Yeboah Marfo for support. AH received financial support from the German Research Foundation (DFG-grant Ho 2009/1-1) and the Edna McConnell-Clark Foundation, NY, USA. 1
PCR Number of nodules/patients Bacterial 16S rDNA (median), ⫻10⫺15 mol/L Nematode 5S DNA (median), ⫻10⫺15 mol/L Index 16S/5S (median) Number of nodules with undetectable 16S rDNA
13/7
56/22
35 1 260 210 0·063 0·007 0
45
<0·0002‡ <0·4‡ <0·0001‡ <0·0001
2
3
*Judged by hsp-60 expression: numerous means well over 200 bacteria per slide; few <10 per slide; †9 of 112 worms contained very low numbers of embryos, mostly degenerated; ‡ Mann Whitney U test: otherwise tested by the 2 test.
Immunohistological and PCR-based comparison of onchocercomata
4 5
versus nematode DNA. Two series of PCR reactions per nodule sample were undertaken: one in which 16S rDNA was amplified with endobacterial primers and serial dilutions of an endobacterial competitor plasmid against a fixed amount of sample; and the other in which 5S rDNA was amplified with nematode primers and serial dilutions of nematode competitor. An index was calculated between the dilutions at equivalence of the competitor plasmids for bacterial versus nematode DNA. In most worms from controls, numerous wolbachia endobacteria were detected by immunohistology (figure A, table) at the typical sites as described, with use of an antiserum against bacterial heat shock protein-60.4 Semiquantitative PCR showed a 16S/5S index of 0·06 (PCR index, table). 44 of 48 nodules harboured living microfilariae, and 65 of 106 female worms showed an intact embryogenesis (table). By contrast only five of 90 worms from doxycyclinetreated patients were positive for bacteria (figure B, table), showing only few organisms. Consistent results were obtained by PCR, showing an almost tenfold reduced 16S/5S index. The true index reduction is probably greater, since greater than 80% of the onchocercomata from treated patients had 16S values below the detection limit (2·5⫻10⫺15 mol/mL) and were calculated as less than 1⫻10⫺15 mol/mL. Only nine of 112 female worms showed embryos, and all had very low numbers (table). Thus, none of the treated worms had usual bacterial loads or normal embryogenesis. Notably, there was a clear trend to more frequent degeneration or death of adult worms. We have shown successful endobacterial targeting in the treatment of human filariasis. As with animal filariae3,4 wolbachia seem essential for worm fertility. By contrast with invermectin, a drug that mainly affects mature microfilariae, doxycycline totally suppresses normal embryonic development during the early phase—ie, the oocyte/morula stages. Endobacterial targeting could be developed as a treatment not only for onchocerciasis but also for lymphatic filariasis, in view of the presence of endobacteria in the respective species. Studies are underway to determine whether a shorter treatment time with higher doses of doxycycline will show equivalent efficacy. The major advantage of this new therapy is that doxycycline is a registered drug, so that high development costs could be largely avoided. Additionally, similar to targeting apicoplast
THE LANCET • Vol 355 • April 8, 2000
WHO. Chagas disease, leprosy, lymphatic filariasis, onchocerciasis: prospects for elimination. Geneva: WHO, TDR/Gen/97-1, 1997: 1–35. Plasier AP, Alley ES, van Oortmarssen GJ, Boatin BA, Habbema JD. Required duration of combined annual invermectin treatment and vector control in the Onchocerciasis Control Programme in West Africa. Bull World Health Organ 1997; 75: 237–45. Hoerauf A, Nissen-Pähle K, Schmetz C, et al. Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility. J Clin Invest 1999; 103: 11–18. Taylor M, Hoerauf A. Wolbachia bacteria of filarial nematodes. Parasitol Today 1999; 15: 437–42. Jomaa H, Wiesner J, Sanderbrand S, et al. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 1999; 285: 1573–76.
Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany (A Hoerauf MD, L Volkmann MSc, B Fleischer MD, D W Büttner MD); Kumasi Centre for Collaborative Research, Kumasi, Ghana (C Hamelmann MD); University of Science and Technology, Kumasi, Ghana (O Adjei PhD); and Max von Pettenkofer Institute, Ludwig Maximilian University, 80336 Munich, Germany (I B Autenrieth MD) Correspondence to: Achim Hoerauf (e-mail: [email protected])
Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement Sean A Spence, Helen L Crimlisk, Helen Cope, Maria A Ron, Paul M Grasby The clinical distinction between hysterical symptoms and those that are feigned awaits objective validation. We used functional neuroimaging to examine the neural correlates of these two disorders.
Since the time of Freud, hysterical symptoms (eg, paralyses) have been attributed to an unconscious psychological mechanism (‘conversion’),1 based on the assumption that they are not consciously feigned. However, such impairments commonly resemble voluntary behaviours, complicating this distinction.2 We postulate that positron emission tomography (PET) will provide objective evidence of hysterical pathophysiology, distinct from feigning; and that the former will involve a cortical region involved in voluntary action—the left dorsolateral prefrontal cortex (DLPFC).2 This region is activated in control individuals choosing actions, and dysfunctional in patients with neuropsychiatric disorders that affect volition.2,3 We studied two men with hysterical motor symptoms affecting their left arms. Aged 30 and 50 years, they had exhibited substantial limb weakness for 12 and 10 months,
1243
RESEARCH LETTERS
Statistical parametric maps on a smoothed magnetic resonance image of the anterior surface of the brain (the right prefrontal cortex is on the left of the image) Red: regions where patients with hysterical motor symptoms exhibit hypofunction relative to controls; green: feigners exhibit hypofunction relative to controls.
respectively. Full neurological investigations had excluded structural disease. In both, psychosocial precipitants had been identified and psychological interventions commenced. Though each had had previous episodes of depression, neither patient was depressed nor receiving psychotropic medication when studied. They could make limited movements with their affected limbs, permitting them to be scanned as they moved a joystick. Each gave informed, written consent to participate in this study (as did all individuals studied), and this and following studies were approved by the ethics committees of the participating hospitals. We studied two healthy individuals instructed to feign difficulty moving their left upper limbs (feigners); and six healthy individuals who did movement tasks normally (controls). All individuals were age-matched and strongly right handed. Feigners were required to pretend they had difficulty, they slowed their responses to match those of patients (whom we studied first). Controls moved their limbs normally. The movement task involved a simplified form of the joystick task used previously to study controls and neuropsychiatric patients in the PET scanner.3 Individuals moved a joystick in freely-chosen sequences in two possible directions (right or left) at a low rate (one movement every 6 s), paced by an auditory tone. The task measurements facilitated patients’ performance. Individuals were studied under three conditions: moving Region (Brodmann area)
Tailarach co-ordinates (mm)
Z score
⫺50, 32, 20 ⫺50, 36, 28
3·51 3·46
⫺48, 36, 28 ⫺50, 32, 20
3·97 3·63
Feigners versus controls Right anterior prefrontal cortex (BA 10)
38, 62, 16
3·41
Feigners versus patients Right anterior prefrontal cortex (BA 10)
26, 62, 16
3·77
Hysteria patients versus controls Left dorsolateral prefrontal cortex (BA 9/46) Hysteria patients versus feigners Left dorsolateral prefrontal cortex (BA 9/46)
We thank all the patients who participated in the studies; D Silbersweig and E Stern for their helpful comments; and L Schnorr and W Engelien for their technical assistance. S Spence and P M Grasby were supported by the MRC (UK); S Spence is currently supported by the De Witt, Wallace Fund, New York Hospital; L Crimlisk was supported by research funds from the National Hospital for Neurology and Neurosurgery; and M A Ron is partly supported by the Scarfe Trust. 1 2 3
4
BA=Brodmann areas.
Prefrontal regions showing hypofunction during left-hand movement in two patients with hysteria and two feigners
1244
the left hand; moving the right hand; and at rest. Each individual received 12 PET scans, four under each condition, in a counterbalanced sequence (controlling for temporal effects). Performances were videotaped and all individuals completed the tasks successfully. We used our PET technique3 and statistical parametric mapping4 to study regional cerebral blood flow. The maps were spatially normalised and tested for significance (p<0·001) to minimise the risk of false positives. Comparing brain activations during movement of the left hand (relative to the resting state) in patients with hysteria versus controls and feigners showed that patients exhibited relative hypoactivity of left DLPFC on both comparisons (table). Feigners exhibited hypofunction of the right anterior prefrontal cortex. Both these findings were significant (p<0·001). Subsequently, we studied a right-handed man (aged 32 years, with a past history of depression), who exhibited hysterical weakness of the right upper limb (of 6 months duration), and also two healthy, age-matched, feigners who feigned abnormality of the same limb. Combined data analyses showed that left prefrontal hypofunction was common to all patients with hysteria when they moved an affected limb, irrespective of symptom-lateralisation. Right prefrontal hypofunction characterised feigned disorder of either side (although the foci implicated were less well circumscribed than those of hysteria; figure). Although patients with hysteria were not hypofrontal at rest, they deactivated left DLPFC when moving their affected limbs. Although the sample size in this study is small and our data preliminary, they nevertheless support the hypothesis that hysteria involves the left DLPFC, and differs neurophysiologically from conscious feigning. Functional neuroimaging might help in the diagnosis of hysteria. Left DLPFC is specifically activated by the internal generation (‘choice’) of action;3 its selective dysfunction in hysterical motor symptoms involves the higher components of volition. This accords well with pre-Freudian notions of hysteria, which commonly invoked disordered will: ‘the patient [says] “I cannot”; it looks like “I will not”; but it is “I cannot will”’ (Paget, 1873).1 A fuller investigation of volitional disturbance in these patients is required.
Merskey H. The analysis of hysteria. London: Gaskell, 1995. Spence SA. Hysterical paralyses as disorders of action. Cog Neuropsychiatry 1999; 4: 203–06. Spence SA, Hirsch SR, Brooks DJ, Grasby PM. Prefront cortex activity in people with schizophrenia and control subjects: evidence from positron emission tomography for remission of ‘hypofrontality’ with recovery from acute schizophrenia. Br J Psychiat 1998; 172: 316–23. Friston KJ, Holmes AP, Worsley KJ, Poline J-B, Frith CD, Frackowiak RSJ. Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995; 2: 189–210.
Functional Neuroimaging Laboratory, Department of Psychiatry, New York Hospital, Cornell Medical Center, New York (S Spence MRCPsych); Institute of Neurology, Queen Square, London (H Crimlisk MRCPsych, H Cope MRCPsych, M Ron MRCPsych); and MRC Cyclotron Unit, Hammersmith Hospital, London (P Grasby MRCPsych) Correspondence to: Dr Sean Spence, Functional Neuroimaging Laboratory, Department of Psychiatry, Box 140, New York Presbyterian Hospital, Cornell Medical Center, New York, NY 10021, USA (e-mail: [email protected])
THE LANCET • Vol 355 • April 8, 2000
Controls Doxycycline p Immunohistology Number of nodules/patients Number of female worms Live, not degenerated Live, degenerated Dead
48/14
50/21
122 96 10 16
112 71 19 22
Number of live females with Numerous* bacteria Few* bacteria Bacteria not detected
92 10 4
0 5 85
Number of live females with intact embryogenesis Number of nodules with living microfilariae
65 44
0† 11
} }
<0·03
<0·0001 <0·0001 <0·0001
endosymbionts in malaria,5 doxycycline targets metabolic pathways unique to endosymbionts and therefore causes little harm to mammalian hosts. This study was approved by the ethical committees of the Medical Board Hamburg, and of the School of Medical Sciences of the University of Science and Technology, Kumasi, Ghana. Study procedures were in accordance with the Helsinki Declaration of 1975 (as revised 1983). Pfizer Inc, Karlsruhe, Germany, provided Vibramycin® tabs. We thank Peter Konadu, Marcelle Büttner, Kerstin Nissen-Pähle, Ingeborg Albrecht, Christel Schmetz, and Yeboah Marfo for support. AH received financial support from the German Research Foundation (DFG-grant Ho 2009/1-1) and the Edna McConnell-Clark Foundation, NY, USA. 1
PCR Number of nodules/patients Bacterial 16S rDNA (median), ⫻10⫺15 mol/L Nematode 5S DNA (median), ⫻10⫺15 mol/L Index 16S/5S (median) Number of nodules with undetectable 16S rDNA
13/7
56/22
35 1 260 210 0·063 0·007 0
45
<0·0002‡ <0·4‡ <0·0001‡ <0·0001
2
3
*Judged by hsp-60 expression: numerous means well over 200 bacteria per slide; few <10 per slide; †9 of 112 worms contained very low numbers of embryos, mostly degenerated; ‡ Mann Whitney U test: otherwise tested by the 2 test.
Immunohistological and PCR-based comparison of onchocercomata
4 5
versus nematode DNA. Two series of PCR reactions per nodule sample were undertaken: one in which 16S rDNA was amplified with endobacterial primers and serial dilutions of an endobacterial competitor plasmid against a fixed amount of sample; and the other in which 5S rDNA was amplified with nematode primers and serial dilutions of nematode competitor. An index was calculated between the dilutions at equivalence of the competitor plasmids for bacterial versus nematode DNA. In most worms from controls, numerous wolbachia endobacteria were detected by immunohistology (figure A, table) at the typical sites as described, with use of an antiserum against bacterial heat shock protein-60.4 Semiquantitative PCR showed a 16S/5S index of 0·06 (PCR index, table). 44 of 48 nodules harboured living microfilariae, and 65 of 106 female worms showed an intact embryogenesis (table). By contrast only five of 90 worms from doxycyclinetreated patients were positive for bacteria (figure B, table), showing only few organisms. Consistent results were obtained by PCR, showing an almost tenfold reduced 16S/5S index. The true index reduction is probably greater, since greater than 80% of the onchocercomata from treated patients had 16S values below the detection limit (2·5⫻10⫺15 mol/mL) and were calculated as less than 1⫻10⫺15 mol/mL. Only nine of 112 female worms showed embryos, and all had very low numbers (table). Thus, none of the treated worms had usual bacterial loads or normal embryogenesis. Notably, there was a clear trend to more frequent degeneration or death of adult worms. We have shown successful endobacterial targeting in the treatment of human filariasis. As with animal filariae3,4 wolbachia seem essential for worm fertility. By contrast with invermectin, a drug that mainly affects mature microfilariae, doxycycline totally suppresses normal embryonic development during the early phase—ie, the oocyte/morula stages. Endobacterial targeting could be developed as a treatment not only for onchocerciasis but also for lymphatic filariasis, in view of the presence of endobacteria in the respective species. Studies are underway to determine whether a shorter treatment time with higher doses of doxycycline will show equivalent efficacy. The major advantage of this new therapy is that doxycycline is a registered drug, so that high development costs could be largely avoided. Additionally, similar to targeting apicoplast
THE LANCET • Vol 355 • April 8, 2000
WHO. Chagas disease, leprosy, lymphatic filariasis, onchocerciasis: prospects for elimination. Geneva: WHO, TDR/Gen/97-1, 1997: 1–35. Plasier AP, Alley ES, van Oortmarssen GJ, Boatin BA, Habbema JD. Required duration of combined annual invermectin treatment and vector control in the Onchocerciasis Control Programme in West Africa. Bull World Health Organ 1997; 75: 237–45. Hoerauf A, Nissen-Pähle K, Schmetz C, et al. Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility. J Clin Invest 1999; 103: 11–18. Taylor M, Hoerauf A. Wolbachia bacteria of filarial nematodes. Parasitol Today 1999; 15: 437–42. Jomaa H, Wiesner J, Sanderbrand S, et al. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 1999; 285: 1573–76.
Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany (A Hoerauf MD, L Volkmann MSc, B Fleischer MD, D W Büttner MD); Kumasi Centre for Collaborative Research, Kumasi, Ghana (C Hamelmann MD); University of Science and Technology, Kumasi, Ghana (O Adjei PhD); and Max von Pettenkofer Institute, Ludwig Maximilian University, 80336 Munich, Germany (I B Autenrieth MD) Correspondence to: Achim Hoerauf (e-mail: [email protected])
Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement Sean A Spence, Helen L Crimlisk, Helen Cope, Maria A Ron, Paul M Grasby The clinical distinction between hysterical symptoms and those that are feigned awaits objective validation. We used functional neuroimaging to examine the neural correlates of these two disorders.
Since the time of Freud, hysterical symptoms (eg, paralyses) have been attributed to an unconscious psychological mechanism (‘conversion’),1 based on the assumption that they are not consciously feigned. However, such impairments commonly resemble voluntary behaviours, complicating this distinction.2 We postulate that positron emission tomography (PET) will provide objective evidence of hysterical pathophysiology, distinct from feigning; and that the former will involve a cortical region involved in voluntary action—the left dorsolateral prefrontal cortex (DLPFC).2 This region is activated in control individuals choosing actions, and dysfunctional in patients with neuropsychiatric disorders that affect volition.2,3 We studied two men with hysterical motor symptoms affecting their left arms. Aged 30 and 50 years, they had exhibited substantial limb weakness for 12 and 10 months,
1243
RESEARCH LETTERS
Statistical parametric maps on a smoothed magnetic resonance image of the anterior surface of the brain (the right prefrontal cortex is on the left of the image) Red: regions where patients with hysterical motor symptoms exhibit hypofunction relative to controls; green: feigners exhibit hypofunction relative to controls.
respectively. Full neurological investigations had excluded structural disease. In both, psychosocial precipitants had been identified and psychological interventions commenced. Though each had had previous episodes of depression, neither patient was depressed nor receiving psychotropic medication when studied. They could make limited movements with their affected limbs, permitting them to be scanned as they moved a joystick. Each gave informed, written consent to participate in this study (as did all individuals studied), and this and following studies were approved by the ethics committees of the participating hospitals. We studied two healthy individuals instructed to feign difficulty moving their left upper limbs (feigners); and six healthy individuals who did movement tasks normally (controls). All individuals were age-matched and strongly right handed. Feigners were required to pretend they had difficulty, they slowed their responses to match those of patients (whom we studied first). Controls moved their limbs normally. The movement task involved a simplified form of the joystick task used previously to study controls and neuropsychiatric patients in the PET scanner.3 Individuals moved a joystick in freely-chosen sequences in two possible directions (right or left) at a low rate (one movement every 6 s), paced by an auditory tone. The task measurements facilitated patients’ performance. Individuals were studied under three conditions: moving Region (Brodmann area)
Tailarach co-ordinates (mm)
Z score
⫺50, 32, 20 ⫺50, 36, 28
3·51 3·46
⫺48, 36, 28 ⫺50, 32, 20
3·97 3·63
Feigners versus controls Right anterior prefrontal cortex (BA 10)
38, 62, 16
3·41
Feigners versus patients Right anterior prefrontal cortex (BA 10)
26, 62, 16
3·77
Hysteria patients versus controls Left dorsolateral prefrontal cortex (BA 9/46) Hysteria patients versus feigners Left dorsolateral prefrontal cortex (BA 9/46)
We thank all the patients who participated in the studies; D Silbersweig and E Stern for their helpful comments; and L Schnorr and W Engelien for their technical assistance. S Spence and P M Grasby were supported by the MRC (UK); S Spence is currently supported by the De Witt, Wallace Fund, New York Hospital; L Crimlisk was supported by research funds from the National Hospital for Neurology and Neurosurgery; and M A Ron is partly supported by the Scarfe Trust. 1 2 3
4
BA=Brodmann areas.
Prefrontal regions showing hypofunction during left-hand movement in two patients with hysteria and two feigners
1244
the left hand; moving the right hand; and at rest. Each individual received 12 PET scans, four under each condition, in a counterbalanced sequence (controlling for temporal effects). Performances were videotaped and all individuals completed the tasks successfully. We used our PET technique3 and statistical parametric mapping4 to study regional cerebral blood flow. The maps were spatially normalised and tested for significance (p<0·001) to minimise the risk of false positives. Comparing brain activations during movement of the left hand (relative to the resting state) in patients with hysteria versus controls and feigners showed that patients exhibited relative hypoactivity of left DLPFC on both comparisons (table). Feigners exhibited hypofunction of the right anterior prefrontal cortex. Both these findings were significant (p<0·001). Subsequently, we studied a right-handed man (aged 32 years, with a past history of depression), who exhibited hysterical weakness of the right upper limb (of 6 months duration), and also two healthy, age-matched, feigners who feigned abnormality of the same limb. Combined data analyses showed that left prefrontal hypofunction was common to all patients with hysteria when they moved an affected limb, irrespective of symptom-lateralisation. Right prefrontal hypofunction characterised feigned disorder of either side (although the foci implicated were less well circumscribed than those of hysteria; figure). Although patients with hysteria were not hypofrontal at rest, they deactivated left DLPFC when moving their affected limbs. Although the sample size in this study is small and our data preliminary, they nevertheless support the hypothesis that hysteria involves the left DLPFC, and differs neurophysiologically from conscious feigning. Functional neuroimaging might help in the diagnosis of hysteria. Left DLPFC is specifically activated by the internal generation (‘choice’) of action;3 its selective dysfunction in hysterical motor symptoms involves the higher components of volition. This accords well with pre-Freudian notions of hysteria, which commonly invoked disordered will: ‘the patient [says] “I cannot”; it looks like “I will not”; but it is “I cannot will”’ (Paget, 1873).1 A fuller investigation of volitional disturbance in these patients is required.
Merskey H. The analysis of hysteria. London: Gaskell, 1995. Spence SA. Hysterical paralyses as disorders of action. Cog Neuropsychiatry 1999; 4: 203–06. Spence SA, Hirsch SR, Brooks DJ, Grasby PM. Prefront cortex activity in people with schizophrenia and control subjects: evidence from positron emission tomography for remission of ‘hypofrontality’ with recovery from acute schizophrenia. Br J Psychiat 1998; 172: 316–23. Friston KJ, Holmes AP, Worsley KJ, Poline J-B, Frith CD, Frackowiak RSJ. Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995; 2: 189–210.
Functional Neuroimaging Laboratory, Department of Psychiatry, New York Hospital, Cornell Medical Center, New York (S Spence MRCPsych); Institute of Neurology, Queen Square, London (H Crimlisk MRCPsych, H Cope MRCPsych, M Ron MRCPsych); and MRC Cyclotron Unit, Hammersmith Hospital, London (P Grasby MRCPsych) Correspondence to: Dr Sean Spence, Functional Neuroimaging Laboratory, Department of Psychiatry, Box 140, New York Presbyterian Hospital, Cornell Medical Center, New York, NY 10021, USA (e-mail: [email protected])
THE LANCET • Vol 355 • April 8, 2000