5. Peterson BS, Bronen RA, Duncan CC. Three cases of symptom change in Tourette’s syndrome and obsessive-compulsive disorder associated with paediatric cerebral malignancies. J Neurol Neurosurg Psychiatry 1996;61:497–505. 6. Pantoni L, Poggesi L, Repice A, et al. Disappearance of motor tics after Wernicke’s encephalopathy in a patient with Tourette’s syndrome. Neurology 1997;48:381–383. 7. Babel TB, Warnke PC, Ostertag CB. Immediate and long term outcome after infrathalamic and thalamic lesioning for intractable Tourette’s syndrome. J Neurol Neurosurg Psychiatry 2001;70:666 – 671. 8. Peterson B, Riddle MA, Cohen DJ, et al. Reduced basal ganglia volumes in Tourette’s syndrome using three-dimensional reconstruction techniques from magnetic resonance images. Neurology 1993;43:941–949. 9. Singer HS, Reiss AL, Brown JE, et al. Volumetric MRI changes in basal ganglia of children with Tourette’s syndrome. Neurology 1993;43:950 –956. 10. Hyde TM, Stacey ME, Coppola R, et al. Cerebral morphometric abnormalities in Tourette’s syndrome: a quantitative MRI study of monozygotic twins. Neurology 1995;45: 1176 –1182. 11. Peterson BS, Thomas P, Kane MJ, et al. Basal ganglia volumes in patients with Gilles de la Tourette syndrome. Arch Gen Psychiatry 2003;60:415– 424. 12. Peterson BS, Staib L, Scahill L, et al. Regional brain and ventricular volumes in Tourette syndrome. Arch Gen Psychiatry 2001;58:427– 440. 13. Ashburner J, Friston KJ. Voxel-based morphometry—the methods. Neuroimage 2000; 11:805– 821. 14. Garraux G, Bauer A, Hanakawa T, et al. Changes in brain anatomy in focal hand dystonia. Ann Neurol 2004;55: 736 –739. 15. Good CD, Johnsrude I, Ashburner J, et al. Cerebral asymmetry and the effect of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains. Neuroimage 2001;14:685–700. 16. Genovese CR, Lazar NA, Nichols T. Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 2002;15:870 – 878. 17. Duvernoy HM. The human brain. Surface, blood supply, and three dimensional sectional anatomy. 2nd ed. New York: Springer-Verlag, 1999. 18. Siebert S, Jurgens U. Vocalization after periaqueductal grey inactivation with the GABA agonist muscimol in the squirrel monkey. Neurosci Lett 2003;340:111–114. 19. Singer HS, Szymanski S, Giuliano J, et al. Elevated intrasynaptic dopamine release in Tourette’s syndrome measured by PET. Am J Psychiatry 2002;159:1329 –1336. 20. Albin RL, Koeppe RA, Bohnen NI, et al. Increased ventral striatal monoaminergic innervation in Tourette syndrome. Neurology 2003;61:310 –315.
Contralateral Hand Anesthesia Transiently Improves Poststroke Sensory Deficits Bernhard Voller, MD,1,2 Agnes Flo¨el, MD,1,3 Konrad J. Werhahn, MD,1,4 Shashi Ravindran, MPH,1 Carolyn W. Wu, PhD,1 and Leonardo G. Cohen, MD1
Objective: To test a possible strategy to alleviate somatosensory deficits after stroke. Methods: Here, we applied ischemic nerve block to the intact hand of patients with chronic stroke, which in healthy subjects elicits improvements in sensibility of the other hand. Results: We found that sensibility in the affected hand improved with intact hand anesthesia, but not with intact foot anesthesia or no anesthesia. Interpretation: We conclude that reduction of sensory input from the intact hand leads to site-specific improvements in tactile discriminative skills in the affected hand after the period of anesthesia, a potentially relevant finding in designing neurorehabilitative interventions. Ann Neurol 2006;59:385–388
Somatosensory deficits, commonly present after stroke, influence the outcome of rehabilitative treatments.1 Neurorehabilitation of somatosensory deficits, a condition for which there is no extensively accepted treatment, has limited success.2 In healthy volunteers3,4 and in patients with peripheral nerve injuries,5 it has been shown that anesthesia of one hand results in improvements in tactile discriminative skills of the other hand, possibly through modulation of interhemispheric interactions. In patients with chronic stroke, motor function in the paretic hand, which is associated with abnormal interhemispheric inhibition,6 improved after cutaneous anesthesia of the intact hand.7 Therefore, it is conceivable that anesthesia of the intact hand could influence somatosensory function in the form of tactile
From 1Human Cortical Physiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; 2Department of Neurology, Medical University of Vienna, Austria; 3Department of Neurology, University of Mu¨nster, Mu¨nster; and 4Department of Neurology, University of Mainz, Mainz, Germany. Received Jun 15, 2005, and in revised form Aug 30. Accepted for publication Sep 1, 2005. Published online Dec 15, 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.20689 Address correspondence to Dr Cohen, Human Cortical Physiology Section, NINDS, NIH, Building 10/5N226, 10 Center Drive, Bethesda, MD 20892. E-mail:
[email protected]
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Table. Patient Characteristics and Individual Results Patient No. 1
2
3
4
5
6
7
Age (yr) Sex Stroke (yr) Side Site
65 F 12.5 R BG, CES, COR
79 M 5 R CES,
71 M 3 L BG, CES
63 F 1 R CES, temp
4.5
4.4
4.7
4.4
60 F 3 L COR, CTX front pariet 3.8
34 F 5 R BG, COR
MRC Touch a (lgmg) i (lgmg) GOT a (mm) i (mm) Grating (mm) GOA Base(%)
35 M 3.5 R BG, COR front insula 4.8
4.0
4.6
2.9
2.8 2.4
2.9 2.8
3.0 2.8
3.0 2.9
2.8 2.5
4.0 2.4
2.6 2.5
3.4 3.1
2.32 2.00 2
3.47 2.60 3
4.63 2.67 5
3.33 2.67 3
3.00 2.11 3
3.60 1.58 4
3.20 1.20 3
80
74
71
66
84
86
79
Characteristic
a
8
9
Mean ⫾ SE
10
11
45 M 2.5a L THAL
55.2 ⫾ 4.3
4.3
45 F 2.5 L CES, CTX pariet occ 4.8
3.1 2.8
3.7 2.6
3.0 2.4
3.1 ⫾ 0.1 2.7 ⫾ 0.1
2.78 2.50 3
3.50 1.13 4
4.00 1.35 4
1.11 0.92 1.2
3.2 ⫾ 0.3 1.9 ⫾ 0.2 3.3 ⫾ 0.3
72
83
68
69
75.6 ⫾ 2.1
57 53 F M 7.5 1.5 R R BG, SUBC CES front temp
4.2 ⫾ 1.0
4.3 ⫾ 0.2
Hemorrhagic stroke.
R ⫽ right hemisphere; L ⫽ left hemisphere; BG ⫽ basal ganglia; CES ⫽ centrum semiovale; COR ⫽ corona radiata; CTX ⫽ cortical; SUBC ⫽ subcortical; THAL ⫽ thalamus; temp ⫽ temporal; front ⫽ frontal; pariet ⫽ parietal; occ ⫽ occipital; MRC ⫽ Medical Research Council (mean score of hand and finger strength of the affected side); Touch ⫽ touch/pressure threshold elicited by von Frey filaments expressed as the logarithm of the bending force (mg) to the base of 10 (lgmg); GOT ⫽ grating orientation task threshold8; a ⫽ affected hand; i ⫽ intact hand; Grating ⫽ particular grating with the groove width closest to the GOT, which was used for all GOA measurements in each individual; GOA Base ⫽ baseline.
discriminative skills in the affected hand of patients with chronic stroke, the focus of our investigation. Patients and Methods We studied 11 stroke patients aged 55.2 ⫾ 14.4 years (mean ⫾ S.D.), 10 of them with ischemic infarcts at least 12 months earlier. On examination, all patients had hypoesthesia as shown by touch/pressure (von Frey monofilament) and grating orientation task thresholds (the endpoint measure of our investigation) and variable motor deficits as measured by Medical Research Council scores (Table). All patients gave their written informed consent, and the NINDS institutional review board approved the study protocol. The limits of tactile spatial resolution were measured by the application of gratings to the fingertip of the index finger (middle finger of one patient) in a two-alternative forcedchoice orientation discrimination paradigm. The grating orientation task (GOT) yields reliable and reproducible measures of spatial acuity that are dependent on the spatial response profiles of slowly adapting afferents.8 Stimuli consisted of plastic domes in which ridges and grooves of equal width are engraved with a spatial period of 1.2, 1.5, 2, 3, 4, and 5mm (JVP Domes, Stoelting, Wood Dale, IL). Gratings were applied with the ridges and grooves randomly oriented perpendicular or parallel to the axis of the finger, and the patients, who were blindfolded, had to identify the correct alignment. Patients received feedback after each trial. The experiment consisted of four sessions. In the initial (training) session, patients practiced the task until they
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reached stable performance, and we determined GOT thresholds, defined as the groove width at which responses were 75% correct (Table). For details, see previous studies.3,8 Because GOT threshold testing requires concentrated attention for a period of time that may be lengthy in some stroke patients, we measured the grating orientation accuracy (GOA). First, the grating with the groove width closest to the GOT threshold was chosen to make sure that each patient started at a standardized baseline. GOA defined as the percentage of correct responses reported for the groove width closest to the GOT threshold was determined at the end of the training session and during each of three randomly ordered additional sessions: (1) anesthesia of the intact hand, (2) anesthesia of the intact foot, and (3) no anesthesia. GOA in the affected hand was measured four times during each session (in blocks of 80 trials each): baseline, during, and 15 and 45 minutes after the end of anesthesia (Fig 1). Anesthetic ischemic nerve block was applied to the wrist (intact hand anesthesia) and ankle (intact foot anesthesia) according to a procedure previously described.3,8 Cutaneous anesthesia was defined as the loss of touch detection during application of a von Frey filament exerting a force of 4N to the distal pad of the second finger or toe. Patients rated their perception on a scale ranging from 0 to 10 of cuff-induced discomfort, attention to the task, and fatigue levels in each session using scales with good internal consistency, reliability, and objectivity.7 Data, expressed as mean ⫾ standard error, were analyzed by repeated measures analysis of variance (ANOVARM) with factors TIME (baseline, during, and 15 and 45
of anesthesia interaction (F(6,90) ⫽ 4.5, p ⬍ 0.01) on GOA. No effect was shown for SITE of anesthesia (F(2,20) ⫽ 0.07, NS). Post hoc testing showed a significant improvement in GOA in the affected hand 15 minutes after anesthesia of the healthy hand (84.8 ⫾ 2.8% vs 76.6 ⫾ 3.3% at baseline, p ⬍ 0.01) in the absence of changes in the other two sessions (Fig 2). GOA was significantly better 15 minutes after hand anesthesia than after foot anesthesia ( p ⬍ 0.01) or no anesthesia ( p ⬍ 0.01; see Fig 2).
Fig 1. Timeline of the experiment. In the initial (training) session, patients practiced the task, and grating orientation task (GOT) and grating orientation accuracy (GOA) were determined (see Patients and Methods). The following three sessions (intact hand and foot anesthesia and no anesthesia) included four measurements of GOA (arrows).
minutes after anesthesia) and SITE of anesthesia (intact hand, intact foot, no anesthesia) followed by post hoc testing Bonferroni-corrected for multiple comparisons.
Results Touch/pressure (von Frey monofilament) and grating orientation task (GOT) thresholds were worse in the affected than in the intact hand in every patient ( p ⬍ 0.01, see Table for individual data). During the training session, GOT thresholds in the affected hand improved to 3.2 ⫾ 0.3mm from 4.1 ⫾ 0.3mm (paired t test, p ⬍ 0.01), reaching a GOA of 75.6 ⫾ 2.1%. Grating width used for GOA in each subject and baseline performance values are shown in the table. GOA at the end of the training session was comparable to values obtained at baseline in the following three sessions (76.3 ⫾ 2.4%, 77.8 ⫾ 3.0%, and 77.9 ⫾ 2.4%, respectively). Duration of tourniquet inflation was similar between sessions (30.5 ⫾ 1.0 minutes with ischemic nerve block at the healthy arm and 32.9 ⫾ 1.0 minutes at the healthy foot, paired t test, p ⬎ 0.05). ANOVARM for fatigue and attention did not show effects of TIME (F(3,30) ⫽ 0.88, not significant [NS], and F(3,30) ⫽ 0.88, NS, respectively), SITE of anesthesia (F(2,20) ⫽ 0.06, NS, and F(2,20) ⫽ 0.15, NS, respectively), or TIME ⫻ SITE of anesthesia interaction (F(6,90) ⫽ 0.40, NS, and F(6,90) ⫽ 0.15, NS, respectively). Discomfort was present only during hand and foot anesthesia. No significant difference in pain between sessions with hand and foot anesthesia was found (paired t test, p ⬎ 0.05). On the other hand, there was a significant effect of TIME (F(3,30) ⫽ 3.09, p ⬍ 0.03) and TIME ⫻ SITE
Discussion The main finding of this study was that anesthesia of the intact hand resulted in improved tactile capabilities in the affected hand of chronic stroke patients. The GOT accurately characterizes the limits of tactile spatial resolution in humans, corresponding well with subjective reports of sensory deficits in patient groups.3,9 Our findings in patients with chronic stroke documented reproducible performance at baseline and comparable attention and fatigue across the three randomly ordered sessions. Duration of ischemic block was similar with hand and foot anesthesia. Comparable discomfort during hand and foot anesthesia was absent during postanesthesia GOA determinations. At the same time, intact hand (but not intact foot) anesthesia resulted in a significant improvement of the sensibility in the affected hand. These results are consistent with the report of transient improvement in tactile spatial acuity of one hand with anesthesia of the other hand in healthy volunteers and in patients with peripheral nerve injury, proposed to rely on modulation of interhemispheric inhibitory interactions.3,5 Intact hand anesthesia in patients with
Fig 2. Grating orientation accuracy. Comparable baseline grating orientation accuracy (GOA) (open bars) shows consistent performance at baseline across sessions. Anesthesia of the intact hand led to a GOA improvement of almost 11% relative to baseline, but no changes occurred with foot anesthesia or no anesthesia (*p ⬍ 0.01).
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chronic stroke may have decreased the net inhibitory drive from the deafferented intact hand sensory representation over the homologous representation in the affected hemisphere, resulting in the documented improvement in GOA. This is consistent with work from animal experiments showing interhemispheric interactions between somatosensory cortices.10,11 Regardless of the underlying mechanism, our findings underline the importance of somatosensory input originating in the intact hand on tactile function of the affected hand after stroke. The reported transient improvement of hand sensibility may be relevant to the design of interventional strategies in rehabilitation of somatosensory function after stroke.
This research was supported by the NIH (Intramural Research Program, National Institute of Neurological Disorders and Stroke). We thank D. G. Schoenberg, MSc, for skillful editing.
References 1. Reding MJ, Potes E. Rehabilitation outcome following initial unilateral hemispheric stroke. Life table analysis approach. Stroke 1988;19:1354 –1358. 2. Carey LM, Matyas TA, Oke LE. Sensory loss in stroke patients: effective training of tactile and proprioceptive discrimination. Arch Phys Med Rehabil 1993;74:602– 611. 3. Werhahn KJ, Mortensen J, Van Boven RW, et al. Enhanced tactile spatial acuity and cortical processing during acute hand deafferentation. Nat Neurosci 2002;5:936 –938. 4. Bjorkman A, Rosen B, van Westen D, et al. Acute improvement of contralateral hand function after deafferentation. Neuroreport 2004;15:1861–1865. 5. Bjorkman A, Rosen B, Lundborg G. Enhanced function in nerve-injured hands after contralateral deafferentation. Neuroreport 2005;16:517–519. 6. Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol 2004;55:400 – 409. 7. Floel A, Nagorsen U, Werhahn KJ, et al. Influence of somatosensory input on motor function in patients with chronic stroke. Ann Neurol 2004;56:206 –212. 8. Van Boven RW, Johnson KO. The limit of tactile spatial resolution in humans: grating orientation discrimination at the lip, tongue, and finger. Neurology 1994;44:2361–2366. 9. Van Boven RW, Johnson KO. A psychophysical study of the mechanisms of sensory recovery following nerve injury in humans. Brain 1994;117:149 –167. 10. Calford MB, Tweedale R. Interhemispheric transfer of plasticity in the cerebral cortex. Science 1990;249:805– 807. 11. Clarey JC, Tweedale R, Calford MB. Interhemispheric modulation of somatosensory receptive fields: evidence for plasticity in primary somatosensory cortex. Cereb Cortex 1996;6: 196 –206.
Lrrk2 and Lewy Body Disease Owen A. Ross, PhD,1 Mathias Toft, MD,1 Andrew J. Whittle, BSc,1 Joseph L. Johnson, PhD,1 Spiridon Papapetropoulos, MD, PhD,2 Deborah C. Mash, PhD,2 Irene Litvan, MD,3 Mark F. Gordon, MD,4 Zbigniew K. Wszolek, MD,5 Matthew J. Farrer, PhD,1 and Dennis W. Dickson, MD 1,6
Objective: The Lrrk2 kinase domain G2019S substitution is the most common genetic basis of familial and sporadic parkinsonism. Patients harboring the G2019S substitution usually present with clinical Parkinson’s disease. Methods: Herein, we report that the most common neuropathology of G2019S-associated Parkinson’s disease is Lewy body disease. Results: Lrrk2 G2019S was observed in approximately 2% (n ⴝ 8) of our Parkinson’s disease/ Lewy body disease cases (n ⴝ 405). The mutation was also found in one control subject and one Alzheimer’s disease patient, reflecting reduced penetrance. Interpretation: Therapeutic strategies targeted at modulating Lrrk2 kinase activity may be important to treat patients with genetically defined familial or typical sporadic Parkinson’s disease. Ann Neurol 2006;59:388 –393
Pathogenic Lrrk2 substitutions have become recognized as one of the most important causes of both familial and sporadic forms of parkinsonism.1–5 Pleomorphic pathology, including lesions immunoreactive for ␣-synuclein (Lewy bodies [LBs]), tau (neurofibrillary tangles), or ubiquitin in kindreds with different Lrrk2 substitutions (Family D: R1441C; Family A: Y1699C)6,7 has led us to postulate that Lrrk2 lies in a pathway upstream of other proteins implicated in the pathogenesis of neurodegeneration.2 Lrrk2 G2019S is the most common pathogenic substitution identified, and it is the most frequent genetic
From the 1Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville; 2Department of Neurology, University of Miami, School of Medicine, Miami, FL; 3Department of Neurology, University of Louisville School of Medicine, Louisville, Kentucky; 4Department of Neurology, North Shore Long Island Jewish Health System, New Hyde Park, NY; and Departments of 5Neurology and 6Pathology, Mayo Clinic College of Medicine, Jacksonville, FL. Received May 23, 2005, and in revised form Aug 29. Accepted for publication Aug 30, 2005. Published online Jan 23, 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.20731 Address correspondence to Dr Farrer, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail:
[email protected]
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