AFTER STROKE, THE SIZE OF THE cortical representation

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1 1052 ORIGINAL ARTICLE Cortical Reorganization Following Modified Constraint-Induced Movement Therapy: A Study of 4 Patients With Chronic Stroke Jerzy P. Szaflarski, MD, PhD, Stephen J. Page, PhD, Brett M. Kissela, MD, Jing-Huei Lee, PhD, Peter Levine, BA, PTA, Stephen M. Strakowski, MD From the Department of Neurology (Szaflarski, Kissela), Center for Imaging Research (Szaflarski, Lee, Strakowski), and Department of Physical Medicine and Rehabilitation (Page, Levine), University of Cincinnati Medical Center, Cincinnati, OH; Neuromotor Recovery and Rehabilitation Laboratory, Drake Rehabilitation Center, Cincinnati, OH (Page, Levine); and Department of Biomedical Engineering, University of Cincinnati College of Medicine, Cincinnati, OH (Lee). Presented in part to the 30th International Stroke Conference, February 2005, New Orleans, LA. Supported by the Neuroscience Institute, Cincinnati, OH. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Stephen J. Page, PhD, Dept of Physical Medicine and Rehabilitation, University of Cincinnati College of Medicine, 3202 Eden Ave, Ste 275, Cincinnati, OH 45267, Stephen.Page@uc.edu /06/ $32.00/0 doi: /j.apmr ABSTRACT. Szaflarski JP, Page SJ, Kissela BM, Lee J-H, Levine P, Strakowski SM. Cortical reorganization following modified constraint-induced movement therapy: a study of 4 patients with chronic stroke. Arch Phys Med Rehabil 2006;87: Objective: To determine whether cortical changes occur following participation in a program of modified constraintinduced movement therapy (mcimt). Design: Pre-post, case series. Setting: Outpatient rehabilitation hospital. Participants: Two men and 2 women with unilateral stroke occurring more than 1 year prior to study entry and moderate stable motor deficits. Intervention: Subjects participated in mcimt, comprised of structured, 30-minute therapy sessions emphasizing affected arm use in valued activities, which occurred 3 days a week for 10 weeks. Their unaffected arms were restrained 5 days a week for 5 hours. Main Outcome Measures: The Action Research Arm Test (ARAT), upper-extremity portion of the Fugl-Meyer Assessment (FMA), Motor Activity Log (MAL), and functional magnetic resonance imaging (fmri) at 4T were administered before and after mcimt. Results: Three subjects exhibited score increases on the MAL, ARAT, and FMA, representing increased affected arm use, impairment, and function. These subjects reported new ability to perform valued activities with the affected hand, such as writing. These subjects also displayed cortical reorganization on fmri. One subject exhibited minimal affected arm use changes, modest function changes, and no cortical fmri changes. Conclusions: Increased affected arm use during mcimt appears to induce cortical reorganization, as measured by fmri. In patients who responded to mcimt, cortical reorganization was positively related to degree of increase in affected arm use and ability. Because mcimt is more easily administered than longer duration protocols, mcimt may be a more practicable way of studying plasticity. Key Words: Magnetic resonance imaging; Neuronal plasticity; Physical therapy techniques; Rehabilitation; Stroke by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation AFTER STROKE, THE SIZE OF THE cortical representation of the affected hand is known to decrease, 1,2 possibly due to limb nonuse. 3 However, during task-specific protocols in which the affected arm is repetitively and functionally used, the size of the cortical areas representing the limb increases. 4-7 For example, patients with chronic hemiparesis ( 1y poststroke) participating in constraint-induced movement therapy (CIMT) exhibit increased use and function of the affected arm CIMT emphasizes affected arm use in 2 ways: (1) participants unaffected arms are restricted during 90% of waking hours of a 2-week period; and (2) participants engage in 6-hour activity sessions using their affected arms on the 10 weekdays of the same 2-week period. Shaping (see Taub 11 for a description) is also applied during the 6-hour therapy sessions, in which the patient is verbally encouraged to perform progressively more difficult components of the movement that advance him/her beyond current motor ability. Previous neuroimaging studies 12,13 determined that increased affected arm use patterns observed via participation in CIMT cause cortical reorganization. Although results have been promising, CIMT may be difficult to implement in clinical situations. For example: (1) a recent CIMT case study reported that the patient grew tired of wearing the mitt and had difficulty with full adherence 14(p851) ; (2) a survey 15 found that many patients with stroke would not want to participate in CIMT, preferring therapy lasting for more weeks with shorter activity sessions and/or less hours wearing the restrictive devices; and (3) both American 16 and European 17 researchers have reported similar findings. Given CIMT shortcomings, shorter protocols have been developed. 16,18 The most notable example has been modified constraint-induced movement therapy (mcimt), which combines 30-minute activities of daily living (ADL) practice sessions with restriction of the unaffected arm 5 days a week for 5 hours per day, both during a 10-week period. Besides being reimbursable using existing current procedural terminology codes, mcimt increases affected arm use and function in randomized, controlled pilot studies with acute, 19 subacute ( 3mo to 12mo poststroke), 20,21 and chronic 22 patients with stroke. Increased affected arm use via mcimt participation has been suggested to cause cortical reorganization, but the mcimt mechanism remains unknown. Given that mcimt has already shown promise, the main goal of this study was to examine mcimt neural mechanisms in patients with chronic stroke. Our primary hypothesis was that patients exhibiting increased

2 CORTICAL REORGANIZATION, Szaflarski 1053 affected arm use after mcimt would exhibit changes in their cortical output maps corresponding to the affected hand, arm, and finger regions using functional magnetic resonance imaging (fmri). No changes were expected in the cortical output maps of patients who did not exhibit sizable affected arm use changes after mcimt participation. To our knowledge, this was the first study to examine the possibility of use-dependent cortical changes following participation in an outpatient clinical protocol. METHODS Participants A research team member screened volunteers with chronic hemiparesis due to a stroke who had responded to advertisements placed in therapy clinics in the midwestern United States, using the following inclusion criteria from previous mcimt research: (1) ability to actively extend at least 10 at the metacarpophalangeal and interphalangeal joints and 20 at the wrist; (2) a single, unilateral, index stroke, experienced more than 1 year prior to study enrollment; (3) a score of 70 or more on the Modified Mini-Mental Status Examination 23 ; (4) age between 18 and 95 years; (5) no excessive spasticity at the affected fingers, wrist, and elbow, as defined as a score of 3 or more on the Modified Ashworth Scale 24 ; (6) no excessive pain in the affected arm, as measured by a score of 4 or more on a 10-point visual analog scale; (7) affected arm nonuse, defined as an amount of use score of less than 2.5 on the Motor Activity Log (MAL); (8) discharged from all forms of physical rehabilitation; (9) not participating in any experimental rehabilitation or drug studies; (10) no implants such as pacemaker and/or neurostimulator containing electric circuitry (eg, cardiac pacemaker), or implants, which generate electric signals and/or have moving metal parts; (11) no anxiety and/or claustrophobia; and (12) preserved ability to communicate with the personnel operating the magnetic resonance scanner. Using these criteria, we initially found 7 patients eligible, who agreed to participate, and completed approved consent forms (3 men, 4 women; mean age, y; age range, 54 68y; mean time since stroke, mo; range, mo). However, due to unaffected arm mirror movements (ie, movement of the unaffected arm during attempts to move the affected arm) that were visually observed during fmri scanning, 3 subjects were eliminated after the preintervention fmri, but before therapy was begun. Thus, demographic data for subjects with stroke included in the final sample (n 4) are shown in table 1. Interpretation of informal interviews, MAL scores, and clinical judgments confirmed affected arm nonuse in all subjects with stroke prior to enrollment in the study. In addition to subjects with stroke, we recruited 10 control volunteers (5 men; mean age, y; age range, 34 66y) to provide data regarding typical activation patterns in response to the finger-tapping tasks. Controls had no history of orthopedic or neurologic disease, nor any diagnosis of impairments Table 1: Subject Characteristics Subject Age (y) Sex Months Since Stroke Side of Infarct Patient 1 56 Female 178 Right Patient 2 59 Male 59 Left Patient 3 54 Male 22 Right Patient 4 68 Female 30 Right that resembled those commonly observed in people with stroke. Both stroke and control subjects performed the same motor task in a 4-T fmri scanner (described below). Instruments The following instruments were applied in this study due to their use in previous mcimt work, and due to their responsiveness to motor change following CIMT in chronic patients with stroke. 25 Fugl-Meyer Assessment. The 66-point, upper-extremity section of the Fugl-Meyer Assessment of motor recovery after stroke (FMA) 26 assesses impairment using a 3-point ordinal scale (anchored at 0 [cannot perform] and 2 [can perform fully]). The FMA demonstrates high levels of test-retest reliability (total range,.98.99; subtest range, ), 27 interrater reliability, and construct validity. 28 Action Research Arm Test. The Action Research Arm Test (ARAT), 29 a 19-item, 57-point, test divided into 4 categories (grasp, grip, pinch, gross movement), has each item graded on a 4-point ordinal scale (anchored at 0 [can perform no part of the test] and 3 [performs test normally]). The ARAT has high intrarater (r.99) and retest (r.98) reliability and validity. 29,30 Motor Activity Log. The MAL is a semi-structured interview measuring how patients use their affected limbs for ADLs. Patients and caregivers independently rate how much and how well the patient used the affected arm for 30 ADLs during the past week using a 6-point amount of use (AOU) scale and a 6-point quality of movement scale. Several subjects lived alone or did not have substantial familial support. Thus, the MAL was administered only to patients in this study. Pretesting We applied a multiple baseline, pre-post, case series design. Specifically, after screening and informed consent, the FMA and ARAT were administered on 2 occasions, 1 week apart, while the MAL was administered once. All of the instruments were administered by a research assistant (PL) with 5 years of experience in using these measures. One week after the second administrations of the FMA and ARAT, each subject underwent fmri. After the procedure was explained, subjects were scanned using a 4-T whole body MRI scanner. a The fmri evaluator (JPS) was blinded to subject identity and each subject s therapy outcomes. The fmri testing began with an initial, fast localizer scan (12s) obtained to assure that the head was appropriately positioned. If necessary, adjustments to the head position were made at this point. Head padding specifically designed for this scanner was used to restrict patients head from movement. Next, a 3-dimensional modified driven equilibrium Fourier transform high-resolution anatomic T1-weighted scan was acquired using the following protocol: time-modified driven equilibrium Fourier transform, 1.1 seconds; repetition time (TR), 13ms; echo time (TE), 6ms; field of view (FOV), cm; matrix, pixels; and flip angle, 20. This scan was acquired in an axial orientation, which produces high-quality images with voxel size of 1 1 1mm. Finally, with each finger-tapping task (described below), we obtained a T2-weighted spin-echo echo planar imaging (EPI) pulse sequence (TR/TE, 3000/45ms; FOV, cm; matrix, pixels; slice thickness, 4mm; flip angle, 90 ). Finger-tapping task description. While in the scanner, subjects performed 3 self-paced motor tasks, each lasting 5 minutes 30 seconds: right-handed, left-handed, and both-hands finger-tapping. Each paradigm began with an auditory prompt

3 1054 CORTICAL REORGANIZATION, Szaflarski telling the subject to relax the hand(s). Then, in alternating fashion, subjects were presented with an auditory stimulus telling them to tap their fingers or rest, with each rest or tap session lasting 30 seconds. During tapping tasks (eg, tap the fingers of the right hand ) subjects were asked to tap their right thumb, left thumb, or both thumbs concurrently, to the 2nd, 3rd, 4th, and 5th fingers sequentially on the same hand during each EPI sequence. During the resting task ( relax ), subjects were asked to hold their hands along the body and not to move. In total, each task incorporated 6 rests intertwined with 5 finger-tapping sequences. Performance was visually monitored for adherence to the task and for the presence of mirror movements. fmri data processing. The fmr image postprocessing was performed on an offline workstation using Cincinnati Children s Hospital Image Processing software (CCHIPS), developed in the IDL software b environment. CCHIPS generates statistical parametric maps from fmri data with options for spatial or temporal filtering for mapping data onto stereotactic (Talairach) coordinates; CCHIPS also incorporates coregistration capabilities for motion correction between frames. 31 To process the data, we extracted 30 fmri planes from the 3-dimensional anatomic data set by interpolation for use as an anatomic underlay for activation maps. Hamming filter was applied to the raw EPI data prior to reconstruction to reduce the truncation artifacts at the edges of k space and to reduce highfrequency noise in the images. 32 Next, we performed baseline drift correction using a quadratic baseline correlation on a pixelby-pixel basis We computed cross-correlation values on a pixel-by-pixel basis. The data were then correlated with a boxcar reference waveform. In controls, we transformed the statistical parametric maps of the cross-correlation coefficient into Talairach space for composite mapping (fig 1). 36 Finally, we calculated blood oxygenation level-dependent (BOLD) contrast changes for each stroke subject in their native space based on the individual cross-correlation activation maps (fig 2). Calculating the BOLD signal changes based on average correlations avoids the biases introduced by arbitrary thresholding and clustering schemes. 37 Intervention Procedures Following the preintervention neuroimaging session, each subject participated in individualized 30-minute therapy sessions occurring 3 times a week for 10 weeks, all administered by the same occupational therapist. Approximately 25 minutes of therapy concentrated on affected limb use in 3 ADLs chosen by patient and the treating therapist, including writing, picking up a hairbrush and combing hair, typing on a computer, and picking up a cup and drinking from it. Approximately 5 minutes of therapy was spent on affected limb range of motion as needed. Shaping techniques (see Page et al for a description) were used with the chosen ADLs. During the same 10 weeks, subjects unaffected hands and wrists were restrained every weekday for 5 hours identified as a time of frequent arm use. Their hands and wrists were restrained using polystyrene-filled mitts with self-adhesive straps around the wrist. c Because patients unaffected limbs were restricted while they were at home, logs were administered to document device use time, as well as activities performed during restraint hours. Posttesting After 10 weeks, all patients returned to the same laboratory at which pretests were administered. The FMA, ARAT, and MAL were administered by the same examiner who performed pretests. On the same day, patients returned to the neuroimaging center, where they were administered a postintervention fmri scan using the same apparatus and procedures as pretesting. RESULTS Amount of Affected Limb Use and Function Informal interviews determined that subjects were exhibiting nonuse of their affected hands and arms, which was corroborated by AOU scores less than 2.5 (table 2). Subjects also exhibited stable motor deficits before intervention, as evidenced by FMA and ARAT scores during the pretesting phase (table 3). Fig 1. fmri activation map for the finger-tapping task in a single healthy subject showing cross-correlation statistics for the representative axial slices. Pictures are in neurologic convention (right on the picture corresponds to the right side of the brain). (A) Both hands finger-tapping task (Talairach coordinates of the centroid for right hemisphere: 32, 24, 48; for left hemisphere: 31, 24, 48). (B) Left hand finger-tapping task (Talairach coordinates of the centroid: 32, 24, 49). (C) Right hand finger-tapping task (Talairach coordinates of the centroid: 31, 24, 48). The color bar represents the significance level of activation: blue, r 0.3, red, r 0.7.

4 CORTICAL REORGANIZATION, Szaflarski 1055 Fig 2. fmri activation maps of patients 1, 3, and 4 in response to finger-tapping tasks performed with the affected hand; all pictures are in neurological convention. In patient 3, the proximal and distal motor improvement was associated with shift from scattered (A) pre-mcimt BOLD signal changes in the left pre- and postcentral gyrus and right precentral gyrus to (B) the post-mcimt BOLD signal changes in the subcortical and cortical structures in the right hemisphere. Patient 3 shows change in BOLD signal distribution from (C) the left inferior frontal gyrus to (D) the left middle frontal gyrus. Patient 4 shows no substantial change between (E) the pre-mcimt and (F) post-mcimt scans. The color bar represents the significance level of activation: blue, r.45; red, r 0.8. After intervention, amount of affected limb use for ADLs, as measured by the MAL AOU scale, increased in all subjects (from 0.11 to 2.79) (see table 2). The above increases in affected limb use were accompanied by modest increases on the FMA (see table 3). Larger and more uniform improvement scores were observed on the ARAT, which largely measures more distal function. Clinically, the 3 subjects exhibiting large AOU changes reported that they were now integrating their affected limbs in valued activities. Furthermore, these subjects, who also displayed improvements in motor function, reported Table 2: Patient Scores by Group on the MAL AOU Scale Before and After Intervention Subject Pre Post Change Patient Patient Patient Patient new ability to perform valued ADLs, such as gardening, holding ski poles, holding small animals, and writing. We organized the listing of subjects in table 2 from lowest AOU change score (at top of table 2) to highest AOU change Table 3: Patient Scores on the FMA and ARAT Before and After Intervention ARAT FMA Subject Pre 1 Pre 2 Post Change Pre 1 Pre 2 Post Change Patient Patient Patient Patient Mean NOTE. Pre 1 denotes mean score obtained during first pretesting period; Pre 2 denotes mean score obtained during second pretesting period. Post denotes mean score obtained during posttest. Change refers to mean change, which is computed using the following formula: Post mean (Pre 1 Pre 2)/2.

5 1056 CORTICAL REORGANIZATION, Szaflarski score (at bottom). Interestingly, those subjects with the largest AOU changes (at bottom of table 2) also exhibited the largest changes on the FMA and/or ARAT; individuals exhibiting the least amount of change on the AOU exhibited inconsistent FMA and ARAT changes. Neuroimaging Data Controls. In the control subjects, significant activation was noted in the bilateral precentral gyrus corresponding to the hand area (for left hemispheric activation in response to bilateral finger-tapping task the Talairach coordinates of the centroid were 34, 21, 51; for right hemisphere, coordinates were 30, 22, 51). Representative images for a single subject for bilateral, right, and left finger-tapping task are depicted on figures 1A, 1B, and 1C. Subjects with stroke. No subjects exhibited fmri changes when moving the unaffected arm. Patient 1 (right hemispheric stroke) did not respond to mcimt (see figs 2E, 2F). fmri scans for this patient also did not show changes between pre- and posttesting. Indeed, on both scans, the patient activated bilateral motor cortex when performing finger-tapping task with the affected (left) hand. The pre-mcimt activated areas included left precentral gyrus (31, 23, 46) and to a lesser extent right precentral gyrus and supplemental motor cortex ( 34, 2, 33). After mcimt, the activated areas included predominantly left precentral gyrus (34, 8, 46) and to a lesser degree right precentral gyrus and supplemental motor cortex ( 37, 4, 42). Clinically, patient 2 (left hemispheric stroke) showed only modest ARAT and FMA score changes. Consistently, there was BOLD signal change in the peristroke area in the left hemisphere and additional activation in the right hemisphere (shift from the posterior margin of the ischemic changes in the pre- and postcentral gyri [ 24, 35, 44] to the lateral/inferior part of the precentral gyrus in the right hemisphere [ 37, 1, 16]). Patient 3, who experienced a right hemispheric stroke, exhibited larger motor changes (ARAT score increased by 9 points, FMA score increased by 6.5 points) than other subjects. During affected (left) hand testing, a shift of the fmri activation was noted from scattered BOLD signal changes seen on the pre-mcimt scan (see fig 2A) in the pre- and postcentral gyri of the left hemisphere (32, 28, 43;) and precentral gyrus of the right hemisphere ( 29, 13, 39) to the subcortical and cortical structures in the right hemisphere ( 32, 22, 23; preand postcentral gyrus and underlying white matter) after mcimt (see fig 2B). Patient 4, who experienced a stroke in the subcortical white matter of the right hemisphere, exhibited motor changes primarily in the distal areas of her affected arm, as evidenced by marked changes on the ARAT grip and grasp scales. She showed clear changes in BOLD signal distribution from the left inferior frontal gyrus (54, 0, 24) (see fig 2E) to the left middle frontal gyrus (25, 36, 21) (see fig 2F) from testing of the affected (left) hand. Also, a substantial increase in the volume of activated tissue in the middle frontal gyrus and ipsilateral cerebellum (not shown) was noted when she performed the affected hand tapping test. DISCUSSION Plastic changes occur after neurologic insult, including stroke, primarily in response to diminished excitability and affected limb nonuse. However, increased affected limb use can lead to increased cortical representation of the affected extremity. mcimt increases affected limb use and function in controlled studies with acute, subacute, and chronic patients with stroke, but mcimt mechanisms remain unknown. This study examined whether cortical changes were associated with mcimt-induced affected arm use increases, as determined by fmri. We found that 3 subjects exhibited score increases on the MAL, ARAT, and FMA, representing increased affected arm use, impairment, and function. These subjects reported new ability to perform valued activities with the affected hand. These subjects also displayed cortical reorganization on fmri. One subject (patient 1) exhibited minimal affected arm use changes, modest function changes, and no cortical fmri changes. We conjectured that the mcimt mechanism of action was cortical reorganization, and that this event is brought about by increased affected limb use during mcimt participation. Data in this study are in agreement with this hypothesis. For example, patient 1 exhibited minimal changes in amount of affected arm use and motor status following intervention. Consistent with these findings, this subject s fmri patterns after intervention revealed relatively unchanged activation patterns. On the other hand, patient 3 exhibited sizable use and motor changes. Not surprisingly, this subject exhibited marked cortical changes, with activation patterns shifting to the subcortical and cortical structures in the right hemisphere. Other subjects exhibiting affected limb use and motor changes also displayed correlative cortical reorganization. Our fmri findings are in agreement with other poststroke cortical reorganization studies, 13,14 but also illustrate the lack of consensus regarding the type of cortical plasticity that occurs in patients with poststroke hemiparesis after successful rehabilitation. For example, using fmri, Hamzei et al 38 reported BOLD signal intensity changes in the primary sensorimotor cortex after CIMT participation. Yet, using the same CIMT protocol, Levy et al 13 reported widespread activation patterns in 1 subject in the sensorimotor cortex, supplementary motor area, and the premotor area, and large areas of activation near the lesion site and in the supplementary motor area near the lesion in their second subject. The heterogeneity of these findings underscore the need for further studies examining the mechanisms of cortical plasticity. Before intervention, patients never or only occasionally used their affected arms for ADLs. These reported behaviors were corroborated by scores less than 2.5 on the AOU score of the MAL. After intervention, patients exhibited increased affected limb use for ADLs, as reflected by changes on the MAL ranging from 0.11 to Patients also reported that they were attempting more ADLs with the affected limb, including writing, eating, and/or grooming. The finding that mcimt increases affected limb use was consistent with those reported in previous mcimt studies The above changes in affected arm use were manifest in behavioral changes. Specifically, whereas patients exhibited stable motor deficits before intervention, they exhibited motor improvements after intervention. Those who exhibited larger AOU changes also exhibited greater motor changes. Subjects also reported subjective, but tangible, improvements in the valuable ADLs (eg, subject 2 reported ability to garden again; subject 3 was able to manipulate ski poles and use computer; subject 4 was able to handle animals [zoo-keeper] and write using large letters). Certainly, changes in study measures (ARAT, FMA, or MAL) are important, but these subjective changes were much more significant, because they allowed subjects to reintegrate into their homes and communities. A limitation of this study was the inability to obtain interpretable scans on 3 of 7 eligible subjects due to movement artifact. At the same time, although our findings are encouraging, additional subjects are needed to confirm our findings. To

6 CORTICAL REORGANIZATION, Szaflarski 1057 overcome the former limitation, we now prescreen subjects for mirror movements as part of general mcimt screening procedures. In our ongoing work with mcimt in stroke, intended to address the latter limitation of small sample sizes, we are finding that this simple screening procedure allows us to screen out half of the patients with stroke who would move in the scanner. Increased sample size will also permit statistical analyses in future work, overcoming a limitation of this study. Given that subjects were many months after stroke, and the narrow timeframe during which subjects exhibited changes, the possibility of spontaneous recovery seems unlikely. To our knowledge, this is the first study reporting use-dependent cortical changes following administration of mcimt; an outpatient, reimbursable therapy regimen. A key remaining question is whether fmri scans can be used as a sensitive, precise, objective biomarker in situations where motor change may be difficult or too subtle to measure. The insults exhibited in our sample were too diverse, and some scans were less interpretable, to answer this important research question, which constitutes an additional study limitation. Currently, we are determining the utility of fmri as a dose-response and efficacy biomarker in a larger funded study. Use of a randomized, controlled design, which will evenly distribute subject characteristics, will further compensate for current study shortcomings. CONCLUSIONS This is the first study to show use-dependent cortical changes following participation in a reimbursable, outpatient protocol: mcimt. Additional research is now warranted to further examine mcimt mechanisms using randomized controlled methods and a larger sample. References 1. Cicinelli P, Traversa R, Rossini PM. 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