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Restorative Neurology and Neuroscience 32 (2014) 507–515 DOI 10.3233/RNN-130380 IOS Press
Usage of the middle finger shapes reorganization of the primary somatosensory cortex in patients with index finger amputation M. Oelschl¨agera,1 , J. Pfannm¨ollera,1 , I. Langnerb and M. Lotzea,∗ a Functional
Imaging Unit, Center for Diagnostic Radiology, University of Greifswald, Greifswald, Germany of Trauma and Orthopaedic Surgery, University of Greifswald, Greifswald, Germany
b Department
Abstract. Purpose: The primary somatosensory cortex (S1) is somatotopically reorganized after limb amputation. The duration of the amputation, the intensity of phantom limb pain but also a multifactoral model of altered cerebral input have been discussed to be associated with cortical changes. Patients with finger amputation rarely show phantom limb pain, the deafferented cortical area is small but other fingers might well overtake function. Method: We selected a group of index finger amputated patients and performed a high resolution (in plane: 1.5 mm2 ) S1-mapping during tactile stimulation of finger tips. Result: We found an interhemispheric imbalance of the distance between the thumb and middle finger only for the patient-group. When patients used their middle finger more they showed less interhemispheric imbalance, increased spatial tactile discrimination and increased fMRI-activation in response to stimulation. Phantom limb pain was not associated with somatotopic representation parameters in S1. Conclusions: Overall, our fMRI-data point to a usage dependent plasticity of Brodmann’s area 3b in man. Keywords: Amputation, cortical plasticity, usage factor, somatotopy, primary somatosensory cortex, S1, reorganization, fMRI
1. Introduction Investigations in monkeys (Merzenich, 1998; Pons et al., 1991) as well as magnetoencephalographic (MEG) studys (Birbaumer et al., 1997; Elbert et al., 1994; Flor et al., 1995), functional magnetic resonance 1 Both
authors contributed comparably. author: Martin Lotze, Functional Imaging Unit, Center for Diagnostic Radiology and Neuroradiology, University of Greifswald, Walther-Rathenau-Str. 46, D-17475 Greifswald, Germany. Tel.: +49 3834 866899; Fax: +49 3834 866898; E-mail: [email protected]. ∗ Corresponding
imaging (fMRI) studies (Bjorkman et al., 2012; Lotze et al., 2001; Lotze et al., 1999) or transcranial magnetic stimulation (TMS) studies (Cohen et al., 1991; Karl et al., 2001; Roricht et al., 1999) in humans suggested that the remapping after limb amputation occurs at the level of the primary motor (M1) or somatosensory (S1) cortices. On the cortical level a decrease of lateral inhibition as a result of amputation might account for some of the cortical reorganization (see Calford and Tweedale 1991). Recent studies in monkeys show that after sensory loss, notable reorganization takes weeks to emerge (Darian-Smith and
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Brown, 2000). When investigating the somatosensory domain it is important to consider that S1 is subdivided in 4 cytoarchitecturally different areas 1, 2, 3a and 3b (Brodmann, 1909). Each of these shows separate body representations (Merzenich et al., 1978). While BA3b represents the information from the skin, BA3a represents the information for limb proprioception. The information from BA3b is further processed in BA1 for texture discrimination, and combined with information from BA3a in BA2 for size and shape recognition (Kandel et al., 2000). BA3b is shown to process information before BA1 and might therefore be the primary region for processing of stimuli from the body surface (Papadelis et al., 2011). For the owl and squirrel monkey micro-electrode mapping techniques in BA3b showed robust enlargement of fingers with somatosensory innervation from the radial and the ulnar nerve after median nerve transsection. The invasion of deafferented cortical territories by neighboring representation areas was much more variable in BA1 (Merzenich et al., 1983). In humans only anecdotic data on reorganization after finger amputation have been reported using MEG (Weiss et al., 1998, 2000). This method does not allow to differentiate between cytoarchitectural representation sites, a technique which is available for high resolution fMRI-studies (Fischl et al., 2008). Up to now, group data of patients with amputated fingers are absent although methods demonstrating precise somatotopic mapping of the digits in S1 using high resolution fMRI have been published (Martuzzi et al., 2012; Schweizer et al., 2008; Weibull et al., 2008a). Currently, there is a vivid discussion on how phantom limb pain (PLP) after amputation might be provoked and maintained (Flor et al., 2013, 2006; Makin et al., 2013). Overall, multiple associations of adaptive plastic changes have been reported to factors such as the duration of the deafferentation (Lotze et al., 2006), changes in spontaneous activity of the peripheral nerve (Nystrom and Hagbarth, 1981), the intensity of PLP (Flor, 2008) but also the increased usage of body parts represented in neighboring areas (Lotze et al., 1999). Patients after finger amputation do less frequently present phantom limb pain than those after amputation of the hand or even larger parts of the upper limb. Karle and colleagues (Karle et al., 2002) reported only about 19% of their sample of 58 finger amputated patients with PLP. In comparison, about 50%–80% of patients with amputation of at least the whole hand show PLP
(Nikolajsen et al., 2006). One reason for a lower occurrence rates of PLP in these patients might be a lower degree of functional reorganization of M1 and S1. This assumption is based on the smallness of the deafferented cortical area after amputation of one finger and a good functional compensation of the amputation by other fingers. We were interested in associations of these parameters and especially in the contribution of a functional overtake of the middle finger (D3), e.g. for pinch grip movements. Therefore, we investigated the somatosensory finger tip representation in a small group of patients with a traumatically amputated index finger (D2). The distance between these representations were compared to the other hemisphere and to the corresponding representations in a group of 18 healthy participants. In addition, we carefully tested the compensational functional usage of D3 in different hand motor tasks, tested somatosensory function (von Frey hair and spatial tactile resolution) of thumb (D1) and D3 and selected clinical data (PLP, phantom sensations, stump pain).
2. Material and methods 2.1. Participants We studied 7 patients with D2 amputation each aged between 18–54 years (average 39± [standard deviation] 15). Demographics and an overview on the tests are shown in Table 1. 6 patients were strongly right handed (laterality quotient (LQ) = 95.83 ± 4,17; range 89–100) and 1 patient was left handed (LQ = −80) according to the Edinburgh Handedness Inventory (Oldfield, 1971). Overall, amputation was 61.29 ± 20.25 months before investigation (range 26–84 months). From the medial carpal joint the stump had a lenght of 4.07 ± 2.31 cm on average. Data of the patients were compared to those of a group of 18 healthy participants (aged 31.4 ± 12; 11 women; Edinburgh Handedness Inventory score: range = 0.77–1, average = 0.92). None of the participants suffered from any neurological disorder or vascular disease. Two patients were medicated (one with Ibuprofen and one with beta blockers). All participants gave their written and informed consent according to the Declaration of Helsinki, and the study was approved by the ethics committee of the Medical Faculty of the University of Greifswald.
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Table 1 Clinical, behavioral and demographic data of each participant Subject/ Age Time since Side/dominance Amputation Stump PLP/VAS Stump Telescoping Non-painfulgender1 [years] amputation [months] level2 length [cm] Pain/VAS phantom sensation 01/f 02/m 03/m 04/f 05/m 06/m 07/m 1 f:
54 39 24 18 53 52 36
26 57 48 70 84 62 82
R/R R/R R/L L/R R/R R/L R/R
2 0 2 2 2 1 0
5.5 1.5 6.5 3.5 6.0 5.0 0.5
Y/2.0 Y/4.5 N N N N N
Y/7,2 Y/2 N N Y/3,4 N N
N Y N N N N N
N Y N N N N Y
female; m: male. level: 0 = proximal phalanx or parts missing; 1 = medial phalanx or parts missing; 2 = distal phalanx only missing.
2 amputation
2.2. Clinical and functional scores For spatial tactile resolution (STR) of the finger tips a Grating Orientation Task (GOT) was used as described by Van Boven et al. (2000). D1 and D3 on the left hand and right hand were tested. Due to amputation D2 was only tested on the non-affected hand. Nine different types of hemispherical domes were used for assessment, measuring grating distances between 0.5 and 3.0 mm. For each size type 16 trials were performed, and testing started with the greatest distance of gratings (3.0 mm). Participants were required to make an instant statement about the perceived orientation of the gratings. Testing was aborted when the error-rate of 25% was reached. A better STR is equal to a lower test score within the GOT. In order to ease understanding of performance we inversely plotted GOT-values in Fig. 4C. High values in STR in Fig. 4C therefore mean high performance. For assessment of minimal force-detection threshold, von Frey hair testing was performed at the fingertips of D1–D3 of both hands. On the affected hand only D1 and D3 were tested. The order of digits being tested was randomized. Participants were asked to close their eyes and report whenever they felt a sensation on their skin. The filaments were pressed against the skin up to three times at a 90◦ angle until they bowed and were held in place for 1.5 seconds. A questionnaire provided by the Department of Trauma and Orthopaedic Surgery from the University of Greifswald was used to asses a possible functional overtake of the amputated D2 by D3. We calculated a usage factor from 5 different questions (ordinal scaled from 0 to 100 in 11 steps; 0 = no functional overtake of D3; 100 = full functional overtake of D3). The questions asked in detail about an overtake of function of the impaired finger by the neighboring finger for pinch-
ing small objects, for turning keys, for holding objects during manipulation with the other hand, for pointing towards objects, and for gestical manipulations. The same questionnaire was used to assess if the stump of D2 was still in usage (0 = stump of D2 was not used; 100 = stump was used as much as the former intact D2). In addition we applied the DASH-questionnaire, a self-report about disabilities of the arm, shoulder and hand consisting of 30 items (Hudak et al., 1996). 2.3. MRI measurements Examinations were carried out on a 3T MRI-scanner (Verio, Siemens, Erlangen, Germany) using a 32 channel head coil. Functional imaging was performed with a standard gradient-echo EPI sequence modified after a protocol suggested by Schweisfurth et al. (2011). We measured 17 slices with an in plane resolution of 1.5 × 1.5 mm2 and a slice thickness of 2 mm. The field of view was 191 × 179 mm2 corresponding to an acquisition matrix of 128 × 120 with a flip angle of 76◦ . Slices were oriented parallel to the post central gyrus, corresponding to the phase encoding direction using the auto align scout head and a transversal t2-weighted sequence. Prior to each functional run seven dummy scans were performed in order to achieve identical pulse to pulse magnetization properties. The absolute scan time per run was 3 min 34 sec. A 3DTOF MR-angiography with a spatial resolution of 0.26 × 0.26 mm2 in plane and a slice thickness of 0.5 mm was recorded with transversal-coronal slices, oriented using the inferior points of the frontal brain and the cerebellum. A total of 48 slices was recorded with a slice partial Fourier factor of 7/8, PAT mode GRAPPA with acceleration factor PE 2, reference lines PE 32 and a HF-pulse with a bandwidth of 186 Hz/Px. The repetition time TR = 21 ms, echo time TE = 3.6 ms
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Fig. 1. Procedure of the evaluation method for somatotopic representation in BA 3b demonstrated for the right hemisphere. (a) The cytoarchitectural probability map for S1 is overlaid in white. The omega indicates the primary motor cortex (M1) hand knob. (b) BA 3b is overlaid and indicated as part of S1 after inflation of the brain. (c) The overlay of S1 and BA 3b is shown in black after applying cuts for a 2 dimensional flatmap. (d) The BA 3b is restricted to the confidence interval of finger tip representation after the results presented by Weibull et al. (2008). (e) Zoom on the 2D-region of interest (ROI) with BA 3b and the confidence interval of the D1 and D3 representation maxima.
Fig. 2. Method of measurement of distances on the cortical surface flat map between representation sites of D1 and D3 (black spots) in the BA 3b region of interest (indicated by a white line). (a) D 1, 2, 3 representation in BA 3b of the left hemisphere of a healthy participant; (b) representation of D1 and D3 of a patient after index finger amputation. Distances between the activation maxima between D1 and D3 are indicated with a white line. The omega indicates the M1 hand knob.
and absolute scan time 8 min and 12 sec. Structural imaging was carried out using a standard Siemens sagittal T1-weighted 3D MPRAGE and the FreeSurfer protocol recommended for segmentation of the cortex. 2.4. Functional paradigm Pneumatic stimulus finger clips (MEG International Services Ltd., Coquitlam, Canada) were used to apply tactile stimuli to the subject’s finger tips. Finger tips of D1, D2 (if existing) and D3 of the right and left hand were stimulated separately in each run and runs were randomized to avoid time effects between fingers. The stimulators were composed of a support structure and a membrane, where the membrane has a diameter of about 1 cm. Stimulators were mounted via the support structure and adhesive tape was used to retain their positioning. The membrane was actuated by a
computer controlled pneumatic valve. During stimulation pulses with a length of 50 ms and a randomly chosen inter-stimulus interval, with an average duration of 300 ms, were applied for 10 s. Resulting in a stimulation frequency of about 3 Hz, which elicited a feeling of pulsating pressure mainly transmitted by Merkel cells (McGlone and Reilly, 2010). Followed by a rest period of 10 s, this blocked design was repeated 10 times resulting in a total number of 300 stimulations per fingertip. In order to focus the attention of the subjects to the stimulation, to avoid habituation to an unattended stimulation and to monitor the participant’s attention we applied several stimulation pulses with a length of 150 ms (about 1 to 5 per stimulation block). The particular number and time at which these pulses were presented was randomly chosen for each block. Subjects were instructed to count the total number of the 150 ms second pulses and to report those in the pause between stimulation sessions. Their result
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was compared to the applied pulses and the session was rated as valid if at least 50% of the 150 ms pulses were correctly perceived. Prior to the examination a short training session, including a maximum number of three stimulation blocks, was performed in order to ensure a proper perception of the 150 ms pulses. An additional benefit of this procedure was an identical instruction for each of the subjects, which avoided effects induced by different instructions (Braun et al., 2000). Stimuli application and scanner synchronization were controlled by presentation (Neurobehavioral Systems Inc., Albany, USA). 2.5. Data processing Figure 1 illustrates data processing. Data were analyzed with the FreeSurfer software suite 5.1 (Fischl, 2012). Structural scans of each subject were reconstructed using recon-all. The functional scans were evaluated using fs-fast, from which the surface-based stream and native space features were used. After motion correction the functional images were coregistered to the subjects anatomical scans using boundary based register (BBR). The same was performed with the angiography. The resulting transformation matrices were combined with mri matrix multiply to register the functional activation to the angiography. This result was used to quantify the effect of individual draining vessels on the activation pattern. The contrast of the activation was computed against baseline using a general linear model (GLM) without further smoothing. Functional maps were thresholded at p = 0.001, uncorrected. The analysis was restricted to the FreeSurfer BA3b region (Fischl et al., 2008). In superior-inferior direction the BA3b region was limited using the position of the thumb and middle finger defined in previous investigations (Weibull et al., 2008b). Therefore, the average position of the thumb served as the inferior limit the average position of the middle finger as the superior limit. The limits were enlarged by two standard deviations for the position of the thumb and the middle finger in order to account for the full confidence interval of each finger. Since the average values were known only for the right hand (Weibull et al., 2008b), the region for the left hand was generated by mirroring the region to the right hemisphere. In order to account for the uncertainty due to the mirroring, four standard deviations were used to enlarge the region on the right hemisphere. This was necessary
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to include the somatotopic thumb region for all of the subjects. BA3b overlaps with the other BAs in SI (Fischl et al., 2008). A large inter-individual variability in the fingertip somatotopy in BA3b was reported before (Schweisfurth et al., 2011). Therefore, data evaluation in group space was avoided in this publication and data analysis was performed on the individual brains (see Fig. 2). Activation from neighboring BAs was removed from the surface based analysis, by weighting the activation using the probabilities given in the BA3b ROI. Clusters remaining after the weighting were analyzed in native volume space. In order to remove partial volume effects only voxels with an overlap to the gray matter of more than 50% were included in the analysis. The MR-angiography was used to minimize contributions from vessel activation (Schweisfurth et al., 2011) by exclusion of voxels with an overlap to vessels. Overall we applied the following 3 criteria for activation maxima selected: I) Localization within the BA 3b and reference area of the fingers, II) Overlap with the cortex of more than 50%, and III) No overlap with detected vessels of the angiography. In addition, we calculated a lateralization index (LI) for the highest amplitude of the blood oxygenation level dependent effect (BOLD) within the BA 3b ROI of each hemisphere (Mohamed, 2008).
3. Results 3.1. Behavioral data and testing Somatosensory testing with von Frey hair filaments revealed comparable values for both hands with an average value of 3.46 ± 0.67 for D1 and 3.34 ± 0.52 for D3 on the affected hand and 3.47 ± 0.48 for D1 and 3.38 ± 0.58 for D3 on the non-affected hand. The spatial tactile resolution (STR) showed thresholds of 2.48 ± 0.52 for D1 and 2.66 ± 0.99 for D3 of the affected and 2.20 ± 0.57 for D1 and 2.81 ± 0.74 for D3 of the unaffected hand. These data were again comparable between sides. The usage factor for D2 of the affected side was 35.71 ± 35.11 and for D3 60.57 ± 35.45 on average. This indicates that D3 is overtaking the D2 stump function in most of the patients.
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Fig. 3. Schematic drawing of group results. The left side shows the hemisphere contralateral to the affected hand (as symbolized with a hand without an index finger), the right side shows the hemisphere contralateral to the intact hand. Average distances between the D1–D3 representation maxima are plotted.
3.2. fMRI- evaluation of distances between finger representation maxima Whereas in healthy controls (HC) the distances D1 to D3 did not differ between hemispheres (t(17) = 1.18; n.s) and the lateralization index (LI) was quite symmetric (−0.04 ± 0.14) patients showed an imbalance of the LI (−0.22 ± 0.23; see Fig. 3). Overall, the LI did significantly differ between patients compared to HC (t(23) = 2.43; p = 0.024). The imbalance was caused by a significant difference between the D1–D3 distances in the patients between the affected (average: 9.70 ± 5.23 mm) and non-affected (average: 14.05 ± 3.83 mm) hemispheres (t(6) = 2.64; p = 0.038). BOLD-magnitude during D3-stimulation in BA 3b of the affected hemisphere was increased in comparison to healthy controls (t(23) = 1.92; p = 0.034; one sided). This was not observed for the non-affected hemisphere (t(23) = 0.91; n.s.). 3.3. Correlation between imaging data and behavioral and clinical measures Correlation analysis revealed positive associations between the DASH score and the usage of D3 (r = 0.75; p < 0.05). Higher usage of D3 was associated with increased BOLD-magnitude during D3-stimulation in BA 3b (r = 0.75; p < 0.05; Fig. 4A). When correlating the brain imaging data of distance and BOLD-magnitude we used the lateralization indexes. The more the middle finger (D3) was used (usage factor) the more symmetric was the LI (r = −0.69; p < 0.05; Fig. 4B). We found an association between LI of D1–D3 distance and LI of BOLD-magnitude during D3 stimulation (r = −0.67; p ≤ 0.05). The BOLD-response to
Fig. 4. Correlation graphs between behavioral and mapping parameters in the patients investigated. R2 -indicates the goodness of fit. A) Positive correlation between the usage of D3 with BOLD-magnitude (beta estimates) during D3-stimulation in BA 3b (r = 0.75; p = 0.026). B) Positive correlation between the usage of D3 and the distance between D1 and D3 as calculated for the lateralization index (LI; affected versus non-affected hemisphere). The more the middle finger was used of the the more symmetric the representation distances between hemispheres were (r = 0.69; p = 0.043). C) Positive correlation between the lateralization index for the distance between D1 and D3 and the spatial tactile resolution (STR, inverse domes grid; r = 0.76; p = 0.025).
D3-stimulation in BA 3b in patients showed a tendency for an increase on the affected side (average affected: 4.52 ± 1.77; unaffected: 2.97 ± 0.99;
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t(6) = 1.85; n.s.) and D1–D3 distance was significantly different between hemispheres. Thus, a large BOLDresponse to D3-stimulation was positively associated with a large distance between D1–D3 (trend: r = 0.64; p = 0.06). There was also an association between the STR of D3 and the BOLD-magnitude in response to D3-stimulation in BA 3b (r = 0.69; p < 0.05). In addition, LI of the surface distance between D1 and D3 representation was positively associated with STR (r = 0.76; p < 0.05; Fig. 4C). There was no association between the distance between D1 and D3 and PLP (r = 0.27; n.s).
4. Discussion When comparing the activation maxima in BA 3b of fingers adjacent to the amputated index finger we found a decrease in the distance between D1 and D3 (D1–D3) on the affected side, both in comparison to healthy controls and to the non-affected side. In addition, we found that BOLD-magnitude during D3 stimulation, on the affected hemisphere, was positively associated with use of the finger and somatosensory discrimination performance (both von Frey hair and spatial tactile resolution; STR). In contrast to numerous investigations on patients with upper limb amputation, we found no associations of fMRI-parameters (D1–D3 distance, BOLD-magnitude) with the intensity of painful or nonpainful phantom sensations. Our result of a decreased D1–D3 distance in BA 3b is in line with findings from monkey studies (Merzenich et al., 1983, 1984) and anecdotal reports of single-case finger amputee studies (Weiss et al., 1998, 2000). However, there was no association of the distance between somatosensory finger representations and phantom limb pain, as reported for S1 and M1 after amputation of large parts of the upper limb, i.e. the hand (Birbaumer et al., 1997; Diers et al., 2010; Elbert et al., 1994; Flor et al., 1995; Karl et al., 2001). This apparent discrepancy might be best explained by two substantial differences between the loss of a finger and the loss of a hand. The first is that finger amputation leads to a relatively small deafferented S1 area (we measured a cortical surface D1–D3 distance in healthy participants of approximately 12 mm). This is in sharp contrast to the situation after amputation of the whole hand; the somatotopic representation of the elbow and the lip are more than 30 mm apart on average (for M1 see Lotze et al., 2000). The second possible
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explanation is that the remaining fingers might take over the function of the former index finger. Thus, the amount of functional impairment resulting from loss of the index finger is somehow neglectable. However, an increase in the use of a limb–in this case the middle finger – does have an impact on its representation size in healthy people (Elbert et al., 1995). Associations between phantom limb pain and cortical representation changes in S1 are rather due to re-routing, than to anatomical changes in S1 for patients with traumatic loss of large parts of the upper limb (Ramachandran and Hirstein, 1998). It is well conceivable that only after considerable deafferentation this re-routing is triggered. The positive correlation between the D1–D3 representation distance and the STR is in agreement with findings in musicians (Ragert et al., 2004). In the primary motor cortex, a positive association has been found to exist between repetitive use of a finger and increased primary motor cortex representation in extent and amplitude, in monkeys (Nudo et al., 1996) and humans (Classen et al., 1998; Karni et al., 1995). Thus, the association of increased middle finger usage with increased D3-BOLD-magnitude, and a larger D1–D3 distance on the affected side, might indicate a higher symmetry in D1–D3 distance between hemispheres the more the middle finger was used. A symmetric representation in BA 3b was indeed shown, using the same mapping techniques, in the healthy participants. This supports the argument that enhanced use of the affected hand is reflected in near-to-normal representation maps. A discussion on alterations in the internal representation of the body and their association with maladaptive behaviors and painful, as well as non-painful, phantom limb phenomena is given in (Maihofner and Peltz, 2011). We found a slight increase in activation magnitude for D3, but not for D1. Both are neighboring the deafferentation site. Reports of an increase in activation (BOLD-magnitude, TMS-excitability) of neighboring representation sites to the deafferented area are inconsistent (motor system: TMS: Karl et al., 2001; fMRI: Lotze et al., 2001). This might not simply be explained by the different investigation techniques, because the TMS–MEP amplitude during TMS-elicitation of a movement pattern and the fMRI-magnitude during performance of a comparable movement have been found to be highly associated (Lotze et al., 2006). The increase in BOLD-magnitude might not be caused by a general effect of decreased lateral inhibition, but more
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probably by increased usage of the middle finger after amputation, a proposition which is indeed strengthened by the association of use with BOLD-magnitude in the current results. We selected a homogeneous patient group with respect to the amputated finger (D2) and the cause of amputation (traumatic). However, patients were quite different with respect to the length of the stump and the duration of the amputation. Variation in both of these parameters increased the power of correlation analyses. An important limitation of this study is the small number of patients recruited. Larger groups of patients with finger amputations should, however, confirm the high association between functional use and reorganization. Especially with respect to more definite conclusions on the interaction of small deafferentation areas in S1 and PLP larger samples are needed. Even the amputation of a finger such as the index finger, which is frequently used, can functionally be compensated by increased usage of the middle finger. This functional compensation is associated with a more normal representation of the fingers – at least with respect to the distances between somatosensory representation maxima in BA 3b. A small functional impact of an amputation might therefore well be associated with less maladaptive processes and a lower risk for phantom limb pain.
Acknowledgments
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ML was supported by a grand of the BMBF (01DR12044) and the DFG (LO 795/12-2). We would like to thank Flavia Di Petro for help with language correction.
Flor, H., Elbert, T., Knecht, S., Wienbruch, C., Pantev, C., Birbaumer, N., Larbig, W., & Taub, E. (1995). Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature, 375, 482-484.
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Restorative Neurology and Neuroscience 32 (2014) 507–515 DOI 10.3233/RNN-130380 IOS Press
Usage of the middle finger shapes reorganization of the primary somatosensory cortex in patients with index finger amputation M. Oelschl¨agera,1 , J. Pfannm¨ollera,1 , I. Langnerb and M. Lotzea,∗ a Functional
Imaging Unit, Center for Diagnostic Radiology, University of Greifswald, Greifswald, Germany of Trauma and Orthopaedic Surgery, University of Greifswald, Greifswald, Germany
b Department
Abstract. Purpose: The primary somatosensory cortex (S1) is somatotopically reorganized after limb amputation. The duration of the amputation, the intensity of phantom limb pain but also a multifactoral model of altered cerebral input have been discussed to be associated with cortical changes. Patients with finger amputation rarely show phantom limb pain, the deafferented cortical area is small but other fingers might well overtake function. Method: We selected a group of index finger amputated patients and performed a high resolution (in plane: 1.5 mm2 ) S1-mapping during tactile stimulation of finger tips. Result: We found an interhemispheric imbalance of the distance between the thumb and middle finger only for the patient-group. When patients used their middle finger more they showed less interhemispheric imbalance, increased spatial tactile discrimination and increased fMRI-activation in response to stimulation. Phantom limb pain was not associated with somatotopic representation parameters in S1. Conclusions: Overall, our fMRI-data point to a usage dependent plasticity of Brodmann’s area 3b in man. Keywords: Amputation, cortical plasticity, usage factor, somatotopy, primary somatosensory cortex, S1, reorganization, fMRI
1. Introduction Investigations in monkeys (Merzenich, 1998; Pons et al., 1991) as well as magnetoencephalographic (MEG) studys (Birbaumer et al., 1997; Elbert et al., 1994; Flor et al., 1995), functional magnetic resonance 1 Both
authors contributed comparably. author: Martin Lotze, Functional Imaging Unit, Center for Diagnostic Radiology and Neuroradiology, University of Greifswald, Walther-Rathenau-Str. 46, D-17475 Greifswald, Germany. Tel.: +49 3834 866899; Fax: +49 3834 866898; E-mail: [email protected]. ∗ Corresponding
imaging (fMRI) studies (Bjorkman et al., 2012; Lotze et al., 2001; Lotze et al., 1999) or transcranial magnetic stimulation (TMS) studies (Cohen et al., 1991; Karl et al., 2001; Roricht et al., 1999) in humans suggested that the remapping after limb amputation occurs at the level of the primary motor (M1) or somatosensory (S1) cortices. On the cortical level a decrease of lateral inhibition as a result of amputation might account for some of the cortical reorganization (see Calford and Tweedale 1991). Recent studies in monkeys show that after sensory loss, notable reorganization takes weeks to emerge (Darian-Smith and
0922-6028/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
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Brown, 2000). When investigating the somatosensory domain it is important to consider that S1 is subdivided in 4 cytoarchitecturally different areas 1, 2, 3a and 3b (Brodmann, 1909). Each of these shows separate body representations (Merzenich et al., 1978). While BA3b represents the information from the skin, BA3a represents the information for limb proprioception. The information from BA3b is further processed in BA1 for texture discrimination, and combined with information from BA3a in BA2 for size and shape recognition (Kandel et al., 2000). BA3b is shown to process information before BA1 and might therefore be the primary region for processing of stimuli from the body surface (Papadelis et al., 2011). For the owl and squirrel monkey micro-electrode mapping techniques in BA3b showed robust enlargement of fingers with somatosensory innervation from the radial and the ulnar nerve after median nerve transsection. The invasion of deafferented cortical territories by neighboring representation areas was much more variable in BA1 (Merzenich et al., 1983). In humans only anecdotic data on reorganization after finger amputation have been reported using MEG (Weiss et al., 1998, 2000). This method does not allow to differentiate between cytoarchitectural representation sites, a technique which is available for high resolution fMRI-studies (Fischl et al., 2008). Up to now, group data of patients with amputated fingers are absent although methods demonstrating precise somatotopic mapping of the digits in S1 using high resolution fMRI have been published (Martuzzi et al., 2012; Schweizer et al., 2008; Weibull et al., 2008a). Currently, there is a vivid discussion on how phantom limb pain (PLP) after amputation might be provoked and maintained (Flor et al., 2013, 2006; Makin et al., 2013). Overall, multiple associations of adaptive plastic changes have been reported to factors such as the duration of the deafferentation (Lotze et al., 2006), changes in spontaneous activity of the peripheral nerve (Nystrom and Hagbarth, 1981), the intensity of PLP (Flor, 2008) but also the increased usage of body parts represented in neighboring areas (Lotze et al., 1999). Patients after finger amputation do less frequently present phantom limb pain than those after amputation of the hand or even larger parts of the upper limb. Karle and colleagues (Karle et al., 2002) reported only about 19% of their sample of 58 finger amputated patients with PLP. In comparison, about 50%–80% of patients with amputation of at least the whole hand show PLP
(Nikolajsen et al., 2006). One reason for a lower occurrence rates of PLP in these patients might be a lower degree of functional reorganization of M1 and S1. This assumption is based on the smallness of the deafferented cortical area after amputation of one finger and a good functional compensation of the amputation by other fingers. We were interested in associations of these parameters and especially in the contribution of a functional overtake of the middle finger (D3), e.g. for pinch grip movements. Therefore, we investigated the somatosensory finger tip representation in a small group of patients with a traumatically amputated index finger (D2). The distance between these representations were compared to the other hemisphere and to the corresponding representations in a group of 18 healthy participants. In addition, we carefully tested the compensational functional usage of D3 in different hand motor tasks, tested somatosensory function (von Frey hair and spatial tactile resolution) of thumb (D1) and D3 and selected clinical data (PLP, phantom sensations, stump pain).
2. Material and methods 2.1. Participants We studied 7 patients with D2 amputation each aged between 18–54 years (average 39± [standard deviation] 15). Demographics and an overview on the tests are shown in Table 1. 6 patients were strongly right handed (laterality quotient (LQ) = 95.83 ± 4,17; range 89–100) and 1 patient was left handed (LQ = −80) according to the Edinburgh Handedness Inventory (Oldfield, 1971). Overall, amputation was 61.29 ± 20.25 months before investigation (range 26–84 months). From the medial carpal joint the stump had a lenght of 4.07 ± 2.31 cm on average. Data of the patients were compared to those of a group of 18 healthy participants (aged 31.4 ± 12; 11 women; Edinburgh Handedness Inventory score: range = 0.77–1, average = 0.92). None of the participants suffered from any neurological disorder or vascular disease. Two patients were medicated (one with Ibuprofen and one with beta blockers). All participants gave their written and informed consent according to the Declaration of Helsinki, and the study was approved by the ethics committee of the Medical Faculty of the University of Greifswald.
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Table 1 Clinical, behavioral and demographic data of each participant Subject/ Age Time since Side/dominance Amputation Stump PLP/VAS Stump Telescoping Non-painfulgender1 [years] amputation [months] level2 length [cm] Pain/VAS phantom sensation 01/f 02/m 03/m 04/f 05/m 06/m 07/m 1 f:
54 39 24 18 53 52 36
26 57 48 70 84 62 82
R/R R/R R/L L/R R/R R/L R/R
2 0 2 2 2 1 0
5.5 1.5 6.5 3.5 6.0 5.0 0.5
Y/2.0 Y/4.5 N N N N N
Y/7,2 Y/2 N N Y/3,4 N N
N Y N N N N N
N Y N N N N Y
female; m: male. level: 0 = proximal phalanx or parts missing; 1 = medial phalanx or parts missing; 2 = distal phalanx only missing.
2 amputation
2.2. Clinical and functional scores For spatial tactile resolution (STR) of the finger tips a Grating Orientation Task (GOT) was used as described by Van Boven et al. (2000). D1 and D3 on the left hand and right hand were tested. Due to amputation D2 was only tested on the non-affected hand. Nine different types of hemispherical domes were used for assessment, measuring grating distances between 0.5 and 3.0 mm. For each size type 16 trials were performed, and testing started with the greatest distance of gratings (3.0 mm). Participants were required to make an instant statement about the perceived orientation of the gratings. Testing was aborted when the error-rate of 25% was reached. A better STR is equal to a lower test score within the GOT. In order to ease understanding of performance we inversely plotted GOT-values in Fig. 4C. High values in STR in Fig. 4C therefore mean high performance. For assessment of minimal force-detection threshold, von Frey hair testing was performed at the fingertips of D1–D3 of both hands. On the affected hand only D1 and D3 were tested. The order of digits being tested was randomized. Participants were asked to close their eyes and report whenever they felt a sensation on their skin. The filaments were pressed against the skin up to three times at a 90◦ angle until they bowed and were held in place for 1.5 seconds. A questionnaire provided by the Department of Trauma and Orthopaedic Surgery from the University of Greifswald was used to asses a possible functional overtake of the amputated D2 by D3. We calculated a usage factor from 5 different questions (ordinal scaled from 0 to 100 in 11 steps; 0 = no functional overtake of D3; 100 = full functional overtake of D3). The questions asked in detail about an overtake of function of the impaired finger by the neighboring finger for pinch-
ing small objects, for turning keys, for holding objects during manipulation with the other hand, for pointing towards objects, and for gestical manipulations. The same questionnaire was used to assess if the stump of D2 was still in usage (0 = stump of D2 was not used; 100 = stump was used as much as the former intact D2). In addition we applied the DASH-questionnaire, a self-report about disabilities of the arm, shoulder and hand consisting of 30 items (Hudak et al., 1996). 2.3. MRI measurements Examinations were carried out on a 3T MRI-scanner (Verio, Siemens, Erlangen, Germany) using a 32 channel head coil. Functional imaging was performed with a standard gradient-echo EPI sequence modified after a protocol suggested by Schweisfurth et al. (2011). We measured 17 slices with an in plane resolution of 1.5 × 1.5 mm2 and a slice thickness of 2 mm. The field of view was 191 × 179 mm2 corresponding to an acquisition matrix of 128 × 120 with a flip angle of 76◦ . Slices were oriented parallel to the post central gyrus, corresponding to the phase encoding direction using the auto align scout head and a transversal t2-weighted sequence. Prior to each functional run seven dummy scans were performed in order to achieve identical pulse to pulse magnetization properties. The absolute scan time per run was 3 min 34 sec. A 3DTOF MR-angiography with a spatial resolution of 0.26 × 0.26 mm2 in plane and a slice thickness of 0.5 mm was recorded with transversal-coronal slices, oriented using the inferior points of the frontal brain and the cerebellum. A total of 48 slices was recorded with a slice partial Fourier factor of 7/8, PAT mode GRAPPA with acceleration factor PE 2, reference lines PE 32 and a HF-pulse with a bandwidth of 186 Hz/Px. The repetition time TR = 21 ms, echo time TE = 3.6 ms
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Fig. 1. Procedure of the evaluation method for somatotopic representation in BA 3b demonstrated for the right hemisphere. (a) The cytoarchitectural probability map for S1 is overlaid in white. The omega indicates the primary motor cortex (M1) hand knob. (b) BA 3b is overlaid and indicated as part of S1 after inflation of the brain. (c) The overlay of S1 and BA 3b is shown in black after applying cuts for a 2 dimensional flatmap. (d) The BA 3b is restricted to the confidence interval of finger tip representation after the results presented by Weibull et al. (2008). (e) Zoom on the 2D-region of interest (ROI) with BA 3b and the confidence interval of the D1 and D3 representation maxima.
Fig. 2. Method of measurement of distances on the cortical surface flat map between representation sites of D1 and D3 (black spots) in the BA 3b region of interest (indicated by a white line). (a) D 1, 2, 3 representation in BA 3b of the left hemisphere of a healthy participant; (b) representation of D1 and D3 of a patient after index finger amputation. Distances between the activation maxima between D1 and D3 are indicated with a white line. The omega indicates the M1 hand knob.
and absolute scan time 8 min and 12 sec. Structural imaging was carried out using a standard Siemens sagittal T1-weighted 3D MPRAGE and the FreeSurfer protocol recommended for segmentation of the cortex. 2.4. Functional paradigm Pneumatic stimulus finger clips (MEG International Services Ltd., Coquitlam, Canada) were used to apply tactile stimuli to the subject’s finger tips. Finger tips of D1, D2 (if existing) and D3 of the right and left hand were stimulated separately in each run and runs were randomized to avoid time effects between fingers. The stimulators were composed of a support structure and a membrane, where the membrane has a diameter of about 1 cm. Stimulators were mounted via the support structure and adhesive tape was used to retain their positioning. The membrane was actuated by a
computer controlled pneumatic valve. During stimulation pulses with a length of 50 ms and a randomly chosen inter-stimulus interval, with an average duration of 300 ms, were applied for 10 s. Resulting in a stimulation frequency of about 3 Hz, which elicited a feeling of pulsating pressure mainly transmitted by Merkel cells (McGlone and Reilly, 2010). Followed by a rest period of 10 s, this blocked design was repeated 10 times resulting in a total number of 300 stimulations per fingertip. In order to focus the attention of the subjects to the stimulation, to avoid habituation to an unattended stimulation and to monitor the participant’s attention we applied several stimulation pulses with a length of 150 ms (about 1 to 5 per stimulation block). The particular number and time at which these pulses were presented was randomly chosen for each block. Subjects were instructed to count the total number of the 150 ms second pulses and to report those in the pause between stimulation sessions. Their result
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was compared to the applied pulses and the session was rated as valid if at least 50% of the 150 ms pulses were correctly perceived. Prior to the examination a short training session, including a maximum number of three stimulation blocks, was performed in order to ensure a proper perception of the 150 ms pulses. An additional benefit of this procedure was an identical instruction for each of the subjects, which avoided effects induced by different instructions (Braun et al., 2000). Stimuli application and scanner synchronization were controlled by presentation (Neurobehavioral Systems Inc., Albany, USA). 2.5. Data processing Figure 1 illustrates data processing. Data were analyzed with the FreeSurfer software suite 5.1 (Fischl, 2012). Structural scans of each subject were reconstructed using recon-all. The functional scans were evaluated using fs-fast, from which the surface-based stream and native space features were used. After motion correction the functional images were coregistered to the subjects anatomical scans using boundary based register (BBR). The same was performed with the angiography. The resulting transformation matrices were combined with mri matrix multiply to register the functional activation to the angiography. This result was used to quantify the effect of individual draining vessels on the activation pattern. The contrast of the activation was computed against baseline using a general linear model (GLM) without further smoothing. Functional maps were thresholded at p = 0.001, uncorrected. The analysis was restricted to the FreeSurfer BA3b region (Fischl et al., 2008). In superior-inferior direction the BA3b region was limited using the position of the thumb and middle finger defined in previous investigations (Weibull et al., 2008b). Therefore, the average position of the thumb served as the inferior limit the average position of the middle finger as the superior limit. The limits were enlarged by two standard deviations for the position of the thumb and the middle finger in order to account for the full confidence interval of each finger. Since the average values were known only for the right hand (Weibull et al., 2008b), the region for the left hand was generated by mirroring the region to the right hemisphere. In order to account for the uncertainty due to the mirroring, four standard deviations were used to enlarge the region on the right hemisphere. This was necessary
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to include the somatotopic thumb region for all of the subjects. BA3b overlaps with the other BAs in SI (Fischl et al., 2008). A large inter-individual variability in the fingertip somatotopy in BA3b was reported before (Schweisfurth et al., 2011). Therefore, data evaluation in group space was avoided in this publication and data analysis was performed on the individual brains (see Fig. 2). Activation from neighboring BAs was removed from the surface based analysis, by weighting the activation using the probabilities given in the BA3b ROI. Clusters remaining after the weighting were analyzed in native volume space. In order to remove partial volume effects only voxels with an overlap to the gray matter of more than 50% were included in the analysis. The MR-angiography was used to minimize contributions from vessel activation (Schweisfurth et al., 2011) by exclusion of voxels with an overlap to vessels. Overall we applied the following 3 criteria for activation maxima selected: I) Localization within the BA 3b and reference area of the fingers, II) Overlap with the cortex of more than 50%, and III) No overlap with detected vessels of the angiography. In addition, we calculated a lateralization index (LI) for the highest amplitude of the blood oxygenation level dependent effect (BOLD) within the BA 3b ROI of each hemisphere (Mohamed, 2008).
3. Results 3.1. Behavioral data and testing Somatosensory testing with von Frey hair filaments revealed comparable values for both hands with an average value of 3.46 ± 0.67 for D1 and 3.34 ± 0.52 for D3 on the affected hand and 3.47 ± 0.48 for D1 and 3.38 ± 0.58 for D3 on the non-affected hand. The spatial tactile resolution (STR) showed thresholds of 2.48 ± 0.52 for D1 and 2.66 ± 0.99 for D3 of the affected and 2.20 ± 0.57 for D1 and 2.81 ± 0.74 for D3 of the unaffected hand. These data were again comparable between sides. The usage factor for D2 of the affected side was 35.71 ± 35.11 and for D3 60.57 ± 35.45 on average. This indicates that D3 is overtaking the D2 stump function in most of the patients.
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Fig. 3. Schematic drawing of group results. The left side shows the hemisphere contralateral to the affected hand (as symbolized with a hand without an index finger), the right side shows the hemisphere contralateral to the intact hand. Average distances between the D1–D3 representation maxima are plotted.
3.2. fMRI- evaluation of distances between finger representation maxima Whereas in healthy controls (HC) the distances D1 to D3 did not differ between hemispheres (t(17) = 1.18; n.s) and the lateralization index (LI) was quite symmetric (−0.04 ± 0.14) patients showed an imbalance of the LI (−0.22 ± 0.23; see Fig. 3). Overall, the LI did significantly differ between patients compared to HC (t(23) = 2.43; p = 0.024). The imbalance was caused by a significant difference between the D1–D3 distances in the patients between the affected (average: 9.70 ± 5.23 mm) and non-affected (average: 14.05 ± 3.83 mm) hemispheres (t(6) = 2.64; p = 0.038). BOLD-magnitude during D3-stimulation in BA 3b of the affected hemisphere was increased in comparison to healthy controls (t(23) = 1.92; p = 0.034; one sided). This was not observed for the non-affected hemisphere (t(23) = 0.91; n.s.). 3.3. Correlation between imaging data and behavioral and clinical measures Correlation analysis revealed positive associations between the DASH score and the usage of D3 (r = 0.75; p < 0.05). Higher usage of D3 was associated with increased BOLD-magnitude during D3-stimulation in BA 3b (r = 0.75; p < 0.05; Fig. 4A). When correlating the brain imaging data of distance and BOLD-magnitude we used the lateralization indexes. The more the middle finger (D3) was used (usage factor) the more symmetric was the LI (r = −0.69; p < 0.05; Fig. 4B). We found an association between LI of D1–D3 distance and LI of BOLD-magnitude during D3 stimulation (r = −0.67; p ≤ 0.05). The BOLD-response to
Fig. 4. Correlation graphs between behavioral and mapping parameters in the patients investigated. R2 -indicates the goodness of fit. A) Positive correlation between the usage of D3 with BOLD-magnitude (beta estimates) during D3-stimulation in BA 3b (r = 0.75; p = 0.026). B) Positive correlation between the usage of D3 and the distance between D1 and D3 as calculated for the lateralization index (LI; affected versus non-affected hemisphere). The more the middle finger was used of the the more symmetric the representation distances between hemispheres were (r = 0.69; p = 0.043). C) Positive correlation between the lateralization index for the distance between D1 and D3 and the spatial tactile resolution (STR, inverse domes grid; r = 0.76; p = 0.025).
D3-stimulation in BA 3b in patients showed a tendency for an increase on the affected side (average affected: 4.52 ± 1.77; unaffected: 2.97 ± 0.99;
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t(6) = 1.85; n.s.) and D1–D3 distance was significantly different between hemispheres. Thus, a large BOLDresponse to D3-stimulation was positively associated with a large distance between D1–D3 (trend: r = 0.64; p = 0.06). There was also an association between the STR of D3 and the BOLD-magnitude in response to D3-stimulation in BA 3b (r = 0.69; p < 0.05). In addition, LI of the surface distance between D1 and D3 representation was positively associated with STR (r = 0.76; p < 0.05; Fig. 4C). There was no association between the distance between D1 and D3 and PLP (r = 0.27; n.s).
4. Discussion When comparing the activation maxima in BA 3b of fingers adjacent to the amputated index finger we found a decrease in the distance between D1 and D3 (D1–D3) on the affected side, both in comparison to healthy controls and to the non-affected side. In addition, we found that BOLD-magnitude during D3 stimulation, on the affected hemisphere, was positively associated with use of the finger and somatosensory discrimination performance (both von Frey hair and spatial tactile resolution; STR). In contrast to numerous investigations on patients with upper limb amputation, we found no associations of fMRI-parameters (D1–D3 distance, BOLD-magnitude) with the intensity of painful or nonpainful phantom sensations. Our result of a decreased D1–D3 distance in BA 3b is in line with findings from monkey studies (Merzenich et al., 1983, 1984) and anecdotal reports of single-case finger amputee studies (Weiss et al., 1998, 2000). However, there was no association of the distance between somatosensory finger representations and phantom limb pain, as reported for S1 and M1 after amputation of large parts of the upper limb, i.e. the hand (Birbaumer et al., 1997; Diers et al., 2010; Elbert et al., 1994; Flor et al., 1995; Karl et al., 2001). This apparent discrepancy might be best explained by two substantial differences between the loss of a finger and the loss of a hand. The first is that finger amputation leads to a relatively small deafferented S1 area (we measured a cortical surface D1–D3 distance in healthy participants of approximately 12 mm). This is in sharp contrast to the situation after amputation of the whole hand; the somatotopic representation of the elbow and the lip are more than 30 mm apart on average (for M1 see Lotze et al., 2000). The second possible
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explanation is that the remaining fingers might take over the function of the former index finger. Thus, the amount of functional impairment resulting from loss of the index finger is somehow neglectable. However, an increase in the use of a limb–in this case the middle finger – does have an impact on its representation size in healthy people (Elbert et al., 1995). Associations between phantom limb pain and cortical representation changes in S1 are rather due to re-routing, than to anatomical changes in S1 for patients with traumatic loss of large parts of the upper limb (Ramachandran and Hirstein, 1998). It is well conceivable that only after considerable deafferentation this re-routing is triggered. The positive correlation between the D1–D3 representation distance and the STR is in agreement with findings in musicians (Ragert et al., 2004). In the primary motor cortex, a positive association has been found to exist between repetitive use of a finger and increased primary motor cortex representation in extent and amplitude, in monkeys (Nudo et al., 1996) and humans (Classen et al., 1998; Karni et al., 1995). Thus, the association of increased middle finger usage with increased D3-BOLD-magnitude, and a larger D1–D3 distance on the affected side, might indicate a higher symmetry in D1–D3 distance between hemispheres the more the middle finger was used. A symmetric representation in BA 3b was indeed shown, using the same mapping techniques, in the healthy participants. This supports the argument that enhanced use of the affected hand is reflected in near-to-normal representation maps. A discussion on alterations in the internal representation of the body and their association with maladaptive behaviors and painful, as well as non-painful, phantom limb phenomena is given in (Maihofner and Peltz, 2011). We found a slight increase in activation magnitude for D3, but not for D1. Both are neighboring the deafferentation site. Reports of an increase in activation (BOLD-magnitude, TMS-excitability) of neighboring representation sites to the deafferented area are inconsistent (motor system: TMS: Karl et al., 2001; fMRI: Lotze et al., 2001). This might not simply be explained by the different investigation techniques, because the TMS–MEP amplitude during TMS-elicitation of a movement pattern and the fMRI-magnitude during performance of a comparable movement have been found to be highly associated (Lotze et al., 2006). The increase in BOLD-magnitude might not be caused by a general effect of decreased lateral inhibition, but more
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probably by increased usage of the middle finger after amputation, a proposition which is indeed strengthened by the association of use with BOLD-magnitude in the current results. We selected a homogeneous patient group with respect to the amputated finger (D2) and the cause of amputation (traumatic). However, patients were quite different with respect to the length of the stump and the duration of the amputation. Variation in both of these parameters increased the power of correlation analyses. An important limitation of this study is the small number of patients recruited. Larger groups of patients with finger amputations should, however, confirm the high association between functional use and reorganization. Especially with respect to more definite conclusions on the interaction of small deafferentation areas in S1 and PLP larger samples are needed. Even the amputation of a finger such as the index finger, which is frequently used, can functionally be compensated by increased usage of the middle finger. This functional compensation is associated with a more normal representation of the fingers – at least with respect to the distances between somatosensory representation maxima in BA 3b. A small functional impact of an amputation might therefore well be associated with less maladaptive processes and a lower risk for phantom limb pain.
Acknowledgments
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ML was supported by a grand of the BMBF (01DR12044) and the DFG (LO 795/12-2). We would like to thank Flavia Di Petro for help with language correction.
Flor, H., Elbert, T., Knecht, S., Wienbruch, C., Pantev, C., Birbaumer, N., Larbig, W., & Taub, E. (1995). Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature, 375, 482-484.
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