Neurol Sci DOI 10.1007/s10072-011-0604-6
ORIGINAL ARTICLE
fMRI of the sensorimotor cortex in patients with traumatic brain injury after intensive rehabilitation F. P. S. Lima • M. O. Lima • D. Leon • P. R. G. Lucareli C. Falcon • J. C. Cogo • N. Bargallo´ • J. Vidal • M. Bernabeu • C. Junque´
•
Received: 24 November 2009 / Accepted: 23 April 2011 Ó Springer-Verlag 2011
Abstract For evaluating the patterns of brain activation in sensorimotor areas following motor rehabilitation, seven male patients diagnosed with TBI underwent an fMRI study before and after being subjected to motor rehabilitation. Six patients showed a reduction in the BOLD signal of their motor cortical areas during the second fMRI evaluation. A decrease in cerebellum activation was also observed in two patients. Newly activated areas, were observed in four patients after treatment. In addition, an
increase in the activation of the supplementary motor area (SMA) following rehabilitation was observed in only one test subject. The findings show that motor rehabilitation in TBI patients produces a decrease in the BOLD signal for the sensorimotor areas that were activated prior to treatment. In addition, we observed the recruitment of different brain areas to compensate for functional loss due to TBI in line with the cortical reorganisation mechanism. Keywords fMRI Cortical reorganisation Plasticity Traumatic brain injury Motor rehabilitation Body-weight-supported treadmill training
F. P. S. Lima (&) M. O. Lima J. C. Cogo Laborato´rio de Engenharia de Reabilitac¸a˜o Senso´rio Motora, Instituto de Pesquisa e Desenvolvimento-IP&D, Universidade do Vale do Paraı´ba, Rua Benedito Freire 326, CEP 12244-875 Urbanova Sa˜o Jose dos Campos, SP, Brazil e-mail:
[email protected] D. Leon J. Vidal M. Bernabeu Institut Guttmann, Hospital de Neurorreabiltacio´n, Camı´ de Can Ruti, s/n, 08916 Badalona, Barcelona, Spain P. R. G. Lucareli Universidade Nove de Julho, Hospital Albert Einstein, Sa˜o Paulo, Brazil C. Falcon IDIBAPS, GIB-UB CIBER-BBN, Rossello 153, 08036 Barcelona, Spain N. Bargallo´ C. Junque´ IDIBAPS, Rossello 153, 08036 Barcelona, Spain N. Bargallo´ Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain C. Junque´ Universidad de Barcelona, Casanova 143, 08036 Barcelona, Spain
Introduction Traumatic brain injury (TBI) is the most common cause of morbidity and mortality in people between the ages of 15 and 25. The main effects of TBI include a disturbed cerebral blood flow [1], an alteration in the sensorimotor pathway connectivity [2], injury to both neuronal cell bodies and axonal processes and atrophy of several encephalic structures [3–5]. Studies using Diffusion Tensor Imaging (DTI) techniques performed 8 weeks and 12 months after a severe TBI showed significant atrophy in the brain stem, cerebellum, thalamus, internal and external capsules, putamen, longitudinal fasciculus, corpus callosum and corona radiate [3]. Additional research has also indicated a reduction in the size of the corpus [5, 6] in addition to the internal and external capsule [5]. When sensorimotor areas are affected, the functional consequences of TBI include motor dysfunction such as muscle weakness, coordination deficits and gait disturbances [7, 8]. According to a previous study, TBI patients had more difficulty maintaining dynamic stability when
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Neurol Sci Table 1 Characteristics and the initial and final training parameters for each patient Patient
Age
Gender
Time from injury (days)
Body weight supported (% body weight) Initial
Body weight supported (% body weight) Final
Treadmill speed (kmph) Initial
Treadmill speed (kmph) Final
Gait speed (cm/s) Initial
1
34
M
54
40
20
1.5
2.0
33
2
41
M
152
35
15
1.5
2.1
50
74
3
39
M
95
40
20
1.5
2.0
55
62
4
19
M
357
40
40
1.5
1.7
50
115
5
27
M
87
40
20
1.5
2.0
19
22
6
21
M
84
40
20
1.5
2.0
27
66
7
28
M
38
25
25
1.5
2.3
21
37
Gait speed (cm/s) Final 47
The percentage of body weight supported and training treadmill speeds at the beginning and end of BWSTT reported for each patient in addition to their over-ground gait speed and the outcome of the assessment through the Walking Index for gait speed BWSTT Body-weight-supported treadmill training, M male
performing gait manoeuvres involving challenging walking tasks. The goals of rehabilitation after TBI are to enhance function, increase the levels of the affected patient’s independence, prevent complications and provide an acceptable environment for the patient to recover [9]. Activities such as ‘sit to stand’ training, walking, reaching for items and manipulation of those items are all used in treatment of disorders caused by TBI [10]. Others resources including robotic devices applied to patients with TBI may promote motor improvement by inducing neuroplasticity and reducing the therapeutic effort required during treatment [11]. Functional enhancement following locomotor training in patients with central gait disorders is related to the principle of the neuroplasticity mechanism by task-specific training [12]. Studies using the catwalk automated gait analysis method showed changes in the sensitivity of the plantar surface of the paw in TBI mice. This may have occurred due to an impairment of the sensorimotor function [13]. Children suffering from severe TBI were characterised by a decreased ability to maintain balance, decreased gait speed and increased step length variability as compared to age-matched healthy control individuals [14]. Other scientists suggest that the recovery of function lost due to cortical injury may be attributable to adaptive plasticity in the remaining cortical motor network [15]. Several studies have suggested that after brain injury, areas without lesions contribute to the recovery of function through plastic changes and cerebral reorganisation [16, 17]. Electroencephalogram (EEG) analyses showed decreased neuronal input into the SMA and/or bilateral sensorimotor areas during paretic hand use for 22 patients suffering from unilateral brain lesions after frontal TBI [18]. Timofeev [19] verified a homoeostatic synaptic plasticity compensating for the decreased activity, weeks after cortical trauma through the use of extracellular spikes
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to compute the spike-triggered averages of intracellular membrane potential. Previous fMRI studies have shown that the pattern of brain activation can change during the course of the motor recovery process [20, 21]. According to Robertson and Murre [22], the plasticity mechanism can be induced through movement repetition emphasising one specific task while inhibiting others during sensorimotor rehabilitation. Plastic changes may occur to compensate for lost function after an injury [23]. Thus, the purpose of this study was to evaluate changes in the brain activation patterns in sensorimotor areas following an intensive motor rehabilitation programme, placing emphasis on the enhancement of gait disorders by means of fMRI studies.
Methodology Subjects Seven male patients diagnosed with traumatic brain injury were included in the study. The time from the TBI injury to the start of rehabilitation was, on average, 4 months (Table 1). The patients were admitted in the Hospital of Neurorehabilitation, Institute Guttmann, to participate in the specific motor treatment protocol, and they were submitted to a motor task fMRI acquisition at the Hospital Clinic of Barcelona before and after the rehabilitation treatment. The inclusion criteria were patients with medical indication to the rehabilitation programme, motor function sufficient to participate in all stages of treatment, ability to cooperate with instructions that the fMRI motor task procedure required and the requirement to fulfil the general conditions necessary for an MRI exploration.
Neurol Sci
The selected subjects underwent a motor task fMRI acquisition test at the Hospital Clinic of Barcelona before and after the rehabilitation treatment. The motor task involved performing ankle plantar flexion and toe flexion in both directions. Patients with uncontrollable spasticityinduced body movements were excluded from the study. The study began after the protocol was approved by the ethics committees of both hospitals, and once written consent was obtained from each patient or person responsible for the patients. Motor rehabilitation The patients were subjected to the rehabilitation programme for 5 h each day, five times a week for a period of 1 month (20 sessions). The treatment protocol included kinesiotherapy (passive and active mobilisations, muscle lengthening), mechanical locomotor training, bicycling, manual therapy (with and without assistance of a mechanical device), hydrotherapy and daily life activities’ training. The duration of each event was approximately 1 h in length. Table 1 shows the neurophysiological variables used both pre- and post-treatment to assess the efficacy of the therapy administered. The initial time of the treatment for the body-weightsupported treadmill training (BWSTT) was 20 min, and the modification of the time depended on the endurance and capability of each patient. Training sessions began at a level equivalent to 40% of the total body weight supported and at treadmill speeds of at least 1.5 km per hour. The treadmill speed was increased progressively to 2.5 km per hour, and the level of the weight supported was adjusted within sessions to achieve appropriate knee extension. fMRI protocol The subjects were scanned using a 3T Siemens TIM TRIO. The MRI protocol consisted of a two motor-task fMRI and one high-resolution 3D structural sequence. The fMRI protocol consisted of two BOLD-sensitive EPI sequences (TE 29 ms, TR 2,000 ms, number of slices 36, matrix 128 9 128, FOV 240 mm, slice thickness 3 mm, FA 908). The subjects were provided instructions for the motor task that the subject was required to perform prior to each scan. The subjects were positioned with comfortable pads located below each knee to allow an ankle movement without restrictions. During the functional imaging process, each motor activation period was signalled with a short instruction to the subjects, by headphones. The movement exercises were controlled visually by two examiners (F.P.S.L and M.O.L) in order to monitor any movement or apparent changes in movement during the rest periods of the non-moving limbs. The motor task used for fMRI
exploration involved foot movements including the ankle plantar flexion and toe flexion. The block design began with a 20 s rest period, followed by 30 s periods of movement of the right foot, 30 s of left foot movement and 10 s of rest. This cycle was repeated three times. The patients were oriented to perform the motor task according to the voluntary movement present. Approximately 15 repetitions were made during each period. Finally, a T1weighted MPRAGE structural sequence of the whole brain was acquired to achieve perfect localisation of the activation areas. The acquisition parameters of the structural image were TE 2.98 ms, TR 2,300 ms, TI 900 ms, matrix 256 9 256, FA 98 and voxel size 1 9 1 9 1 mm3. fMRI data analysis The analysis of the functional imaging data was performed using SPM5 (http://www.fil.ion.ucl.ac.uk/spm) implemented on Matlab 6.5 (Mathworks, Sherborn, MA, USA). Pre-processing steps involved the realignment of the fMRI scans to remove any head movement effects and to reduce unwanted variance components in the voxel time series. Following this process, the realigned images were co-registered to the structural MRI, previously segmented into the cerebral spinal fluid, grey and white matter, normalised to a template using the structural segmentation normalisation parameters and smoothed with a Gaussian filter using a kernel of 8 mm. High pass filters of 160 s for the hand motor fMRI and 260 s for the foot motor fMRI were used to remove low frequency components in time series prior to statistical analysis. Movement parameters from the realignment were used as a nuisance variable in statistical analysis to reduce the effect of the movement in the results. A statistical threshold of FWE corrected p value of 0.05 was established to determine the levels of significance for the activation of the cerebral regions. Activation area labelling was made by means of the AAL toolbox (http://www.cyceron.fr/freeware/).
Results Table 2 shows the activated cerebral areas of the patients who participated in the motor rehabilitation programme. Patient 1 showed activation of three new areas after treatment in the pre-central, post-central and paracentral gyrus. Supplementary motor area (SMA) activation was observed only in the contralateral region post-treatment. The results for patient 2 showed a decrease in cerebellum and SMA activation. In addition, the patient’s pre-central area was activated only after completion of the rehabilitation programme. Patient 3 showed activation in the putamen and paracentral areas only after the completion of the
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Neurol Sci Table 2 Description of the main cerebral regions (two bigger clusters or all the clusters bigger than 100 voxels) that achieved statistical significance during the motor-task exercises performed using the right and left foot before and after treatment Patient
1
Before treatment
R
L 2
R L
3
4
K
Region*
Coordinates (x, y, z) of the maxima
Supp Motor_L
-4, 10, 50
6,777
Supp Motor_L
0, -12, 58
443
Cerebelum_L
-52, -56, -30
172
Cerebelum_R
30, -50, -22
119
Precentral_R
54, 2, 50
190
Postcentral_L
-58, -18, 28
126 215
Parietal_R
62, -36, 48
273
Paracentral_L
-6, -34, 72
Occipital_R
34, -76, 2
971
Paracentral_R
6, -38, 70
Frontal_L
-36, 34, 40
37
Supp Motor_R
6, -14, 60
Cerebelum_L
-30, -86, -32
Cerebelum_R
30, -80, -42
Precentral_L
-48, -6, 24
2,393
K
70 38 5,870 458
40, -80, -30
350
Cerebelum_R
52, -56, -38
-8, -86, -30
132
Cerebelum_L
-48, -58, -36
125
Pallidum_L
-22, -10, 2
666
Supp Motor_R
6, -10, 70
103
Precentral_L
-50, -2, 24
288
R
Supp Motor_R
12, -22, 52
19
Paracentral_L
-4, -20, 72
370
L
Paracentral_L Supp Motor_R
-8, -28, 54 12, -22, 50
15 1,102
Putamen_L Supp Motor_R
-28, -4, 6 6, -12, 74
40 851
Supp Motor_R
14, 8, 64
R
Paracentral_L
-8, -14, 74
2,095
Paracentral_L
-4, -16, 66
1,388
Paracentral_R
4, -28, 68
406
Supp Motor_R
6, -4, 46
45
Precentral_L
-18, -20, 74
2,115
R
R
L
7
Coordinates (x, y, z) of the maxima
Cerebelum_L
L
6
Region*
Cerebelum_R
L 5
After treatment
5,573
26 1,399
Paracentral_R
6, -28, 66
Postcentral_L
-60, -22, 24
130
Paracentral_L
-12, -22, 78
76
Paracentral_L
-2, -28, 56
46
Supp Motor_R
10, -20, 70
210
Precentral_L
-20, -20, 74
107
Supp Motor_R
4, -2, 62
244
Supp Motor_L
-8, 10, 50
651
Cerebelum_R
42, -74, -44
134
Paracentral_L
-8, -32, 66
198
Supp Motor_L
-6, -10, 72
Supp Motor_L
-8, -6, 62
182
Precentral_L
-36, 10, 46
179
Cerebelum_R
20, -84, -38
113
Cerebelum_R
28, -56, -50
152
Precentral_R
12, -28, 70
149
Paracentral_R
10, -26, 74
Postcentral_L Supp Motor_R
-58, -4, 38 4, -10, 60
111 218
13,987
16,589
Cerebelum_R
12, -90, -26
1,238
Cerebelum_R
28, -42, -48
204
Cerebelum_L
-26, -32, -36
148
Putamen_R
30, 12, 6
282
R
Paracentral_L
-6, -18, 76
708
Paracentral_L
-8, -22, 80
1,414
L
Postcentral_R
20, -42, 76
928
Postcentral_R
16, -38, 76
1,664
Supp Motor_R
8, -4, 50
46
Supp Motor_R
8, -2, 50
46
For all cases except 1L the maxima are inside the reported region. In 1L it is reported de nearest region (less than 2 cm) *p \ 0.05 FEW corrected voxel level
rehabilitation programme, where an increase in the SMA activation was observed. The data indicate that patient 4 showed a decrease in the level of activation in the paracentral area. In this patient, the SMA was activated bilaterally after treatment. Patient 5 showed a decrease in the SMA activation. Pre- and post-central areas were activated
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following the rehabilitation programme. The results for patient 6 revealed an increase in the SMA and the cerebellum activation. The SMA and paracentral area activation levels were found to decrease in patient 7. The images of patient 4 were chosen randomly to represent the overall results of the study (Fig. 1).
Neurol Sci Fig. 1 3D cortical activations corresponding to patient 4 before (a) and after (b) treatment (Brigthen area in left motor cortex in (a) corresponds to shared areas)
The parameters provided by the BWSTT showed a reduction in the percentage of the body weight sustained in patients 1, 2, 3, 5 and 6 after treatment. Patients 4 and 7 maintained the same value. All of the patients improved in terms of the treadmill and gait speed parameters (Table 1) measured in this study. Notably, the age and time of the injury were not related with the activation of different areas among the patients of this study.
Discussion The main approach of the motor rehabilitation protocol for this investigation involved the evaluation of lower limb movement. For the assessment of motor recovery following treatment, were observed the parameters provided by the BWSTT. The results obtained in this study revealed that all of the exercises performed by the TBI patients improved in terms of the treadmill and gait speed. When considering the body-weight-supported tests, patients 4 and 7 maintained the value obtained before treatment, while others underwent decreases in these values. Ultimately, these data indicate that BWSTT was efficient in the treatment of these patients. The current investigation verifies that changes occurred in the level of fMRI activation in TBI patients following intensive motor rehabilitation. A reduction of the BOLD signal in the cortical areas of patients 1, 2, 4, 5, 6 and 7 were observed. A number of previous neuroimaging studies have noted that cerebral activation decreased in a manner that was related with an increase in the neural efficiency following some stimulus or motor task [24–26]. Research performed on patients with cerebral palsy showed activation in the bilateral primary sensorimotor cortex (cSM1) and in the ipsilateral SMA before treatment. After treatment, only the cSM1 in the contralateral side of the lesion remained activated. The authors suggest that these
changes can be associated with the neuroplasticity mechanism inherent to motor function improvement [27]. The results also indicated that the level of activation in patients 2 and 6 decreased in the cerebellum. An investigation performed using positron emission tomography (PET) showed that during new learning, the cerebellum is strongly activated and the level of activation decreased when the subject performed the task automatically [28]. In the fMRI analyses for patient 3, the area of activation identified after treatment was the putamen. According to Jenkins [28], the basal ganglia can also be frequently activated in pre-learned sequence tasks. The cerebellum has been described as an ‘‘on-line’’ comparator and corrector of movement. In the later stages of TBI, recent investigations suggest that the cerebellum may also play a role [29]. After treatment, some patients invoked the use of novel areas of the brain, such as pre-central (patients 1, 2 and 5), paracentral (patients 1 and 3) and post-central (patients 1 and 5). We think that this engagement of new brain regions during the motor performance occurred in an attempt to compensate for the functional loss of the affected areas resulting from brain injury. An increase in the activity of the AMS following rehabilitation was observed only in patient 4. Kim et al. [30] also observed an increase in the level of activation in the SMA and motor cortex region during finger-thumb opposition studies with the paretic arm in TBI patients using fMRI. These patients were evaluated following constraint-induced therapy. The authors interpreted these findings as the capability for neuroplastic changes to occur in preserved regions after an event causing brain injury. Celnik and Cohen [31] and Nudo et al. [17] observed the activation in the intact contralateral motor cortex to brain lesions following motor recovery. Some investigations performed on stroke patients showed that motor recovery in these patients is represented by the activation of the motor network in the bilateral motor cortex [32, 33].
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Several cerebral regions are also involved in the motor learning process. Motor learning is associated with skilled movements that subsequently develop into permanent memory. Patients with neurological diseases perform below average when attempting to relearn previously learned skills. A compromised brain area may influence the motor skills inherent to the relearning process [29]. Mani et al. [34] observed that cerebral areas activated in control group were observed to be activated in patients within the first year after brain injury through the evaluation of motor and visual tasks performed during fMRI. In this work, we observed a clinical enhancement in patients through the evaluation of quantitative parameters provided by BWSTT, and therefore, these findings suggest that changes in cerebral activation occurred not only through spontaneous formation, but also due the efficacy of the motor rehabilitation protocol administered to these patients. In conclusion, our findings demonstrated motor function enhancement in TBI patients due to an intensive rehabilitation-training programme that produced a decrease in the BOLD signal inherent to the sensorimotor areas that were previously activated (functional recovery). In addition, we observed the recruitment of different brain areas to compensate for functional loss due to TBI in line with the cortical reorganisation mechanism (plasticity). The limitations of this study were the sample size and the heterogeneity of the sample. Future research will be performed to increase the sample size to allow for the performance of group analysis according to TBI subtype and to generate reliable correlations between clinical and physiological parameters. Acknowledgments We gratefully acknowledge support from the Alban Programme (European Union Programme of High Level Scholarships for Latin America).
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