Alteration of Resting-State Brain Sensorimotor Connectivity following Spinal Cord Injury: A Resting-State Functional Magnetic Resonance Imaging Study.

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Journal of Neurotrauma Alteration of resting-state brain sensorimotor connectivity following spinal cord injury: A resting-state fMRI study (doi: 10.1089/neu.2014.3661) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

1 Alteration of resting-state brain sensorimotor connectivity following spinal cord injury: A resting-state fMRI study Yu-Sun Min, MD1,+, Jang Woo Park, MS2, +, Seong Uk Jin, MS2, Kyung Eun Jang2, Hyun Uk Nam, MD1, Yang-Soo Lee, MD1, Tae- Du Jung, MD1,*,Yongmin Chang, Ph.D3,4,*

1

Department of Physical Medicine and Rehabilitation, Kyungpook National University Hospital,

Korea 2

Department of Medical & Biological Engineering, Kyungpook National University, Korea

3

Department of Radiology, Kyungpook National University Hospital, Korea

4

Department of Molecular Medicine, Kyungpook National University School of Medicine, Korea

+

Both authors equally contributed to this work

Running Head: Alteration of brain connectivity following SCI

*Corresponding Author: Yongmin Chang, Ph.D Department of Molecular Medicine & Radiology Kyungpook National University School of Medicine 200 Dongduk-Ro Jung-Gu, Daegu Korea Tel: 82-53-420-5471 Fax: 82-53-422-2677 E-mail: [email protected]

Tae-Du Jung, MD Department of Physical Medicine and Rehabilitation Kyungpook National University Hospital 200 Dongduk-Ro Jung-Gu, Daegu Korea Tel: 82-53-200-3251 Fax: 82-53-200-3259 E-mail: [email protected]

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2

Abstract Motor and sensory deficits after spinal cord injury (SCI) result in functional reorganization of the sensorimotor network. While several task-evoked functional magnetic resonance imaging (fMRI) studies demonstrated functional alteration of the sensorimotor network in SCI, there has been no study of the possible alteration of resting-state functional connectivity using resting-state fMRI (rs-fMRI). The aim of this study was to investigate the changes of brain functional connectivity in the sensorimotor cortex of patients with SCI. We evaluated the functional connectivity scores between brain areas within the sensorimotor network in 18 patients with SCI and 18 controls. Our findings demonstrated that compared to control subjects, patients with SCI showed increased functional connectivity between primary motor cortex (M1) and other motor areas such as the supplementary motor area (SMA) and basal ganglia (BG). However, decreased functional connectivity between primary somatosensory cortex (S1) and secondary somatosensory cortex (S2) was also found in patients with SCI compared to controls. These findings therefore demonstrated alteration of the resting-state sensorimotor network in patients with SCI, who showed increased connectivity between motor components, and decreased connectivity between sensory components, within the sensorimotor network suggesting that motor components within the motor network increased in functional connectivity in order to compensate for motor deficits whereas the sensory network did not show any such increases, or compensation for sensory deficits.

Keywords: spinal cord injury, cortical reorganization, brain plasticity

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3 Spinal cord injury (SCI) leads to the loss of motor and sensory function below the level of the injury due to degenerative processes affecting the ascending and descending pathways that convey information between the brain and the spinal cord.1-3 Previous studies have demonstrated that spinal cord atrophy, cortical atrophy, and cortical reorganization in the sensorimotor cortex are seen in patients with SCIs.2,4,5 Although multilevel changes are shown both below and above the site of injury, the change in the supraspinal level of the injury is considered an important factor in predicting the degree of recovery.3,4

Previous studies using task-evoked fMRI after SCI have revealed contradictory results. Some fMRI studies demonstrated an expansion of task-related brain activation.1,6 Others found unaltered brain activity during a task involving the arm7,8 as well as reduced brain activation in patients with SCI with persistent motor deficits.9 Recently, measurement of the temporal correlation of BOLD signal between distant regions at rest has emerged as a useful tool to map the functional organization of the brain.10,11 This resting-state fMRI (rs-fMRI) has been successfully applied for various neurological diseases such as stroke, traumatic brain injury, and multiple sclerosis.11-15 Furthermore, because task-evoked fMRI is often difficult to apply to the patients with SCI who had severe motor deficits, rs-fMRI is a good alternative functional imaging tool to investigate the functional organization of the brains of patients with SCI.

However, to the best of our knowledge, there has been no rs-fMRI study on patients with SCI except a single case report.16 Therefore, the aim of this study was to use rs-fMRI to investigate possible alterations in functional connectivity of the sensorimotor network in patients with SCI compared to controls. Based on animal studies and a case report demonstrating the change of functional connectivity between sensorimotor and other

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4 networks in cases of SCI16-18, we hypothesized that there would be a neuroplastic change in the resting-state sensorimotor network after SCI.

Eighteen patients with incomplete cervical SCI (12 males, 6 females; age 57.7 ± 11.94 years) and eighteen healthy subjects (8 males, 10 females; age 52.1 ± 13.8 years) were included in this study. Only patients with SCI who fulfilled the following inclusion criteria were enrolled: (i) they displayed a cervical spinal cord injury that was proved by MRI images, (ii) were a minimum of 3 months postinjury, (iii) had an incomplete injury based on American Spinal Injury Associations Impairment (ASIA) classification, (iv) had impairment of the upper or lower limb, (v) had no head or brain lesion related with the trauma, and (vi) had no medical or mental illnesses, and no seizures. Bilateral upper and lower extremity motor power was evaluated by the ASIA criteria at the point of study enrollment. The visual analogue scale (VAS) and the Beck depression index (BDI) were administered for measuring the severity of pain and depression at the time of MRI acquisition. Experiments were conducted with the written consent of each participant and were approved by the Institutional Review Board of the Kyungpook National University Hospital (IRB number: 2011-09-011)

All MRI data were acquired with a 3.0T MR scanner (HD, General Electric Healthcare). Resting-state BOLD images were obtained using an echo planar-imaging sequence (repetition time (TR) = 2000 ms, echo time (TE) = 30 ms, flip angle = 90, matrix = 64 x 64, field of view (FOV) = 210 mm, and 4 mm thickness with no gap). The subjects had no task but were instructed to stay alert and keep their eyes closed during scanning. Anatomical T1-weighted images were obtained using a 3D-fast spoiled gradient echo sequence (TR) = 7.8 ms, TE = 3 ms, flip angle = 20, matrix = 256x256, FOV = 210 mm, 1.3 mm thickness, and no gap).

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5

Preprocessing of rs-fMRI data was carried out with the statistical parametric mapping software (SPM8,http://www.fil.ion.ucl.ac.uk/spm/) on Matlab (MathWorks, Inc., Natick, MA, USA). The images were performed to correct slice timing, realigned and unwrapped, and coregister. The corrected images were spatially normalized to a Montreal Neurological Institute template (MNI) brain based on the standard stereotaxic coordinate system. The normalized images were smoothed by using a Gaussian kernel of 8 mm FWHM. To estimate the head motion, translation parameters which are the x (left/right), y (anterior/posterior), and z (superior/ inferior) directions were used to calculate the mean displacement (displacement = square root (x2+y2+z2)) of each brain volume as compared to the first volume.19 The estimated mean displacement of each experiment did not exceed 2mm (See also supplemental figure S1).20 There were no mean displacement difference (p = 0.389) between the patient (mean displacement 0.61 ± 0.37mm) and control groups (mean displacement 0.52 ± 0.28mm).

A seed-based method was used to determine the resting-state functional connectivity. In brief, the functional connectivity toolbox in SPM8 (http://web.mit.edu/swg/software.htm) was used to identify the sensorimotor network with a strong temporal correlation to a seed point in the right primary motor cortex, which identified the sensorimotor network consistently (Supplementary Table 1). The M1 (in spheres of 5-mm radius), which is a key node in the motor network, was identified by using the MarsBar ROI tool (http://marsbar.sourceforge.net/) on MNI coordinates. Noise, cerebrospinal fluid, white matter and motion parameters were used to correct time fluctuations of the BOLD signal as nuisance covariates, and a band-pass filter (from 0.008 Hz to 0.09 Hz) was used. The results

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6 of individual functional connectivity maps from the M1 seed were used for within-group analysis of the patients with injuries and control groups at a threshold of p < 0.05 (false discovery rate corrected for multiple comparisons) and a cluster size of 64 voxels. Age and gender were treated as covariate of no interest in the analysis. The functional connectivity was also estimated from the “Asia D” individuals among 18 patients.

Fourteen ROI positions (spheres of 5-mm radius), namely, the primary motor cortices (M1: hand knobs), supplementary motor area (SMA), primary somatosensory cortex (S1), secondary somatosensory cortex (S2), basal ganglia (BG), dorsolateral premotor cortex (dlPM), and ventrolateral premotor cortex (vlPM), were selected based on the results of the within-group analysis and were identified within the bilateral hemispheres using Marsbar on MNI coordinates (Supplementary Table 1). In addition, a voxel-voxel functional connectivity group analysis was performed using the SPM-compatible CONN toolbox to know whether functional connectivity group differences are not driven by other functional connectivity differences such as a cognitive frontal-parietal regions. Functional connectivity scores between pairs of ROIs in each subject were calculated using the functional connectivity toolbox in SPM8. After averaging the functional connectivity scores across subjects, the average functional connectivity matrices were plotted in a color map using MATLAB. The functional connectivity matrices were produced with dimensions 14 × 14 for each group and for each hemisphere, respectively.

To assess differences in the functional connectivity scores between the two groups (patients with cord injury and controls) for each pair of ROIs, two sample t-tests were conducted. All statistical analyses were performed using the Statistical Package for the Social Sciences (Version 21; SPSS, Chicago, IL). p < 0.05 was considered significant.

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There were no age and gender differences between the patient and control groups (p = 0.202 and p = 0.186 respectively). The time since SCI was 49.7 ± 33.6 weeks. Demographic and clinical characteristics of the 18 patients with SCI are summarized in Table 1. The correlation matrix of patients with SCI showed a statistically significant difference in connectivity strengths between M1 and other sensorimotor brain regions compared with the correlation matrix of controls. The diagonal components of each matrix had no connectivity strength because they represent a single brain region (Fig. 1b). There was increased functional connectivity between right M1-right SMA (p = 0.044), right M1-left SMA (p = 0.032) and left BG-left S2 (p = 0.014) in patients with SCI compared to controls. There was decreased functional connectivity between right M1-right S1 (p = 0.007), right M1-right S2 (p = 0.046), right S1-left S1 (p = 0.016), right S1-right S2 (p = 0.002), right S1-left S2 (p = 0.015), left S1-right S2 (p = 0.026) and right S2-right dlPM in patients with SCI compared to controls (Fig. 1c). A voxel-voxel functional connectivity group analysis using the SPM-compatible CONN toolbox showed that the observed functional connectivity differences in the selected ROI’s were not driven by other functional connectivity differences (Data are shown in supplemental figure S2). The connectivity which showed statistically significant changes, and the severity of pain and depression, were not correlated (Supplementary Table 2). In addition, compared to the results from the combined Asia D and C individuals, FC scores from the “Asia D” individuals were slightly but non-significantly decreased in motor networks (Data are shown in supplemental figure S3).

The current study therefore demonstrated that the functional connectivity between motor components within the sensorimotor network was significantly increased, whereas connectivity between sensory components was decreased following SCI. Our results showed

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8 that the functional connectivity between M1 and motor areas such as the SMA, BG, and vlPM was increased compared to controls. The SMA plays a crucial role in the sensorimotor circuits of patients with SCI who are damaged in their afferent feedback system.1 Nishimura et al. observed changes in the activation of motor networks after SCI using PET. They found that bilateral M1 plays a prominent role in the early recovery stage, whereas the contralateral M1 and bilateral vlPM are major contributors in the lateral stage.21 Therefore, the increase in functional connectivity between motor-related brain regions seems to suggest strong neural synchrony between these brain regions, which allows them to recruit more neural substrates from the SMA, BG and vlPM to compensate for motor deficits in patients with SCI.

Several task-evoked fMRI studies have demonstrated extensive reorganization of the motor system at the supraspinal level, with relative over-activation of the motor network after SCI.1,6 Our findings may therefore suggest that extensive changes of the motor system would be possible even at rest, and may serve to compensate for impaired motor functions, although the mechanisms underlying motor reorganization at the cortical and subcortical level are currently not well understood.

Our results also demonstrated decreased connectivity between sensory components within the sensorimotor network. The patients with SCI had decreased sensation below the level of their injury. They receive little-to-no sensory input from their limbs or torso from the level of the injury. Hence, the decreased connectivity between sensory components may be explained by decreased sensory input after SCI. Decreased sensory connectivity can be either indicative of atrophy due to retrograde degeneration22, or indicative of a reduction in angiogenesis.23 Contrary to the motor network showing increased connectivity to compensate the motor deficits, the sensory network did not show such increases in connectivity to compensate for

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9 the sensory deficit. To gain insight into the fundamental processes of cortical reorganization, it is crucial to consider the contribution of the motor and sensory system independently.24

Finally, our results suggested the pivotal role of the BG within the sensorimotor network. Namely, the connectivity of the basal ganglia with S2 was increased in patients. The BG play an essential role as a ‘relay station’ between the neocortex and brain stem to modulate motor and sensory function though the ‘basal ganglia-subcortical loop’.25 One possible interpretation of the pivotal role of the BG is that they affect movement by gating sensory inputs in motor areas.26

The current study had limitations. First, the severity of pain and depression might influence the connectivity of sensory components. However, we confirmed that there was no correlation between the connectivity and the severity of pain and depression. Therefore, the influence of pain and depression can be ruled out in this analysis. Second, plasticity not only at the brain level but also at the cord level might influence changes of connectivity in the sensorimotor network. However, we did not evaluate individual changes in the spinal cord, such as atrophy. Further study would be needed to evaluate the influence of cord atrophy by quantitative measurements.27

In conclusion, our resting-state fMRI study demonstrated alterations in resting-state functional connectivity in the sensorimotor network after SCI. Specifically, it showed increased connectivity between the motor components and decreased connectivity between the sensory components within the sensorimotor network. These findings therefore suggest that motor components within the motor network increased in functional connectivity in order to compensate for motor deficits whereas the sensory network did not show any such


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increases, or compensation for sensory deficits.

Journal of Neurotrauma Alteration of resting-state brain sensorimotor connectivity following spinal cord injury: A resting-state fMRI study (doi: 10.1089/neu.2014.3661) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Page 11 of 24

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Acknowledgments

This work was supported by Biomedical Research Institute grant, Kyungpook National

University Hospital (2013)

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TABLE1. DEMOGRAPHIC DATA AND BASELINE CLINICAL VALUES OF THE SCI SUBJECTS Subjects Gender

Age (years)

Time Injury ASIA ASIA ASIA VAS BDI since Level Scale Motor Motor injury Score(U/E) Score(L/E) (weeks)

1

M

64

24

C2/C2

D

14/13

20/20

30

10

2

M

66

97

C2/C2

D

20/13

20/19

60

20

3

F

69

56

C3/C3

D

25/25

16/18

81

33

4

F

69

74

C3/C3

D

25/25

25/25

51

45

5

M

29

18

C4/C3

D

22/17

25/25

20

7

6

M

64

28

C4/C3

D

13/10

14/14

55

48

7

M

75

58

C4/C4

D

16/17

19/20

39

5

8

F

68

14

C4/C4

C

16/16

7/11

8

16

9

F

51

126

C4/C4

D

20/20

19/19

82

33

10

M

42

30

C4/C4

C

11/10

14/5

69

28

11

F

60

34

C4/C4

D

13/13

12/10

29

54

12

M

64

19

C4/C4

D

14/10

20/20

50

17

13

M

46

58

C4/C4

C

5/4

4/7

10

12

14

F

53

86

C5/C5

D

11/18

9/19

80

34

15

M

57

104

C5/C5

D

12/12

15/15

46

48

16

M

66

13

C5/C5

C

13/9

20/15

20

19

17

M

54

27

C5/C5

D

15/15

15/15

40

13

18

M

43

30

C7/C7

C

18/18

15/2

69

29

ASIA, American Spinal Injury Association; ASIA C, sensorimotor incomplete with half of key muscles below the neurological level have a muscle grade less than 3; ASIA D, at least half of key muscles have a muscle grade of 3 or more; ASIA Motor Score, maximum 100 points; F, female; M, male; C, cervical; VAS, visual analogue scale; BDI, Beck depression index.


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Figure Legends

Journal of Neurotrauma Alteration of resting-state brain sensorimotor connectivity following spinal cord injury: A resting-state fMRI study (doi: 10.1089/neu.2014.3661) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Page 17 of 24

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FIG. 1. (a) Functional connectivity maps for a seed region in right primary motor cortex in both controls and SCI patients (b) Correlation matrix of sensorimotor cortex in SCI show the significant differences compared with controls (c) There was increased functional connectivity between right M1-right SMA, right M1-left SMA and left BG-left S2 in patients with SCI compared to controls. There was decreased functional connectivity between right M1-right S1, right M1-right S2, right S1-left S1, right S1-right S2, right S1-left S2, left S1right S2 and right S2-right dlPM in patients with SCI compared to controls. M1, primary motor cortex; S1, primary sensory cortex; S2, secondary sensory cortex; SMA, supplementary motor area; BG, basal ganglia; dlPM, dorsolateral premotor cortex; vlPM, ventrolateral premotor cortex, * p

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