Neural Substrates for the Motivational Regulation ofMotor Recovery after Spinal-Cord Injury
Yukio Nishimura1,2,3,7*, Hirotaka Onoe3,4, Kayo Onoe5, Yosuke Morichika1, Hideo Tsukada3,6, Tadashi
Isa1,3,7
1 Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Japan, 2 Precursory Research for Embryonic Science and Technology,
Japan Science and Technology Agency, Tokyo, Japan, 3 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan,
4 Functional Probe Research Laboratory, RIKEN Center for Molecular Imaging Science, Kobe, Japan, 5 Molecular Dynamics Laboratory, RIKEN Center for Molecular Imaging
Science, Kobe, Japan, 6 Central Research Laboratory, Hamamatsu Photonics, Hamamatsu, Japan, 7 Graduate University for Advanced Studies (SOKENDAI), Hayama, Japan

Abstract
It is believed that depression impedes and motivation enhances functional recovery after neuronal damage such as spinalcord injury and stroke. However, the neuronal substrate underlying such psychological effects on functional recovery
remains unclear. A longitudinal study of brain activation in the non-human primate model of partial spinal-cord injury using
positron emission tomography (PET) revealed a contribution of the primary motor cortex (M1) to the recovery of finger
dexterity through the rehabilitative training. Here, we show that activity of the ventral striatum, including the nucleus
accumbens (NAc), which plays a critical role in processing of motivation, increased and its functional connectivity with M1
emerged and was progressively strengthened during the recovery. In addition, functional connectivities among M1, theventral striatum and other structures belonging to neural circuits for processing motivation, such as the orbitofrontal cortex,
anterior cingulate cortex and pedunculopontine tegmental nucleus were also strengthened during the recovery. These
results give clues to the neuronal substrate for motivational regulation of motor learning required for functional recovery
after spinal-cord injury.
Citation: Nishimura Y, Onoe H, Onoe K, Morichika Y, Tsukada H, et al. (2011) Neural Substrates for the Motivational Regulation of Motor Recovery after SpinalCord Injury. PLoS ONE 6(9): e24854. doi:10.1371/journal.pone.0024854
Editor: Kelvin E. Jones, University of Alberta, Canada
Received March 22, 2011; Accepted August 22, 2011; Published September 28, 2011
Copyright: ß 2011 Nishimura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The research was supported by Precursory Research for Embryonic Science and Technology (PRESTO) and Core Research for Evolutional Science andTechnology (CREST), Japan Science and Technology Agency (JST), the Molecular Imaging Program on ‘‘Research Base for Exploring New Drugs’’ from the Ministryof Education, Culture, Sports, Science and Technology (MEXT) and Nakayama Foundation for Human Science. The funders had no role in study design, datacollection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: yukio@nips.ac.jp

movement repertories are equipped only in higher primate species
including humans and macaque monkeys. The macaque monkeys
were trained to reach for a small piece of food through a narrowvertical slit, and to grasp it between the pads of their index finger
and thumb (Fig. 1B, see Video S1 for details). We performed anear-complete or complete lesion of the lateral corticospinal tract(l-CST) at the mid-cervical spinal segment, which impaired the
direct cortico-motoneuronal connections while the indirect
pathways from the motor cortex to motoneurons, mediated bybrainstem or spinal cord interneurons whose axons were locatedventrally to those of the l-CST, were mostly left intact (Fig. 1A). As
described in the previous study, the precision grip was impaired
immediately after the spinal-cord injury. However, the success rateof precision grip recovered almost completely within 4–5 weeks inall the 3 monkeys tested (Fig. 1B and C, see Video S1 for details).
We performed PET scans during the preoperative, early(approximately 3 weeks to 1.5 month postoperatively) and latestages of recovery (approximately 3–4 months postoperatively) andmeasured the regional cerebral blood flow (rCBF) as an index of
the neuronal activity. We found that activities of the bilateral M1
increased during the early recovery stage (Fig. 2Ab). During thelater stage of recovery, the activity of the bilateral ventral premotor
cortices (PMv) increased and the activated area of the contralesional M1 was expanded, while activation of the ipsilesional M1

Introduction
Current basic researches on the neuro-rehabilitation focus
mainly on neuronal plasticity and motor learning for functional
restoration of affected limbs after neuronal damage such as spinalcord injury and stroke. Depression is a common psychologicalproblem after neuronal damage [1–4], and it has been shown toimpede the recovery process [3]. Therefore, motivation is a key
issue for enhancing the effect of rehabilitation therapy. However,the neuronal substrate underlying such psychological effects on
functional recovery remains obscure.
Recently, we showed the neuronal mechanisms of functional
recovery in a non-human primate model of partial spinal cord
injury (Fig. 1A) [5–9]. Advantages of the experiments on nonhuman primate models are, for instance, that the extent of thelesion can be well defined and that the recovery time course can becontrolled. Furthermore, longitudinal and quantitative behavioral
evaluation from pre-lesional state are possible which is usuallyunavailable in patient studies [7,10]. Moreover, especially themacaque monkeys are indispensable model animals for this kind ofresearch, because they are close enough to humans both in the
structure of the brain and body architecture [11,12]. Especiallyloss of the dexterous hand movements is one of the major causes ofsuffering for the patients with spinal cord injury and such
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Motivation and Motor Recovery after Neuronal Damage

Figure 1. Recovery of finger dexterity after spinal-cord injury. (A) Extent of the l-CST lesion at the C4–C5 segment (indicated by black hatch)in three monkeys. (B) Representative video frames showing the recovery of finger dexterity in monkey T. Red arrows towards B indicate thecorresponding day on the plot of recovery time course. Intact: Day 220, Early: Day 27, Late: Day 137. (C) Recovery time course of precision grip in
three monkeys. A successful trial was defined as any trial that resulted in the successful precision grip with the index finger and thumb and removalof the food from the pin without dropping it. The graph in C was modified from our previous study [6] with permission.
doi:10.1371/journal.pone.0024854.g001

stages: (i) preoperative stage, (ii) early recovery stage, and (iii) laterecovery stage. PET scans during the early recovery stage were
initiated when the success rate for retrieval reached 80%. PET
scans during the late recovery stage were initiated when the
success rate for retrieval consistently reached 100% at 3 months
post-operation. In Monkey H, PET scans during the earlyrecovery stage were conducted between postoperative days 15 to29, and those during the late recovery stage were conducted
between postoperative days 90 to 112. In Monkey K, PET scans
during the early stage were conducted between postoperative days
22 to 41, and those during the late stage were conducted between
postoperative days 92 to 115. In Monkey T, PET scans during theearly stage were conducted between postoperative days 36 to 64,
and those during the late stage were conducted between
postoperative days 106 to 122.

was reduced. Moreover, the contribution of these cortical regions
to recovery has been demonstrated by a reversible inactivation
with the microinjection of muscimol. On the other hand, we also
found that the activity of the contralesional ventral striatum (VSt),
including the nucleus accumbens (NAc), increased during therecovery (Fig. 2Aa) [6,7]. In this study, in order to explore therelationship between these motor cortices and motivation centers,
we examined the functional connectivity of the VSt with otherbrain regions by the correlational analysis of rCBF [13,14] using
the same set of the PET data in our preceding study [6].

Results
Functional recovery of finger dexterity after l-CST lesion
As described in previous study [6], dexterous finger control was
impaired immediately after the spinal-cord injury. The success rateof precision grip recovered to more than 80% of that before thelesion within 3 weeks in all the 3 monkeys. Then the success raterecovered almost completely within 4–5 weeks (Fig. 1A and B).
The recovery time course of each animal was not uniform(Fig. 1C), although we intended the lesions to be as similar in size
as possible (Fig. 1A). The timing of PET scans at each stage wasdetermined by the recovery level in the behavioral test. We
performed the PET scans when each monkey reached similar
performance level. On the basis of recovery course of precision
grip, we performed PET scanning during the following three
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Functional connectivity between the ventral striatum
and motor cortex emerged and was strengthened
through the recovery course
Regions of interest (ROIs) for the contralesional ventral
striatum (co-VSt, Fig. 2Aa), contralesional motor cortex (coM1, Fig. 2Ab) and ipsilesional motor cortex (ip-M1, Fig. 2Ab),
which included the activated foci revealed by SPM analysis, wasdetermined by the results of the main effect of the functional
recovery, which were reported in our previous study [6]. Scatterplot diagrams in Figure 2B show the correlations of signal
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Figure 2. The correlation of rCBF between the ventral striatum (VSt) and the primary motor cortex (M1) before and after spinalcord injury. (A) Region of interest (ROI) in the ventral striatum (a, co-VSt), contralesional primary motor cortex (left on b, co-M1) and ipsilesional
primary cortex (right on b, ip-M1). Each ROIs were indicated by crossed point of the red lines. (B) The correlation of rCBF between the VSt and the M1
before and after the spinal-cord injury. Scatter plot diagrams show the correlation of rCBF between the VSt and the co-M1, and between the VSt and
ip-M1 during intact (a and e), early recovery (1–2 months after lesion, b and f), late recovery (3–4 months after lesion; c and g) and recovery(including the data from both early and late recovery; d and h) stages. Individual data points indicate the data from individual sessions of the PET
scan in each monkey that are shown with different symbols. Numerals beside the regression lines indicate Pearson’s correlation coefficients (r)(dotted line: P,0.05, thin line: P,0.01, bold line: P,0.001) and P-values (p). The plots without the r and p-value, indicate no significant correlation (Allthe r- and p-values are shown in Table S1).
doi:10.1371/journal.pone.0024854.g002

intensity in the co-VSt with that in the co- (Fig. 2Ba–d) or ip(Fig. 2Be–h) M1 in each monkey before and after the spinal-cord
injury. A positive correlation between the co-VSt and both theco- and ip-M1 was not observed prior to the lesion (Fig. 2Ba ande), but emerged during the recovery, especially during the laterecovery stage (Fig. 2Bb–d, Bf–h) in all the 3 monkeys. All the rand p-values of correlation at the individual stages are indicatedin Table S1.

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Functional connectivity of the ventral striatum with othermotivation centers
Summary of multiple comparisons of the whole brain regions of
the 3 monkeys are shown in Figure 3 and Table 1. During therecovery, significant positive correlations with the VSt (ROI in
Fig. 2Aa) were also observed in bilateral orbitofrontal cortices(OBF, Fig. 3Bd), the rostral part of the anterior cingulate cortex(rACC, Fig. 3Be), the caudal part of the ACC (cACC, Fig. 3Bf and3

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Motivation and Motor Recovery after Neuronal Damageg), the ipsilesional pedunculopontine tegmental nucleus (PPTN,
Fig. 3Bi) and the putamen (Pu, Fig. 3Bg), all of which have been
described to be involved in the processing of motivation andemotion [15–28] (see also Table 1). Such correlation was notobserved preoperatively, but, emerged during recovery (Fig. 3).
To confirm whether these brain sites are mutually correlated,
we calculated correlation of signal intensity within these brain sites.
In figure 4, the significant level of correlation between two areas
among M1, ACC, OBF, VSt, PPTN and Ventral Tegmental Area
(VTA) in the intact state and during the recovery process isindicated with the color of the lines connecting the two areas. As

Table 1. Statistical analysis of correlation of the rCBF in the
co-VSt with that in other brain regions during the recovery
stage.

Brain region

Laterality

t-value

Location in Fig. 3B

OBF

contra

3.73

d

OBF

ipsi

3.42

d

rACC

ipsi

3.18

e

cACC

ipsi

3.37

f

Pu

contra

4.26

g

M1

contra

5.46

H

M1

ipsi

3.19

h

IPS

contra

4.31

i

PPTN

ipsi

3.06

i

Cb

ipsi

3.40

j

Cb

Contra3.94

j

The level of the significance was set at P,0.001 (t.3.15). The t-values at thecenter of individual masses of activation (the locations are indicated with lettersthat correspond with those in Fig. 3Bd–j) are indicated.
doi:10.1371/journal.pone.0024854.t001

clearly indicated, only the M1 and ACC showed positive
correlation in the intact state (Figure S2Ab–c and S4Aa, TableS2 and S5 in intact). However, the correlation between the M1
and these motivation centers including the ACC, OBF, VSt,
PPTN and VTA, and correlation within motivation centers were
strengthened during the recovery process (Figure S1, S2, S3, S4,
S5, S6, Table S2, S3, S4, S5, S6, S7). Thus, functional
connectivity between the M1 and the motivation centers andmutual functional connection among the motivation centers were
strengthened throughout the period of recovery process.

Discussion
The present study has shown that the functional connectivity
among the M1, the VSt and other structures belonging to theneural circuits for processing motivation emerged and were
strengthened during recovery. The present study thus demonstrated plasticity in the functional connectivity of the motivational
networks with the M1, which might be specifically correlated withthe extent of functional recovery of finger dexterity after the
spinal-cord injury.
The VSt, in particular the NAc, has been shown to beimportant in information processing for motivation and reward.
Neuronal activity [21] and dopamine [22] release in the NAc havebeen reported to increase during expectation and experience of
rewards. Patients with dysfunction of the NAc suffer fromdepression [24], and the NAc may act as a gateway to enhanceor degrade processing of motivational information that controls
emotional actions and behaviors [18,19,23,24]. A recent clinicalstudy demonstrated that deep brain stimulation to the NAc
alleviated anhedonia during depression, and accompanied increases in activity of the fronto-striatal networks and limbic system[26]. Furthermore, repetitive transcranial magnetic stimulation(rTMS) to the prefrontal cortex has been used as a potential
treatment in neuropsychiatric disorders such as depression[16,17,20]. In addition, the ACC has been shown to play animportant role in effort-related decision-making [27,28]. Thus,
activity of fronto-striatal networks including the NAc may play a
critical role in the control of motivation and its activation might be

Figure 3. Strength of functional connectivity of individual
brain regions with the contralesional ventral striatum before
and after spinal-cord injury. (A) Preoperatively, (B) postoperatively.
Average data obtained from the three monkeys. The correlations were
calculated between the rCBF value of the ROI in the contralesional
ventral striatum (co-VSt, see Fig. 2Aa) and that in other regions during
the precision grip task. Brain areas that have significant positive
correlation (P,0.01, uncorrected for multiple comparisons) areindicated on a three-dimensional reconstruction of a template brain
MRI of macaque monkeys. The significance level is given in terms of
t-values represented in a colored scale. (A) and (B) are the results
during the intact and recovery stages (including the data from both
early and late recovery), respectively. Views are from the contralesional
hemisphere (a), top (b), ipsilesional hemisphere (c), and coronal
sections (d–j). Lines drawn on the lateral views of the brain in C
correspond to the levels of coronal sections of (d–j) in A and B.
doi:10.1371/journal.pone.0024854.g003

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Figure 4. The functional connectivity among individual brain regions during the preoperative and postoperative stages. Strength offunctional connectivity between two regions out of M1, VSt, ACC, OBF, PPTN and VTA are indicated by the color of individual lines connecting thetwo regions. (A): Intact, (B): Recovery stage. The colors of lines indicate the intensity of the connectivity represented by p-values of correlation.
doi:10.1371/journal.pone.0024854.g004

helpful to enhance motivational state during the functional
recovery of finger dexterity after the spinal-cord injury.
It is important to examine how the ‘‘functional connectivity’’ ofthe motivational networks with the M1 observed in the present
study emerged. One possibility that should be excluded is that it
simply reflects the change in amount of reward. On this aspect,because the PET scans were performed after the success rate
exceeded 80%, the amount of reward that the monkeys got during
the sessions was constant both preoperatively and postoperatively,or slightly less only during the early recovery stage. Therefore, thecorrelation observed in this study was not likely to have resulted
from pseudo-correlation between the increase in the reward
amount and increased activity of M1, both of which might beparallel the recovery of success rate.
On the other hand, task difficulty would be increased after
spinal cord injury, which needs higher level of motivation toachieve the demanding task that requires activation of mesolimbic
system. Task difficulty might also require higher level of M1
activation, that might lead to emergence of the correlation
between the two areas. We assume this may not be the sole
explanation of the present result, because correlation became
higher at the later stage of recovery when performance of the task
became easier, than the early phase, when the performing the task
was difficult. Thus, at this stage, it is difficult to make clear
explanation on how the correlation between the VSt and M1
emerged during the recovery from the spinal-cord injury. Further
experiments are needed, such as recording of neural activity from
VSt, and testing the effects of activation/inactivation of the VSt
neural activity on the M1 activity and functional recovery of thehand dexterity. However, it might be suggested that functional
recovery of finger dexterity requires skill learning and may require
higher level of M1 activity, and increased synaptic efficacy in thepathways between M1 and motivation centers through the NAc
might underlie such reorganization of the neural circuits involving
the M1. Then a question may arise on how the M1 and NAc are
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connected with each other. By using transsynaptic labelingtechnique, it has been shown that the NAc provides strong
multisynaptic projections to all the body-part representations in
the M1 through the substantia innominata [29], which is also apart of the VSt. rTMS on the M1 can evoke the release of
dopamine in the VSt, including the NAc, in anesthetized monkeys[30]. Thus, the M1 and NAc have oligosynaptic mutualinterconnections.
It has been reported that the dopaminergic system is essential
for reinforcement learning [31–33]. Currently, skill learning andreinforcement learning tend to be discussed in different contexts.
Our results might have identified the neural substrates that bridge
the reinforcement learning to motor learning for functional
recovery after the neuronal damage. The present findings may
promote the development of psychological therapies that enhancethe efficacy and quality of rehabilitation.

Methods
Subjects
Three monkeys [two Macaca mulatta (Monkey T: male 8.1 kg,
Monkey K: male 6.5 kg) and a Macaca fuscata (Monkey H: female
6.7 kg)] were used in the present study. The data of the present
study were obtained for our previous studies [6,29] and reanalyzed with a different method for the present study. The
experiments were approved by the animal experimental committee of the National Institute of Natural Sciences (Approved No.:
A15-85-58) and were performed in accordance with the NIH
Guidelines for the Care and Use of Laboratory. Monkeys weremonitored closely and animal welfare was assessed on a daily basis,
and if necessary several times a day. This includes veterinary
examinations to make sure animals are not suffering. If animals
experience pain they receive pain medications. If pain cannot be
relieved, or if veterinary examination reveals signs of suffering thatcannot be relieved by analgesics, antiemetics, or antibiotic therapy,
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animals are euthanized. The details of animal welfare and steps
taken to ameliorate suffering were in accordance with therecommendations of the Weatherall report, ‘‘The use of nonhuman primates in research’’.

Data Analysis
The reconstruction was performed on projection data, after
which images were corrected for attenuation using a transmission
scan with a 4.0 mm Hanning filter. Reconstructed brain images(voxel size, 1.261.263.6 mm), which were scalped and smoothedwith a 4.0 mm FWHM isotropic kernel, were processed using
statistical analysis of the parametric mapping (SPM99) software.
For the inter-subject analysis, brain shapes of individual monkeys
were morphologically normalized to a pseudo-brain template
MRI, which was constructed by averaging 8 brain MRI images
from young adult male macaque monkeys using a [18F]FDG-PET
image of each subject. PET images obtained from the scan sessions
that satisfied the behavioral criteria were summated for their first
60 s epochs, and were used for statistical analysis by parametricmapping (SPM99) software (see Text S1). Regions of interest(ROIs) for the co-VSt, which included the activated foci revealed
by SPM analysis, was determined by the results of the main effectof the functional recovery (Fig. 2Ab), which was reported in ourprevious study [6]. The correlations were calculated between
rCBF values in the VSt on the contralesional hemisphere and inother regions during the precision grip task. Additional ROIs forthe neuronal substrate for motivation such as the rostral andcaudal part of the anterior cingulated cortex (rACC Fig. 3Be andcACC Fig. 3Bf), orbitofrontal cortex (OBF, Fig. 3Bd on
contralesional side), and pedunculopontine tegmental nucleus(PPTN, Fig. 3Bi on ipsilesional mid-brain) were determined by the
results of correlation analysis with rCBF on the VSt during the
precision grip task at the recovery stage. Additional ROI for the
motor center such as the primary motor cortex (M1, Fig. 3Bh on
contralesional side) were also determined by the results ofcorrelation analysis with rCBF on the VSt during the precisiongrip task at the recovery stage. The rCBF values of 9 voxels
around the center voxel on each activation spot during each scansession were used for correlation analysis. The statistical threshold
was set at P,0.01, uncorrected (t.2.38 for intact, early and latestage, t.2.35 for recovery stage).

Spinal Cord Injury
In order to obtain a partial spinal-cord injury, the l-CST
located in the dorsolateral funiculus of the spinal cord wastransected under general deep anesthesia [5–9]. Briefly, theborder between the C4 and C5 segments was exposed bylaminectomy of the C3 and C4 vertebrae, and a transverse
opening was made in the dura. The CST lesion was made undera surgical microscope. First, a small opening in the pia mater was
made at the lateral convexity of the spinal cord. A horizontal strip
in a mediolateral direction relative to the lateral funiculus wasmade by inserting a minute L-shape hook that could not be
inserted the gray matter. Next, the dorsal part of the lateralfuniculus was transected using forceps from the dorsal root entry
zone ventrally to the level of the horizontal strip of the lesion
described above. Finally, the lesion was extended ventrally to themost lateral part of the lateral funiculus. The opened dura mater
was closed, and skin and back muscles were sutured with nylon orsilk strings.

Behavioral test
As described in a previous report [5–9], in order to assess thecapacity of dexterous finger movements before and after spinal
cord injury, the monkeys were trained to be seated on a monkey
chair and to reach, grasp and retrieve a small piece of sweet
potato or carrot (about 7 mm cubic) through a narrow vertical slit
using both the index finger and thumb of the forelimb (Fig. 1B,
see also Video S1). The food piece was positioned in the center ofa vertical slit located at the height of the monkey’s shoulder andat a sagittal distance of 15 cm. Each experiment (approximately
30 min every third day) consisted of 100 trials. In each trial, theanimal reached for the food piece from a fixed position. A highspeed digital video camera (33 frames/s at a shutter speed of 1/
1000 of a second) was used to record the reach-retrieval
sequences from a lateral view. A successful trial was defined as
any trial that resulted in the successful precision grip with theindex finger and thumb, and removal of the food from the pin
without dropping it.

Histological assessment of lesion completenessAt the end of the experiments, the monkeys were deeply
anesthetized with an overdose of sodium pentobarbital (50–75 mg/kg, i.v.) and perfused transcardially with 0.1 M phosphatebuffered saline (PBS, pH 7.3), followed by 4% paraformaldehyde
in 0.1 M PBS (pH 7.3) and, finally, the same fresh PBS containing
10%, 20% and then 30% sucrose. The spinal cords were removed
from the bone immediately, saturated with 30% sucrose in 0.1 M
PBS (pH 7.3), then cut serially into 50 mm thick coronal sections
on the freezing microtome. The sections processed for KlüverBarrera staining or Nissl-staining with 1% Cresyl Violet were used
for assessing the lesion extent.

PET experiments
A series of PET scans was conducted during the intact andrecovery stages as descried elsewhere [6,34] (see also text in
RESULTS). Briefly, thirty-one slices of 3.6 mm intervals werecollected simultaneously by the PET scanner. After the delivery
of a bolus of [15O]H2O via a cannula placed into the sural vein,
the scan was initiated automatically when the radioactivity in thebrain reached greater than 30 kcps. The monkey was allowed to
begin the behavioral task (20 trials) at about 10 s before the startof the PET scan. During the scan, the monkeys performed aseries of reach-grip-retrieve-eat movements every 5 s. PET data
were collected for 80 s (one 40 s frame followed by four 10 sframes). Video recording of the scanning session was performed,
and if the monkey did not start from the fixed starting point or
did not start reaching immediately (within less than 15
frames = 500 ms) after presentation of the food or did not movethe hand directly to the food piece, the data from the session was
excluded from analysis. Twenty scans were conducted in Monkey
H and K in both tasks for every stage, and 24 scans wereconducted in Monkey T.
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Supporting Information
Video S1 Recovery time course of finger dexterity after
spinal cord injury.
(WMV)
Figure S1 Strength of functional connectivity with theco-VSt. Strength of functional connectivity derived fromcorrelations between the rCBF value in the co-VSt and that inother regions during the precision grip task were calculated. The
data were obtained from 3 monkeys. Brain areas with a significant
positive correlated rCBF (P,0.01, uncorrected for multiple
comparisons) are superimposed on a three-dimensional reconstruction of a template brain MRI of macaque monkeys that wasmade by our group. The significance level is given in terms of t
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Motivation and Motor Recovery after Neuronal Damage

Table S3 Statistical analysis of correlation of the rCBF

values represented on a colored scale. (A), (B) (C) and (D) areresults during the intact, early and late stages of recovery, and all
recovery stages (including the data from both the early and laterecovery stages), respectively. (a) to (g), coronal sections. (C) shows
lateral views of the brain. Lines (d) to (f) in (C) indicate the levels ofcoronal sections of (a) to (g), respectively.
(TIF)

in the co-M1 with that in other brain regions during theintact, early, late stage of recovery and recovery stage.
The same arrangement as Table S2.
(DOCX)
Table S4 Statistical analysis of correlation of the rCBF

in the co-OBF with that in other brain regions during theintact, early, late stage of recovery and recovery stage.
The same arrangement as Table S2.
(DOCX)

Figure S2 Strength of functional connectivity with theco-M1. The same arrangement as Figure S1.
(TIF)
Figure S3 Strength of functional connectivity with theco-OBF. The same arrangement as Figure S1.
(TIF)

Table S5 Statistical analysis of correlation of the rCBF

in the rACC with that in other brain regions during theintact, early, late stage of recovery and recovery stage.
The same arrangement as Table S2.
(DOCX)

Figure S4 Strength of functional connectivity with therACC. The same arrangement as Figure S1.
(TIF)

Table S6 Statistical analysis of correlation of the rCBF

in the cACC with that in other brain regions during theintact, early, late stage of recovery and recovery stage.
The same arrangement as Table S2.
(DOCX)

Figure S5 Strength of functional connectivity with thecACC. The same arrangement as Figure S1.
(TIF)
Figure S6 Strength of functional connectivity with the
ip-PPTN. The same arrangement as Figure S1.
(TIF)

Table S7 Statistical analysis of correlation of the rCBF

in the ip-PPTN with that in other brain regions during
the intact, early, late stage of recovery and recovery
stage. The same arrangement as Table S2.
(DOCX)

Table S1 Statistical analysis of correlation of the rCBF
between the co-VSt and the primary motor cortex at
different stages before and after the spinal-cord injury.
The values indicate Pearson’s correlation coefficients (r) and pvalues. r and p-values correspond with each scatter plot in
figure 2B in main text. ‘‘n.s.’’ indicates no significant. co-M1:
contralateral M1, ip-M1: ipsilateral M1.
(DOCX)

Text S1 Supporting information for Methods.

(DOCX)

Acknowledgments
We thank H. Oba, D. Fukumoto and K. Isa for technical support.

Statistical analysis of correlation of the rCBF
in the co-VSt with that in other brain regions during theintact, early, late stage of recovery and recovery stage.
The level of the coefficients was set at P,0.01 (t = 2.38 for the
intact, early, late stage of recovery, t = 2.35 for recovery stages). tvalues at the center of individual masses of activation are
indicated.
(DOCX)
Table S2

Author Contributions
Conceived and designed the experiments: YN HO TI HT. Performed theexperiments: YN HO YM HT. Analyzed the data: YN HO KO MY.
Contributed reagents/materials/analysis tools: HT. Wrote the paper: YN
HO TI. Surgery of the animals: YN HO TI.

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