Adaptation in the motor cortex following cervical spinal cord injury

D. J. Mikulis, M. T. Jurkiewicz, W. E. McIlroy, W. R. Staines, L. Rickards, S.

KalsiRyan, A. P. Crawley, M. G. Fehlings and M. C. Verrier
Neurology 2002;58;794-801

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Adaptation in the motor cortex following

cervical spinal cord injury
D.J. Mikulis, MD; M.T. Jurkiewicz, BSc; W.E. McIlroy, PhD; W.R. Staines, PhD; L. Rickards, RN;
S. KalsiRyan, BSc, PT; A.P. Crawley, PhD; M.G. Fehlings, MD; and M.C. Verrier, MHSc

AbstractBackground: The nature of the adaptive changes that occur in the cerebral cortex following injury to the
cervical spinal cord are largely unknown. Objective: To investigate these adaptive changes by examining the relationship
between the motor cortical representation of the paretic right upper extremity compared with that of the tongue. The
tongue was selected because the spinal cord injury (SCI) does not affect its movement and the cortical representation of
the tongue is adjacent to that of the paretic upper extremity. Methods: FMRI was used to map cortical representations
associated with simple motor tasks of the right upper extremity and tongue in 14 control subjects and 9 patients with
remote (5.5 months) cervical SCI. Results: The mean value for the site of maximum cortical activation during upper limb
movement was identical between the two groups. The site of maximum left hemispheric cortical activation during tongue
movement was 12.8 mm (p 0.01) medial and superior to that of control subjects, indicating the presence of a shift in
cortical activation. Conclusion: The findings indicate that the adult motor cortex does indeed adapt following cervical SCI.
The nature of the adaptation and the underlying biological mechanisms responsible for this change require further
investigation.
NEUROLOGY 2002;58:794 801

There is considerable evidence that the brain adapts

to injuries occurring within the peripheral and central nervous systems. Transcranial magnetic stimulation (TMS) and high-resolution EEG performed in
patients with spinal cord injury (SCI) have shown
spatial expansion of the cortical representation of
the musculature proximal to the level of the com-

plete injury and have shown shifts in the focus of

activation during motor tasks.1-4 This has been interpreted as reorganization of the cortical motor system. The inference from these studies is that cortex,
formerly active in producing movement in the paralyzed body segments, becomes active during movement of the unaffected body parts proximal to the

From the Departments of Medical Imaging (Drs. Mikulis and Crawley), Surgery (Dr. Fehlings and L. Rickards), and Physical Therapy (S. KalsiRyan),
Toronto Western Hospital of the University Health Network; and Departments of Rehabilitation Science (Drs. McIlroy and Staines, M. Verrier), Physiology
(Dr. McIlroy, M. Jurkiewicz, and M. Verrier), and Physical Therapy (Dr. McIlroy, M. Verrier), University of Toronto, Ontario, Canada.
Supported by the Ontario Neurotrauma Foundation (99119) and the National Sciences and Engineering Research Council of Canada (PGS-A).
Received July 13, 2001. Accepted in final form November 27, 2001.
Address correspondence and reprint requests to Dr. D.J. Mikulis, Department of Medical Imaging, Toronto Western Hospital, McLaughlin 3-404, 399
Bathurst Street, Toronto, Ontario, Canada M5T 2S8; e-mail: mikulis@uhnres.utoronto.ca
794

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Table 1 Patient demographics

ASIA motor
score (right)
Patient no.

Age, y

Time since
injury, mo

Motor paradigm

ASIA
grade*

ASIA motor
level (right)

Upper/lower limb

Wrist

Tongue

22

5.5

C6

13/0

17

5.5

C7

14/0

65

5.5

C5

13/15

51

27.0

C7

16/0

42

9.0

C6

12/0

48

86.0

C7

17/10

67

29.0

C5

11/15

39

242.0

C6

9/0

29

156.0

C7

22/5

10

36

182.0

C6

14/0

11

35

180.0

C4

0/0

n
Mean SD
Range

X
X

11

11

11

11

11

10

10

41.0 16.0

84.3 89.1

1767

5.5242

* American Spinal Injury Association (ASIA) grade: A complete: no motor function or sensory function is preserved in the sacral segments S4 to S511; B incomplete: sensory but not motor function is preserved below the neurologic level and extends through the
sacral segments S4 to S5.11

level of the lesion. These changes can occur relatively

quickly and have been documented as early as 6
days after the injury.2 In SCI, the relative volume of
disconnected cortex changes as a function of the level
of injury. It therefore follows that the higher the
injury, the greater is the degree of cortical adaptation. This relationship has been examined in subjects
with SCI using PET cerebral blood flow analysis. In
addition to expansion of the upper extremity cortical
representation, the degree of activation was positively correlated with the level of the injury (cervical,
thoracic, and lumbar); that is, the higher the injury,
the greater the increase in regional cerebral blood
flow during performance of the motor task.5 The first
use of fMRI in assessing cortical adaptation following SCI showed a medial displacement of the foci of
cortical activation during movement of the biceps
muscle in individuals with either complete thoracic
or incomplete lumbar injury.6 Similar observations
have been made in subjects with facial nerve palsy,
in which the representation of hand motor function
was observed to expand laterally into the primary
sensorimotor cortex that controls facial movement.7
Enlargement of the abductor pollicis brevis representation that reversed the expansion of facial representation has been observed in patients with hemifacial
spasm following local neuromuscular blockade with
botulinum toxin.8 These studies clearly indicate the
existence of interactions between the hand and face
representations in the motor system. Evidence of
direct neuronal connections between these representations has now been documented in humans
through observation of co-activation of orbicularis

oculi muscle measured by electromyography in

normal subjects during ipsilateral wrist extension.9 Furthermore, there is structural evidence in
monkeys suggesting that powerful -aminobutyric
acid (GABA)-mediated lateral inhibitory cortical
interconnections help to maintain stable cortical representations.10 A disruption of this inhibitory network secondary to de-efferentation/de-afferentation
might provide the stimulus for the cortical reorganization observed in these studies.
If it is assumed that horizontal cortical connections access the de-afferented/de-efferented zone in
the primary sensorimotor cortex, then an expansion
or migration of tongue representation in subjects
with cervical SCI is expected, since the control of the
tongue is not directly influenced by the injury and the
representation of the tongue region is in close proxim-

Table 2 Inclusion/exclusion criteria

Inclusion

Exclusion

Quadriparesis

Post-traumatic brain injury

Level C4 to C8

History of seizure activity

ASIA score A or B

Unsafe for MRI*

Able to give informed consent

Medically stable post halo
* Metallic implants, implanted medical devices, metallic foreign
bodies (contraindications to MRI unless known to be safe in a
magnetic environment).
ASIA American Spinal Injury Association.
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Table 3 Location of FMA and COM during right wrist extension

Location of

M/L

A/P

I/S

Controls, n 14

33.7 8.2

27.2 3.7

57.7 7.4

Patients, n 10

32.8 5.8

27.8 7.1

57.0 5.6

0.766

0.794

0.800

Controls, n 14

35.2 6.0

29.1 5.3

57.0 4.0

Patients, n 10

33.9 5.2

28.3 7.5

57.8 4.2

0.582

0.783

0.648

upper extremity will be decreased compared

with normal control subjects.
b. The spatial separation will increase with increasing degree of impairment of upper extremity movement.
c. The spatial separation will increase with
higher levels of SCI.

FMA

p Value
COM

p Value

All values given in mm 1 SD displaced from the anterior commissure in Talairach space in the medial/lateral (M/L), anterior/
posterior (A/P), and inferior/superior (I/S) planes.
FMA focus of maximum activity; COM center of mass.

ity to that of the upper limb. Based on these concepts,

we derived the following aims and hypotheses:
1. Our aim was to study cortical adaptation in individuals with nonacute cervical SCI using fMRI in
order to:
a. Assess the spatial relationship between the
motor cortex representation of the paretic right
upper extremity compared with that of the
tongue.
b. Determine if the degree of spatial change in the
cortical representation of the tongue is correlated with the segmental level of the SCI or the
degree of functional impairment of the upper
limb.
2. Our hypotheses were that:
a. The spatial separation between maximum cortical activation of the tongue and that of the

Methods. After approval from the University Health

Network Ethics Review Board and written informed consent, 12 patients with varying degrees (by cervical level
and American Spinal Injury Association [ASIA] scale; table
1) of cervical SCI and 14 normal control subjects participated in the study. Data from one patient were not analyzed owing to movement artifact resulting from muscle
spasm during scanning.
Patient inclusion/exclusion criteria. Table 2 outlines
the specific inclusion and exclusion criteria used for patient enrollment. Fourteen control subjects with a mean
age of 28.9 7.4 years were recruited from the community. They must have been considered healthy without a
history of neurologic illness, been right hand dominant,
and have met all exclusion criteria. Patient demographics
are summarized in table 1.
Functional impairment. Functional impairment was
measured using the standard neurologic classification of
SCI according to the ASIA11 (see table 1). All patients
sustained traumatic injuries with a mean duration since
injury of 84.3 89.1 months (range 5.5 to 242 months),
resulting in motor complete (ASIA A or B) SCI. All patients were right hand dominant except for one left-handed
patient with a C4 injury who had no upper extremity
movement.
fMRI. The motor paradigms consisted of self-paced
movements involving the wrist and tongue. The subjects
flexed and extended the wrist at a rate of 1 cycle/second for
15 seconds alternating with a 15-second resting period carried out over 5 minutes. The tongue movement consisted of

Table 4 Location of FMA and COM during tongue tapping

Left hemisphere
Location of

Right hemisphere

M/L

A/P

I/S

M/L

A/P

I/S

Controls, n 13

56.5 3.9

10.5 5.7

28.1 5.6

56.3 5.0

9.4 4.1

27.1 5.2

Patients, n 9

50.1 5.6

12.8 5.7

40.1 10.7

49.3 6.0

9.4 5.6

31.4 4.7

FMA

Difference

6.4

2.3

12.0

7.0

0.0

4.3

p Value

0.005*

0.373

0.002*

0.008*

0.977

0.058

COM
Controls, n 13

55.8 4.0

10.2 5.9

31.0 9.2

55.1 3.7

10.6 3.0

29.9 3.8

Patients, n 9

50.8 5.5

13.6 6.7

41.8 10.6

50.3 3.8

10.3 5.8

32.9 5.7

Difference

5.0

3.4

10.8

4.8

0.3

3.0

p Value

0.024

0.217

0.019

0.008

0.869

0.144

All values given in mm 1 SD displaced from the anterior commissure in Talairach space in the medial/lateral (M/L), anterior/posterior (A/P), and inferior/superior (I/S) planes.
* Significant at p 0.05.
FMA focus of maximum activation; COM center of mass.
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Table 5 Location (1 SEM) of M1 cortex controlling upper extremity function (knob) in patients and controls in medial/lateral (M/L),
anterior/posterior (A/P), and inferior/superior (I/S) planes
Left hemisphere
Location in

Right hemisphere

M/L

A/P

I/S

M/L

A/P

I/S

Controls, n 14

35.9 1.47

27.2 1.02

52.4 0.67

33.4 1.39

25.8 1.12

53.2 0.83

Patients, n 11

34.5 1.96

30.1 1.78

54.3 1.51

31.7 1.09

28.0 1.30

52.9 0.87

1.4 2.45

2.9 2.05

2.10 2.02

1.7 1.76

2.2 1.71

0.3 1.20

Difference

Shown is location of knob (hand representation within primary sensorimotor cortex) in mm.

tapping of the upper incisors at 1 cycle/second for 15 seconds alternating with a 15-second resting period carried
out over 5 minutes.
MRI was performed on a 1.5-T clinical scanner (Signa
Echospeed; GE Medical Systems, Milwaukee, WI) using a
spiral gradient echo sequence. Twenty-eight contiguous
slices of 4.5-mm thickness were obtained from the foramen
magnum to the vertex. One spiral trajectory was collected
per slice to give a 3.75-mm in-plane resolution. Other sequence parameters were repetition time (TR) 2,240 ms,
echo time 40 ms, 80 ms/spiral, flip angle 85 (set to
the Ernst angle for maximum signal-to-noise ratio within
gray matter for TR 2,240 ms and T1 of gray matter
850 ms). High-resolution T1-weighted fast inversion recovery spoiled gradient-recalled (SPGR) images were acquired
at 1.5-mm slice thickness for coregistration with the functional images.
Image and data analysis. Image analysis was performed off-line using Stimulate12 (available at: http://
www.cmrr.drad.umn.edu/stimulate) and AFNI13 software
(available at: http://afni.nimh.nih.gov/afni). Regions of activation were determined by cross-correlating the fMRI data
to the predicted hemodynamic response (boxcar waveform)
for each task using a voxel-by-voxel statistical analysis.
Voxels with a correlation coefficient (r value) falling above
the 99th percentile were deemed significant. Two methods
were used to localize task-related cortical activation measured contralaterally for wrist movement and bilaterally
for tongue movement. In the first method, the position of
the voxel with the highest r value within primary motor
cortex (M1) was recorded and was termed the focus of
maximum activation (FMA). In the second method, the
center of mass (COM) for the cluster of significant voxels
in M1 was determined. The x, y, and z coordinates for the
FMA and COM were then determined for each task. In all
cases, the FMA and COM fell within M1 determined visually by locating the central sulcus and the motor strip
directly anterior to it. The volume of contiguous voxels
exceeded 220 mm3 in all subjects. The results of the FMA
are used for the purpose of discussion as reference to the
COM data would have been redundant because the COM
measurements were within 2 mm of the FMA data. Nevertheless, COM data are reported in tables 3 and 4. Each
scan was subsequently normalized into standard stereotactic anatomic (Talairach) space.14 Although the Talairach
normalization procedure is not a necessary step in the
analysis of fMRI data, it allowed us to perform a group
analysis and compare our results with those in the literature. Distance between FMA for wrist extension and FMA
for tongue movement was calculated as the square root of
the sum of the squares of the difference between each FMA

in each of the three spatial planes. SigmaStat 2.03 (SPSS,

Chicago, IL) was used to 1) compare (one-tailed t-test) the
mean location of the FMA and mean volume for each task
between the control and patient groups, 2) compare (onetailed t-test) the distance between the FMA during wrist
and tongue movements between the two groups, and 3) to
determine the relationship (Spearman correlation) between ASIA right upper limb motor score, FMA displacement, level of injury, and shifts in FMA. All patients
except Patient 11 performed wrist extension using a range
of motor strategies depending on the level of injury. Although all subjects could perform the tongue task, data for
one control and one patient did not meet our criteria for
significant activation. Movements within and around the
mouth may produce distortion by causing changes in homogeneity within the local magnetic field. Other investigators have had difficulty mapping the tongue representation
within M1.15 Patient 11 could not perform wrist extension
owing to the level of lesion (C4) and performed tongue
movement only. The data obtained for Patient 11 were not
included in the group comparisons but were included for
the ASIA motor score vs FMA displacement and level vs
FMA shift correlations.
Assessment of post-traumatic changes in brain morphology. A confounding factor in the measurement of the
displacement of centers of functional activation is brain
atrophy. The possible existence of post-traumatic atrophy
within the primary sensorimotor cortex representing the
arm, trunk, and leg required a comparison of the position
of this cortex in patients and control subjects. This was
achieved by outlining the knob, which is a highly reliable
anatomic landmark that defines the site of motor control
for the hand.16 The image best representing the knob was
chosen from the three-dimensional SPGR volumetric acquisition, the apex of the knob in Talairach space was
recorded, and group means were compared (two-tailed
t-test), with the data summarized in table 5.

Table 6 Volume of activation 1 SD within M1 during right

wrist extension

Volume in

Actual
volume, mm3

Controls, n 14

1,403 836

1,327 852

Patients, n 10

1,577 928

1,508 1,115

0.635

0.656

p Value

Volume in Talairach
space, mm3

Actual volume and Talairach volumes differ because of spatial

warping introduced by the Talairach method.
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Figure 1. Location of focus of maximum activation (FMA) within M1 (left

hemisphere) during tongue movement.
Points represent individual data (patients in blue, control subjects in red).
Cross-hairs represent the group mean
1 SD. The data are superimposed on an
averaged anatomic image in Talairach
space. Data are shown in the axial (A),
coronal (B), and sagittal (C) planes.
The FMA is more medial and superior
in patients (p 0.05). A/P anterior/
posterior; M/L medial/lateral.

Results. Table 5 shows that the morphologic position of

the primary sensorimotor cortex controlling upper extremity function (the knob) is virtually identical in patients and
control subjects, differing by 3 mm in any of the three
spatial directions. There were therefore no differences in
the anatomy of M1 between the patients and control
subjects within the standard error of the measurement.
The degree of motor cortical atrophy, if present, would
not have been sufficient to produce the observed spatial
shifts in the FMA.
The location of activation in M1 during wrist movement
as determined by the FMA was no different between patients and control subjects (see table 3), most likely owing
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NEUROLOGY 58

to the residual upper extremity movement capability

present in all but one patient. Analysis of activation volumes as seen in table 6 indicates that there was no significant difference in the volume of primary sensorimotor
cortex activated during wrist movement between patients
and control subjects.
Based on our current understanding of cortical adaptation, changes in the location of the FMA would be expected
along the line connecting the tongue motor area and the
upper extremity motor area in M1, that is, a superior,
medial, and posterior displacement. Table 4 shows significant differences in the medial and superior position for the
FMA in the left hemisphere, but only for medial displace-

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Table 7 Volume 1 SD of activation within primary sensorimotor cortex during tongue tapping
Left hemisphere

Right hemisphere

Actual volume,
mm3

Volume in Talairach
space, mm3

Actual volume,
mm3

Volume in Talairach
space, mm3

Controls, n 13

1,592 1,041

1,145 743

1,352 800

1,225 835

Patients, n 9

1,128 786

1,094 846

1,181 573

1,051 577

0.883

0.589

0.594

Volume in

p Value

0.271

ment in the right hemisphere. No significant shift was

seen in the posterior direction, but this is probably because
of the almost true medial and lateral orientation of the
precentral gyrus. Figure 1 shows the position of the FMA
in the left hemisphere of the patients and the control subjects, with each point representing one subject. The FMA
was positioned 6.4 mm medially, 2.3 mm posteriorly, and
12.0 mm superiorly (see table 4). The mean spatial separation of the FMA during wrist extension and the FMA during tongue movement was smaller in patients, 30.3 13.8
mm, than in control subjects, 43.1 7.0 mm (p 0.01).
Table 7 shows that the volume of activation generated
during the tongue movement task between control subjects
and patients was not significantly different. It therefore
appears that differences in the position of the FMA were
not merely the result of differences in the volume of activation. However, the large standard deviations observed in
the volume of activation combined with the small sample
size preclude reliable inferences from these data.
The relationship between segmental level of injury and
position of the tongue FMA referable to the anterior
posterior commissural line (figure 2) is strongly correlated

in all three spatial directions (r 0.69, p 0.03). This

indicates that the FMA moves medially, superiorly, and
posteriorly with higher (more cephalad) levels of SCI. This
is exactly what one would expect given the orientation of
the primary motor cortex in the brain. The position of the
primary motor cortex controlling upper extremity function
is medial, superior, and posterior compared with that controlling tongue function. This is further confirmed by assessing the overall difference in the position of the tongue
FMA, comparing patients against control subjects across
ASIA motor score, as shown in figure 3. The root of the
sum of the squares of the anterior/posterior, left/right, and
superior/inferior distances between the FMA for patients
and FMA for controls (shortest distance in three dimensions between the FMA of the patient group and that of
the control group) was compared with the ASIA right upper limb motor score, showing a strongly linear correlation
(r 0.77, p 0.01).

Discussion. Our data indicate that the most active

region within M1 controlling tongue movement in

Figure 2. Motor level vs location of focus of maximum activation (FMA). The relationship between
level of injury and tongue FMA displacement is
shown for displacements in the medial/lateral (A),
anterior/posterior (B), and inferior/superior (C)
planes. AC-PC line joining the anterior and posterior commissures. Displacement of the FMA in
each of the three spatial dimensions is strongly (r
0.69, p 0.03) correlated to the level of the cervical
spine injury.

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Figure 3. Focus of maximum activation (FMA) displacement vs American Spinal Injury Association (ASIA) motor
score. The spatial difference in FMA (in three dimensions)
between patients and control subjects during tongue movement vs degree of upper limb functional impairment
(ASIA right upper limb motor score) in the 10 patients is
shown. Displacement represents the square root of the sum
of the squares of the x, y, and z displacements away from
the mean location found in the control group. It can be
seen that the displacement increases with increasing
impairment.

patients with chronic complete cervical SCI is positioned superiorly and medially toward the adjacent
disconnected hand cortex compared with that in control subjects, whereas the location of the cortex controlling wrist movement is unchanged. Together, the
findings suggest that cortical adaptation or reorganization has occurred in the motor cortex of individuals with chronic cervical SCI in the form of shifts in
the location of maximum activation of normally efferented and afferented cortex. The disconnected cortex represents an available motor network that
becomes partially involved with, or is simply cofunctional with, motor control of a body part that is already directed by adjacent motor cortex (in this case,
the tongue) with preserved efferent and afferent connections. The possibility that these spatial shifts in
activation are the result of post-traumatic atrophy in
the disconnected cortex appears unlikely since the
position of the primary sensorimotor cortex controlling upper extremity function was not shifted. The
lack of a difference in the location of wrist control
between patients and normal volunteers is assumed
to be due to the fact that all patients, except for the
C4-injured patient, had some preservation of wrist
movement. However, it can be argued that even this
representation should have migrated superiorly and
medially since it also borders on the adjacent disconnected lower extremity cortex. The absence of such
changes in representation associated with wrist
movement remain unclear. As with all fMRI studies,
the assessment of the spatial extent of activation is
problematic owing to thresholding issues. It is therefore difficult to address expansion/enlargement of
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NEUROLOGY 58

the cortical representation of tongue control. Nevertheless, the effect, if it exists, is not pronounced in
this group of patients since we were unable to detect
differences in the mean volume of activation compared with control subjects using conventional
thresholding (99th percentile) methods. If we had
studied a group of individuals with higher complete
cervical injuries (C4 and above), cortical expansion
might have been more obvious. It does appear, however, that the amount of shift is related to both the
level of the SCI and the degree of residual motor
function. These are not independent variables since
lower cervical injuries result in greater sparing of
upper extremity function.
Because a cross-section of patients with chronic
injuries (5.5 to 242 months) was assessed, the pattern of temporal evolution that leads to the observed
brain changes is unknown. It is unclear whether the
observed cortical adaptation evolves within hours of
the injury or if it occurs slowly over months or years.
There is evidence that cortical adaptation can occur
within minutes following pseudo-amputation of the
upper extremity in which all nerve conduction ceases
after temporary arterial occlusion.17 Once established, the nature of the adaptation, in terms of permanence and the degree of functional reassignment,
is of considerable interest. In a study of upper extremity amputees with long-term de-afferentation,
the cortical representation of primary orofacial sensation (the lips) migrated medially and superiorly
into the hand representation, exactly as we have
shown for the motor system in our spinal cordinjured subjects. This migration, however, could be
reversed within minutes of local anesthetic blockade
of the brachial plexus (but only in those patients
with phantom limb pain).18 Therefore, the observed
plastic changes are not likely mediated by new anatomic links, but more probably by rapid changes,
perhaps mediated by GABA, in the excitability of
particular pathways. The degree of functional reassignment of the disconnected cortex has also been
studied in chronic SCI, where TMS was used to
show that parts of the disconnected cortex retain
the ability to process sensations perceived by the
subject arising from the de-afferented region of the
body.19
These observations raise very important questions
concerning the nature of adaptation. Does it represent reorganization, with formation of new neural
connections, or is an unmasking phenomenon revealed in which absence of the sensory feedback to
the motor cortex leads to a loss of inhibition and an
overall increase in the excitability of a highly distributed motor network? The latter would be true if the
FMA remained stable or shifted only slightly, because it would be difficult to explain how increased
excitability would preferentially affect areas outside
of the main focus of activation. This evidence points
toward a true form of cortical reorganization consisting of new neural connections supported by data
from the C4-injured subject in whom the FMA actu-

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ally became coincident with the knob area of the

cortex that controls upper extremity movement.
However, because we are unable to confirm the presence of new neuronal connections, a more balanced
overview would suggest that following SCI, some
parts of the brain reorganize through changes in excitability, new neuronal connections, or both. For the
somatosensory cortex, some parts process new information, while others remain linked to the originally represented body parts. This also appears to be
true for the motor cortex because the exact area controlling hand function in M1 again becomes the center of activation, as has been reported after
successful attachment of hand grafts in a bilateral
hand amputee.20
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Adaptation in the motor cortex following cervical spinal cord injury

D. J. Mikulis, M. T. Jurkiewicz, W. E. McIlroy, W. R. Staines, L. Rickards, S.
KalsiRyan, A. P. Crawley, M. G. Fehlings and M. C. Verrier
Neurology 2002;58;794-801
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