Keywords
Functional magnetic resonance imaging (fMRI) - Cortical plasticity - Peripheral nervous
system (PNS) - Central nervous system - Nerve injury - BOLD
Introduction
Nerve regeneration following peripheral nerve injury has been of interest to surgeons
and neuroscientists for decades [[1],[2],[3],[4],[5]]. New surgical methods, such as partial nerve transfer and cross-C7 transfer, have
been introduced to treat peripheral nerve injury [[1],[6],[7],[8]]. Despite these advances in peripheral nerve surgery, functional recovery continues
to have clinical shortcomings. A universal hypothesis examining this is that knowledge
of the central nervous system’s (CNS) response post nerve injury and repair will lead
to improved clinical procedures. This CNS plasticity following nerve injury and repair
has been increasingly studied in recent years [[9],[10],[11],[12],[13],[14],[15]]. A recent study showed brain activation maps of the four major branches of the
rat brachial plexus using functional magnetic resonance imaging (fMRI) [[16]]. Chen et al. [[17]] observed cortical rearrangement using fMRI following human toe-to-finger transplantation.
Beaulieu et al. [[6]] reported that after cross-C7 grafts of the brachial plexus, cerebral plasticity
could be observed using fMRI. They found that flexion of the neurotized arm is associated
with bilateral cortical network activity. The contralateral cortex originally involved
in control of the rescued arm still participates in the elaboration and control of
the task through the bilateral premotor and primary motor cortices.
Functional MRI techniques are used in this investigation. These experiments are based
on blood oxygen level dependent (BOLD) MRI contrast, which arises from change in oxygenation
of hemoglobin that is associated with neural activity [[18]], noting that deoxyhemoglobin (dHb) is paramagnetic and oxyhemoglobin is diamagnetic
[[19]]. A previous paper from our group reported detailed BOLD fMRI cortical representation
maps of the rat that were obtained by stimulation of each of the four terminal branches
of the brachial plexus [[16]].
Total deafferentation is the most severe case of peripheral nerve injury in the upper
limb. The methodology of fMRI has been used to observe inter-hemispheric neuroplasticity
following total forelimb deafferentation [[20]]. In another study, inter-hemispheric cortical plasticity deafferentation was also
reported by Pelled et al. [[15]] following complete deafferentation.
In the present study, we report results obtained by transection in the rat forearm
not only of a single nerve but also of nerve pairs. Given this, it was hypothesized
that patterns of cortical plasticity caused by these types of peripheral nerve injuries
would be different from those induced by total deafferentation. These differences
could potentially lead to new and more refined rehabilitation and reeducation programs
that may improve clinical outcomes.
Specifically, this study involves three major terminal branches of the brachial plexus
in the rat upper extremity: the median, ulnar, and radial nerves ([Figure 1]). The radial nerve supplies sensory innervation to the dorsum of the forearm and
dorsal aspect of the second, third, and a portion of the fourth digits. Other sensory
input is conducted through median and ulnar nerve pairs. The median and ulnar nerves
are responsible for flexion of the forearm and digits, while the radial nerve is responsible
for extension. The fact that the median and ulnar nerves form a nerve pair with similar
function allows us to study the different degrees of cortical plasticity arising from
damage to one or both. This study uses surgical implantation of electrodes on the
terminal branches of the rat brachial plexus for direct nerve stimulation [[16],[21]]. This permits study of motor and sensory components of the cortical representations
of the rat upper extremity.
Figure 1 Cutaneous innervation of the four terminal branches of the brachial plexus
is shown. Left: volar. Right: dorsal.
Materials and methods
Animal preparation
Institutional Review Board approval was obtained, and all studies were performed in
compliance with federal regulations and the guidelines of our institution’s animal
care and use committee. Twenty-four male Sprague–Dawley rats (150–200 g) were used
in this study. They were divided equally into four groups based on the type of nerve
injury and whether the injury was studied in the acute (30 minutes after injury) or
subacute (two-week) stage of nerve injury. Animals that received only right median
nerve transection and were examined in the acute stage constituted the “acute single
nerve injury” (ASNI) group. Animals in the subacute single nerve injury (SSNI) group received the same median nerve injury but were examined in the subacute setting.
Similarly, the double nerve injury groups—ADNI and SDNI—received right ulnar and median nerve transection followed by acute and subacute
examinations, respectively. Schematic representations of the experimental setups for
the ASNI and SSNI groups are shown in [Figure 2]A, with an intra-operative photo shown in [Figure 2]B. Similar schematic and intra-operative photos for the ADNI and SDNI groups are
shown in [Figure 2]C and D, respectively.
Figure 2 The experimental design of the four groups is shown. All nerve injuries were made to the right forelimb 1 cm proximal to the elbow. A: The experimental setup for rats in the ASNI and SSNI groups is illustrated. Here,
the right median nerve was transected, and an electrode was placed on the proximal
end of the transected nerve. A second electrode was placed on the ipsilateral right
ulnar nerve. Third and fourth electrodes were placed on the contralateral left ulnar
and median nerves, respectively. (These additional electrodes served as a control.)
C: The experimental setup for rats in the ADNI and SDNI groups is shown. These rats
had the right median and ulnar nerves transected, and electrodes placed on the proximal
ends of the median and ulnar nerves. A second electrode was placed on the ipsilateral
right radial nerve, a third was placed over the median and ulnar nerve bundle on the
contralateral left side, and a fourth was placed on the contralateral left radial
nerve. The left side also served as a control. B and D are intraoperative photos of the rat forelimb after electrodes were attached for
the experimental setups in A and C, respectively. Note that the spiral electrode, designed in our laboratory, provides
easy access to nerve stimulation with minimal damage to the nerve.
In each rat, the brachial plexus was exposed bilaterally by an incision made along
the medial aspect of the upper extremity and extending into the axilla and a portion
of the flank. A plastic-sheet barrier was used to isolate the nerve, ensuring that
the electrode fixed to the nerve contacted only the nerve to be stimulated. Stainless-steel,
150-μm-diameter bipolar electrodes (AISI 304, Plastics One, Roanoke, VA) were used
in all experiments. All nerve injuries were made on the right side of the rat.
Rats in the ASNI and SSNI groups had the right median nerve transected 1 cm proximal
to the elbow. Four electrodes were used in each rat: (i) the proximal end of the transected
right median nerve, (ii) the right ulnar nerve, (iii) the left median nerve, and (iv)
the left ulnar nerve. ASNI rats had electrodes placed at the time of injury, while
SSNI rats were rested for two weeks followed by surgical implantation of electrodes
just prior to the fMRI studies. All incisions were closed after surgery.
Rats in the ADNI and SDNI groups had the right median and ulnar nerves surgically
transected 1 cm proximal to the elbow. Four electrodes were used in each rat: (i)
the proximal ends of the transected right median and ulnar nerves bundled together,
(ii) the right radial nerve, (iii) the left median and ulnar nerve bundle, and (iv)
the left radial nerve. Electrodes were placed in ADNI rats at the time of injury.
SDNI rats were rested for two weeks followed by surgical implantation of electrodes
just prior to the fMRI studies. All incisions were closed after surgery.
Prior to fMRI acquisition, the right femoral artery and vein of each rat was cannulated
for blood pressure monitoring and continuous intravenous (IV) drug administration.
The trachea was cannulated to allow mechanical ventilation. The total surgical time,
including nerve transection and placement of electrodes, varied from 1.5 to 2 hours.
Rats in the ASNI and ADNI groups were scanned immediately after surgery to acquire
data of cortical activation following acute nerve injury. Rats in the SSNI and SDNI
groups underwent fMRI data acquisition after the second surgery to study the effects
of subacute nerve injury.
Anesthesia
Medetomidine hydrochloride (Domitor, Pfizer, New York, NY) has been used successfully
in prior fMRI studies [[22],[23],[24]] and was used here. The rat was placed supine, and anesthesia was provided by 1%
isoflurane vaporized into 30–70% O2/N2 during surgery. Isoflurane was tapered off during the fMRI portion of the study,
and a continuous IV infusion of Domitor (Pfizer, USA. 0.1 mg/kg/hr) and pancuronium
bromide ( Hospira, Lake Forest, IL. 2 mg/kg/hr) was used for maintenance of anesthesia
and muscle paralysis. The rat was placed on a mechanical ventilator (MRI-1 Ventilator,
CWE, Ardmore, PA) using 30–70% O2/N2.
fMRI protocol
Each rat was placed on a custom-designed cradle fabricated from G-10 fiberglass material.
The cradle was equipped with a warming pad controlled by a water-pump-driven temperature
regulator (Medi-Therm III, Gaymar Industries, Orchard Park, NY).
Mild electrical stimulation at 10 Hz frequency, 0.5 mA current, and 1 ms duration
was applied to the nerve trunk in all groups using a square-pulse electrical stimulator
(S88 Square Pulse Stimulator, Grass Telefactor, West Warwick, RI) [[16]]. This stimulation intensity is non-noxious, and it does not require the participation
of sensory bodies in the skin and cutaneous tissue that generate most of the painful
sensation. It is the same technique that is used clinically to test nerve continuity
intra-operatively on humans and has been shown to be innocuous [[25]]. We confirmed the non-noxious stimulation state by physiological monitoring. Throughout
the stimulation session, there were no significant changes in arterial blood pressure,
core temperature, or heart rate. Each nerve stimulation sequence began with an OFF
period of 40 s followed by three repetitions of ON for 20 s and OFF for 40 s (total
scan time = 3 min 40 s). This time sequence defines a reference waveform. The stimulation
sequence was computer-controlled with LabVIEW software (National Instruments, Austin,
TX) and started by a trigger pulse delivered by the scanner. Gradient echo (GE) scans
(TE = 18.4 ms, TR = 2 s, matrix 96 × 96 and zero filled to 128 × 128, FOV = 4 cm,
number of repetitions = 110, 10 contiguous 1 mm scans) were acquired using an echo-planar
imaging (EPI) sequence on the 9.4 T/30 cm Bruker AVANCE MRI scanner (Bruker BioSpin,
Billerica, MA) equipped with a receiving surface-coil (T9208) and a linear transmit-coil
(T10325). Two sets of GE data were collected for each stimulation in order to ensure
the reproducibility of our results. Each set of GE data consisted of a time course
of images. In fMRI, a pixel time course waveform can be formed from the intensity
of a given pixel in each image of an image time course. Cross-correlation of the reference
waveform with every pixel time course was performed on each individual animal before
group analysis. Maps of colorized correlation coefficients were overlaid on an anatomical
image to produce an fMRI image. See Cho et al. [[16]] for more detail.
Physiologic monitoring
During fMRI acquisition, invasive blood pressure, core body temperature, respiratory
rate (Model 1025, SA Instruments, Stony Brook, NY), pulse oximetry (8600V, Nonin Medical,
Plymouth, MN), arterial blood gases (i-Stat, Heska, Loveland, CO), and inspired/expired
O2 and CO2 (POET IQ2, Criticare Systems, Waukesha, WI) were monitored (WinDaq Pro, DataQ Instruments,
Akron, OH) and maintained within normal physiologic ranges. Rats were euthanized upon
completion of the study.
Data analysis
EPI scans were registered to ideal anatomy using the Oxford Center for Functional
Magnetic Resonance Imaging of the Brain (FMRIB) Linear Image Registration Tool (FLIRT)
software [[26]]. Data for each nerve and stimulation protocol were averaged and masked using Analysis
of Functional NeuroImages (AFNI) software [[27]]. Activation was determined with a P-value threshold of 0.005 in group analysis after multiple comparison corrections
(AlphaSim). Voxels were classified as active if the statistic was above threshold
and counted (3dmaskave) across all slices. Voxel color-coding was determined by the
amplitude of the fit coefficient. Regions of interest (ROIs) were drawn by consulting
the activation map and cross-referencing it with the Paxinos and Watson rat atlas
[[28]]. In this study, bilateral somatosensory cortex (S1) and motor cortex (M1) areas
were selected as primary ROIs. With this method, the degree of cortical activation
in different functional areas can be quantified by the area (or number) of activated
voxels.
Results
[Figure 3] shows averaged results of coronal slices (-0.28 mm from bregma—the intersection
between the coronal and sagittal sutures) from rats in the ASNI and SSNI groups. [Figure 3]A through H represent the cortical response during electrical stimulation of the specified nerve.
[Figure 3]I shows an alternative means to quantify cortical activation by counting the number
of activated voxels in the sensorimotor region of the cortex. The error bars in [Figures 3]I (and [4]I) represent the standard deviation across animals. The right side of each coronal
image shows the right cortex as by animal-imaging convention. The color scale depicts
the intensity of the fMRI BOLD signal with the orange-yellow color range indicating
a positive BOLD signal—a proxy for cortical activation. For example, [Figure 3]A shows cortical representation following stimulation of the left median nerve immediately
after transection of the right median nerve. The midline positive BOLD region represents
the motor and cingulate regions activated by median nerve stimulation, while the positive
BOLD activation seen to the right of the midline represents the sensory region of
the left median nerve. This is consistent with previous rat brain-mapping studies
using direct nerve stimulation [[16]] [Figure 3]B is the cortical representation when the proximal end of the transected median nerve
is stimulated. In this figure, the sensory region is no longer evident while the motor
and cingulate regions, as well as some deeper structures of the basal ganglia, exhibit
enhanced BOLD signals. This is a natural cortical response to acute injury and may
be related to stress when animals are conscious or under light anesthesia [[16],[20],[29],[30],[31],[32]]. This response to stimulation of the proximal end of the right median nerve is
absent when the animal is examined in the subacute stage ([Figure 3]D).
Figure 3 Shown in Figure 3A through H, cortical activation following nerve trunk stimulation in the ASNI and SSNI
groups (P = 0.005). Expansion was found in the ulnar nerve cortical representation, shown in Figure 3F and H. Figure 3I shows the statistical analysis of voxel-counting across slices. A significant change
in voxel number between the acute and subacute stages was found in the representation
of the right ulnar nerve (★ P < 0.05).
Figure 4 Shown in Figure 3 A through H, cortical activation following nerve trunk
stimulation in the ADNI and SDNI groups (
P
= 0.005). Obvious expansion can be seen in the ulnar nerve cortical representation in Figure
4 A and C. The right radial nerve also became overactivated in comparison to the healthy state,
although this was not as prominent as the median and ulnar nerve bundle on the healthy
side. The expansion not only became diffuse, but also entered the other hemisphere
and occupied the motor area that previously represented the right median and ulnar
nerve bundle. Figure 4I shows the statistical analysis of voxel-counting across slices.
A significant change in voxel number between the acute and subacute stages was found
in the representations of the left median and ulnar nerve bundles and the right radial
nerve (★ P < 0.05; ★★ P < 0.01).
In the subacute stage, stimulation of the left median nerve continues to result in
distinct localized sensorimotor activation ([Figure 3]C) that is similar to the activation observed in the acute stage ([Figure 3]A), with differences not of statistical significance ([Figure 3]I, left median). [Figure 3]E to H show cortical activation during the acute and subacute period arising from
ulnar nerve stimulation on the right and left sides, respectively. There is no significant
change in the activation area of the left-side ulnar nerve between acute and subacute
stages (compare [Figure 3]E and G). The area of activation corresponding to the right ulnar nerve, however,
increased when comparing the subacute to the acute stage (compare [Figure 3]F and H). This difference was shown to be statistically significant ([Figure 3]I). The expansion of the right ulnar nerve representation after right median nerve
injury remained within the same hemisphere as the cortical representation of the right
median nerve.
[Figure 4] shows averaged results of coronal slices (-0.28 mm from bregma) for the ADNI and
SDNI groups that underwent transection of the right median and ulnar nerve pair. [Figures 4]A to D show cortical activation in the acute and subacute injury stages when the
median and ulnar nerve pairs on both sides were stimulated. In the acute stage, localized
activation was found in the right sensorimotor cortex when stimulating the left nerve
pair. In the subacute stage, stimulation of the left median and ulnar nerve pair showed
an expanded area of cortical activation in the right sensorimotor area that also expanded
into the left sensorimotor regions of the cortex ([Figure 4]C). The voxel count analysis shows this expansion to be statistically significant
([Figure 4]I, right median and ulnar). Cortical activation is absent in the subacute stage following
stimulation of the injured right median and ulnar nerve pair ([Figure 4]D). Cortical activation in response to radial nerve stimulation is shown in [Figure 4]E through H. Cortical activation following stimulation of the left radial nerve remained
essentially unchanged from the acute to subacute stages ([Figure 4]E and G). Stimulation of the right radial nerve resulted in a marked increase in
sensorimotor activation in the left hemisphere and a moderate expansion into the motor
regions of the right hemisphere. Stimulation of either the right radial nerve or the
left median and ulnar nerve pair showed expansion of representation into the hemisphere
contralateral to the stimulated side as well as into the ipsilateral hemisphere, which
demonstrates inter-hemispheric cortical reorganization in response to nerve injury.
In order to better demonstrate the cortical plasticity under different conditions,
all fMRI signals from the sensorimotor cortex was extracted. Using the result from
acute stage of each group as the baseline, voxel-wise t-test was performed at a p
value of 0.05. Comparing to the voxel counting analysis in previous results, this
analysis is able to show voxel-wised amplitude change. The result is demonstrated
in [Figure 5]. In the single median nerve injury group ([Figure 5]A-D), all the plasticity happened intra-hemispherically. Despite the very localized
and mixed changes when nerves from the healthy side were stimulated, cortical response
was noticeably reduced when damaged median nerve was stimulated in the subacute stage
([Figure 5]B), shown in blue color. For this median nerve injury group, the most significant
cortical plasticity occurred to the ulnar nerve of the same injury side ([Figure 5]D, circled by red). When compared to the acute stage, sensory activation was markedly
increased in the amplitude. In the combined nerve injury group ([Figure 5]E-H), when median and ulnar nerve bundle on the healthy side and the radial nerve
on the experimental side were stimulated, inter-hemispheric plasticity dominated the
cortical changes ([Figure 5]E, H). The neuronal response also decreased when damaged nerves were simulated ([Figure 5]F). Only minimal changes could be detected when radial nerve on the healthy side
was stimulated.
Figure 5 Voxel-wise t-test showing amplitude change for all groups (p = 0.05). All the analysis was done using acute stage of each group as baseline. A-D were from single median nerve injury groups. Significant intra-hemispheric cortical
plasticity was demonstrated when right ulnar nerve was stimulated (D. circled in red). E-H were acquired from combined nerve injury group. Both inter-and intra-hemispheric
plasticity were found during nerve stimulations, with the healthy nerve bundle on
the healthy side being dominant (E,
H circled in red).
Discussion
Interaction between the CNS and PNS in nerve injury and repair
A well-functioning extremity requires not only a healthy peripheral nervous system
including muscular and sensory end-organs, but also a healthy CNS. Peripheral nerve
injuries remain one of the most challenging surgical problems and may result in devastating
function loss that can have profound social consequences
Nerve injuries result not only in changes at the site of injury but also cause distal
atrophy of target muscles or permanent loss of sensation. These injuries have been
shown to cause long-lasting cortical reorganization [[33],[34]]. Functional reorganization in the somatosensory and motor regions of the brain
may explain the often disappointing results from severe peripheral nerve injuries
and subsequent attempts at surgical repair. Clinically, there is no surgical repair
technique that can assure full functional recovery following peripheral nerve repair.
Many studies have demonstrated that the functional outcome after nerve repair is superior
in children than in adults [[35],[36]]. Lundberg suggested that sensory recovery is based on a learning process that is
analogous to learning a new language, which is a CNS function and is a type of cortical
plasticity [[37]]. Based on these theories, many functional reeducation programs that focus on manipulating
CNS plasticity have been used successfully in adult patients to improve functional
outcomes following nerve repair. Sensory reeducation based on vision-guided touch
[[38]] and constraint-induced therapy [[39],[40]] have been shown to improve surgical outcome. In addition, pharmacological intervention
studies have indicated that norepinephrine can improve functional outcome when combined
with physical therapy [[41],[42]].
As long as nerve repair is carried out with care and reasonable technical skill, the
outcome appears to depend largely on CNS factors including functional cortical reorganization
caused by misdirection in axonal outgrowth in the PNS [[37]]. Many studies suggest that the nature of cortical plasticity is to activate existing
cortical pathways that are normally suppressed under healthy conditions [[43],[44],[45]]. Other studies insist that cortical plasticity is caused by newly formed axons
[[46],[47]]. Both may be correct. It is possible that different types of cortical plasticity.
This is parallel to what was demonstrated in this study. We presume that both intra-
and inter-hemispheric cortical expansion arise from activation of existing pathways
since the actual functions of the median and ulnar nerves overlap and the left and
right cortical representation areas for each nerve are connected across hemispheres
by the corpus callosum. Our study established a reliable methodology in an animal
model for visualization of cortical plasticity caused by nerve injury and/or repair,
so that new intervention and reeducation procedures can be designed and evaluated.
When unrepaired nerve residue was stimulated, the neuronal activity in the corresponding
cortex decreases markedly, resulting in a negative signal in voxel-wise t-test analysis
([Figure 5]B and F). Following cortical plasticity, the original cortical area of the damaged
nerve seems to be partially taken by other nerves. This phenomenon has been well studied
and documented in physiologic studies [[9],[48],[49]].
Intra-hemispheric cortical plasticity
This study fills the gap the previous two studies left in which only inter-hemispheric
plasticity was discussed[[50],[51]]. In the present investigation, rapid changes were seen after injury. The sensory
representation in the cortex upon stimulation of the proximal end of the cut nerve
(compare [Figure 3]A and B) disappeared within two weeks ([Figure 3]D). More interesting are changes in the patterns of cortical activation that occur
in response to stimulation of adjacent nerves on the same side of injury, as well
as stimulation of contralateral nerves. The median nerve carries motor innervation
that is primarily flexor in origin, with the balance of flexor innervation carried
out by the ulnar nerve. When the median nerve is transected, the ipsilateral ulnar
nerve representation in the cortex appears to expand during a two-week period to include
more of the sensorimotor region. Apparently, the cortex reallocates resources to enhance
sensorimotor interaction with the ulnar nerve in response to the loss of function
resulting from injury to the median nerve. This finding is consistent with prior electrophysiology
studies as well [[34]].
Intra-hemispheric cortical plasticity may occur because the resulting median nerve
injury has not fully compromised flexor functioning of the forepaw digits and wrist.
In addition, previous studies have demonstrated that there is overlap in cortical
representation of the sensory components of the median, ulnar, and radial nerves [[16]]. Thus, with median nerve injury, it is not surprising for the ipsilateral ulnar
nerve to exhibit expanded cortical representation ([Figure 3]H). This is further evidenced by studying the ADNI and SDNI groups. In these two
collections, the left and right radial nerves were stimulated after injury to the
right median and ulnar nerve pair ([Figure 4]E through H). In this setting, Intra-hemispheric cortical expansion was evident at
two weeks upon stimulation of the right radial nerve ([Figure 4]H) but absent with stimulation of the left side radial nerve ([Figure 4]G). Voxel-wise t-test analysis for both single median nerve injury group and combined
median+ulnar nerve injury group clearly demonstrates this intra-hemispheric cortical
plasticity. It also substantiates that this increase in the neuronal activity during
the subacute stage is caused by not only the increased neurons being fired during
task, but also the increased intensity when each neuron fires.
Inter-hemispheric cortical plasticity
The degree of functional loss was greater with transection of both the median and
ulnar nerves compared to an isolated median nerve injury. Double nerve injury condition
is fundamentally similar as previous published studies in which three and four major
nerves of forelimb were destroyed in the sense that the entire biological function
was knocked out. With this injury, the forepaw has only limited sensory and motor
function, which is provided through the radial nerve. With the nerve pair injury used
in this study, the involved limb completely loses the flexion function that is very
essential to the daily movement of the animal. While in the previous studies, animals
lost both flexion and extension functions as the result of complete limb deafferentation
surgery. In order to deal with this complete function loss, appropriately, the cortical
allocates resources to enhance interactions with the remaining uninjured ipsilateral
radial nerve in order to maximize the remaining function of the injured extremity.
This observation of changing cortical representation reinforces the notion that any
given region of the cortex may have multiple secondary synaptic connections beyond
the primary innervation to that cortical region. These secondary connections are normally
inhibited or masked in the non-injured state. In the setting of nerve injury, it is
hypothesized that the primary innervation fails, resulting in an unmasking of these
secondary connections and thus explaining the cortical expansion seen in representations
of adjacent non-injured nerves [[33]].
Inter-hemispheric cortical expansion was observed in the setting of combined median
and ulnar nerve injury, but absent with isolated median nerve injury. With median
and ulnar nerve injuries, flexion of the forepaw digits and wrist is absent along
with complete loss of volar sensation and a partial loss of dorsal sensation of the
forepaw. With this degree of function loss, the rat becomes much more dependent on
the uninjured forepaw compared to an isolated loss of median nerve function. Thus,
stimulation of the left uninjured median and ulnar nerve pair displays significant
intra- and inter-hemispheric cortical expansion. Inter-hemispheric cortical expansion
implies that the two hemispheres are connected. However, stimulation of the left radial
nerve displays neither intra- or inter-hemispheric cortical expansion, suggesting
that the cortex does not need to enhance or devote more resources to the extensor
function of the non-injured hand.
Only voxel-wise t-test analysis from the combined median and ulnar nerve injury group
shows this inter-hemispheric cortical plasticity pattern ([Figure 5]E and H). Similar as it is in the single nerve injury group, for higher degree of
nerve injury, both the neuron number and the intensity of neuronal response increase
during the subacute stage. The difference is this over activation pattern involving
both hemispheres.
What is clear from these two sets of experiments is that the gradation of functional
loss produced by different degree of nerve injuries impacts the pattern of cortical
reorganization. In addition, inter-hemispheric cortical expansion appears more likely
to occur when there is a higher degree of functional loss in one extremity as the
body and cortex try to response.
Cortical expansion and cortical plasticity
Many studies have shown that reorganization of the rat cortex in response to peripheral
nerve by either expansion of the representation of adjacent nerves on the same extremity
or the representation of corresponding nerves on the side contralateral to nerve injury.
This reorganization may be important when considering nerve repair options. It is
not always possible for direct nerve repair or the use of cable grafts [[52],[53]] to restore function to the denervated muscles or sensory end-organs. In these circumstances,
a donor nerve may be an option, but choosing the appropriate donor can be challenging.
A donor nerve on the same side as the nerve injury may exacerbate the degree of functional
loss observed in the injured extremity. Choosing a contralateral donor nerve (such
as the C7 nerve root) may be technically more challenging [[7],[54],[55],[56]] and may require a longer period for the nerve-regeneration process. The emerging
use of partial nerve transfers [[57],[58],[59]] may make sense in terms of impact on the cortical changes that occur in response
to partial nerve redirection. The intra-hemispheric cortical expansion observed with
stimulation of the ulnar nerve two weeks after median nerve injury suggests that a
partial ulnar nerve transfer could be used to restore the relationship between the
expanded cortical regions and reinnervated portions of the median nerve. Similarly,
the implications of the intra-hemispheric cortical expansion observed with the right
radial nerve stimulation two weeks after the right median and ulnar nerve injury suggests
that a partial right radial donor nerve will help to restore the relationship between
the expanded cortical region with some flexor function or protective volar sensation.
Both intra- and inter-hemispheric cortical expansion of the representations of the
left median and ulnar nerves is observed two weeks after right nerve pair transection.
It may be possible to use left median or ulnar nerve fascicles in a partial-nerve-transfer
surgical strategy, which will help to reestablish the relationship with the expanded
cortical regions and the motor and sensory regions of the reinnervated portions of
the injured nerve pair. Similarly, stimulation of the left radial nerve two weeks
after injury of the right median and ulnar nerve pair showed neither patterns of cortical
expansion, suggesting that it may be more difficult to restore the cortical relationship
with portions of the reinnervated right nerve pair when using a portion of the left
radial nerve as a donor.
A possible concern about this study is that scar tissue around the nerve and electrodes
could affect the efficiency of stimulation of the nerves in the subacute stage groups.
Histology confirmed the presence of scarring in these groups. Scarring would be expected
to reduce the effects reported here. Other uninjured nerves were not studied in these
experiments, and the degree of cortical reorganization that might be observed in response
to stimulation of these nerves could lead to additional candidate donors. Changes
in the cortex in response to nerve injury and repair, including the use of different
donor nerves, will need to be studied in future work.
Conclusions
In conclusion, this study describes cortical plasticity in the sensorimotor cortex
caused by peripheral nerve injury using direct nerve stimulation and fMRI. According
to our study, when a nerve of the rat forelimb is injured, a nearby nerve with a similar
function to the injured nerve becomes significantly over-activated. Under this condition,
intra-hemispheric cortical expansion becomes the most significant component of cortical
plasticity. When all nerves responsible for a certain function are injured, the same
nerves on the contralateral side of the body are affected and become significantly
over-activated during task. Both intra- and inter-hemispheric cortical expansion exist,
while the latter dominates cortical plasticity.
Competing interests
The authors declare that we have no competing interests. We declare that the interpretation
of our data or the presentation of the comprehending information, are not influenced
by a personal or financial relationship with other people or organizations. In the
past five years we did not receive any reimbursements, fees, funding or salary from
an organization that may in any way gain or lose financially from the publication
of this manuscript, either now or in the future. We declare that we do not hold any
stocks or shares in an organization that may in any way gain or lose financially from
the publication of this manuscript, either now or in the future. We declare that we
are not currently applying for any patents relating to the content of the manuscript.
We declare that we do not have any other financial competing interests. Additionally,
we declare that there are no non-financially competing interests (i.e. political,
personal, religious, ideological, academic, intellectual, commercial or any other).
Authors’ contributions
RL: has made contribution to experiment design, animal surgery and management, data
collection & analysis, data interpretation, manuscript writing & critical revision.
PCH: has made contribution to animal surgery & management and data collection. XL:
has made contribution to experiment design, data collection & analysis, and manuscript
revision. JBS: has made contribution to animal surgery, data collection and manuscript
revision. CPP: has been involved to experiment design. JAM: has made contribution
to experiment design and manuscript revision. JGY: has made contribution to experiment
design and manuscript revision. HSM: has made contribution to experiment design, data
interpretation and critical manuscript revision. JSH: PI of this study program, he
has made contribution to experiment design, data collection interpretation, hardware
support and critical manuscript revision. All authors have read and approved the final
manuscript.
Cite this article as: Li et al.: Cortical plasticity induced by different degrees of peripheral nerve injuries: a rat
functional magnetic resonance imaging study under 9.4 Tesla. Journal of Brachial Plexus and Peripheral Nerve Injury 2013 8:4.
