Anderson 2022 - Natural and Targeted Circuit Reorganization After Spinal Cord Injury

nature neuroscience
Review Article https://doi.org/10.1038/s41593-022-01196-1
Natural and targeted circuit reorganization

after spinal cord injury
Received: 7 September 2021 Mark A. Anderson 1,2,3,4,5, Jordan W. Squair 1,2,3,5, Matthieu Gautier ,
1,2,3
Thomas H. Hutson1,2,3,4, Claudia Kathe 1,2,3, Quentin Barraud 1,2,3,

Accepted: 5 October 2022
Jocelyne Bloch1,2,3 & Grégoire Courtine 1,2,3
Published online: 17 November 2022
Check for updates A spinal cord injury disrupts communication between the brain and
the circuits in the spinal cord that regulate neurological functions. The
consequences are permanent paralysis, loss of sensation and debilitating
dysautonomia. However, the majority of circuits located above and below
the injury remain anatomically intact, and these circuits can reorganize
naturally to improve function. In addition, various neuromodulation
therapies have tapped into these processes to further augment recovery.
Emerging research is illuminating the requirements to reconstitute
damaged circuits. Here, we summarize these natural and targeted
reorganizations of circuits after a spinal cord injury. We also advocate for
new concepts of reorganizing circuits informed by multi-omic single-cell
atlases of recovery from injury. These atlases will uncover the molecular
logic that governs the selection of 'recovery-organizing' neuronal
subpopulations, and are poised to herald a new era in spinal cord medicine.
The circuits that regulate motor and autonomic functions reside in Until recently, probing the functional role of neuronal subpopula-
the spinal cord. While these circuits are often regarded as rudimentary tions has been a laborious endeavor. Our knowledge on the reorgani-
components of the CNS under the authoritative control of the brain and zation of circuits after SCI primarily derived from the interrogation of
brainstem, we are beginning to uncover remarkable sophistication and broadly defined pathways and circuits that are known to regulate motor
diversity in the molecular architecture of the neuronal subpopulations and autonomic functions.
that forge these circuits1,2. Equally refined is the organization of the Here, we summarize our knowledge on how the circuits located
brain and brainstem regions that interact with neurons in the spinal in the brain, brainstem and spinal cord respond to SCI, and how their
cord. Interrogation of neuronal subpopulations based on their identity reorganization can contribute not only to natural recovery but also to
and/or projection targets have revealed that these regions can no longer degradation of neurological functions. We focus on motor functions,
be schematized with interacting boxes delivering executive commands but also consider autonomic functions when relevant. We discuss how
to the spinal cord through specialized descending pathways3. Instead, neuromodulation technologies can engage and reorganize the intact
each region is composed of specific neuronal subpopulations with neuronal subpopulations above and below an SCI to improve these
distinct receptomes and projectomes that contribute uniquely to the functions. We then lay out our understanding of the requirements to
production of behavior4. Deciphering how the neuronal subpopula- reconstitute damaged circuits. Finally, we advocate for a shift away
tions from the brain, brainstem and spinal cord interact to regulate from vaguely defined pathways, circuits or regions. We must increase
motor and autonomic functions is a daunting task. Even more intimidat- the resolution of our nervous system interrogation by uncovering
ing is the attempt to understand how these neuronal subpopulations 'recovery-organizing' neurons—the specific neuronal subpopulations
respond to, and reorganize after, a spinal cord injury (SCI). that reorganize anatomically to restore function after SCI—and how
1
NeuroX Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. 2Department of Clinical Neuroscience,
Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. 3Defitech Center for Interventional Neurotherapies
(NeuroRestore), EPFL/CHUV/UNIL, Lausanne, Switzerland. 4Wyss Center for Bio and Neuroengineering, Geneva, Switzerland. 5These authors contributed
equally: Mark A. Anderson, Jordan W. Squair. e-mail: [email protected]
Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1584

they can be targeted to further improve spinal cord repair and func- The formation of relays through reticulospinal and rubrospinal neu-
tional recovery. rons underscores the important role of brainstem-derived projec-
tions26 and suggests the existence of recovery-organizing neurons
Adaptive and maladaptive circuit reorganization located in distributed regions of the brainstem.
An SCI induces the death of neurons and glia in and around spinal cord
lesions and the interruption of axons passing in the vicinity. However, Reorganization of brainstem circuits
circuits located far from the injury, both above and below the SCI, also Studies have documented the growth of reticulospinal5, rubrospi-
undergo profound changes that can contribute to natural recovery5,6 or nal27 and serotonergic28 projections within territories located below
instead be detrimental7,8. Local growth of residual descending fibers, incomplete SCIs (Fig. 1). This growth often recapitulates the natural
sprouting of synaptic terminals, adaptations in synaptic transmission innervation pattern of these projections5,29, suggesting an attempt to
and multifaceted changes in molecular properties of neurons have been reestablish the pre-injury connectivity of these pathways. Electrophysi-
documented in numerous regions of the brain, brainstem and spinal ological, lesion-specific and projection-specific silencing experiments
cord. These adaptive and maladaptive modifications primarily depend have linked this reorganization with recovery5,28.
on the severity of SCI, as summarized below (Fig. 1). However, the involvement of subcortical structures cannot be
restricted to pathways that project directly to the spinal cord. One
Reorganization of brain circuits example is the necessary contribution of the nucleus accumbens to
Neuronal populations embedded in the cerebral cortex are essential for the execution of dexterous hand movements, especially early after
hand dexterity, are the most experimentally accessible neurons, and SCI30. Another unexpected contribution of evolutionary ancient sub-
subserve the motor skills of primate species. Experiments in nonhu- cortical regions comes from the mesencephalic locomotor region
man primate (NHP) models have shown that dexterous movements (MLR)31. While this region is not necessary to produce walking in the
are not possible when corticospinal tract projections are interrupted9. absence of injury32, neurons distributed within the MLR are capable of
Accordingly, the integrity of the corticospinal tract is a key predictor recruiting reticulospinal neurons with surviving projections to produce
of natural functional recovery after SCI in humans10. locomotion after SCI33.
One of the most striking mechanisms of recovery involves Limiting the survey of recovery-organizing brainstem neurons to
time-dependent, bilateral reorganization of cortical dynamics. This regions with residual projections below the SCI also fails to acknowledge
mechanism has been described after lateralized SCI in NHP models11. the diversity of circuits within and across brainstem regions. For exam-
These studies found a bilateral increase in activity of the motor and ple, the MLR contains distinct subpopulations of glutamatergic neurons
sensory cortices early after SCI. Once recovery had taken place, how- that project to specific targets to regulate distinct behaviors34. It is also
ever, the increased activity was restricted to the contralesional motor well established that reticulospinal neurons cluster in spatially defined
and sensory cortices and to both ventral premotor cortices. Silencing regions based on their contribution to the control of specific limbs35 or
experiments confirmed that ipsilesional cortical regions are necessary behaviors36. Moreover, projection-stratified neuronal subpopulations
for movement execution, but only during the early phase after the SCI11. of the brainstem encode discrete phases of actions, and they may even
Functional remapping of cortical regions during recovery from SCI in serve as building blocks for regulating complex movements37.
rodents also illustrated the importance of time-dependent changes This stratification of brainstem neuronal subpopulations into
in cortical dynamics12,13. When cortically derived projections in the interactive, hierarchically organized layers suggests that multiple
spinal cord below injury were silenced, the recovery of movement regions may interact to pass executive commands downstream. Natu-
vanished immediately, showing the relevance of this reorganization ral recovery from SCI may involve multifaceted changes in the flow
to the restoration of function after SCI5,14. of communication among these subcortical neuronal populations.
Anatomical reorganization of cortically derived projections15 and Concomitant adaptations in the receptome and projectome of these
ascending pathways16 parallels these adaptations of cortical dynamics. recovery-organizing neuronal subpopulations are likely to take place
When the SCI spares a subset of fibers from the corticospinal tract, to support recovery.
these fibers undergo directed growth to invade the gray matter ter- These observations reveal that functional recovery after SCI may
ritories that have been deprived of supraspinal projections17,18. After a rely on unexpected circuit reorganization, including evolutionarily
lateral SCI, corticospinal tract fibers can branch from the contralesional conserved mechanisms that are not essential to produce behaviors in
dorsolateral column, cross the spinal cord midline, and develop dense the absence of injury, but that become essential to support recovery
synaptic projections into the ventral gray matter where they contact after SCI. The critical role of mesolimbic and mesencephalic regions
neuronal subpopulations producing hand function19. Interventions provides perfect illustrations of this mechanism, but similar examples
that enhance this growth further augment hand function recovery20. have also been described in the spinal cord.
Although the mechanisms that trigger this process remain unclear,
regression of corticospinal tract neurons to a transcriptional state Reorganization of spinal circuits above the injury
similar to that of developing neurons appears responsible for enabling The motor cortex is essential for regaining motor functions after SCI,
this growth21. The reorganization of cortically derived projections has especially in primates. Yet, cortical commands do not have to be trans-
been exposed in rodent and NHP models, but evidence suggests that ferred directly to the spinal cord below the injury. A remarkable example
this mechanism also supports recovery in humans22. comes from the ability of propriospinal neurons located in C3–C4 seg-
When the SCI interrupts all corticospinal tract projections, the ments to relay cortical signals past an SCI to restore hand dexterity in
commands from the motor cortex can also be rerouted through alterna- NHP models38. Importantly, these evolutionarily conserved neurons
tive pathways with surviving projections below the injury (Fig. 1). For are not critical in the absence of injury, but they become essential for
example, the growth of cortically derived projections onto neurons recovery of hand functions when direct corticospinal tract projections
located in the reticular formation restores walking after contusion SCI5. are interrupted (Fig. 1).
Owing to the ubiquitous location of reticulospinal fibers within the rim The same mechanism supports recovery of walking after dorsal or
of spinal cord white matter, a subset of these fibers survives contu- lateral hemisection SCI13, and even temporally and spatially separated
sion SCI, regardless of the inherently variable topology of damage5. hemisection SCI. In this scenario, all the direct pathways from the
Similarly, sprouting of cortically derived projections within the red brain are interrupted as a result of the two hemisections on opposite
nucleus enables the motor cortex to convey information to the spinal sides. Yet, the neurons located between the hemisections can form
cord through the rubrospinal tract to regain upper limb function23–25. relays that transfer sufficient information past the injury to restore

Descending tracts leg movements18,39,40. Again, these neurons are not necessary for walk-
Corticospinal
ing before the SCI40, but they become essential after the SCI. Many
Reticulospinal
descending projections from propriospinal relay neurons survive SCIs.
Rubrospinal
However, injury-mediated downregulation of the potassium–chloride
Serotonergic spinal projections
cotransporter KCC2 in inhibitory neurons located in the vicinity of the
injury leads to excessive inhibition of relay circuits, rendering them
Brainstem nonfunctional39. Experimental prevention of KCC2 downregulation
New projections maintains the balance between inhibition and excitation, which is
New cortical
dynamics sufficient to restore walking39. The molecular identities of these relay
neurons and the computational principles that enable the transfer of
meaningful commands past the SCI remain unknown.
Directed reorganization of spinal circuits below the injury

The interruption of supraspinal projections triggers a reorganization
Above injury of spinal circuits located below the injury. When residual supraspinal
projections are abundant, these surveying fibers extend collaterals
onto reorganizing circuits below the injury, which supports functional
recovery5,19,26. Neurorehabilitation can also direct a reorganization of
circuits below the injury that improves recovery, even following com-
plete SCI41,42. When deprived of sufficient guidance, however, spinal
circuits undergo maladaptive reorganization that provokes clinical
syndromes. Below, we summarize our knowledge on directed (adap-
Between injuries tive) and undirected (maladaptive) reorganization of spinal circuits
below the injury (Fig. 1).
Spinal circuits can produce complex motor behaviors without any
contribution from the brain and brainstem43,44. Central to this compe-
tence is their ability to transform task-specific sensory information into
patterns of muscle activity that meet the intrinsic biomechanical con-
straints and extrinsic environmental demands45. When supraspinal pro-
jections are compromised, sensory information must thus become the
Below injury main source of control for movement45. Indeed, limb immobilization
alters functional recovery after SCI46. Instead, neurorehabilitation can
direct activity-dependent functional47 and anatomical48 reorganization
of sensory projections that supports recovery. A logical consequence
is the necessity of feedback circuits to execute and regain motor func-
tions after SCI49, especially those originating from muscle propriocep-
tive organs49. Indeed, the genetic ablation of muscle spindle feedback
circuits abolishes the recovery that naturally occurs after incomplete
Directed reorganization Undirected reorganization SCI. Concomitantly, brainstem and spinal cord relay neurons fail to
respond to injury with the growth of new projections that mediates
this natural recovery6. These observations help to explain why the out-
come of neurorehabilitation depends so singularly on the coincidence
between the flow of sensory information and the volitional drive from
residual supraspinal projections. However, the nature and topology of
Growth of maladaptive
projections the interactions that promote this growth remain unknown. Proprio-
ceptive neurons are thus recovery-organizing cells that steer beneficial
reorganization of circuits throughout the nervous system. Moreover,
targeting alterations in histone acetylation of proprioceptive neurons
after SCI endows their axons with increased regenerative capacities,
which can contribute to augmenting recovery50.
It is difficult to identify neurons below an SCI that are not pro-
foundly perturbed when a severe spinal cord damage occurs. Yet, func-
tional recovery is likely to rely more prominently on the reorganization
of specific neuronal subpopulations45,51. For example, the recruitment
Fig. 1 | Adaptive and maladaptive reorganization of brain, brainstem and of developmentally defined V2a neurons during the recovery of walk-
spinal circuits following spinal cord injury. An SCI triggers functional and ing1,52 and breathing53 suggests that these cells modify how they interact
anatomical changes throughout the nervous system. Extensive functional
with the circuits that produce these functions. Neurons located in
and anatomical reorganization of projections from neurons located in the
spinal cord deep layers (dl3) have also been implicated54.
brain, brainstem and spinal cord above the injury occur naturally after SCI.
These observations stress the importance of shifting the focus
The topological distribution of these reorganizations is illustrated, including
on clearly defined neuronal subpopulations. Single-cell technologies
alterations in cortical dynamics and growth of new axonal projections from
neurons in the brain, brainstem and spinal cord. The profound changes that these have exposed a remarkable diversity of neuronal subpopulations in
circuits undergo can contribute to natural recovery or instead be detrimental the spinal cord. Original nomenclatures were derived from the known
to neurological functions and result in neuropathic pain, autonomic dysreflexia cardinal lineages in the developing and postnatal spinal cord1,55. More
or spasticity. To a large extent, the severity of the SCI determines whether this recently, a top-down approach identified orderly genetic tiers that
reorganization is directed or undirected. divide neuronal subpopulations according to their motor–sensory,

local–long range and excitatory–inhibitory features2. We anticipate Deep brain stimulation

that this developmentally driven taxonomy will lead to a harmonized Transcranial
catalog of neuronal subpopulations in the developing and adult spinal magnetic stimulation
cord56 that will guide the rapid identification of recovery-organizing
neurons in the spinal cord after SCI.
Undirected reorganization of spinal circuits below the injury MLR

The massive depletion of supraspinal projections induces a collection
Vagus nerve
of maladaptive compensatory responses that are responsible for vari- stimulation
ous clinical syndromes (Fig. 1).
Following deafferentation of a region in the CNS, new synapses Spinal cord stimulation
derived from unaffected afferent pathways form spontaneously57. Large-diameter afferents
After SCI, this compensatory homeostatic response58 contributes
to the aberrant sprouting of afferents originating from dorsal root Transcranial magnetic stimulation
ganglia neurons7,59, the chaotic growth of new propriospinal connec- Corticospinal tract
tions60 and the ubiquitous genesis of excitatory synapses below the SCVsx2::Hoxa10 neurons
injury7,61. Moreover, the disruption of blood flow below the injury leads
Spinal circuits
to a chronic state of hypoxia owing to paradoxical excess activity of
monoamine receptors on pericytes, which impairs neuronal function62. Spinal cord
electrical stimulation Deep brain stimulation
Parallel changes in the molecular properties of neurons take place.
Reticulospinal tract
These include an increase in constitutive activity of monoaminergic
receptors63, serotonin hypersensitivity64, upregulation of intracellular
chloride concentration65, increased excitability of various classes of
neurons66 and hyperactivity of L-type calcium channels67. Fig. 2 | Neuromodulation of anatomically intact circuits. Neuromodulation
Unlike the directed reorganization that occurs when sufficient strategies, which are primarily based on electrical stimulation methods,
supraspinal projections persist, this undirected formation of circuits tap into anatomically intact circuits of the brain, brainstem and spinal cord
after severe SCI leads to clinical syndromes, including abnormal pro- to improve neurological functions immediately and/or promote long-term
prioceptive reflex responses7,68, increased muscle tone69, spontaneous recovery of neurological functions after SCI. When the SCI is incomplete,
electrical stimulation is delivered in the brain or brainstem to reactivate circuits
spasms7, bladder overactivity70, neuropathic pain71 and autonomic
in the spinal cord or to reinforce the strength of connections between the
dysreflexia72.
brain and spinal cord. When an SCI is severe, the circuits in the spinal cord lack
Various types of interneurons and circuits have been implicated
the source of modulation and excitation that they require to be functional.
in these clinical syndromes73. Yet, we surmise that this chaos involves Electrical spinal cord stimulation, in particular EES, can reactivate these circuits
the recruitment of specific neuronal subpopulations whose individual through the modulation of large-diameter afferents. When combined with
responses are directed toward predictable targets. neurorehabilitation, the stimulation directs the growth of residual projections
from the brain and brainstem (arrows) to SCVsx2::Hoxa10 neurons that are activated by
Perspectives on natural circuit reorganization the stimulation52. This reorganization promotes recovery of volitional movement
This unstructured registry of pathways, regions and circuits that may even when the stimulation is turned off.
contribute to the recovery or deterioration of neurological functions
underscores the incompleteness of our knowledge. Moreover, obser-
vations that recovery may rely on unexpected mechanisms or regions vast majority of neurons that compose them. Consequently, various
not critical to neurological functions in the absence of injury leaves the neuromodulation strategies based on electricity have tapped into
possibility that critically important recovery-organizing neuronal sub- anatomically intact neurons of the brain, brainstem and spinal cord
populations may have been overlooked by previous studies that were to improve neurological functions after SCI (Fig. 2).
merely informed by principles identified in uninjured animal models.
The identification of recovery-organizing neuronal subpopulations Neuromodulation of cortical circuits
is contingent on catalogs of genetically accessible neurons. These cata- Targeting cortical circuits provides broad access to a multitude of
logs are now available for most brain regions74, but the brainstem and circuits located downstream. A perfect example of this hierarchical
spinal cord have remained comparatively less explored. Consequently, organization is illustrated in the immediate recovery of walking when
previous studies were forced to rely on developmentally defined neu- the motor cortex is stimulated after a lateral hemisection78. Despite the
ronal subtypes or broadly defined neuronal subtypes, which may or interruption of corticospinal tract projections on one side, adjusting
may not reflect the diversity of neuronal subpopulations in the adult the amplitude of intracortical closed-loop stimulation patterns was
nervous system1,2,75. However, current high-throughput technologies are sufficient to control the amplitude of stepping movements from the
now enabling us to generate spatially resolved catalogs of neuronal sub- paralyzed leg on the denervated side78. The same observations were
populations52,76, auguring the imminent availability of comprehensive obtained during graded optogenetic activation of cortical projection
atlases over the entire nervous system. Moreover, the statistical meth- neurons after contusion SCI5. Because this injury abolished all corti-
ods to navigate these uncharted territories are expanding quickly1,52,77. cospinal projections, the optogenetically evoked signals were relayed
Understanding the recovery-organizing neuronal subpopulations through glutamatergic reticulospinal neurons that retained projections
in the brain, brainstem and spinal cord that contribute to natural recov- below the SCI. These results indicate that activation of cortical circuits
ery of function after SCI is essential, because this knowledge can be propagates commands that cascade downstream through brainstem
harnessed to develop neuromodulation and biological repair therapies neurons with spared yet functionally silent projections below the SCI.
that target these neurons to augment recovery, as we discuss below. Activity-dependent stimulation protocols can also strengthen
the residual connections between the brain and spinal cord (Fig. 2).
Neuromodulation of anatomically intact circuits The molecular mechanisms remain unclear, but it is now established
Spinal cord damage disrupts the flow of communication between the that the repeated activation of the motor cortex with noninvasive or
circuits that regulate motor and autonomic functions, but spares the invasive electrical stimulation methods promotes activity-dependent

Hemodynamics
Large-diameter EES stimulation

afferent fibers
Increase in blood pressure

Blood pressure
Blood vessel
Mobility
EES stimulation
Low thoracic
Flexor
Lumbosacral
Extensor muscle activity Alternative recruitment of muscles
Fig. 3 | Mechanisms through which epidural electrical stimulation restores stimulation methods act through the same mechanisms. The recruitment of
hemodynamics and mobility. Evidence suggests that EES elicits electrical large-diameter afferent fibers activates visceral and somatic motor neurons both
currents that do not modulate neurons directly, but instead flow around the directly and indirectly, and helps to transform spinal circuits from a dormant to
spinal cord within the cerebrospinal fluid where they depolarize large-diameter a highly excitable state. Because flexor and extensor motor pools are located in
afferent fibers. Owing to their low impedance and heavy myelin contents, different spinal segments, targeting the dorsal roots that project to the segments
these fibers are prone to depolarization, especially where they enter the spinal wherein these motor pools reside enables the modulation of specific muscles
cord through the dorsal root entry zones. There is evidence that alternative with a timing that reproduces the natural activation of these muscles.
growth of corticospinal tract projections79. Pairing motor cortex stimu- to recruit these spared projections to elicit movement. For example,
lation with precisely timed recruitment of peripheral nerves or even the delivery of deep brain stimulation within the MLR activates reticu-
intraspinal stimulation further enhances transmission along residual lospinal neurons, which improved walking after SCI33 (Fig. 2). These
neural pathways80. The resulting spike-timing-dependent reorganiza- results are comparable to those observed during motor cortex stimula-
tion of circuits has mediated lasting improvement of motor functions tion, suggesting that the brain fails to engage the entire population of
and reduced spasticity in animal models81 and people with SCI82. reticulospinal neurons with spared projections below an SCI.
Neuromodulation of cortical circuits can also be indirect. For The relevance of this ancestral locomotor system remains unclear
example, vagus nerve stimulation activates diverse nuclei throughout in humans. Moreover, this region is difficult to target surgically because
the brainstem, provoking a release of acetylcholine and norepinephrine the MLR is primarily defined functionally within the scattered topology
throughout the brain that predisposes vicariously distributed circuits of the pedunculopontine nucleus. Accordingly, deep brain stimulation
to increase their responses to neurorehabilitation83 (Fig. 2). As with of this region to improve gait after Parkinson’s disease led to variable
most neuromodulation therapies, the timing of the stimulation must outcomes85. Recent studies have segregated the MLR into anatomi-
coincide with relevant motor events to maximize recovery84. When cally distinct nuclei with defined populations of projection-stratified
delivered after cervical SCI, closed-loop vagus nerve stimulation pro- neurons that regulate specific behaviors36. These studies open the pos-
moted the growth of neuronal projections involved in the control of sibility that more refined targets could be identified, or even upstream
hand musculature84. Improvement of manual dexterity paralleled this regions with more circumscribed anatomical topology.
anatomical reorganization, but whether and how specific neuronal
populations contributed to this recovery remains unknown. Neuromodulation of spinal circuits
Ultimately, spinal circuits generate the muscular contractions that
Neuromodulation of brainstem circuits regulate motor actions. Therefore, it is logical that tapping into these
The majority of SCIs spare bridges of white matter within which mixed circuits results in the generation of organized muscular activity. Experi-
populations of brainstem-derived projections reside. When few pro- ments from the past century documented the initiation of walking
jections are spared, they fail to mediate volitional muscular contrac- when the isolated spinal cords of cats and dogs were stimulated electri-
tions. This understanding led to neuromodulation therapies that aim cally86. The same observations were made in humans during the 1980s87.

It is now well established that delivering electrical stimulation to the

lumbar spinal cord using epidural88,89, intraspinal90 or transcutaneous91
methods can elicit rhythmic leg movements, weight-bearing standing,
Box 1
and even independent stepping in animal models18 and humans with
SCI88,89,92 (Fig. 2). Pharmacological neuromodulation based on mono- Neurotechnologies to improve
aminergic agents can also reactivate the spinal cord below an SCI93,
and acts synergistically with electrical neuromodulation therapies to autonomic functions
promote movement45. When a sufficient number of supraspinal pro-
jections is spared, these therapies even enable these otherwise silent Preliminary studies in feline models and humans have shown that
residual projections to engage spinal circuits5. This mechanism, which EES applied over the sacral spinal cord could modulate spinal
was unmasked in preclinical models5, has restored volitional control circuits involved in the regulation of bladder and bowel functions134.
over the activity of paralyzed muscles in humans88,89. Even more conclusive were studies targeting hemodynamic
These observations motivated studies that dissected the mecha- instability135,136. People with cervical and upper thoracic SCI
nisms of epidural electrical stimulation (EES). It was found that EES elic- experience frequent drops in blood pressure that not only affect
its electrical currents that do not modulate neurons directly, but instead their quality of life but also lead to life-threatening conditions.
flow within the cerebrospinal fluid where they depolarize large-diameter These hemodynamic events, which are referred to as orthostatic
afferent fibers94. Owing to their relatively low impedance, these fibers hypotension, are due to the interruption of descending signals
are prone to depolarization, especially where they enter the spinal cord from brainstem vasomotor regulatory circuits136. Consequently,
through the dorsal root entry zones94,95 (Fig. 3). Alternative stimulation the sympathetic circuits in the spinal cord no longer respond to
methods are likely to act through the same mechanisms96. The recruit- orthostatic challenges.
ment of large-diameter afferent fibers activates motor neurons both Circuits embedded in the low thoracic spinal cord are enriched
directly and indirectly, and contributes to the transformation of spinal in sympathetic preganglionic neurons136. Engaging these neurons
circuits from a dormant to an excitable state95,97. recruits ganglionic neurons, which release norepinephrine to
These experiments revealed that the biophysical properties of the activate alpha1 receptors on splanchnic blood vessels and thus
spinal cord operate as functional filters that direct unspecific electri- provoke arterial vasoconstriction136. Large-diameter afferent fibers
cal currents toward specific neuronal subpopulations. EES leverages recruited with EES can activate sympathetic preganglionic neurons
large-diameter afferent fibers as a gateway to modulate motor neurons. through an intermediary glutamatergic interneuron136 (Fig. 3). This
Since large-diameter afferent fibers primarily modulate motor neurons mechanism enables the precise regulation of sympathetic circuits.
located in the spinal segment innervated by the root wherein these Closed-loop control of EES targeting these circuits maintained
afferents reside89,98, targeting individual dorsal roots enables the modu- blood pressure stability during transient, varying, and sustained
lation of distinct motor pool ensembles89,98,99. This biological principle orthostatic challenges in rat and NHP models, as well as in
led to stimulation strategies98–101 that target the individual dorsal root humans136,137. Large clinical trials are underway to turn this strategy
entry zones with a temporal structure aiming to reproduce the natural into a treatment for people who suffer from severe orthostatic
spatiotemporal activation pattern of motor neurons102 (Fig. 3). This hypotension.
principle enables the configuration of activity-dependent biomimetic
stimulation programs to support standing, walking, biking, swimming
and even trunk movements in people with paralysis103. Perspectives on neuromodulation therapies
While the lumbar spinal cord has been the primary focus of studies Neuromodulation of anatomically intact circuits in the brain, brainstem
on EES, experiments in NHP models104 and two humans with tetraple- and spinal cord have shown realistic promise to improve neurological
gia105 suggested that targeting the cervical dorsal root entry zones also functions after SCI. However, current approaches exclusively based
improves hand dexterity. However, complex hand gestures may rely on electricity are poorly specific. Even when the biophysical and/or
on more complex stimulation programs that are controlled directly functional properties of neural tissues steer electrical currents toward
by the brain. Brain-controlled regulation of EES can be achieved using specific neuronal subpopulations, the resolution of these physiological
brain–computer interface technologies99. filters remains limited regarding the highly specialized flow of com-
Neurorehabilitation supported by EES improves functional recov- munication that circulates in the intact nervous system. Identifica-
ery89. Individuals with chronic SCI have regained volitional control over tion of the neuronal subpopulations that are engaged and remodeled
previously paralyzed muscles, and some could even walk naturally in response to electrical stimulation might open avenues for more
without any stimulation. This recovery involved an unexpected reduc- targeted interventions that may be combined with pharmacological
tion in the neural activity in the lumbar spinal cord during walking, agents. However, neuromodulation therapies mediate improvements
suggesting that specific neuronal subpopulations are selected dur- that remain incomplete, and thus not fully satisfying. Consequently,
ing neurorehabilitation. Indeed, interrogation of a single-cell atlas of the reconstitution of circuits with biological repair strategies remains
recovery in mice revealed that excitatory interneurons expressing Vsx2 essential to maximize recovery.
are selected during neurorehabilitation supported by EES52. These cells
are nested within the intermediate lamina of the spinal cord, where Biological strategies to reconstitute circuits
they receive projections from large-diameter afferents and brainstem The reconstitution of circuits following spinal cord damage comes
neurons with surviving projections5,18. Neurorehabilitation reinforces in several interpretations, each targeting specific mechanisms and
these projection patterns, enabling these recovery-organizing neurons comprising unique challenges (Box 2). The more accomplishable inter-
to transform information from brainstem locomotor regions and pretation consists of densifying the projectome of neurons that retain
large-diameter afferents into commands that are broadcasted to the axons below the injury. When the SCI is complete, however, reconsti-
ventrally located neurons to produce movement (Fig. 3). tution of circuits implies the regeneration of severed axons through
The understanding that EES utilizes large-diameter afferents as hostile tissues to repair damaged circuits or form new relay circuits
gateways to circuits in the spinal cord opened up the possibility of that bypass the lesion and restore communication across the injury.
developing neuromodulation therapies that improve other neurologi- Alternatively, these hostile tissues can be repopulated with grafts that
cal functions, especially autonomic functions, which are ranked among reconstitute functional spinal cord environments. Below, we summa-
the top priorities for people with SCI (Box 1). rize the biological strategies that target each of these interpretations,

with a focus on the reconstitution of circuits after SCI to adhere to the

Box 2 theme of this review (Fig. 4).
Densification of projections from spared circuits

Specific challenges in each Natural recovery from SCI largely correlates with the relative number of
spared neuronal pathways106. This trivial etiology makes it abundantly
compartment of the injured clear that augmenting recovery after SCI will require the densification
region of projections from spared circuits. Neutralizing inhibitory molecules

or targeting intrinsic neuronal growth competence promotes this
remodeling (Box 3).
Damage to the spinal cord is typically inflicted by mechanical When axons are severed within the adult CNS, they fail to regen-
insults such as laceration or contusion. This primary injury tears erate. Extrinsic inhibitors found in degenerating myelin and astro-
axons apart and causes severe bleeding, which triggers a secondary cyte borders were once thought to be responsible for this failure6.
injury response involving a cascade of cellular and molecular This understanding launched a race to identify inhibitory molecules
events such as immune cell infiltration, cell death, demyelination and develop strategies to neutralize them. Initial experiments sug-
and scar formation. These secondary events lead to the formation of gested that these therapies act by promoting the regeneration of
three cellularly distinct compartments, starting from a core fibrotic severed axons across the site of injury107. However, modern methods
scar or cavity that is surrounded by an astrocyte border, and spared revealed that these interventions do not promote the regenera-
but reactive and reorganizing neural tissue109. tion of corticospinal tract axons through scars, but rather mediate
short-distance growth of axon collaterals over short distances in
Fibrotic scar (core) healthy tissue6,108. Early efforts were conducted with the hope that
Severe inflammation provokes the formation of the fibrotic scar, a singular solution would be sufficient to neutralize inhibition and
which is composed of fibroblasts, pericytes, endothelial and thus overcome regenerative failure. These hopes have declined with
inflammatory cells. While the origin of the cell types responsible the realization that reducing inhibition does not promote sufficient
for fibrotic scarring has been intensely debated138–140, we know regrowth of severed axons6,108.
that the origin is neither neuronal nor glial; therefore, the fibrotic In parallel, others have focused on identifying regeneration-
component of the scar must be distinguished from the glial scar. associated genes to reactivate intrinsic growth programs of neurons109
Because the fibrotic scar has been ascribed an inhibitory role, and stabilize growth cones110 (Box 3). Regrowth of severed axons from
many interventions sought to ablate the cellular constituents of the corticospinal, retinal and propriospinal neurons has been achieved with
fibrotic scar with the goal of decreasing the extracellular matrix110,141. the manipulation of the phosphatase and tensin homolog (PTEN)111,
Partial ablations have been reported to result in decreased suppressor of cytokine signaling 3 (SOCS3)112, STAT3 (ref. 112), SOX11
extracellular matrix deposition and improved behavioral outcomes, (ref. 113), osteopontin (OPN)114,115, insulin growth factor 1 (IGF-1)114,115,
while complete ablation of the same cells resulted in larger tissue ciliary neurotrophic factor (CNTF)115 and Krüppel-like family of tran-
damage and worsened behavioral outcomes141. In striking contrast, scription factors (KLFs)116 and neuronal RHOA117, among others118.
recent studies revealed that the fibrotic scar can act as a permissive Transcription and growth factors can be manipulated concurrently
scaffold that supports stimulated axons to regrow through this to augment this regrowth. Activation of mMTOR and STAT3 pathways
scar115,121. Differences between these studies are likely to result from with co-deletion of PTEN and SOCS3, or overexpression of the growth
the specific types of extracellular matrix that are upregulated and factors IGF-1 and OPN, induced synergistic regrowth of axons across
deposited by each intervention. Deconstructing the biology of astrocyte bridges and into topologically relevant targets below the
fibrotic scarring will provide actionable pathways to manipulate the injury, which was sufficient to restore some function114. Transient
extracellular matrix in order to foster the repair of damaged circuits. exposure to reduced oxygen levels, called intermittent hypoxia, is an
alternative strategy to modulate raphe serotonergic neurons, trigger
Astrocyte border (surrounding the core) brain-derived neurotrophic factor synthesis, and promote the growth
Fibrotic scars are surrounded by a thin and densely packed border of serotonergic projections below the injury119. Likewise, neuronal
of astrocytes, termed the astrocyte border, which is regulated activity promotes the release of various neurotrophic factors that aug-
through signal transducer and activator of transcription 3 (STAT3)142 ment the growth of spared neuronal projections. Neurorehabilitation
and leucine zipper-bearing kinase (LZK) signaling143. Astrocyte leverages this mechanism to improve functional recovery42.
borders are almost exclusively composed of newly proliferated While impressive, these circuit reconstitutions present limitations.
and reactive astroglia144,145. This border was long regarded as First, the regrowth of severed axons was obtained only for axons origi-
a physical and chemical barrier to axon growth. However, the nating from specific populations of neurons. The remarkable diversity
supposedly negative properties of border-forming astrocytes have of projection neurons in the brain, brainstem and spinal cord suggests
now been dismantled. We know that they are not the principal that unique combinations of transcription and growth factors may
cause of regenerative failure121, but instead restrict the spread of be necessary to induce axon regrowth from each subpopulation115,120.
inflammation into viable neural tissue121,144,146. Moreover, they are not Second, the accessibility of active gene regulatory regions may limit the
the primary producers of purportedly inhibitory chondroitin sulfate efficacy of transcription factor manipulation. Understanding spatial
proteoglycans (CSPGs)121, but can instead support the growth of and temporal changes in transcriptional and chromatin environments
stimulated axons115,121. These observations imply that border-forming in neuronal subpopulations could lead to the development of targeted,
astrocytes support neural repair and that hindering astrocyte border temporally controlled strategies to improve chromatin accessibility
formation is likely to be detrimental to recovery. and transcriptional initiation in recovery-organizing neurons. Third,
increasing the intrinsic growth competence of neurons promotes
Spared but reactive neural tissue (neighboring the core) axon repair through healthy spinal cord tissue, but stimulated axons
Adjacent to the astrocyte borders lies spared but reactive neural abruptly stop when encountered with fibrotic scar tissue115,121. There-
tissue, which contains hypertrophic reactive astroglia combined fore, the reconstitution of damaged circuits or formation of new cir-
with neurons forming circuits and undergoing synaptic turnover. cuits that reestablish communication across complete SCI remains a
formidable challenge.

Increase neuronal growth capacity
Box 3
Digestion of inhibitors
Overcoming inhibition
versus reactivation of growth
programs
Neutralizing inhibitory molecules and targeting intrinsic neuronal
Increase neuronal growth capacity
growth competence have been the main strategies to promote the
Induce supportive substrate anatomical remodeling of residual neuronal projections after SCI.
Chemoattractive gradient
Neutralizing inhibitory molecules
The most established strategy involves the delivery of the enzyme
chondroitinase (ChABC), which digests the glycosaminoglycan side
chain of CSPGs. CSPGs are the key constituents of perineuronal
nets that regulate the opening and closing of the neurogenesis
critical period. Devoid of perineuronal nets, neurons become
Neural stem cell relay circuits
available to receive synapses from newly formed axons of residual
projections. Multiple independent laboratories have demonstrated
that ChABC mediates functional improvements in both rodent
and NHP models20,147. Activity-dependent neurorehabilitation
further enhances this recovery41. Equally popular are strategies
Fig. 4 | Biological strategies to reconstitute damaged circuits. Schematic targeting the nogo receptor reticulon 4 (RTN4), which neutralizes
summarizing the primary biological strategies to reconstitute circuits after SCI. myelin-associated inhibition107. Positive outcomes in rodent and NHP
The reconstitution of circuits following spinal cord damage depends on the models have led to a multinational clinical trial that is evaluating
severity of injury. For incomplete injuries, regeneration of severed axons is not
the efficacy of antibodies against this receptor to augment manual
required, as a sufficient number of axon projections remain intact. Densifying
dexterity after incomplete SCI (NCT03935321).
the projectome of neurons that retain axons below the injury can be achieved by
either activating intrinsic neuronal growth competence or digesting inhibitors
Targeting intrinsic neuronal growth competence
associated with degenerating myelin or chondroitin sulfate proteoglycans (top).
When the SCI is complete, reconstitution of circuits necessitates regrowing One of the transformative moments for neural repair came from
severed axons across injury sites to restore connectivity. This regrowth systematic screenings in optic nerve injury models. It was found
can be achieved for propriospinal neurons by deploying a multipronged, that the genetic deletion of PTEN induces unprecedented regrowth
developmentally inspired repair strategy that sequentially upregulates intrinsic of injured axons from retinal ganglion cells111. Suppressing this
neuronal growth competence, induces supportive substrates and provides transcription factor in cortical neurons induced long-distance
chemoattraction (middle). Alternatively, these hostile tissues can be repopulated regrowth of corticospinal tract axons through spared astrocyte
with the engraftment of supportive neural stem cells that receive input from bridges following SCI148. These findings revealed that reactivating
key supraspinal centers and relay information across injury sites to restore intrinsic neuronal growth mechanisms enables true regeneration of
connectivity (bottom). severed axons that become insensitive to extrinsic inhibitors. Many
discoveries followed, as summarized in the main text.
Reconstitution of damaged circuits

A complete SCI not only interrupts communication across the injury, Equally mysterious is whether other neuronal subpopulations located
but also provokes the formation of fibrotic scar tissues with different in the brain and brainstem could be similarly guided through complete
lesion compartments that each present challenges to reconstitute SCI and to relevant targets below the injury.
spinal circuits (Box 2). Cajal posited that regrowing axons through
such hostile tissues would require recapitulation of the conditions that Engraftment of new circuits
stimulate and guide the growth of axons during development122. Certain A cure for SCI will require reconstituting the natural topology of the
components of this hypothesis were documented123–125, culminating in CNS. However, demonstrating that intraspinal neurons may relay suf-
a developmentally inspired, multipronged strategy that reactivated ficient information downstream to produce behaviors led to a more
the intrinsic growth capacity of neurons, induced the formation of optimistic definition of the requirements for meaningful recovery
substrates to support axon growth within the core lesion compart- after SCI.
ment, and guided axons downstream using spatially and temporally Efforts to repopulate the hostile lesion environment with relay
controlled release of growth factors115. Stimulated, supported and circuits followed. Various types of cells, including neural progeni-
chemoattracted axons regrew through astrocyte borders, across the tor cells (NPCs), have been grafted into the injured spinal cord with
fibrotic scar, and into healthy tissues where they formed contacts with widely differing success125 (Fig. 4). Only when NPCs were harvested
neurons below the SCI (Fig. 4). This strategy targeted propriospinal from homologous spinal cord tissue, supported with growth factors
neurons with the assumption that these cells would become relay cir- and embedded in stabilizing matrices or scaffolds, did they survive
cuits capable of mediating recovery. Despite the pronounced regrowth the engraftment. NPCs matured into glial cells and neurons that filled
of electrophysiologically conductive axons, no recovery of function the fibrotic tissue lesion and propelled thousands of axons along the
was observed115. Various mechanisms may explain this lack of recovery, entire rostrocaudal extent of the rodent and primate spinal cords126,127.
including the absence of activity to shape these new circuits, innerva- Differentiated neurons attracted projections from various host neu-
tion of improper targets, poor remyelination and even axon retraction. rons located in the brain and brainstem, thus establishing relay circuits

that could restore electrophysiological connectivity across complete 5. Asboth, L. et al. Cortico-reticulo-spinal circuit reorganization
SCI126. However, these new circuits mediated limited recovery126–128. enables functional recovery after severe spinal cord contusion.
Various mechanisms may be invoked to account for this discrepancy, Nat. Neurosci. 21, 576–588 (2018).
including the importance of activity-dependent factors, guidance of 6. Sofroniew, M. V. Dissecting spinal cord regeneration. Nature 557,
axons to relevant targets, and even the necessity to differentiate NPCs 343–350 (2018).
into specific neuronal subpopulations. For example, transplantation 7. Kathe, C., Hutson, T. H., McMahon, S. B. & Moon, L. D. F.
of NPCs enriched with V2a interneurons into the injury site improves Intramuscular neurotrophin-3 normalizes low threshold spinal
recovery of diaphragm activity129. reflexes, reduces spasms and improves mobility after bilateral
corticospinal tract injury in rats. Elife 5, e18146 (2016).
Perspectives on biological strategies to reconstitute circuits 8. Taweel, W. A. & Seyam, R. Neurogenic bladder in spinal cord
All of these interpretations on the requirements for reconstituting injury patients. Res. Rep. Urol. 7, 85–99 (2015).
circuits after SCI led to considerable advances42. We now understand 9. Courtine, G. et al. Performance of locomotion and foot grasping
how to densify the projections from spared neurons, regrow severed following a unilateral thoracic corticospinal tract lesion in
axons over long distances, and repopulate the injured spinal cord with monkeys (Macaca mulatta). Brain 128, 2338–2358 (2005).
viable circuits. However, the resulting recovery has so far been insuf- 10. Freund, P. et al. MRI investigation of the sensorimotor cortex and
ficient to translate into impactful clinical applications. We surmise the corticospinal tract after acute spinal cord injury: a prospective
that directing interventions to specific neuronal subpopulations118 and longitudinal study. Lancet Neurol. 12, 873–881 (2013).
guiding their regrowing axons to relevant targets may be necessary to 11. Nishimura, Y. et al. Time-dependent central compensatory
achieve recovery. Single-cell methods are opening a path to support mechanisms of finger dexterity after spinal cord injury. Science
this shift of resolution. Even following pronounced spinal circuit repair, 318, 1150–1155 (2007).
however, complementary interventions must counteract the maladap- 12. Hollis, E. R. 2nd et al. Ryk controls remapping of motor cortex
tive changes that take place in circuits located below a severe SCI, as during functional recovery after spinal cord injury. Nat. Neurosci.
observed following multiple sclerosis130. 19, 697–705 (2016).
13. Bareyre, F. M. et al. The injured spinal cord spontaneously
Molecular choreography of recovery from SCI forms a new intraspinal circuit in adult rats. Nat. Neurosci. 7,
The cure for SCI is unforeseeable, but we can already forecast that cur- 269–277 (2004).
rent strategies will not complete this long-haul quest. Throughout this 14. Hilton, B. J. et al. Reestablishment of cortical motor output maps
review, we have argued that we must operate a radical transition in the and spontaneous functional recovery via spared dorsolaterally
resolution of our CNS interrogation. Instead of focusing on vaguely projecting corticospinal neurons after dorsal column spinal cord
defined circuits and pathways, we must establish multi-omic cartogra- injury in adult mice. J. Neurosci. 36, 4080–4092 (2016).
phies at single-cell resolution over the entire CNS to map the landscape 15. Ghosh, A. et al. Rewiring of hindlimb corticospinal neurons after
of neurons that can orchestrate the natural recovery of function after spinal cord injury. Nat. Neurosci. 13, 97–104 (2010).
SCI—thus capturing the changing properties of recovery-organizing 16. Kaas, J. H. et al. Cortical and subcortical plasticity in the brains
neuronal subpopulations. These large-scale, multi-omic cartogra- of humans, primates, and rats after damage to sensory afferents
phies will also identify whether and how other cell types and epigenetic in the dorsal columns of the spinal cord. Exp. Neurol. 209,
mechanisms contribute to improving or impairing recovery. 407–416 (2008).
Imaging whole nervous systems131, single-cell technologies132 and 17. Rosenzweig, E. S. et al. Extensive spontaneous plasticity of
cell-specific interrogations133 have established the analytical tools to corticospinal projections after primate spinal cord injury. Nat.
catalog the molecular choreography of recovery from spinal cord dam- Neurosci. 13, 1505–1510 (2010).
age with exquisite detail. We now possess technologies to dissect the 18. Brand, Rvanden et al. Restoring voluntary control of locomotion
molecular signatures and growth requirements one neuron at a time, after paralyzing spinal cord injury. Science 336, 1182–1185 (2012).
across all the neurons of the CNS and over timescales ranging from min- 19. Rosenzweig, E. S. et al. Extensive spontaneous plasticity of
utes to months. The resulting space–time catalogs of recovery from SCI corticospinal projections after primate spinal cord injury. Nat.
are poised to uncover the transcriptional programs that will support Neurosci. 13, 1505–1510 (2010).
the regrowth of any neuronal subpopulation from the brain, brainstem 20. Rosenzweig, E. S. et al. Chondroitinase improves anatomical
and spinal cord. We must then harness this knowledge to inform these and functional outcomes after primate spinal cord injury. Nat.
evidence-based repair programs that engage and reconstitute the Neurosci. 22, 1269–1275 (2019).
projections from each recovery-organizing neuronal subpopulation 21. Poplawski, G. H. D. et al. Injured adult neurons regress to an
to their respective targets. embryonic transcriptional growth state. Nature 581, 77–82 (2020).
This new era will unlock the blueprints to reconstitute the natural 22. Friedli, L. et al. Pronounced species divergence in corticospinal
topology of all the relevant recovery-organizing neuronal populations, tract reorganization and functional recovery after lateralized
with the hope that the development of a cure for SCI will then follow. spinal cord injury favors primates. Sci. Transl. Med. 7,
302ra134 (2015).
References 23. Siegel, C. S., Fink, K. L., Strittmatter, S. M. & Cafferty, W. B. J.
1. Skinnider, M. A. et al. Cell type prioritization in single-cell data. Plasticity of intact rubral projections mediates spontaneous
Nat. Biotechnol. 39, 30–34 (2020). recovery of function after corticospinal tract injury. J. Neurosci.
2. Osseward, P. J. et al. Conserved genetic signatures parcellate 35, 1443–1457 (2015).
cardinal spinal neuron classes into local and projection subsets. 24. Mosberger, A. C. et al. Axotomized corticospinal neurons increase
Science 372, 385–393 (2021). supra-lesional innervation and remain crucial for skilled reaching
3. Arber, S. & Costa, R. M. Connecting neuronal circuits for after bilateral pyramidotomy. Cereb. Cortex 28, 625–643 (2017).
movement. Science 360, 1403–1404 (2018). 25. Zaaimi, B., Edgley, S. A., Soteropoulos, D. S. & Baker, S. N.
4. Pivetta, C., Esposito, M. S., Sigrist, M. & Arber, S. Motor-circuit Changes in descending motor pathway connectivity after
communication matrix from spinal cord to brainstem neurons corticospinal tract lesion in macaque monkey. Brain 135,
revealed by developmental origin. Cell 156, 537–548 (2014). 2277–2289 (2012).

26. Filli, L. et al. Bridging the gap: a reticulo-propriospinal detour 49. Takeoka, A., Vollenweider, I., Courtine, G. & Arber, S. Muscle
bypassing an incomplete spinal cord injury. J. Neurosci. 34, spindle feedback directs locomotor recovery and circuit
13399–13410 (2014). reorganization after spinal cord injury. Cell 159, 1626–1639 (2014).
27. Kwon, B. K. et al. Survival and regeneration of rubrospinal neurons 50. Hutson, T. H. et al. Cbp-dependent histone acetylation
1 year after spinal cord injury. Proc. Natl Acad. Sci. USA 99, mediates axon regeneration induced by environmental
3246–3251 (2002). enrichment in rodent spinal cord injury models. Sci. Transl. Med.
28. Alilain, W. J., Horn, K. P., Hu, H., Dick, T. E. & Silver, J. Functional 11, eaaw2064 (2019).
regeneration of respiratory pathways after spinal cord injury. 51. Satkunendrarajah, K., Karadimas, S. K., Laliberte, A. M., Montandon,
Nature 475, 196–200 (2011). G. & Fehlings, M. G. Cervical excitatory neurons sustain breathing
29. Müllner, A. et al. Lamina‐specific restoration of serotonergic after spinal cord injury. Nature 562, 419–422 (2018).
projections after Nogo‐A antibody treatment of spinal cord injury 52. Kathe, C. et al. The neurons that restore walking after paralysis.
in rats. Eur. J. Neurosci. 27, 326–333 (2008). Nature https://doi.org/10.1038/s41586-022-05385-7 (2022).
30. Sawada, M. et al. Function of the nucleus accumbens in motor 53. Zholudeva, L. V., Karliner, J. S., Dougherty, K. J. & Lane, M. A.
control during recovery after spinal cord injury. Science 350, Anatomical recruitment of spinal V2a interneurons into
98–101 (2015). phrenic motor circuitry after high cervical spinal cord injury.
31. Shik, M. L., Severin, F. V. & Orlovskiĭ, G. N. Control of walking and J. Neurotrauma 34, 3058–3065 (2017).
running by means of electric stimulation of the midbrain. Biofizika 54. Bui, T. V., Stifani, N., Akay, T. & Brownstone, R. M. Spinal
11, 659–666 (1966). microcircuits comprising dI3 interneurons are necessary for
32. Ryczko, D. & Dubuc, R. The multifunctional mesencephalic motor functional recovery following spinal cord transection. Elife
locomotor region. Curr. Pharm. Des. 19, 4448–4470 (2013). 5, e21715 (2016).
33. Bonizzato, M. et al. Multi-pronged neuromodulation 55. Sathyamurthy, A. et al. Massively parallel single nucleus
intervention engages the residual motor circuitry to facilitate transcriptional profiling defines spinal cord neurons and their
walking in a rat model of spinal cord injury. Nat. Commun. 12, activity during behavior. Cell Rep. 22, 2216–2225 (2018).
1925 (2021). 56. Russ, D. E. et al. A harmonized atlas of mouse spinal cord cell
34. Caggiano, V. et al. Midbrain circuits that set locomotor speed and types and their spatial organization. Nat. Commun. 12, 5722 (2021).
gait selection. Nature 553, 455–460 (2018). 57. Overman, J. J. & Carmichael, S. T. Plasticity in the injured brain.
35. Esposito, M. S., Capelli, P. & Arber, S. Brainstem nucleus Neuroscientist 20, 15–28 (2014).
MdV mediates skilled forelimb motor tasks. Nature 508, 58. Pozo, K. & Goda, Y. Unraveling mechanisms of homeostatic
351–356 (2014). synaptic plasticity. Neuron 66, 337–351 (2010).
36. Ferreira-Pinto, M. J. et al. Functional diversity for body 59. Squair, J. W., West, C. R. & Krassioukov, A. V. Neuroprotection,
actions in the mesencephalic locomotor region. Cell 184, plasticity manipulation, and regenerative strategies to
4564–4578 (2021). improve cardiovascular function following spinal cord injury.
37. Ruder, L. et al. A functional map for diverse forelimb actions J. Neurotrauma 32, 609–621 (2015).
within brainstem circuitry. Nature 590, 445–450 (2021). 60. Krassioukov, A. V., Johns, D. G. & Schramm, L. P. Sensitivity of
38. Kinoshita, M. et al. Genetic dissection of the circuit for hand sympathetically correlated spinal interneurons, renal sympathetic
dexterity in primates. Nature 487, 235–238 (2012). nerve activity, and arterial pressure to somatic and visceral stimuli
39. Chen, B. et al. Reactivation of dormant relay pathways in injured after chronic spinal injury. J. Neurotrauma 19, 1521–1529 (2002).
spinal cord by KCC2 manipulations. Cell 174, 521–535 (2018). 61. Brennan, F. H. et al. Acute post-injury blockade of α2δ ̣ -1 calcium
40. Courtine, G. et al. Recovery of supraspinal control of stepping via channel subunits prevents pathological autonomic plasticity after
indirect propriospinal relay connections after spinal cord injury. spinal cord injury. Cell Rep. 34, 108667 (2021).
Nat. Med. 14, 69–74 (2008). 62. Li, Y. et al. Pericytes impair capillary blood flow and motor
41. García-Alías, G., Barkhuysen, S., Buckle, M. & Fawcett, J. W. function after chronic spinal cord injury. Nat. Med. 23,
Chondroitinase ABC treatment opens a window of opportunity for 733–741 (2017).
task-specific rehabilitation. Nat. Neurosci. 12, 1145–1151 (2009). 63. D’Amico, J. M. et al. Constitutively active 5-HT2/α1 receptors
42. Courtine, G. & Sofroniew, M. V. Spinal cord repair: advances in facilitate muscle spasms after human spinal cord injury. J.
biology and technology. Nat. Med. 25, 898–908 (2019). Neurophysiol. 109, 1473–1484 (2013).
43. Lanuza, G. M., Gosgnach, S., Pierani, A., Jessell, T. M. & Goulding, 64. Husch, A. et al. Spinal cord injury induces serotonin
M. Genetic identification of spinal interneurons that coordinate supersensitivity without increasing intrinsic excitability of mouse
left–right locomotor activity necessary for walking movements. V2a Interneurons. J. Neurosci. 32, 13145–13154 (2012).
Neuron 42, 375–386 (2004). 65. Boulenguez, P. et al. Down-regulation of the potassium-chloride
44. Gosgnach, S. et al. V1 spinal neurons regulate the speed of cotransporter KCC2 contributes to spasticity after spinal cord
vertebrate locomotor outputs. Nature 440, 215–219 (2006). injury. Nat. Med. 16, 302–307 (2010).
45. Courtine, G. et al. Transformation of nonfunctional spinal circuits 66. Bellardita, C. et al. Spatiotemporal correlation of spinal network
into functional states after the loss of brain input. Nat. Neurosci. dynamics underlying spasms in chronic spinalized mice. Elife 6,
12, 1333–1342 (2009). e23011 (2017).
46. Caudle, K. L. et al. Hindlimb immobilization in a wheelchair alters 67. Marcantoni, M. et al. Early delivery and prolonged treatment with
functional recovery following contusive spinal cord injury in the nimodipine prevents the development of spasticity after spinal
adult rat. Neurorehabil. Neural Repair 25, 729–739 (2011). cord injury in mice. Sci. Transl. Med. 12, eaay0167 (2020).
47. Côté, M.-P., Azzam, G. A., Lemay, M. A., Zhukareva, V. & Houlé, J. D. 68. Beauparlant, J. et al. Undirected compensatory plasticity
Activity-dependent increase in neurotrophic factors is associated contributes to neuronal dysfunction after severe spinal cord
with an enhanced modulation of spinal reflexes after spinal cord injury. Brain 136, 3347–3361 (2013).
injury. J. Neurotrauma 28, 299–309 (2011). 69. Elbasiouny, S. M., Moroz, D., Bakr, M. M. & Mushahwar, V. K.
48. Ichiyama, R. M. et al. Step training reinforces specific spinal Management of spasticity after spinal cord injury: current
locomotor circuitry in adult spinal rats. J. Neurosci. 28, techniques and future directions. Neurorehabil. Neural Repair 24,
7370–7375 (2008). 23–33 (2010).

70. Groat, W. C de & Yoshimura, N. Mechanisms underlying the 92. Harkema, S. et al. Effect of epidural stimulation of the lumbosacral
recovery of lower urinary tract function following spinal cord spinal cord on voluntary movement, standing, and assisted
injury. Prog. Brain Res. 152, 59–84 (2006). stepping after motor complete paraplegia: a case study. Lancet
71. Kramer, J. L. K. et al. Neuropathic pain following traumatic spinal 377, 1938–1947 (2011).
cord injury: models, measurement and mechanisms. J. Neurosci. 93. Barbeau, H. & Rossignol, S. Recovery of locomotion
Res. 95, 1295–1306 (2017). after chronic spinalization in the adult cat. Brain Res. 412,
72. Hou, S. & Rabchevsky, A. G. Autonomic consequences of spinal 84–95 (1987).
cord injury. Compr. Physiol. 4, 1419–1453 (2017). 94. Capogrosso, M. et al. A computational model for epidural
73. Zholudeva, L. V. et al. Spinal Interneurons as gatekeepers electrical stimulation of spinal sensorimotor circuits. J. Neurosci.
to neuroplasticity after injury or disease. J. Neurosci. 41, 33, 19326–19340 (2013).
845–854 (2021). 95. Formento, E. et al. Electrical spinal cord stimulation must
74. Manno, G. L. et al. Molecular architecture of the developing preserve proprioception to enable locomotion in humans with
mouse brain. Nature 596, 92–96 (2021). spinal cord injury. Nat. Neurosci. 21, 1728–1741 (2018).
75. Squair, J. W. et al. Confronting false discoveries in single-cell 96. Meyer, C. et al. Immediate effects of transcutaneous
differential expression. Nat. Commun. 12, 5692 (2021). spinal cord stimulation on motor function in chronic,
76. Cao, J. et al. The single-cell transcriptional landscape of sensorimotor incomplete spinal cord injury. J. Clin. Med. 9,
mammalian organogenesis. Nature 566, 496–502 (2019). 3541 (2020).
77. Zappia, L. & Theis, F. J. Over 1,000 tools reveal trends in the 97. Moraud, E. M. et al. Mechanisms underlying the neuromodulation
single-cell RNA-seq analysis landscape. Genome Biol. 22, of spinal circuits for correcting gait and balance deficits after
301 (2021). spinal cord injury. Neuron 89, 814–828 (2016).
78. Bonizzato, M. & Martinez, M. An intracortical neuroprosthesis 98. Wenger, N. et al. Spatiotemporal neuromodulation therapies
immediately alleviates walking deficits and improves recovery engaging muscle synergies improve motor control after spinal
of leg control after spinal cord injury. Sci. Transl. Med. 13, cord injury. Nat. Med. 22, 138–145 (2016).
eabb4422 (2021). 99. Capogrosso, M. et al. A brain–spine interface alleviating
79. Carmel, J. B., Kimura, H. & Martin, J. H. Electrical stimulation of gait deficits after spinal cord injury in primates. Nature 539,
motor cortex in the uninjured hemisphere after chronic unilateral 284–288 (2016).
injury promotes recovery of skilled locomotion through ipsilateral 100. Minev, I. R. et al. Electronic dura mater for long-term multimodal
control. J. Neurosci. 34, 462–466 (2014). neural interfaces. Science 347, 159–163 (2015).
80. Nishimura, Y., Perlmutter, S. I., Eaton, R. W. & Fetz, E. E. 101. Capogrosso, M. et al. Configuration of electrical spinal cord
Spike-timing-dependent plasticity in primate corticospinal stimulation through real-time processing of gait kinematics. Nat.
connections induced during free behavior. Neuron 80, Protoc. 13, 2031–2061 (2018).
1301–1309 (2013). 102. Cappellini, G., Ivanenko, Y. P., Dominici, N., Poppele, R. E. &
81. McPherson, J. G., Miller, R. R. & Perlmutter, S. I. Targeted, Lacquaniti, F. Migration of motor pool activity in the spinal cord
activity-dependent spinal stimulation produces long-lasting reflects body mechanics in human locomotion. J. Neurophysiol.
motor recovery in chronic cervical spinal cord injury. Proc. Natl 104, 3064–3073 (2010).
Acad. Sci. USA 112, 12193–12198 (2015). 103. Rowald, A. et al. Activity-dependent spinal cord neuromodulation
82. Christiansen, L. & Perez, M. A. Targeted-plasticity in rapidly restores trunk and leg motor functions after complete
the corticospinal tract after human spinal cord injury. paralysis. Nat. Med. https://doi.org/10.1038/s41591-021-01663-5
Neurotherapeutics 15, 618–627 (2018). (2022).
83. Darrow, M. J. et al. Vagus nerve stimulation paired with 104. Barra, B. et al. Epidural electrical stimulation of the cervical dorsal
rehabilitative training enhances motor recovery after bilateral roots restores voluntary upper limb control in paralyzed monkeys.
spinal cord injury to cervical forelimb motor pools. Neurorehabil. Nat. Neurosci. 25, 924–934 (2022).
Neural Repair 34, 200–209 (2020). 105. Lu, D. C. et al. Engaging cervical spinal cord networks to
84. Ganzer, P. D. et al. Closed-loop neuromodulation restores network reenable volitional control of hand function in tetraplegic
connectivity and motor control after spinal cord injury. Elife 7, patients. Neurorehabil. Neural Repair 30, 951–962 (2016).
e32058 (2018). 106. Fouad, K., Popovich, P. G., Kopp, M. A. & Schwab, J. M. The
85. Thevathasan, W. et al. Pedunculopontine nucleus deep brain neuroanatomical–functional paradox in spinal cord injury. Nat.
stimulation in Parkinson’s disease: a clinical review. Mov. Disord. Rev. Neurol. 17, 53–62 (2021).
33, 10–20 (2018). 107. Schnell, L. & Schwab, M. E. Axonal regeneration in the rat spinal
86. Sherrington, C. S. The Integrative Action of The Nervous System cord produced by an antibody against myelin-associated neurite
https://doi.org/10.1037/13798-000 (Yale Univ. Press, 1906). growth inhibitors. Nature 343, 269–272 (1990).
87. Dimitrijevic, M. R., Gerasimenko, Y. & Pinter, M. M. Evidence for 108. Lee, J. K. et al. Assessing spinal axon regeneration and
a spinal central pattern generator in humans. Ann. NY Acad. Sci. sprouting in Nogo-, MAG- and OMgp-deficient mice. Neuron 66,
860, 360–376 (1998). 663–670 (2010).
88. Angeli, C. A. et al. Recovery of over-ground walking after 109. Squair, J. W., Gautier, M., Sofroniew, M. V., Courtine, G. &
chronic motor complete spinal cord injury. N. Engl. J. Med. 379, Anderson, M. A. Engineering spinal cord repair. Curr. Opin.
1244–1250 (2018). Biotech. 72, 48–53 (2021).
89. Wagner, F. B. et al. Targeted neurotechnology restores walking in 110. Hellal, F. et al. Microtubule stabilization reduces scarring and
humans with spinal cord injury. Nature 563, 65–71 (2018). causes axon regeneration after spinal cord injury. Science 331,
90. Holinski, B. J., Mazurek, K. A., Everaert, D. G., Stein, R. B. & 928–931 (2011).
Mushahwar, V. K. Restoring stepping after spinal cord injury using 111. Park, K. K. et al. Promoting axon regeneration in the adult
intraspinal microstimulation and novel control strategies. Annu. CNS by modulation of the PTEN/mTOR pathway. Science 322,
Int. Conf. IEEE Eng. Med. Biol. Soc. 2011, 5798–5801 (2011). 963–966 (2008).
91. Gerasimenko, Y. et al. Transcutaneous electrical spinal-cord 112. Sun, F. et al. Sustained axon regeneration induced by co-deletion
stimulation in humans. Ann. Phys. Rehabil. Med. 58, 225–231 (2015). of PTEN and SOCS3. Nature 480, 372–375 (2011).

113. Wang, Z., Reynolds, A., Kirry, A., Nienhaus, C. & Blackmore, 136. Squair, J. W. et al. Neuroprosthetic baroreflex controls
M. G. Overexpression of Sox11 promotes corticospinal tract haemodynamics after spinal cord injury. Nature 590,
regeneration after spinal injury while interfering with functional 308–314 (2021).
recovery. J. Neurosci. 35, 3139–3145 (2015). 137. Squair, J. W. et al. Implanted system for orthostatic hypotension in
114. Liu, Y. et al. A sensitized IGF1 treatment restores corticospinal multiple-system atrophy. N. Engl. J. Med. 386, 1339–1344 (2022).
axon-dependent functions. Neuron 95, 817–833 (2017). 138. Göritz, C. et al. A pericyte origin of spinal cord scar tissue. Science
115. Anderson, M. A. et al. Required growth facilitators propel axon 333, 238–242 (2011).
regeneration across complete spinal cord injury. Nature 561, 139. Soderblom, C. et al. Perivascular fibroblasts form the
396–400 (2018). fibrotic scar after contusive spinal cord injury. J. Neurosci. 33,
116. Wang, Z. et al. KLF6 and STAT3 co-occupy regulatory DNA and 13882–13887 (2013).
functionally synergize to promote axon growth in CNS neurons. 140. Dorrier, C. E. et al. CNS fibroblasts form a fibrotic scar in response
Sci. Rep. 8, 12565 (2018). to immune cell infiltration. Nat. Neurosci. 24, 234–244 (2021).
117. Stern, S. et al. RhoA drives actin compaction to restrict axon 141. Dias, D. O. et al. Reducing pericyte-derived scarring promotes
regeneration and astrocyte reactivity after CNS injury. Neuron recovery after spinal cord injury. Cell 173, 153–165 (2018).
109, 3436–3455 (2021). 142. Herrmann, J. E. et al. STAT3 is a critical regulator of astrogliosis
118. Anderson, M. A. Targeting central nervous system regeneration and scar formation after spinal cord injury. J. Neurosci. 28,
with cell type specificity. Neurosurg. Clin. N. Am. 32, 7231–7243 (2008).
397–405 (2021). 143. Chen, M. et al. Leucine zipper-bearing kinase is a critical regulator
119. Lovett-Barr, M. R. et al. Repetitive intermittent hypoxia induces of astrocyte reactivity in the adult mammalian CNS. Cell Rep. 22,
respiratory and somatic motor recovery after chronic cervical 3587–3597 (2018).
spinal injury. J. Neurosci. 32, 3591–3600 (2012). 144. Wanner, I. B. et al. Glial scar borders are formed by newly
120. Duan, X. et al. Subtype-specific regeneration of retinal ganglion proliferated, elongated astrocytes that interact to corral
cells following axotomy: effects of osteopontin and mTOR inflammatory and fibrotic cells via STAT3-dependent mechanisms
signaling. Neuron 85, 1244–1256 (2015). after spinal cord injury. J. Neurosci. 33, 12870–12886 (2013).
121. Anderson, M. A. et al. Astrocyte scar formation aids 145. Anderson, M. A., Ao, Y. & Sofroniew, M. V. Heterogeneity of
central nervous system axon regeneration. Nature 532, reactive astrocytes. Neurosci. Lett. 565, 23–29 (2014).
195–200 (2016). 146. Faulkner, J. R. et al. Reactive astrocytes protect tissue and
122. Ramón y Cajal, S., DeFelipe, J. & Jones, E. G. Cajal’s Degeneration preserve function after spinal cord injury. J. Neurosci. 24,
and Regeneration of the Nervous System (Oxford Univ. Press, 2143–2155 (2004).
Oxford, 1991). 147. Bartus, K. et al. Large-scale chondroitin sulfate proteoglycan
123. Alto, L. T. et al. Chemotropic guidance facilitates axonal digestion with chondroitinase gene therapy leads to reduced
regeneration and synapse formation after spinal cord injury. Nat. pathology and modulates macrophage phenotype following
Neurosci. 12, 1106–1113 (2009). spinal cord contusion injury. J. Neurosci. 34, 4822–4836 (2014).
124. Lu, P. et al. Motor axonal regeneration after partial and complete 148. Liu, K. et al. PTEN deletion enhances the regenerative
spinal cord transection. J. Neurosci. 32, 8208–8218 (2012). ability of adult corticospinal neurons. Nat. Neurosci. 13,
125. Assinck, P., Duncan, G. J., Hilton, B. J., Plemel, J. R. & Tetzlaff, W. 1075–1081 (2010).
Cell transplantation therapy for spinal cord injury. Nat. Neurosci.
20, 637–647 (2017). Acknowledgements
126. Lu, P. et al. Long-distance growth and connectivity of neural stem We acknowledge support from Defitech Foundation, the Swiss
cells after severe spinal cord injury. Cell 150, 1264–1273 (2012). National Science Foundation (Ambizione Fellowship PZ00P3_185728
127. Rosenzweig, E. S. et al. Restorative effects of human neural to M.A.A.) and subsidy to G.C. (310030_192558), Swiss National
stem cell grafts on the primate spinal cord. Nat. Med. 24, Science Foundation (32003BE_205563), European Research Council
484–490 (2018). (ERC-2015-CoG HOW2WALKAGAIN 682999; Marie Sklodowska-Curie
128. Abematsu, M. et al. Neurons derived from transplanted neural individual fellowship 842578 to J.W.S.), H2020-MSCA-COFUND-2016
stem cells restore disrupted neuronal circuitry in a mouse model EPFL Fellows program (665667 to C.K.), the Morton Cure Paralysis
of spinal cord injury. J. Clin. Invest. 120, 3255–3266 (2010). Foundation (to M.A.A.), the ALARME Foundation (to M.A.A. and G.C.)
129. Zholudeva, L. V. et al. Transplantation of neural progenitors and and the Human Frontiers in Science Program long-term fellowship
V2a interneurons after spinal cord injury. J. Neurotrauma 35, (LT001278/2017-L to C.K.).
2883–2903 (2018).
130. Rocca, M. A. et al. Clinical and imaging assessment of Competing interests
cognitive dysfunction in multiple sclerosis. Lancet Neurol. 14, G.C., J.B. and J.W.S. hold various patents in relation with some of the
302–317 (2015). present work. G.C. and J.B. are consultants of ONWARD medical. G.C.
131. Chung, K. & Deisseroth, K. CLARITY for mapping the nervous and J.B. are minority shareholders of ONWARD, a company with partial
system. Nat. Methods 10, 508–513 (2013). relationships with some of the presented work. The remaining authors
132. Srivatsan, S. R. et al. Embryo-scale, single-cell spatial declare no competing interests.
transcriptomics. Science 373, 111–117 (2021).
133. Fenno, L. E. et al. Targeting cells with single vectors Additional information
using multiple-feature Boolean logic. Nat. Methods 11, Correspondence should be addressed to Grégoire Courtine.
763–772 (2014).
134. Bruns, T. M., Weber, D. J. & Gaunt, R. A. Microstimulation of Peer review information Nature Neuroscience thanks Vicki Tysseling
afferents in the sacral dorsal root ganglia can evoke reflex bladder and the other, anonymous, reviewer(s) for their contribution to the
activity. Neurourol. Urodyn. 34, 65–71 (2015). peer review of this work.
135. West, C. R. et al. Association of epidural stimulation with
cardiovascular function in an individual with spinal cord injury. Reprints and permissions information is available at
JAMA Neurol. 75, 630–632 (2018). www.nature.com/reprints.

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Anderson 2022 - Natural and Targeted Circuit Reorganization After Spinal Cord Injury

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nature neuroscience

Review Article https://doi.org/10.1038/s41593-022-01196-1

Natural and targeted circuit reorganization

Thomas H. Hutson1,2,3,4, Claudia Kathe 1,2,3, Quentin Barraud 1,2,3,

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1584

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1585

Directed reorganization of spinal circuits below the injury

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1586

local–long range and excitatory–inhibitory features2. We anticipate Deep brain stimulation

Undirected reorganization of spinal circuits below the injury MLR

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1587

Large-diameter EES stimulation

Increase in blood pressure

Extensor muscle activity Alternative recruitment of muscles

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1588

It is now well established that delivering electrical stimulation to the

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1589

with a focus on the reconstitution of circuits after SCI to adhere to the

Densification of projections from spared circuits

region of projections from spared circuits. Neutralizing inhibitory molecules

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1590

Increase neuronal growth capacity

Reconstitution of damaged circuits

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1591

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1592

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1593

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1594

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1595

Nature Neuroscience | Volume 25 | December 2022 | 1584–1596 1596

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