This review paper gave me a vivid image of the plastic nature in brain function. The cortical map is not a static representation. It represents dynamic equilibrium of continuous interactions of the brain and the external world. Such fluidic nature of the brain is remarkable during the sensorimotor learning. It becomes especially important when the brain goes through functional recovery after injury and rehabilitation. Upon spinal cord injury, a change in brain state occurs immediately to start cortical reorganization.
A complete thoracic spinal cord transection immediately changes the state of the brain, decreasing cortical spontaneous activity as evidenced by a slowing of the frequency of anesthesia-induced oscillations, while increases the cortical responses to stimuli delivered above the level of the lesion. The increased responses could be due to a change in the equilibrium between excitation and inhibition at cortical and subcortical levels.
There is a species differences in the cortical reorganization. In human, the spinal lesion induces an enlargement of cortical sensorimotor areas representing preserved muscles above the level of lesion. Primates brain may be more flexible than rodents, in which spontaneous cortical reorganization is more limited.
The authors discussed potential therapy that involves 5-HT and exercises. Activation of 5-HT receptors facilitates cortical reorganization by restructuring connections that could be relevant for behavioral recovery. Cortical reorganization can also be promoted by exercise therapy, which increases brain BDNF levels. This peptide and 5-HT together favors cortical reorganization and functional recovery after spinal cord injury.
In this paper, the authors raise an interesting hypothesis that the plasticity mechanisms underlying learning and memory in higher organisms may have evolved from adaptive responses that repair damaged neuronal processes or body parts. Persistent nociceptive sensitization in Aplysia nervous system displays many functional similarities to alterations in mammalian nociceptors associated with the clinical problem of chronic pain. The original responses induced regrowth of damaged axon, increased excitability, enhanced release of transmitter, and reorganization of cellular network. Such compensatory responses would be critical for survival in the early age.
Before discussing about the origin of chronic pain and synaptic plasticity, the authors also described how great Aplysia is. They compared molluscs with other model systems like arthropod and nematode by comparing the number of gene homologues that are shared by mammals, and their evolutionary distances from mammals. Mollucs are closer to mammals because they split earlier. Slower rate of gene evolution provided molluscs more homologous genes associated with human disease than Drosophila or C. elegans. DNA methylation can also be seen in molluscs. Thus, integration of genomics and physiological studies in molluscan neurons offers a powerful comparative approach to address molecular and cellular aspects of selected neurological problems.
Altogether, molluscan preparations should become increasingly useful for comparative studies across phyla that can provide insight into cellular functions of clinically important genes.
This paper shows that, when a neural circuit failed by losing one of its synapses within, functional recovery can occur through reorganization of the remaining neural circuitry. We show that a molluscan neural circuit recruits additional neurons in response to a lesion. The extent of recruitment predicts the extent of behavioral recovery.
Even in a well-defined (sort of) invertebrate neural circuit, there are indirect, polysynaptic pathways that provide compensatory function or flexibility to the circuit. Such individual variability appears to be hidden under normal conditions but becomes relevant when challenged by neural injury.
Neuronal activity in the isolated mouse spinal cord during spontaneous deletions in fictive locomotion: Insights into locomotor CPG organization
by Guisheng Zhong, Natalia A Shevtsova, Ilya A Rybak, Ronald M Harris-Warrick
Journal of Physiology (2012)
Deletions are spontaneous errors in the rhythmic locomotor pattern when a set of synergist motoneurons (for example, flexor motoneurons on one side) loses rhythmic firing or falls silent during a time period when they are normally active.
In the non-resetting deletions, the phase of the rhythm after the deletion did not change. The resetting deletions show rhythm resetting which was recognized by a shift in the phase of the motor bursts after the deletion. This study follows Rybak-McCrea model of the locomotor CPG, which has two functional levels: a half-center rhythm-generator and pattern formation networks.
Deletions occur simultaneously in motor activity across more than one spinal segment. Spontaneous non-resetting deletions on one side are independent of the other side. The CPG can be functional within an isolated hemisegment. The reduction in locomotor frequency after simulated hemisection results mainly from the elimination of excitatory input to the rhythm-generating ipsilateral RG-F population from the contralateral RG-E population. The resumption of activity an integer number of cyces later does not require input from other parts of the spinal cord. Each hemicord contains an independent rhythmogenic network that can function in the absence of the other hemicord, although the left and right networks are normally coupled via commissural interneurons.
Among V2a interneurons, there are deletion-sensitive types and insensitive type (type I and II V2a interneurons). Type I V2a does not respond to non-locomotory firing in iL2, whereas type II V2a does. Both neurons were depolarized by synaptic drive. The type I V2a interneurons are involved in rhythm generation and/or coordination between left and right networks via the CINs. In contrast, the type II V2a interneurons do not belong to rhythm generator networks, but can be components of the pattern gormation network and/or last-order interneurons that directly project to motoneurons. Commissural interneurons (CINs) send their axons to the opposite side of the cord and coordinate left-right alternation. CINs were not affected by motoneuronal deletion. There was asymmetry in deletion: During all of the flexor deletions, the ipsilateral extensor root showed sustained activity with no interruptions at the times of the missing flexor bursts. In contrast, during all extensor deletions, the ipsilateral flexor root continued unperturbed bursting.
Their computational model combines the Rybak-McCrea concept of the two-level locomotor CPG (Rybak et al., 2006a,b; McCrea and Rybak, 2007,2008) with the Duysens-Pearson concept of an asymmetric rhythm generator with a dominant flexor half-centre (Pearson and Duysens, 1976).
David J. Bennet, Yunru Li, and Merek Siu J. Neurophysiol. 86, 2001
Jerky limb movements often develop after spinal cord injury. This general spasticity syndrome is caused at least in part by enhanced plateau potentials in the MNs. Depolarization in MN triggers the plateau potential and causes its sustained firing, which lead to exaggerated muscle contraction. This paper describes the basic properties of this plateau potential and the sustained firing in MNs after spinal cord transection. The recurrent GABAergic and Glycinergic inhibitions may play a role in suppressing this enhanced plateau potential. This will be studied in following paper.
My latest paper will appear in the Journal of Neuroscience. October 21, 2009 | Volume 29 | Number 42 |
They will introduce my paper in "This Week in The Journal" Development/Plasticity/Repair - "Nerve Transection Induces Circuit Reorganization in Tritonia"
The article title is: "Functional Recovery after Lesion of a Central Pattern Generator" by Akira Sakurai and Paul S. Katz
In this paper, we found that severing a set of connections between some CPG neurons impaired motor pattern production but that the system spontaneously recovered over the course of a few hours to a day. Furthermore, we observed corresponding changes in synaptic strength that can account for the functional recovery.
S. Rossignol, G. Barrière, O. Alluin and A. Frigon
The CPG is defined as a spinal network of neurons capable of generating a rhythmic pattern consisting of alternating activity between flexor and extensor motoneurons on the same side with reciprocal activation of homologous motoneurons in the other limb of the same girdle. In general, during walking or trotting, this network ensures that flexor motoneurons on one side are active with contralateral extensors and vice versa for extensor motoneurons.
...In such a preparation, rhythmic activity, evoked by injecting the noradrenaline precursor l-dihydroxyphenylalanine (L-DOPA), is recorded from peripheral muscle nerves and is termed “fictive locomotion.”
...Indeed, electrical stimulation of a circumscribed brain stem region called the mesencephalic locomotor region (MLR), ... Various gait patterns, such as walk, trot, and gallop, can be evoked with increasing stimulation intensity.
...Other descending pathways release specific neurotransmitters, which are synthesized by cells in well defined brain stem nuclei (e.g., noradrenaline in the locus coeruleus and serotonin in the raphe and parapyramidal nuclei). These neurotransmitters exert powerful effects on the spinal circuitry and can change characteristics of the locomotor pattern.
...it is important to know that, after a complete spinal transection, most quadruped mammals will recover some degree of locomotor function in the limbs below the lesion. Cats, rats, and mice can re-express hindlimb locomotion provided the spinal cord below the complete lesion is properly stimulated, either pharmacologically or through locomotor training.
...locomotion is controlled at multiple levels of the central nervous system, and a subtle and intricate balance is established between these levels of control. This then leads to the question of how an optimal equilibrium is re-established when this exquisite balance is perturbed following lesions of the spinal cord.
...Instead of taking over lost spinal functions, remnant descending pathways or regenerating pathways could direct the reorganization of the spinal circuitry so that it can function optimally and with a greater level of independence so that, after the complete section, the full pattern of hindlimb locomotion can be expressed by an already autonomous CPG.
The main conclusion of this brief review of multiple types of lesions is that there are several ways through which the CNS and peripheral afferent inputs can access the spinal locomotor circuitry. This apparent redundancy points to the fact that the rhythm is generated at the spinal level and that various degrees of control levels can modulate this spinal circuitry through multiple pathways. The removal of certain pathways produces specific locomotor deficits, but the spinal circuitry and other intact pathways are still able to optimize remnant locomotor functions.
Grégory Barrie`re, Hugues Leblond, Janyne Provencher, and Serge Rossignol
The general accepted model of locomotor control is tripartite. 1) CPG 2) sensory feedback 3) descending pathways
After partial spinal cord injury (SCI), this optimal balance is perturbed because communication between the brain and the spinal CPG is altered (Barbeau and Rossignol, 1994).
Q: Are there lastic changes within descending pathways? Or, the spinal CPG retains its function and that changes in descending commands aim at maintaining an optimal control of the spinal locomotor network?
The role of the CPG in the recovery of locomotion after incomplete spinal cord lesion is mostly unknown.
RESULT The first step consisted of an incomplete section of the spinal cord at the thoracic level T10 or T11. The second step was a complete transection of the spinal cord at T13 or L1.
1) The recovery of quadrupedal locomotion after partial lesions is mostly the result of an intrinsic reorganization of the spinal locomotor network below the lesion.
2) Locomotor training is a major factor in facilitating the recovery process because cats intensively trained after the partial lesion expressed a very high locomotor performance bilaterally within hours of the complete spinalization, whereas in untrained animals only a unilateral locomotion was observed in the limb ipsilateral to the partial lesion.
3) Plastic reorganization of the spinal CPG may still occur after the complete spinal section because bilateral locomotor performance improved with training over time in all cats after complete spinalization.
Altogether, this work highlights the importance of promoting spinal neuroplasticity in rehabilitation strategies in SCI patients, especially to maintain the spinal circuitry in an optimal condition to generate locomotion.
Dr. Lorne Mendell's talk at Emory, May 21, 2009 Smashed spinal cord - cell death - activity-based therapy Encouraging functional recovery - reducing cell death - replace absent cells - enhancing performance of sensory circuit a) training b) neurotrophine-induced synaptic potentiation
Neonatal transection: Step training can enhance stepping performance - trained animals can walk when they grew up - shape of the movement is slightly different (less force?) - ankle angle
Recovery reverses transection-induced changes in monosynaptic EPSPs and AHP - Change in population of EPSP size and AHP a) transection reduced the overall size of EPSPs (more small EPSPs than large EPSPs) b) shift of EPSP population to have more large EPSPs c) much more large EPSPs than control d) AHP became larger, but became smaller after training.
Improved stepping performance correlated with change in motoneuron - Change in AHP depth indicates the ability to fire at high frequency - Change in EPSP amplitude indicate changes in the sensory feedback from muscle spindle (ankle)
NT-3 (&BNDF) - motor improvement = both mimicked by NT-3? - electrophysiological changes (EPSP, AHP)
NT-3 is required for motoneuronal projections to muscle spindle Acute sensitization by NTs - neurotrophic factor (NT-3) sensitize motoneurons. - for example, it sensitize GluR
Chronic effects of NT-3 on the strength of the mo...
NT-3 strengthen projections of injured & developing spindle afferent to motoneurons - intraneural NT-3 enhance synapses for axotmized neurons.
Substitute NT-3 for training - virus that has NT-3 is injected into muscle
Delivery of neurotrophines to intact preparations without trauma: Viral vectors - AAV/NT-3; expression, 150 days
NT-3 expression profiles differ according to the preparation, and physiological effects differ accordingly - Cord NT-3 was plotted against DRG NT-3. - In spinal cord, NT-3 expression is larger in the intact than transected animal. - In the intact prep, EPSPs became smaller after transection (probably by increase of the motoneuron's size). - Appearance of large EPSPs for transected animals (by sprouting by presynaptic afferent neurons = DRG neuron)
Input resistance of motor neuron was reduced - by increase of the motoneuron's size - contribute to the reduction of the EPSP size
AAV/NT-3 decreases motoneuronal input resistance - in intact animal, it reduced both EPSP size and Rm - in transected animal, it only reduced Rm size, but increased the EPSP size.
Ventrolateral white matter (VLF?) synapses persist on motoneurons in chronically transected preparation
Changes after AAV/NT-3 in intact preparations - the change in EPSP size was synapse specific
Trained animals are different from AAV/NT-3 treated - Trained animal shows both increase in Rm and EPSP size in the motoneurons. - c-fos
AVV/NT-3 enhances the stretch-reflex by increased performance in stepping NT-3 strengthens MG strech pathway by increased EPSP size.
- K. Pearson Exp Br Res (2003)
- Chen Y et al., 2006, JNsc26: 12537.
- Modeling stepping function by a model: Yakovenko et al., (2004) Stretch reflex enhances stability of CPG circuit Neurotropin treatment of adult transected preparations (preliminary results).
By Ishikawa,M.; Mu,P.; Moyer,J.T.; Wolf,J.A.; Quock,R.M.; Davies,N.M.; Hu,X.T.; Schluter,O.M.; Dong,Y.
Abstract: - Homeostatic mechanisms balances the input-output/synapse-membrane interaction at nucleus accumbens neurons. - Studies on nucleus accumbens (NAc) neurons revealed a novel form of synapse-to-membrane homeostatic regulation (hSMP), homeostatic synapse-driven membrane plasticity (hSMP). - Through hSMP, NAc neurons adjusted their membrane excitability to functionally compensate for basal shifts in excitatory synaptic input. - hSMP is triggered by synaptic NMDA receptors. Introduction:- Homeostatic plasticity is an important cellular mechanism through which neurons use the neuroplasticity mechinery to maintain stable functional output in an ever-changing internal and external environment (Turrigiano and Nelson, 2004). - The functional output of a neuron relies on dynamic integration of synaptic inputs and intrinsic membrane excitability. - It has long been known that homeostatic plasticity can occur independently at either synapses (Turrigiano and Nelson, 2004) or the membrane excitability (Zhang and Linden, 2003).
Results: - hSMP in NAc slice cultures: NAc mediam spiny neuron (MSNs) increased excitability in slice culture. - NMDA receptor mediates hSMP. DCS (D-cycloserine). - hSMP in acute brain slices. - Synapse-specific hSMP. - SK channels mediate the expression of hSMP. - Implication of hSMP in cocaine -induced membrane adaptation.
The authors suggested that a persistent functional recovery from elimination of some of the central nervous inputs on which network operation normally depends.
Central modulatory inputs exert a long-term influence on the CPG in addition to their short-term permissive action on rethymogenesis.
Sometimes this relatively stable situation can be made more plastic even in mature CNS. One of the stimuli, which can induce it, is damage, which leads to destruction of existing connections.
Several studies have shown that cortical injury by itself enhances the plastic potential of cortical dendrites in peri-infarct and in contralateral, unaffected homotopic areas (Kolb and Gibb 1991, Jones and Schallert 1992).
Post injury dendritic arborization is entirely dependent on maintenance of the ipsilateral (unaffected) forelimb activity.
Dendritic arborization necessary for the recovery. Recovery is activity-dependent.
- Intact tissue undergoes structural and functional changes that could play a substantial role in neurological recovery after focal injury to the cerebral cortex. - Waves of growth promotion and inhibition modulate the self-repair processes of the brain. - Entire cortical networks participate in the recovery process.
Early demonstrasions of post-injury plasticity - Behavioral experience is a potent modulator of post-injury cortical plasticity.
New insights into the cellular and molecular mechanisms underlying local reorganization - Neurite outgrowth in the peri-infarct region (increased GAP-43 immunoreactivity). - Synaptogenesis (elevated synaptophysin staining). - Axonal sprouting (traact-tracting methods). - Surviving neurons becme hyperexcitable with upregulation of NMDA receptors and downregulation of GABAA receptors. - Growth-promoting gene expression. - Exploiting this new understanding of cellular and molecular events following injury might provide new treatment approaches for recovery after CNS injury.
Plastic events remotes from the cortical injury - The excitability of areas remote from the site of infarct is altered for significant periods of time after injury by upregulation of NMDA receptors and downregulation of GABAA receptors. - Alteration of intercortical wiring patterns among different cortical fields. - Dendritic arborization and synaptogenesis (2 weeks ~ 1 month) in contralateral side. - role of neural stem cells is still unclear. Re-emmergence of the mass action principle
Is there a sensitive period for post-injury plasticity and recovery potential? - Behavioral training is most effective if done within 1 week. Conclusions - A disruption of cortical motor network triggers a major reassembly of inter- and intra-areal cortical networks. - Post-injury behavioral experience appears to be crucial to the reassemby of adaptive modules. - Basic intracortical wiring plan is substancially altered.
By V. Reggie Edgerton, Niranjala J.K. Tillakaratne, Allison J. Bigbee, Ray D. de Leon, and Roland R. Roy
- A high level of functional recovery can be achieved following a complete spinal cord injury (SCI). - The level of recovery in motor function is defined by the level and types of motor training or experience following the injury (Edgerton et al. 2001a, Wernig et al. 1995).
- Insight into the mechanisms of recovery and motor learning depends on a basic understanding of the neural control of motor functions in the uninjured compared to the injured nervous system.
AUTOMATICITY IN POSTURE AND LOCOMOTION: SOME BASIC NEUROBIOLOGICAL PRINCIPLES OF MOTOR CONTROL BEFORE AND AFTER SCI - Evolutionary learning in shaping the mammalian neural systems that control posture and locomotion. - The automaticity within the spinal cord becomes even more critical for the CPG circuitry to successfully process sensory inputs.
Supraspinal Control of Posture and Locomtion - The specific control features of each of the descending spinal tracts in controlling locomotion are poorly understood.
Spinal Control of Posture and Locomotion 1) CPG 2) SENSORY INPUT - We propose that the spinal cord processes and interprets proprioception in a manner similar to how our visual system processes information (pattern recognition?). - At any instant, the spinal cord receives an ensemble of information from all receptors throughout the body that signals a proprioceptive "image" that represents time and space. - The importance of the CPG is not simply its ability to generate repetitive cycles, but also to receive, interpret, and predict the appropriate sequences of actions during any part of the step cycle, i.e., "state-dependence." - The injured spinal cord interprets sensory changes in load and speed - SCI patients can voluntarily initiate locomotion
3) THE INJURED SPINAL CORD IS AN "ALTERED" SPINAL CORD - The spinal cord processes input and generates motor output in a different manner as a result of injury-related adaptations. - Spasticity is a sign of activity in the spinal circuitry
MOTOR OUTPUT IS ENHANCED BY REPETITIVE TRAINING
Chronic Motor Training Modulates Spinal Plasticity to Enhance Motor Output After SCI - Experiments with spinal cats using chronic locomotor training paradigms sugget that the ability to learn and successfully perform a motor task is dependent on repetitive practice. - The functional state of the cord is shaped by specific locomotor training regimes. - Although the mechanisms underlying locomotor training-enhanced plasticity is not well understood, it is clear that the physiological state of the cord can be affected by activity-dependent processes that can influence its ability to learn and perform a specified motor behavior.
The Spinal Cord Can Respond to Novel, Acute Perturbation - An example of an object placed in front of a spinal cat stepping on a treadmill, a learning and memory-type phenomenon may be taking place ("smartness" of the spinal cord). - Spinal cord is "solving" problems in real time based on the continually changing state of incoming peripehral information to elicit a nearly constant behavior, even though the means to the endpoint differ. - These studies imply that spinal learning can occur in a very short period of time, and a type of memory trace allows for quicker adaptation upon reexposure to a given perturbation (Liu et al., 2003). - The underlying cellular mechanisms are unknown. - Hippocampal learning-like phenomena can occur in the spinal cord, but largely unknown.
Biochemical and Phamacological Evidence for Spinal Cord Plasticity After Injury - The functinally recovered spinal animals showed no evidence of regeneration of descending pathways (Joynes et al. 1999) or showed minimal changes in hindlimb skeletal muscle properties to account for the recoery characteristics, the functinal behavior exhibited by these animals must have been mediated by the plasticity in existing spinal pathways. - This plasticity may occur at any of many spinal cord regions or cell types such as motoneurons, premotor pattern-generating neurons, and/or nonneuronal celly types. - There could also be anatomically altered synaptic connections, increased active zones of synapses, altered sensitivities of neurotoransmitter receptors, or altered pruduction of neurotransmitters. - Data showed a significant role for these neurotransmitter systems in facilitating locomotor activity and thus suggest that these agents might be useful for inducing locomotion in SCI animals. - Administration of 5-HT, its precursor 5-HTP, or the 5-HT agonists are also effective in improving locomotion in cats (Barbeau & Rossignol 1990, 1991) and rats (Feraboli-Lohnherr et al. 1999, Kim et al. 2001). - The mechanism is unknown. - The improvement of motor recovery upon the administration of of strychnine or bicuculline may occur by facilitating neuronal excitation by blocking the abnormally high levels of general inhibition resulting from a complete SCI (de Leon et al. 1999b). - Nontrained spinal rats have increased GABA synthetic enzyme GAD67 and glycine and GABAA receptors in the lumbar spinal cord, whereas step-trained spinal rats have near-normal levels (Edgerton et al. 2001a, Tillakaratne et al. 2000). - Training spinal cats to weight-bear also appears to reduce GABA signaling in some spinal interneurons. - The amount of these enzymes depends on the type of training. - These finding suggest that the inability of stand-trained spinal animals to step is closely linked to an elevated level of inhibition of flexor motor pools. - The elevated level of a GABAA receptor subunit returns toward nearly undetectable control levels after six weeks of step training. - Plasticity of spinal circuit may also be mediated by activity-dependent induction of neurotrophins.
Effects of Electrical Stimulation on Locomotor Recovery After SCI
HUMAN SCI: A PERSPECTIVE
Treadmill Training and the Recovery of Walking Ability After SCI
Use of Pharmacological Therapies in Enhancing Walking after SCI
CONCLUSION - Training to stand improves standing ability and training to step improves stepping ability. - One of the biochemical consequences of a complete SCI is an upregulation of inhibitory neurotransmitter systems, and step training reverses this effect. - Physiological and biochemical state of the spinal conrd will affect how it respond to any given therapeutic intervention.
