Restorative Neurology: Consideration Of The New Anatomy And Physiology .

Restorative Neurology and Motor ControlFirst Meeting of the International Society for Restorative NeurologyMelbourne, Victoria, AustraliaMay 15, 2012Restorative Neurology: Consideration of theNew Anatomy and Physiology of theInjured Nervous SystemKeith Tansey, MD, PhDDirector, Spinal Cord Injury Research, Shepherd CenterDepartments of Neurology and Physiology, Emory UniversitySpinal Cord Injury Clinic, Atlanta VA Medical Center

Restorative NeurologyWhat is the problem?This spinal cordcan walk. How?This one cannot.Why not?

The New Anatomy and PhysiologyAltered InputNormal InputChanged IntegrationNew Output

The New Anatomy and Physiology:The Nervous System and Its DevelopmentNumber of neurons 1011Number of synapses 105 per neuronNot “on/off” switches, rather “dimmer” switches with gradationsDevelopmental Strategies for “wiring together”Spatial molecular cuesTemporal molecular cuesEstablishment of excess neurons and synapsesSubsequent apoptosis and synapse eliminationActivity based shaping of synaptic strengthsShutting down of “wiring” with perineural netsHow much can developmental processes play a role after injury?

The New Anatomy and Physiology:Development and Neural PlasticityDespite long distance wiring established early, function developsand changes over time – walking, talking, playing pianoNeural plasticity, in fact, does not end – learning and memoryThese functions are probably the result of rather local neuralcircuit anatomical plasticitysproutingsynaptogenesisand physiological plasticitylong term potentiation or depressionpre- and post-synaptic modulationsynapse activation or deactivationchanged temporal coding between neuronal populations

The New Anatomy and Physiology:The Physiology of Neural CircuitsNeural circuits are capable of functioning in multiple differentphysiological states despite a single anatomical stateNeural circuits interact with other neural circuits in differentcombinations of activity to add to the repertoire of functionalstatesControl strategies are employed – feed forward, feed back, closedloop, open loop, etc.Some redundancy is built in so it is possible to execute a singlebehavior by different neurophysiological means

The New Anatomy and Physiology:Altered Neural Circuits in Neurological InjuryInjury can cause disruption within circuits, across circuits, in onebut not another of connected circuits and between unaffectedcircuits – diaschesisInjured neural circuits probably have a limited ability to performinput/output functionsUninjured neural circuits must integrate old normal inputs andnew altered inputs to generate new outputsThese circuits may be changed in their processing capacities bythese new conditions so re-establishing lost connections later maynot result in a return to pre-injury functioning

The New Anatomy and Physiology:Altered Function in Neurological InjuryNeurological injury generates sensorimotor “loss of function”weaknessloss of coordinationloss of enduranceloss of sensationand “gain of function”spasticity (hypereflexia, spasms, dysynergias, hypertonia)neuropathic painThe two combined cause functional deficits but treating one(spasticity) might worsen another (weakness)

The New Anatomy and Physiology:Assessment of Residual Function after InjuryAnatomical assessment is partially possible in animal models butlimited to low resolution in humans with current imaging (MRI, DTI)Physiological assessment can be done to some extent with imaging(fMRI) but electrophysiological methods are the gold standardElectrophysiology can assess the possibility of conduction throughthe injured nervous system but this does not tell us what signalsactually come through connections that remain after injuryElectrophysiology can assess input/output processing of signals insome situations, testing reflex modulation for instance, and cancharacterize output patterns during attempts at behaviors in bothanimals and humans

The New Anatomy and Physiology:Assessment of Residual Function after InjuryClinical assessments can be revealing but often clinical scales grouplarge numbers of diverse individuals into few, broad categories andfollowing those groups, as is done in current clinical trials, usuallyfails to adequately detect individual changes or add clarity to themechanisms at play to cause those changes

The New Anatomy and Physiology:Restoring Function in Neurological InjuryAnatomical restoration has been shown to be possible in animalmodels but it is limited at best and not currently translatable toclinical applicationIssues includegenerating axon growthovercoming environmental barrierstarget findingre-re-organizing local neural circuit functionPhysiological restoration is, therefore, the current focus ofRestorative Neurology and uses a variety of methods to generatefunctional change through the physiological mechanisms of neuralplasticity described earlier

The New Anatomy and Physiology:Clinical Practices in Restorative Neurology“The best thing they can give you after neurological injury is a goodphysiotherapist”Early “truths” from current practiceearly activity is importantsustained and repeated activity is importanttask specificity can be importantNext stepsunderstand what physiology is being changed and howdetermine the relationship between substrate and effectbetter clinical assessment and tailored treatmentadd interventions to further drive neural plasticity to gainrecovery in the new anatomy and physiology

The New Anatomy and Physiology: The Physiology of Neural Circuits Neural circuits are capable of functioning in multiple different physiological states despite a single anatomical state Neural circuits interact with other neural circuits in different combinations of activity to add to the repertoire of functional states