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Thesis
- 1. Changes in motor axon excitability in vivo in chronic hemiparetic stroke survivors Sophia del Rio March 14, 2012 Advisor and committee members: Zev Rymer CJ Heckman Jim Baker
- 2. Introduction • A stroke occurs every 40 seconds in the USA • Motor deficit is the leading impairment and affects long-term quality of life
- 3. Significance • The mechanisms behind the changes that are seen post stroke are not understood • A new tool, TROND, developed by Professor Hugh Bostock, could provide valuable information about the health of peripheral MN axons in stroke.
- 4. Aim 1 Quantify the resting membrane potential and electrophysiological properties of the distal MN axons of the median nerve in vivo in healthy persons, and compare dominant and non-dominant side.
- 5. Hypothesis 1 There will be no significant differences between the MN axons of the distal median nerve of the dominant and non-dominant side of healthy subjects.
- 6. Aim 2 Quantify the resting membrane potential and electrophysiological properties of the MN axons of the distal median nerve of persons who have survived a hemiparetic stroke, and compare the paretic to the non-paretic side.
- 7. Hypothesis 2: The MN axons of the distal median nerve of the paretic side will be more depolarized at rest than the MN axons of the median nerve of the non-paretic side in hemiparetic stroke survivors.
- 8. Background What makes us suspect that there could be changes in MN axons? Spasticity Atrophy and denervation Muscle fiber structure changes and degeneration Accumulation of inflammatory trophic factors
- 9. Methods Threshold tracking techniques will be applied to assess the MN excitability properties
- 10. Methods Definition: “Threshold” refers to the minimum current, threshold current, required to excite a group of axons. Threshold in this study is set at 40% of the maximal compound muscle action potential (CMAP)
- 11. Finding the Target Threshold, 40% of maximal CMAP
- 12. Experimental arrangement Krishnan et al 2008
- 13. Threshold tracking Bostock et al 1998
- 14. Summary of the TROND test trends Krishnan et al 2008
- 15. Recovery cycle Krishnan et al 2008
- 16. Recovery cycle
- 17. What the program is doing to get the Recovery cycle
- 18. Recovery cycle Inter-stimulus interval (ms)
- 19. Threshold electrotonus Krishnan et al 2008
- 20. Threshold electrotonus phases (Bostock et al 1998)
- 22. What the program is doing to get the Threshold electrotonus
- 23. Threshold electrotonus Conditioning-test interval (ms)
- 24. Current-threshold (I/V) Krishnan et al 2008
- 25. What the program is doing to get the I/V
- 26. What the program is doing to get the I/V
- 27. I/V relationship Excitability (threshold reduction, %)
- 29. Hypothesis 1: There will be no difference in resting membrane potential in dominant v non-dominant side of controls • No differences were found between dominant and non-dominant side of controls • Conclusion: Handedness is not a confounding factor in bilateral testing of stroke subjects.
- 30. Controls, no significant differences were found due to handedness
- 31. Hypothesis 2: The paretic side will be more depolarized at resting membrane potential • There were no significant findings that support Hypothesis 2 • Conclusion: There is no difference in MN axon membrane potential between paretic and non-paretic side.
- 32. Changes in excitability There were no changes in membrane depolarization between paretic and non- paretic side. However, there were significant changes in excitability between paretic and non-paretic side.
- 33. Data was examined to detect which of the following could be responsible for the changes in excitability: 1) Membrane potential 2) Axonal architecture 3) Ionic conductances Conclusion: Differences in excitability were due to changes in ionic conductances.
- 35. Changes in TE undershoot
- 36. Changes in TE overshoot
- 37. Changes in I/V slope
- 38. Conclusions: • The paretic nerve is more excitable during the superexcitability RC period, the fast K+ current is decreased. • The paretic nerve is less excitable to termination of subthreshold depolarizing an hyperpolarizing currents, the slow K+ and Ih currents are decreased.
- 39. Future studies • Differences in acute vs chronic stroke • Severity of impairment
- 40. Thank you I want to especially thank: Zev Rymer Cj Heckman Jim Baker David Schneeweis Cliff Klein And all the SMU lab members
- 41. Works Cited Bostock H, Cikurel K, Burke D. Threshold tacking techniques in the study of human peripheral nerve. Muscle Nerve. 1998;21:137-58 Jankelowitz SK, Howells J, Burke D. Plasticity of inwardly rectifying conductances following a corticospinal lesion in human subjects. J Physiol. 2007;58:927-40 Katz RT and WZ Rymer. Spastic hypertonia:mechansms and measurements. Arch Phys Med Rehabil. 1989; 70:144-155 Kiernan MC, Burke D, Bostock H. Nerve excitability measures: biophysical basis and use in the investigation of peripheral nerve disease. 2001; 113-129 Krarup C and Moldovan M. Nerve conduction and excitability in peripheral nerve disorders. CurrOpin Neurol. 2009; 5:460-466 Krishnan AV, Lin CS, Park SB, Kiernan MC. 2008. Assessment of nerve excitability in toxic and metabolic neuropathies. J Peripheral Nervous System 13: 7-26 Lin C, Kiernan C, Burke D, Bostock H. Peripheral Nerve Disease: Handbook of Clinical Neurophysiology. Vol 7. J. Kimura (Ed.) Elsevier, 2006 McComas AJ, Sica RE, Upton AR, Aguilera N. Functional changes in motoneurons of hemiparetic patients. J Neurol. 1973; 36: 183-193 Ng K, Howells J, Pollard JD, Burke D. Up-regulation of slow K+ channels in peripheral motor axons: a transcriptional channelopathy in multiple sclerosis. Brain. 2008; 131(11):3062-3071 Schwarz JR, Glassmeier G, Cooper EC, Kao TC, Nodera H, Tabuena D, Kaji R, Bostock H. KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. J Physiol. 2006; 573(1): 17-34
- 42. Continue if there is time to discuss Jankelowitz et al 2007 study findings.
- 43. Comparisons to Jankelowitz et al 2007 Jankelowitz et al 2007, Plasticity of inwardly rectifying conductances following a corticospinal lesion in human subjects, is the only other study that has used the TROND protocol in the stroke population.
- 44. Jankelowitz et al 2007 findings • Significantly greater response to subthreshold hyperpolarizing currents during the threshold electrotonus test on the paretic side • Significantly decreased I/V slope in response to hyperpolarizing currents on the paretic side
- 45. Jankelowitz et al 2007 TE results
- 46. In this study TE differences were found upon termination of polarizing currents
- 47. Jankelowitz et al 2007
- 48. Jankelowitz et al 2007 I/V results
- 49. Recovery cycle, superexcitable period We found differences in the superexcitability period which may mean K+ conductances may change on the paretic side. Jankelowitz et al did not report any differences in the Recovery cycle.
- 50. Summary of the two studies • Both studies found no differences in dominant v non-dominant side of controls • Both studies found no difference in membrane potential in paretic v non-paretic side of stroke subjects • Both studies found evidence for plastic changes in ionic conductances on the paretic side
- 51. Potential mechanisms for the changes in excitability • Trans-synaptic degeneration leads to HCN channel plasticity –Jankelowitz et al 2007 • Changes in peripheral muscle lead to MN axon degeneration, which could lead to damage of the MN cell body.
- 53. Stimulus response Krishnan et al 2008
- 55. Strength-duration (SD) Krishnan et al 2008
- 56. What the program is doing to get the SD When the data for the stimulus response test are analyzed, the ratio between the 0.2ms and 1ms stimuli required to evoke the same responses was used to estimate the strength-duration time constants and rheobases of the axons. Stimulus duration (ms) (Kiernan et al 2000)
- 57. 8 measures that will tell us the membrane is more depolarized: 1) strength-duration time constant will shift down and to the left 2)The duration of the relative refractory period will increase 3) The threshold will increase during the relative refractory period 4) The S1 phase in the depolarizing current in the threshold electrotonus will decrease 5) The maximal threshold produced by the hyperpolarizing currents in the threshold electrotonus will decrease 6) Threshold overshoot following the termination of the hyperpolarization current will decrease 7)The maximal threshold increase to the hyperpolarizing currents will decrease 8) The slope of the current-threshold relationship will become steeper
- 59. Axonal architecture Changes in the axonal architecture include: • Size of diameter shrinking • Demyelination • Thinning of myelin • Changes in internodal length • Loss of axons
- 60. Test results that indicate changes in axon architecture: • Shrinking of the axon would result in a decrease in the slope of the SR. • Demyelination causes a decrease in the slope of the stimulus response relationship and an increase in rheobase. • Thinning of myelin causes decreased capacitance and increased resistance, this would make the RC superexcitability period shorter, and increase the subexcitable period. • An increase in internodal length, would result in prolongation of the strength-duration time constant. • Axonal loss would result in a rightward shift of the stimulus response relationship and increase in rheobase.
- 61. TE accommodation to +40%
Editor's Notes
- A stroke occurs every 40 seconds in the USA and motor deficit leads to long-term changes in the quality of life of stroke survivors. It is imparitive that more research is conducted to understand the mechanisms behind the motor changes so we can better rehabilitate this population.
- Read Slide,The mechanisms behind motor changes in stroke have long been attributed to trans-synaptic degneration, which is the theory that when the central upper MN are no longer able to commmunicate with lower MNs the lower MNsdegerate because of loss of trophic factors , etc. There is another possibilty however, that changes at the preiphery could be causing damages as opposed to centeral changes. The idea that changes at the level of the muscle could be sending harmful signals to the MNs has not been adequately explored. The first step in exploring this possibilty is to determine whether or not the MN axons are degenerating at the periphery. TROND is a new protocol that can be used to explore changes in MN axons. It has been applied in one study before in the stroke population, but this study looks at the same protocol to see if the results are consistent and have the same interptation. Plasticity of inwardly rectifying conducatances following a corticospinal lesion in human subjects
- We would like to apply TROND to investigate the state of the MN axons post-stroke. Because the stroke subjects will be assessed bilaterally it is important to assess intacts in case there is a handedness effect. In AIM 1 we want to quantify the resting membrane potential and electrophysiological properties of the distal median nerve in vivo in healthy persons, and compare dominant and non-dominant side.
- We hypothesize that there will be no handedness effect in healthy intacts.
- In AIM 2 we will bilaterally test the hemiparetic stroke survivors to see if there are differences between paretic and non-paretic side. We will quantify the resting membrane potential and electrophysiological properties of the MN axons of the distal median nerve of persons who have survived a hemiparetic stroke and compare the paretic side to the non-paretic side.
- We hypothesize that the MN axons of the distal median nerve of the paretic side will be more depolarized at rest than the MN axons of the median nerve of the non-paretic side in the hemiparetic stroke survivors.
- Here is a list of changes in muscle that are observed post stroke. If such drastic changes are occuring in muscle, could this effect MNs? The health of the MN may be dependent on the muscle fibers with which they communicate. The connection between fiber and axon are needed for the MN to maintain its health (Bussman and Sofroniew 1999). With out this connection MN can atrophy and lose their axons, as well as die (Bussman and Sofroniew 1999). With so many abnormal changes seen in the muscle post-stroke, it is possible some of these negative changes could be causing secondary changes to the axons they communicate with. , changes in intrinsic MN properties, ionic conductance and passive membrane properties could also be at fault.
- Threshold tracking is the process of adjusting the stimulus so that the response is as close as possible to a target value. The amount required to change the stimulus, following a change in response, can be predicted from the response error (ie the difference between the actual and target response)
- Read slide
- The CMAP is important because it establishes the target threshold for all the other tests. To find the CMAP, the experimenter manually increases the current in 2% steps until the CMAP stops growing in amplitude. Step increase can be seen on the left of the graph, followed by the CMAP. Then, to find the supramaximal CMAP, the experimenter increases the current by 20% of the maximal CMAP current. The CMAP amplitude will be measured from baseline to the negative peak.
- 6 heathyintacts were tested bilaterally, none reported being on any medications10 stroke subjects were tested bilaterallyThe subject is seated comfortably with hand on the table. Surface electrodes are placed over the abductor pollicisbrevis (APB) to record the muscle action potentials elicted by the stimulus, with the refernceelctrode at the distal end of the thumb joint and theground on the back of the hand. The EMG signal was amplified and filtered 3-500 Hz and digitized by a computer with an A to D board and smapled at 10kHz. The stimulus current was applied through nonpolarizable electrode placed over the muscle belly of the brachioradialis, approximately 10 cm proximal to the cathode over the median nerve of the wrist. Anode was placed over the belly of the BRD. Room and skin temperature were monitored with a probe place on the surface of the skin.
- Lin et al 2006, pg 383:The CMAP is recorded from the hypothenar muscles and compared to the target threshold. The error signal between the two is used to adjust the intensity of the test pulse. The test pulse can be combined with a subthreshold polarizing current to alter the membrane potential and threshold. The threshold tracking software automatically increases or decreases the amplitude of the test pulse by a percent step after each response, depending on the difference between the actual, recorded response and the target response.Step sizes are proportional to the error, they are 2% of the error.
- The above tests were run. If the membrane potential was more depolarized it would move as indicated by the red line. If it was more hyperpolarized it would move as indicated by the blue line. I will now go into each test and explain the automated computer protocol, how the figures are calculated, and the results I found.For the sake of time we are going to look at the RC, TE and I/V tests, which were the tests that had significant results. A is the Stimulus Respnse test – B is the strength duration test –C is the Recovery cycle testD is the Threshold electrotonus testE is the current –threshold or current –voltage test.
- What is the recovery cycle? The recovery cycle is a characteristic sequence of events that every axon goes through after it has propagated an AP. 6. Relative refractory period (ms) – this is depended on the transient Na+ channels, it takes a larger than normal stimulus to produce an AP when the axons is in this period. 7. Superexcitabillity period- the superexcitablilty period, the axon becomes more excitable because background depolarization reduces the transient Na+ inward current and increases the K+ outward current this decreases the charge gap during the AP. Depolarization reduces the superexcitable period, wheresahyperpolarization increases it, becauseinternodal K+ channels are open at rest , and short circuit the afterpotential and also reduce its duration. 8. Late-subexcitability period – The late subexcitable period reflects hyperpolarization of the membrane potential due to current passing through the slow K+ channels at the node. It is more a measure of the external K+ ionic gradient.9. Refractoriness at 2.5 ms (%)
- Recovery cycle will be measured following supramaximal conditioning stimulus. There will be 18 conditioning test intervals from 2ms to 200ms at which the recordings will be made. The stimulus combinations used will be unconditioned test stimulus of .1ms duration tracking the control threshold, supramaximal , which is .2 ms duration conditioning stimulus alone. So that the maximal CMAP does not contaminate the measured response when the conditioning-test interval is short, the conditioning stimulus alone will be subtracted from the response to both stimuli. Each of the stimulus combinations will be repeated until four valid threshold estimates are recorded, ie the stimulus must fall with in 10% of the target threshold. The light blue line fluctuating about the purple CMAP target line in the center, left graph depicts the actual threshold response to the current stimulus inputs.
- This is the Recovery cycle. The x-axis is the inter-stimulus interval in msThe y-axis is the percent threshold changeStimulus pulses are sent at 18 different intervals. All the stimulus currents and peak responses for the current and delay are used. The program plots stimulus vs error (i.e. response – target response), fits a regression line and estimates threshold as the stimulus that gives zero. What is plotted is percentage difference between actual threshold and target threshold. To allow for any drift in control threshold there is a separate contorl threshold estimated for every point on the plot. Explain physiology in graph.Computer screen shotEplainx and y- axis and how a single point is caculated on the graph
- In this test prolonged currents that are too weak to elicit AP are delivered to the nerve, these are called conditioning currents. Then test pulses of 1ms are added on to the conditioning current to measure the threshold.10. TEd(10-20ms), corresponds to the S1 phase11. TEd (peak)12. TEd(90-100ms)13. S2 accommodation14. TEd(undershoot)15. The(10-20ms)16. The (90-100ms)17. The (overshoot)
- This figure shows what is occurring to the nerve during this test. Panel A shows motor axon TE relationship and Panel B shows a sensory nerve axon compared to the motor axon. With depolarizing currents there are the following phases:F is the intial fast phase where the current is turned on. S1 phase shows there is a slower phase where the axons are still depolarizing as the current spreads to the internodal membrane. S2 phase shows the threshold starting to slowly return to control level, this reduction in excitability is called accommodation. And is due to the activation of a hyperpolarizing conductance of the voltage-gated K+ slow channels. In response to hyperpolaringcurernts there is:Also an F phase that is the increase in threshold , proportional to the applied current, and is analogous to the F phase in the deolarizing currents. The nerve continues to hyperpolarize as the current spreads to the internode, this is the S2 phase. This phase continues as the fast and slow K+ channels close. The accomoodative phase is the S3 phase, and it produces an inward rectification due to the hyperpolarization-activated current, the Ih current. You don’t really see the S3 phase in the motor axons as much as you do in the sensory axons.
- To establish the threshold electrotonus relationshipprolonged subthreshold currents will be used to alter the potential across the internodal axonal membrane. Subthreshold hyperpolarizing polarizing currents will be 100 ms in duration and set to -40% (green) and -20% (grey), and subthreshold depolarizing currents will be 100 ms in duration and set to +40% (red) and +20 % (blue) of the control threshold current (the current required to produce the unconditioned target CMAP, which is 40% of the maximum CMAP). At different time points, the threshold will be tested, and after the 100 ms polarizing currents. A total of 5 stimulus combinations will be applied in turn: test stimulus to measure the control threshold current, test stimulus plus depolarizing current of +40% or +20%, and test stimulus plus hyperpolarizing current of -40% and -20%. The middle, this traceshows the actual CMAP value fluctuating about the target 40% CMAP threshold in response to the depolarizing and hyperpolarizing currents.
- The TE test has five stimulus conditions it cycles through at each point on the TE plot.Threshold test pulse to measure threshold, Conditioning depolarizing stimulus of 40% pulse the test pulse, conditioning depolarizing pulse of 20% plus the test pulse. Conditioning hyperpolarizing pulse of 40% plus test pulse and conditioning hyperpolarizing pulse plus 20% of threshold.
- How the data is converted into this plot:The x-axis is the cinditioning-test interval. It shows the duration of the conditioning stimulus and the points at which the test stimulus were delivered.The y-axis is the threshold reduction, shown as a percent. The program plots stimulus vs error (ie. actual Response – target response)It fits a regression line and estimates threshold as the stimulus that gives zeroWhat is plotted is a percentage change in threshold , ie the percentage difference between the threshold and the control channel. To allow for any drift in control threshold the control threshold is estimated over the same time period as the TE threshold. Thus, there is a separate control threshold estimated for every point on the plot. The line that connects the points on the plot is a linear interpolation that makes the plots easier to view. ) All stimulus currents and peak responses for the particular polarizing current and delay are used.This is the same way the RC and I/V data are converted into plots
- The x-axis is the Excitabillity , or percent threshold reduction, of the axons. And the y-axis is the current that is the percent threshold of the control current. The bottom left hand quadrant shows the threshold response to hyperpolarizing currents that are increasing in amplitude. These hyperpolarizing currents activate the Ihconductances. The top right hand quadrant shows the threshold response to depolarizing currents that are increasing in amplitude. These currents activate the fast K+ currents. I will go into greater detail about this plot now.
- The computer varies the amplitude of the currents it sends to the axons in 10% steps, from depolarizing currents of 50% down to hyperpolarizing currents of -100%The computer sends a 1ms test pulse 200ms after the start of the conditioning current. The duration of the conditioning currents vary at 50, 100, 250 and 300ms.
- Here you can see the conditoining current is 300 ms long and the test pulse occurs 200ms from the start of the conditioning current. The program calculates the I/V realtionship the same way it calculates the TE realtionship.
- Computer screen shotThe x-axis is the Excitabillity , or percent threshold reduction, of the axons. And the y-axis is the current that is the percent threshold of the control current. Each point on this plot is calculated the same way as the points on the TE and RC plots. All the stimulus currents and peak responses for a particular current and delay are used. The program effectively plots stimulus v error (ie response – target response) fits a regression line and estimates threshold as the stimulus that gives zero error. What is plotted is percentage change in threshold, ie, the percentage difference between the actual thresholds and the control threshold. To allow for any drift in the control threshold the target threshold is estimated over the same period (ie elapsed time in the recording ) as the I/V threshold. Thus there is a separate control threshold estimated for every point on the I/V plot.
- Hypothesis 1 was supported by the results.
- NO differences were found in any of the tests between dominant and non-dominant side of controls. It was concluded that handedness is not a confounding factor in bilateral testing of stroke survivors. A is the TE relatioshipB is the I/V relationshipC is the RCD is the SD
- Significant changes between excitability were found between paretic and non-paretic side. BUT it was concluded that these changes were not due to changes in axon membrane depolarization.
- Read slide,The data was first analyzed to see if there were changes that would indicate a difference in membrane potential between the two sides. It was concluded that there was no difference in membrane potential. Changes in excitability don’t always correspond to changes in membrane depolarization. There were tests that had significant findings that suggested a change in excitability between the two sides. These results were analyzed to see first if changes in axon architecture were correlated with the results. And then analyzed to see if changes in ionic conductances were correlated with the findings.
- After examination of the results it was concluded the changes in excitability were not due to changes membrane depolarization or axonal architecture. The next slides will discuss the findings in further detail.
- Filled circles represent paretic side and empty circles represent non-paretic side. 2ms after an AP has passed the axon enters in to the superexcitable period. In this period the voltage-gated fast K+ channels activate and help repolarize the node. Changes in excitability during this period indicate a change in the fast K+ channel conductance. The bar graph is calculated as the minimum mean of three adjacent points on the recovery cycle , where each point is a threshold change, calculated as the percentage difference between conditioned and unconditioned thresholds (Bostock emails)The superexcitability period on the paretic side was found to be significantly decreased, the paretic axons were more excitable. Meaning the fast K+ channel conductances were decreased (Lin et al 2006). NOTE : if there was a change in slow K+ conductance it would manifest in the subexcitable period, but no such difference was found, This is inconsistent with the TE under and overshoot findings that suggest there is less slow K+ conductance.
- Filled circle represent paretic side and empty circles represent non-paretic side.When depolarizing subthreshold currents are terminated in the TE test the threshold increases rapidly and there is slow undershoot due to acitvation of persistent slow K+ channels. The TE undershoot was significantly less on the pareitc side (Lin et al 2006). Less undershoot is due to a decrease in the slow K+ channel conductance. The Nerve on the pareitc side is less exciable than that of the non-paretic side.
- Filled circles represent paretic side and empty circles represent non-paretic side.Upon termination of subthreshold hyperpolarizing currents the threshold rapidly decreases and then undergoes a slow, depolarizing overshoot as the Ih slowly deactivates and the slow K+ current is reactivated, bringing the axon back to control level (Lin et al 2006). There was less change in threshold on the paretic side. This means that there was less voltage change, indicating that the paretic axons are less excitable. This is likely because there is a drop in the amount of Ih current that is being activated, which would result in less activation of the K+ current. (Schwarz et al 2006).
- Filled circles = paretic side, empty circle = non-paretic side. The top , right quadrant of the curve is the axon’s response to subthreshold depolarizing currents. These currents activate the fast K+ cahnnels. There is no differnce in the slope between the paretic and non-paretic side, indicating that there is no change in fast K+ conductance. BUT , this finding is inconsistent with the decrease in superexcitability. So I am unsure of what to make of this, the Fast K+ channels may or may not be involved in changes in the excitabillity.The bottom left quadrant of the curve shows the axons’ response to subthreshold hyperpolarizing currents which acitvate the Ih current. Here there is a decrease in the slope on the pareitc side indicating there is less Ih current; the paretic axon is less excitable.
- This study and the Jankelowitz study did not examine results looking at differences in stroke persons who have had their injury olnger than others. It is possible more chronic injuries could result in changes that were not measured here. Both studies included stroke persons who were of moderate impairment. It is possible that persons who are severly impaired may show greater changes that were not measured here.
- Jankelowitz et al 2007 reported two significant findings:Significantly greater response to subthreshold hyperpolarizing currents during the threshold electrotonus test on the paretic sideSignificantly decreased I/V slope in response to hyperpolarizing currents on the paretic side
- Jankelowitz is on the leftThreshold electrotonus plots for the paretic and non-paretic sides, in both panels filled circles represent paretic side, empty circles represent non-paretic side. Left panel is taken from Jankelowitz et al 2007, response to hyperpolarizing subthreshold currents created a significantly greater decrease in excitability, P= 0.021; Right panel displays this study’s data, no significant difference was found to hyperpolarizing subthreshold currents between paretic and non-paretic sides of stroke subjects while the conditioning current was on. But our results to the undershoot and overshoot threshold electrotonus test are in accordance with the Jankelowitz finding that there seems to be less Ihconductnace on the paretic side.
- Although we did not see differences in the hyperpolarizing currents while they were on, our TE undershoot and overshoot results are consistent with the Jankelowitz finding of less Ih current on the paretic side
- Jankelowitz et al 2007 did not report their findings to the Overshoot and Undershoot tests, but if we look at their TE plot we see error bars in this region. It is possible they did see significant differences, but just did not report them.
- Jankelowitz is on the leftCurrent-threshold plots for the paretic and non-paretic sides, in both panels filled circles represent paretic side, empty circles represent non-paretic side. Left panel is taken from Jankelowitz et al 2007, the paretic side was significantly less steep; Right panel, this study did not find significant difference between steepness of the current-threshold slope of the paretic and non-paretic sides of stroke subjects.Our I/V slope tests are consistent with Jankelowitz et al I/V slope which indicates less Ih on the paretic sideWe found the same trend in the I/V slope.
- . Test pulses of 0.2 ms or 1ms duration will be applied at intervals of 0.8 to produce a target potential that is on the fast-rising phase of the stimulus response curve, approximately 40% of the maximal CMAP. The x-axis is the amount of stimulus applied and the y-axis is the response to the amount of stimulus applied.Indicates the stimulus (mA) for 40% max responsePeak response\\(mV)Stimulus response slopeThis is an input-output relationship. As the stimulus intensity increases, the size of the compound potential increases until it reaches a peak response. Once it reaches a peak response further increases in stimulus intensity do not increase the size of the compound muscle action potential.
- The stimulus response SR curves will reflect the growth of the CMAP as the stimulus current is increased, and will be recorded separately for test stimuli of 0.2 ms and 1 ms duration. This is a is a screen shot of the automated computer program as it progressively decreases the current (green in bottom trace) to establish the stimulus response curve and determine the 40% CMAP.In the top trace you can see the peak of the CMAP decreasing, the purple horizontal line denotes the point at which the CMAP is at 40% of its maximal value, the target threshold value.
- 4. strength-duration time constant (ms)5. Rheobase (mA) (slope of the line)Strength-duration is a measure of the persistent Na+ channels. These channels are activated near threshold. The rheobase and time constant are a measure of the excitability of the persistent Na+ channels (Lin et al 2006)This is calculated using Weiss’s law, there is a linear relationship between threshold stimulus change and its duration (mAx ms)Strength-duraiont is established by tracking the difference between the error between the actual CMAP and the target threshold of the CMAP.
- Read slide,Activation of a fiber not only depends on the stimulus strength, but also the stimulus duration. Depolarization of an axon requiresa certain amount of charge to flow across the membrane. For shorter stimuli the intensity must be greater to produce the same amount of current flow as that of longer stimuli.
- Of these eight measures only one test result was significant. Number 6, The Threshold electrotonus test for threshold overshoot upon termination of hyperpolarizing currents should have a significant increase if the membrane is more depolarized. However, the results to this test were the opposite. There was a decrease in the amount of overshoot, which suggests the membrane is less excitable. This test result stands on its own and is not enough evidence to suggest there is a difference in membrane potential between sides.
- Changes in the architecture of the membrane without changes in the channel properties can effect excitability. The above changes, except for demyelination, are all changes that occur with aging. As we get older our axons become more excitabile because of these changes. It has been shown that shrinking of the diameter of the axon causes a reduction in the relative refractory period. Demyelination causes a decrease in the slope of the stimulus response relationship and an increase in rheobase. Thinning of myelin causes decreased capacitance and increasd resistance, this would make the Recovery Cylse’ssperexcitability period shorter, while increasing its subexcitable period. Changes internodal length, this actually effects the Na+p current and increases it. Axonal loss would result in a rightward shift of the stimulus respnserealtionship and incerase in the rheobase.
- No significant differences were found between the paretic and non-paretic side
- Is converse to the data that suggests the nerve is less excitable and no where in literature has it been reported that an axon would have a response ot one polarizing current, but not the other in the same direction.