Reciprocal derivative
1Division
Yunyan
1 Wang ,
2 Vasudevan ,
Srikanth
Daniel X.
2 Hammer ,
Pavel
1 Takmakov
2Division of Biomedical Physics of Biology, Chemistry, and Materials Science Office of Science and Engineering Laboratories, Center for Devices and Radiological Health US Food and Drug Administration, White Oak Federal Research Center, Silver Spring, MD, 20993
Introduction
Results
Neural modulation at the peripheral nervous system (PNS) offer valuable clinical tools to treat epilepsy, chronic pain and obesity while posing less risk than brain implants. Safety guidelines for neurostimulators have commonly used the Shannon equation to determine safe limits of charge injection. Evidence supporting Shannon limits are largely based on data obtained in cortex (CNS).
Inflections in potential excursion indicate consumption of charge injected by faradaic reactions
Charge density D, C/cm2
Shannon Equation log (QD) = k - log (Q) D Charge density QD Charge per phase
100
25µs 400µs
Stimulation waveform
k = 1.75
Determining onset of H2 evolution
Recorded potential excursion
No damage cortex (McCreery '89, '90) Damage cortex (McCreery '89, '90) Damage sciatic (McCreery '92)
Derivative of Potential Excursion Cathodic Phase
Cathodic polarization determined by 25µs interphase interval voltage
400µs
Emc
One peak – Pt oxide reduction
10
10um Pt electrode
k = - 0.32
1x PBS 1
10
100
Charge per phase Q, C
*
*
Because peripheral nerves are different than brain tissue, it is expected charge injection limits and mechanisms of nerve damage may be different for peripheral nerves. According toa study by McCreery et al (1992), damage in cat sciatic nerve due to electrical stimulation happens at much lower k values of -0.32. Further, the Shannon equation does not take into account the effects of electrode material, size, or duty cycle, which all play a role in neural damage. To better understand nerve damage mechanisms in PNS, it is necessary to parse contribution from reactions at the electrode-electrolyte interface (electrochemistry) and biological causes such as over-excitation (metabolic overload and excitotoxicity). To characterize the contribution of electrochemistry to nerve damage, we explore a method for observing Faradaic reactions through charge injection using actual stimulation parameters. This way, we can quantitatively evaluate overpotentials for irreversible reactions that may cause generation of noxious chemical species such as pH changes and water electrolysis with gas evolution. These overpotentials are usually measured with cyclic voltammetry on slow time scale, which is different for charge injection during neural stimulation, that occur at much faster rates. The reciprocal derivative chronopotentiometry explored by Musa et al (2011) can be used for measuring the water window for each unique stimulation setup using actual stimulation parameters. These electrochemical experiments allow us to distinguish chemical and biological sources for nerve damage.
Cogan 2016
Based on onset of gas evolution , charge injection limits differ for micro- and macroelectrodes Microelectrode ⌀ 0.2mm
* *
-1.50V k=4.13
-1.53V k=3.1
-1.13V k=2.3
QD = 157 mC/cm2
QD = 1.9 mC/cm2
QD = 0.163 mC/cm2
Future Work - Determining charge injection limits in vivo Compound action potential recording
PC
Pt Cuff Electrode around sciatic nerve ⌀ 0.2 mm; ⌀ 0.4mm disk-shaped contacts
Keithley 6221
Cyclic voltammetry -0.6V Rose and Roblee 1990 Pt macroelectrodes
Counter electrode – Carbon rod Preliminary Ex Vivo data (4ºC)
Conclusions Neuromodulation in the peripheral nervous system may have different damage mechanisms than that in CNS. Therefore, charge injection safety limits for PNS stimulation for should be evaluated independently to reflect occurrence of irreversible chemical reactions and onset of adverse tissue reactions.
Potential excursion analysis in vivo is a valuable tool to dissociate electrochemical sources of nerve damage from biological sources such as the effects of excitotoxicity. These electrochemical experiments can help to identify variables when studying mechanisms for nerve damage during electrical stimulation.
Reciprocal derivative
USB DAQ
H2 evolution overpotential is not absolute
Overpotentials for gas evolution at stimulation parameters differ from that measured through cyclic voltammetry. Safe charge injection limits may be determined through potential excursion analysis in each unique setup using actual stimulation parameters.
Custom stimulation and recording setup Current Source
⌀ 1mm
Reciprocal derivative chronopotentiometry -1.42V Musa 2010 Pt electrode ⌀0.05
Electrodes: Platinum disk electrodes ⌀0.01mm (BASi) , ⌀1mm (eDAQ) and custom Pt cuff electrodes with circular contacts ⌀ 0.4mm (Ardiem Medical) In vitro – 1x PBS; room temperature; exposed to ambient oxygen. Reference electrode: Gamry Ag/AgCl
Macroelectrode
⌀ 0.01mm
Methods
+
Reciprocal Derivative of Potential Excursion Cathodic Phase Two peaks – H2 evolution
1 0.1
Current sensing resistor
Determining electrode polarization / overpotential for H2 evolution
LabView
NI SCB-68
Acknowledgements
Two peaks – H2 evolution Current Channel
This research has been funded by FDA\CDRH Critical Path grant “Evaluation of biomarkers for safety of electrical stimulation of peripheral nerve.” to Dr. Pavel Takmakov and NANS Travel Award to Dr. Yunyan Wang.
Voltage Channel
Electrode polarization -2.15V
Electrochemical Cell C
W
Ref
Or In Vivo setup
k=2.3
*Compare w/ RT PBS k=3.1
www.fda.gov
Disclaimer The information in these materials is not a formal dissemination of information by FDA and does not represent agency position or policy.
Yunyan
1 Wang ,
2 Vasudevan ,
Srikanth
Daniel X.
2 Hammer ,
Pavel
1 Takmakov
2Division of Biomedical Physics of Biology, Chemistry, and Materials Science Office of Science and Engineering Laboratories, Center for Devices and Radiological Health US Food and Drug Administration, White Oak Federal Research Center, Silver Spring, MD, 20993
Introduction
Results
Neural modulation at the peripheral nervous system (PNS) offer valuable clinical tools to treat epilepsy, chronic pain and obesity while posing less risk than brain implants. Safety guidelines for neurostimulators have commonly used the Shannon equation to determine safe limits of charge injection. Evidence supporting Shannon limits are largely based on data obtained in cortex (CNS).
Inflections in potential excursion indicate consumption of charge injected by faradaic reactions
Charge density D, C/cm2
Shannon Equation log (QD) = k - log (Q) D Charge density QD Charge per phase
100
25µs 400µs
Stimulation waveform
k = 1.75
Determining onset of H2 evolution
Recorded potential excursion
No damage cortex (McCreery '89, '90) Damage cortex (McCreery '89, '90) Damage sciatic (McCreery '92)
Derivative of Potential Excursion Cathodic Phase
Cathodic polarization determined by 25µs interphase interval voltage
400µs
Emc
One peak – Pt oxide reduction
10
10um Pt electrode
k = - 0.32
1x PBS 1
10
100
Charge per phase Q, C
*
*
Because peripheral nerves are different than brain tissue, it is expected charge injection limits and mechanisms of nerve damage may be different for peripheral nerves. According toa study by McCreery et al (1992), damage in cat sciatic nerve due to electrical stimulation happens at much lower k values of -0.32. Further, the Shannon equation does not take into account the effects of electrode material, size, or duty cycle, which all play a role in neural damage. To better understand nerve damage mechanisms in PNS, it is necessary to parse contribution from reactions at the electrode-electrolyte interface (electrochemistry) and biological causes such as over-excitation (metabolic overload and excitotoxicity). To characterize the contribution of electrochemistry to nerve damage, we explore a method for observing Faradaic reactions through charge injection using actual stimulation parameters. This way, we can quantitatively evaluate overpotentials for irreversible reactions that may cause generation of noxious chemical species such as pH changes and water electrolysis with gas evolution. These overpotentials are usually measured with cyclic voltammetry on slow time scale, which is different for charge injection during neural stimulation, that occur at much faster rates. The reciprocal derivative chronopotentiometry explored by Musa et al (2011) can be used for measuring the water window for each unique stimulation setup using actual stimulation parameters. These electrochemical experiments allow us to distinguish chemical and biological sources for nerve damage.
Cogan 2016
Based on onset of gas evolution , charge injection limits differ for micro- and macroelectrodes Microelectrode ⌀ 0.2mm
* *
-1.50V k=4.13
-1.53V k=3.1
-1.13V k=2.3
QD = 157 mC/cm2
QD = 1.9 mC/cm2
QD = 0.163 mC/cm2
Future Work - Determining charge injection limits in vivo Compound action potential recording
PC
Pt Cuff Electrode around sciatic nerve ⌀ 0.2 mm; ⌀ 0.4mm disk-shaped contacts
Keithley 6221
Cyclic voltammetry -0.6V Rose and Roblee 1990 Pt macroelectrodes
Counter electrode – Carbon rod Preliminary Ex Vivo data (4ºC)
Conclusions Neuromodulation in the peripheral nervous system may have different damage mechanisms than that in CNS. Therefore, charge injection safety limits for PNS stimulation for should be evaluated independently to reflect occurrence of irreversible chemical reactions and onset of adverse tissue reactions.
Potential excursion analysis in vivo is a valuable tool to dissociate electrochemical sources of nerve damage from biological sources such as the effects of excitotoxicity. These electrochemical experiments can help to identify variables when studying mechanisms for nerve damage during electrical stimulation.
Reciprocal derivative
USB DAQ
H2 evolution overpotential is not absolute
Overpotentials for gas evolution at stimulation parameters differ from that measured through cyclic voltammetry. Safe charge injection limits may be determined through potential excursion analysis in each unique setup using actual stimulation parameters.
Custom stimulation and recording setup Current Source
⌀ 1mm
Reciprocal derivative chronopotentiometry -1.42V Musa 2010 Pt electrode ⌀0.05
Electrodes: Platinum disk electrodes ⌀0.01mm (BASi) , ⌀1mm (eDAQ) and custom Pt cuff electrodes with circular contacts ⌀ 0.4mm (Ardiem Medical) In vitro – 1x PBS; room temperature; exposed to ambient oxygen. Reference electrode: Gamry Ag/AgCl
Macroelectrode
⌀ 0.01mm
Methods
+
Reciprocal Derivative of Potential Excursion Cathodic Phase Two peaks – H2 evolution
1 0.1
Current sensing resistor
Determining electrode polarization / overpotential for H2 evolution
LabView
NI SCB-68
Acknowledgements
Two peaks – H2 evolution Current Channel
This research has been funded by FDA\CDRH Critical Path grant “Evaluation of biomarkers for safety of electrical stimulation of peripheral nerve.” to Dr. Pavel Takmakov and NANS Travel Award to Dr. Yunyan Wang.
Voltage Channel
Electrode polarization -2.15V
Electrochemical Cell C
W
Ref
Or In Vivo setup
k=2.3
*Compare w/ RT PBS k=3.1
www.fda.gov
Disclaimer The information in these materials is not a formal dissemination of information by FDA and does not represent agency position or policy.
