Frequency-dependent antidromic activation in thalamocortical relay neurons: effects of synaptic inputs

OBJECTIVE Deep brain stimulation (DBS) generates action potentials (APs) in presynaptic axons and fibers of passage. The APs may be antidromically propagated to invade the cell body and/or orthodromically transmitted to downstream structures, thereby affecting widespread targets distant from the electrode. Activation of presynaptic terminals also causes trans-synaptic effects, which in turn alter the excitability of the post-synaptic neurons. Our aim was to determine how synaptic inputs affect the antidromic invasion of the cell body. APPROACH We used a biophysically-based multi-compartment model to simulate antidromic APs in thalamocortical relay (TC) neurons. We applied distributed synaptic inputs to the model and quantified how excitatory and inhibitory inputs contributed to the fidelity of antidromic activation over a range of antidromic frequencies. MAIN RESULTS Antidromic activation exhibited strong frequency dependence, which arose from the hyperpolarizing afterpotentials in the cell body and its respective recovery cycle. Low-frequency axonal spikes faithfully invaded the soma, whereas frequent failures of antidromic activation occurred at high frequencies. The frequency-dependent pattern of the antidromic activation masked burst-driver inputs to TC neurons from the cerebellum in a frequency-dependent manner. Antidromic activation also depended on the excitability of the cell body. Excitatory synaptic inputs improved the fidelity of antidromic activation by increasing the excitability, and inhibitory inputs suppressed antidromic activation by reducing soma excitability. Stimulus-induced depolarization of neuronal segments also facilitated antidromic propagation and activation. SIGNIFICANCE The results reveal that synaptic inputs, stimulus frequency, and electrode position regulate antidromic activation of the cell body during extracellular stimulation. These findings provide a biophysical basis for interpreting the widespread inhibition/activation of target nuclei during DBS.

[1]  Danny C. W. Chan,et al.  Therapeutic Deep Brain Stimulation in Parkinsonian Rats Directly Influences Motor Cortex , 2012, Neuron.

[2]  Su-Youne Chang,et al.  Neurotransmitter release from high-frequency stimulation of the subthalamic nucleus. , 2004, Journal of neurosurgery.

[3]  Y. Smith,et al.  Differential synaptic innervation of neurons in the internal and external segments of the globus pallidus by the GABA‐ and glutamate‐containing terminals in the squirrel monkey , 1995, The Journal of comparative neurology.

[4]  C. McIntyre,et al.  Extracellular stimulation of central neurons: influence of stimulus waveform and frequency on neuronal output. , 2002, Journal of neurophysiology.

[5]  J. Dostrovsky,et al.  Microstimulation-induced inhibition of neuronal firing in human globus pallidus. , 2000, Journal of neurophysiology.

[6]  J. Mink,et al.  Effect of stimulation frequency on tremor suppression in essential tremor , 2004, Movement disorders : official journal of the Movement Disorder Society.

[7]  M L Hines,et al.  Neuron: A Tool for Neuroscientists , 2001, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[8]  E. Barrett,et al.  Electrical and morphological factors influencing the depolarizing after‐potential in rat and lizard myelinated axons. , 1995, The Journal of physiology.

[9]  Abdelhamid Benazzouz,et al.  Responses of substantia nigra pars reticulata and globus pallidus complex to high frequency stimulation of the subthalamic nucleus in rats: electrophysiological data , 1995, Neuroscience Letters.

[10]  Matthew D. Johnson,et al.  Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS. , 2015, Journal of neurophysiology.

[11]  Warren M. Grill,et al.  Antidromic propagation of action potentials in branched axons: implications for the mechanisms of action of deep brain stimulation , 2008, Journal of Computational Neuroscience.

[12]  Svjetlana Miocinovic,et al.  Computational analysis of subthalamic nucleus and lenticular fasciculus activation during therapeutic deep brain stimulation. , 2006, Journal of neurophysiology.

[13]  S. Waxman,et al.  The association of the supernormal period and the depolarizing afterpotential in myelinated frog and rat sciatic nerve , 1987, Neuroscience.

[14]  Scott T. Grafton,et al.  Normalizing motor-related brain activity , 2006, Neurology.

[15]  G. Deuschl,et al.  Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor. , 2007, Brain : a journal of neurology.

[16]  Zelma H T Kiss,et al.  Cellular mechanisms preventing sustained activation of cortex during subcortical high-frequency stimulation. , 2006, Journal of neurophysiology.

[17]  Hagai Bergman,et al.  Insights into the mechanisms of deep brain stimulation , 2017, Nature Reviews Neurology.

[18]  S. Waxman,et al.  Activity‐dependent modulation of excitability: Implications for axonal physiology and pathophysiology , 1994, Muscle & nerve.

[19]  Y. Shinoda,et al.  Three‐dimensional analysis of cerebellar terminals and their postsynaptic components in the ventral lateral nucleus of the cat thalamus , 1996, The Journal of comparative neurology.

[20]  J. Hursh CONDUCTION VELOCITY AND DIAMETER OF NERVE FIBERS , 1939 .

[21]  Warren M. Grill,et al.  Short pauses in thalamic deep brain stimulation promote tremor and neuronal bursting , 2016, Clinical Neurophysiology.

[22]  Yoshikazu Shinoda,et al.  Serial electron microscopic reconstruction of axon terminals on physiologically identified thalamocortical neurons in the cat ventral lateral nucleus , 1997, The Journal of comparative neurology.

[23]  Satomi Chiken,et al.  High-Frequency Pallidal Stimulation Disrupts Information Flow through the Pallidum by GABAergic Inhibition , 2013, The Journal of Neuroscience.

[24]  W. Grill,et al.  Pulse-to-pulse changes in the frequency of deep brain stimulation affect tremor and modeled neuronal activity. , 2007, Journal of neurophysiology.

[25]  J. Munson,et al.  Membrane electrical properties and prediction of motor-unit type of medial gastrocnemius motoneurons in the cat. , 1985, Journal of neurophysiology.

[26]  V. Dhawan,et al.  Network modulation in the treatment of Parkinson's disease. , 2006, Brain : a journal of neurology.

[27]  A. Benabid,et al.  The impact on Parkinson’s disease of electrical parameter settings in STN stimulation , 2002, Neurology.

[28]  Warren M. Grill,et al.  Modeling deep brain stimulation: point source approximation versus realistic representation of the electrode , 2010, Journal of neural engineering.

[29]  Z. Mari,et al.  Thalamic physiology of intentional essential tremor is more like cerebellar tremor than postural essential tremor , 2013, Brain Research.

[30]  Bryan Howell,et al.  Quantifying axonal responses in patient-specific models of subthalamic deep brain stimulation , 2018, NeuroImage.

[31]  W. Grill,et al.  Amplitude- and Frequency-Dependent Changes in Neuronal Regularity Parallel Changes in Tremor With Thalamic Deep Brain Stimulation , 2007, IEEE Transactions on Neural Systems and Rehabilitation Engineering.

[32]  Erwin B. Montgomery,et al.  Effects of GPi stimulation on human thalamic neuronal activity , 2006, Clinical Neurophysiology.

[33]  C. McIntyre,et al.  Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition. , 2004, Journal of neurophysiology.

[34]  Bernhard Haslinger,et al.  Frequency-correlated decreases of motor cortex activity associated with subthalamic nucleus stimulation in Parkinson's disease , 2005, NeuroImage.

[35]  P. Brown,et al.  Frequency dependent effects of subthalamic nucleus stimulation in Parkinson's disease , 2005, Neuroscience Letters.

[36]  Matthew D. Johnson,et al.  Quantifying the neural elements activated and inhibited by globus pallidus deep brain stimulation. , 2008, Journal of neurophysiology.

[37]  F. Lenz,et al.  Posture-related oscillations in human cerebellar thalamus in essential tremor are enabled by voluntary motor circuits. , 2005, Journal of neurophysiology.

[38]  C. McIntyre,et al.  Excitation of central nervous system neurons by nonuniform electric fields. , 1999, Biophysical journal.

[39]  C. McIntyre,et al.  Modeling the excitability of mammalian nerve fibers: influence of afterpotentials on the recovery cycle. , 2002, Journal of neurophysiology.

[40]  Erwin B. Montgomery,et al.  Deep Brain Stimulation Programming: Principles and Practice , 2010 .

[41]  A. Benabid,et al.  Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus , 1991, The Lancet.

[42]  Brian Hyland,et al.  Cortical effects of subthalamic stimulation correlate with behavioral recovery from dopamine antagonist induced akinesia. , 2009, Cerebral cortex.

[43]  R. Wennberg,et al.  A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease , 2010, Annals of neurology.

[44]  P. O'Suilleabhain,et al.  Tremor response to polarity, voltage, pulsewidth and frequency of thalamic stimulation , 2003, Neurology.

[45]  H. Kwan,et al.  Single unit analysis of the human ventral thalamic nuclear group. Tremor-related activity in functionally identified cells. , 1994, Brain : a journal of neurology.

[46]  M. Clyde,et al.  Clinical response to varying the stimulus parameters in deep brain stimulation for essential tremor , 2006, Movement disorders : official journal of the Movement Disorder Society.

[47]  E. Růžička,et al.  Functional magnetic resonance imaging during deep brain stimulation: A pilot study in four patients with Parkinson's disease , 2001, Movement disorders : official journal of the Movement Disorder Society.

[48]  Warren M. Grill,et al.  A biophysical model of the cortex-basal ganglia-thalamus network in the 6-OHDA lesioned rat model of Parkinson’s disease , 2016, Journal of Computational Neuroscience.

[49]  A. Nambu,et al.  Mechanism of Deep Brain Stimulation , 2015, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[50]  Alan D Dorval,et al.  Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation. , 2012, Journal of neurophysiology.

[51]  J. Thomas Mortimer,et al.  A Technique for Collision Block of Peripheral Nerve: Frequency Dependence , 1981, IEEE Transactions on Biomedical Engineering.

[52]  I. Ilinsky,et al.  Fine structure of the ventral lateral nucleus (VL) of the Macaca mulatta thalamus: Cell types and synaptology , 1991, The Journal of comparative neurology.

[53]  Izhar Bar-Gad,et al.  Systems Neuroscience , 2018, Advances in Neurobiology.

[54]  J. Bullier,et al.  Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter II. Evidence from selective inactivation of cell bodies and axon initial segments , 1998, Experimental Brain Research.

[55]  W. Grill,et al.  Deep brain stimulation creates an informational lesion of the stimulated nucleus , 2004, Neuroreport.

[56]  Michael J. Jutras,et al.  Resonant antidromic cortical circuit activation as a consequence of high-frequency subthalamic deep-brain stimulation. , 2007, Journal of neurophysiology.

[57]  Matthew D. Johnson,et al.  Deep brain stimulation induces sparse distributions of locally modulated neuronal activity , 2018, Scientific Reports.

[58]  Sergio Martinoia,et al.  Axon-somatic back-propagation in detailed models of spinal alpha motoneurons , 2015, Front. Comput. Neurosci..

[59]  A. Destexhe,et al.  Dendritic Low-Threshold Calcium Currents in Thalamic Relay Cells , 1998, The Journal of Neuroscience.

[60]  C. McIntyre,et al.  Patient-specific models of deep brain stimulation: Influence of field model complexity on neural activation predictions , 2010, Brain Stimulation.

[61]  Martin Deschênes,et al.  Electrophysiology and Pharmacology of the Corticothalamic Input to Lateral Thalamic Nuclei: an Intracellular Study in the Cat , 1990, The European journal of neuroscience.

[62]  A. Schierwagen,et al.  Passive membrane properties, afterpotentials and repetitive firing of superior colliculus neurons studied in the anesthetized cat , 2004, Experimental Brain Research.

[63]  J. Bullier,et al.  Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter I. Evidence from chronaxie measurements , 1998, Experimental Brain Research.