Effects of nicotine on neuronal firing patterns in human subthalamic nucleus Kim Scott Mentor: Henry Lester SURF seminar, January 15, 2009
Smoking tobacco protects against Parkinson s Disease (PD). Identical twins: 10 pack-years difference! (Tanner et al. 2002) Risk increases with years since quitting (Ritz et al. 2007) Nicotine has a protective effect in culture and animal models (Quik et al 2007) Conclusion: Chronic nicotine prevents the degeneration of dopaminergic neurons in the substantia nigra. 2
Deep brain stimulation in PD Electrical stimulation of the subthalamic nucleus (STN) at 120-180 Hz immediately relieves motor symptoms of PD. 3
Deep brain stimulation in PD Bevan et al. 2002 Garcia et al. 2005 Why is this important to us? It s an ethical reason to put electrodes in human brains Suggests a focus on subthalamic nucleus (STN) 4
How does nicotine affect firing patterns in STN: What changes? Experimental protocol Spike detection and sorting 1-2 Hz oscillation Hope for the future 5
Recording procedure Baseline Nasal saline solution (placebo) Nasal nicotine solution 1.2 mm 1.2 mm Currently available STN recordings: 8 patients (2 smokers) Placebo recordings in all but first two patients. Active placebo in newest patient! Variable lengths of recording, ~5 minutes total. Protocol Spike detection Oscillation Hope and plans 6
S i g n a l 0 0 ( µ V ) S i g n a l 0 0 ( µ V ) 160 140 Spike detection isn t automatic 120 100 80 60 40 20 140 0 120-2 0-4 0 100-6 0-8 0 80 60 20 ms 20 μv - 1 0 0 40-1 2 0 20-1 4 0 0-1 6 0-2 0 271260 271280 T im e ( m s ) 271300 271320-4 0-6 0-8 0-1 0 0-1 2 0-1 4 0 Protocol Spike detection 87800 Oscillation Hope 87820and plans T im e ( m s ) 87840 87860 7
Osort: spike detection and sorting filtered trace power signal S detected spikes M Rutishauser et al. 2006 Protocol Spike detection Oscillation Hope and plans 8
count Sample sorted cluster: LUD ch. 2 Interspike interval histogram Protocol Spike detection Oscillation Hope and plans 9
Nothing obvious changes. Peak amplitude, variation therein, variation in shape of waveform Firing rate, coefficient of variation Burst propensity Connections among these factors Protocol Spike detection Oscillation Hope and plans 10
1-2 Hz bursting oscillation is real. 25 s 10 μv 5 s Protocol Spike detection Oscillation Hope and plans 1 s 11
Firing of an STN neuron isn t a renewal process. Protocol Spike detection Oscillation Hope and plans 12
The autocorrelation function Patient LUD, channel 1 Lags (s) Protocol Spike detection Oscillation Hope and plans 13
Properties of 1-2 Hz oscillation Statistically significant oscillation detected in 30 of 47 clusters Tightly clustered frequencies across channels in the same patient: average variance 0.0022 Hz Consistent changes across channels with placebo and nicotine Units tend to synchronize in or out of phase Almost unique to our group Protocol Spike detection Oscillation Hope and plans 14
Brief contralateral stimulation abolishes 1-2 Hz oscillation Percent of units oscillating at 0-2 Hz (Data from Chibirova et al., 2005) Side I Side II Protocol Spike detection Oscillation Hope and plans 15
Possible sources of oscillation Plenz & Kital 1999: STN oscillates in culture! STN-GPe cut: abolishes synchronization and oscillation STN-cortex cut: centers frequency at 0.8 Hz Magill et al. 2001: ~ 1 Hz oscillation in STN phase-locked to slowwave activity in cortex Bursting is more intense in dopamine depletion Protocol Spike detection Oscillation Hope and plans 16
Nothing obvious changes. Peak amplitude, variation therein, variation in shape of waveform Firing rate, coefficient of variation Burst propensity Strength of oscillation (several measures) Variation in oscillation timing Frequency of oscillation Phase variance, strength, or frequency of synchronization Connections among these Protocol Spike detection Oscillation Hope and plans 17
Next steps in analysis Measures of synchrony across all clusters Higher-order features: clustering of bursts Connections between low-frequency components of raw trace and burst timing Future recordings ECG control Blood samples Drug comparison Protocol Spike detection Oscillation Hope and plans 18
Acknowledgments Henry Lester Johannes Schwarz (Universität Leipzig) Shawna Frazier Ueli Rutishauser Pam Fong Lester lab the Caltech SURF program and Richter Memorial Fund 19
References Benarroch, E.E. Subthalamic nucleus and its connections: anatomic substrate for the network effects of deep brain stimulation. Neurology 70, 1991-1995 (2008). Bevan, M.D., Magill, P.J., Terman, D., Bolam, J.B. & Wilson, C.J. Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network. TRENDS in Neurosciences 25, 525-531 (2002). Chibirova O.K., Aksenova T.I., Benabid A., Chabardes S., Larouche S., Rouat J., & Villa A.E.P. Unsupervised spike sorting of extracellular electrophysiological recording in subthalamic nucleus of Parkinsonian patients. BioSystems 79, 159-171 (2005). Garcia, L., D'Alessandro, G., Bioulac, B. & Hammond, C. High-frequency stimulation in Parkinson's disease: more or less? TRENDS in Neurosciences 28, 209-216 (2005). Hahnloser, R.H.R. Cross-intensity functions and the estimate of spike-time jitter. Biol Cybern 96, 497-506 (2007). Levy, R., Hutchison, W.D., Lozano, A.M. & Dostrovsky, J.O. High-frequency synchronization of neuronal activity in the subthalamic nucleus of Parkinsonian patients with limb tremor. J Neurosci 20, 7766-7775 (2000). Magill, P.J., Bolam, J.P. & Bevan, M.D. Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network. Neuroscience 106, 313-330 (2001). Plentz, D. & Kital, S.T. A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature 400, 677-682 (1999). Quik, M., Bordia, T. & O'Leary, K. Nicotinic receptors as CNS targets for Parkinson's disease. Biochem Pharmacol 74, 1224-1234 (2007). Ritz, B., Ascherio, A., Checkoway, H., Marder, K.S., Nelson, L.M., Rocca, W.A., Ross, G.W., Strickland, D., Van Den Eeden, S.K., & Gorell, J. Pooled analysis of tobacco use and risk of Parkinson disease. Arch Neurol 64(7): 990-997 (2007). Rutishauser, U., Schuman, E.M. & Mamelak, A.N. Online detection and sorting of extracellularly recorded action potentials in human medial temporal lobe recordings, in vivo. J Neurosci Methods 154, 204-224 (2006). Tanner, C.M., Goldman, S.M./, Aston, D.A., Ottman, R., Ellenberg, J., Mayeux, R., Langston, J.W. Smoking and Parkinson s disease in twins. Neurology 58:581-588 (2002). 20
Signal 00 (µv) Signal 00 (µv) Signal 00 (µv) 800 Challenge: artifact ID & correction 100 HAE 50 0-50 -100 0 200 400 Time (ms) 600 1000 800 600 VOG 400 200 0-200 -400-600 -800-1000 160065 160070 Time (ms) 160075 1 400 WEN 200 29.93143 s 1.36 µv 0-200 -400 15 20 Time (s) 25 30 Protocol Spike detection Oscillation What changes? Progress and plans 21
Gain changes during recording 22
are removable! 23
Power thresholding 24
We re not limited to studying pairs of clusters The cross-correlation is only defined for two signals, but: 1 Compute pairwise autocorrelations 2 Optimally align spike trains 3 Pool aligned spike trains 4 Compute the autocorrelation 5 Compare to control Protocol Spike detection Oscillation What changes? Progress and plans 25
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Direct pathway: striatum inhibits Gpi/SNr inhibits thalamus Indirect pathway: striatum inhibits Gpe inhibits STN excites Gpi/SNr inhibits thalamus. STN is part of the indirect pathway Disfunction leads to impulsivity B.G. possibly participate in action selection. 27