patterns in human subthalamic nucleus Kim Scott Mentor: Henry - PowerPoint PPT Presentation

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 Garcia et al. 2005 Bevan et al. 2002 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 Nasal saline Nasal Baseline solution nicotine (placebo) 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. 6 Protocol · Spike detection · Oscillation · Hope and plans

Spike detection isn’t automatic 4 0 2 0 0 0 0 0 20 μ V 20 ms 0 0 4 0 0 2 0 0 0 0 0 0 0 0 0 0 0 7 Protocol · Spike detection · Oscillation · Hope and plans

Osort: spike detection and sorting filtered trace power signal S detected spikes M Rutishauser et al. 2006 8 Protocol · Spike detection · Oscillation · Hope and plans

Sample sorted cluster: LUD ch. 2 Interspike interval histogram count 9 Protocol · Spike detection · Oscillation · Hope and plans

Nothing obvious changes. • Peak amplitude, variation therein, variation in shape of waveform • Firing rate, coefficient of variation • Burst propensity • Connections among these factors 10 Protocol · Spike detection · Oscillation · Hope and plans

1-2 Hz bursting oscillation is real. 25 s 10 μ V 5 s 1 s 11 Protocol · Spike detection · Oscillation · Hope and plans

Firing of an STN neuron isn’t a renewal process. 12 Protocol · Spike detection · Oscillation · Hope and plans

The autocorrelation function Patient LUD, channel 1 Lags (s) 13 Protocol · Spike detection · Oscillation · Hope and plans

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 14 Protocol · Spike detection · Oscillation · Hope and plans

Brief contralateral stimulation abolishes 1-2 Hz oscillation Percent of (Data from units Chibirova et al., oscillating at 2005) 0-2 Hz Side II Side I 15 Protocol · Spike detection · Oscillation · Hope and plans

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 slow- wave activity in cortex • Bursting is more intense in dopamine depletion 16 Protocol · Spike detection · Oscillation · Hope and plans

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 17 Protocol · Spike detection · Oscillation · Hope and plans

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 Drug Blood control samples comparison 18 Protocol · Spike detection · Oscillation · Hope and plans

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 dise ase in twins. Neurology 58:581-588 (2002). 20

Challenge: artifact ID & correction HAE 100 50 Signal 00 (µV) 0 -50 -100 0 200 400 600 800 Time (ms) 1000 800 VOG 600 400 200 Signal 00 (µV) 0 -200 -400 -600 -800 -1000 160065 160070 160075 Time (ms) 1 WEN 400 29.93143 s 200 1.36 µV Signal 00 (µV) 0 -200 -400 15 20 25 30 Time (s) 21 Protocol · Spike detection · Oscillation · What changes? · Progress and plans

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: • Compute pairwise autocorrelations 1 • Optimally align spike trains 2 • Pool aligned spike trains 3 • Compute the autocorrelation 4 • Compare to control 5 25 Protocol · Spike detection · Oscillation · What changes? · Progress and plans

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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