1. Basal Ganglia

2. Involved in the control of movement Dysfunction associated with Parkinson’s and Huntington’s disease Site of surgical procedures -- Deep Brain Stimulation (DBS) BASAL GANGLIA

3. STN

4. Deep Brain Stimulation (DBS)

5. Parkinson’s disease associated with: Loss of dopamine:

6. Parkinson’s disease associated with changes in firing patterns. Some neurons within basal ganglia exhibit: Increased synchronization Increased bursting activity

7. Why should these changes in firing patterns lead to the motor symptoms seen in PD? cortex basal ganglia thalamus Inhibitory synapses Strong pathological output patterns of BG inhibit motor activity.

8. MODELING STUDY Construct model GPe/STN network. Plenz & Kitai showed that a GPe/STN network can display synchronous activity. Can the network generate both synchronous, tremor- like rhythms and irregular, uncorrelated activity? Mechanism underlying DBS? Striatum STN GPi GPe Cortex Thalamus inh exc

9. Based on Experiments (Bevan and Wilson) MODEL STN NEURON

10. Firing Properties of STN Cells ExperimentModel

11. Firing Properties of STN/GPE Neurons Post Inhibitory Rebound Firing Profiles STNGPE

12. STRIATUM STN / GPe NETWORK Can this network exhibit both irregular and correlated activity (same architecture, different parameters) ?

13. Irregular firingClustering

14. When does the network exhibit irregular or correlated activity? I GPe  STN inhibition Input to striatum Irregular firing Clustering 10 STN & GPe cells Sparse, structured coupling PCA

15. Consider a Periodically Forced GPe Cell: Outline of Analysis: Fast/Slow Analysis of GPe Cell Phase-Response Curve for GPe Cell Construct a 1-D Map Analysis of Irregular Firing STN GPe

16. MODEL GPe NEURON We consider Ca as a slow variable.

17. GPe bifurcation diagram Stable fixed ptsunstable fixed pts stable periodic orbitsSaddle-node of limit cycles Hopf bifurcation

18. Dynamics Reduce to a Single Equation for the Slow Variable Good Approximation: Ca’ = - S cell silent A cell active V GPe Ca

19. A one-dimensional map

20. Linear Approximation of Map T GPe > T STN π (t) = t + T GPe - T STN T STN - T GPe < t ≤ T STN -T S ( λ s / λ A )(T STN - t) T STN - T S < t ≤ T STN T GPe = period of an isolated, bursting, GPe cell. T STN = interval between STN spikes T S = GPe silent phase T A = GPe active phase T STN T STN -T S T GPe - T STN TATA π (t) Slope - S / A Slope 1

21. Tent map predicts: λ S < λ A : number of spikes per burst is nearly constant λ S > λ A : number of spikes per burst may vary chaotically

22. Numerically Computed Map T GPe > T STN T GPe < T STN

23. Poincare Section Remark: This analysis does a very good job in predicting when irregular activity arises in larger networks.

24. STN

25. Mechanisms Underlying DBS Mysterious Poorly understood: Which neurons DBS acts on. How DBS effects different parts of neurons. How DBS depends on geometry of neurons. Whether DBS is excitatory or inhibitory. That is, does DBS increase or decrease output from stimulated structure?

26. Evidence That DBS is Inhibitory: Clinical effects similar to ablative surgery There is increased BG activity during PD Evidence That DBS is Excitatory: Recent experimental data (Vitek et al.) Question: How can one explain improvement of PD symptoms if DBS increases GPi output activity?

27. Parkinson Normal DBS Basal Ganglia How Does Input From BG Effect Thalamic Ability to Relay Excitatory Input? Thalamus ??? ExcitatoryInput

28. Irregular (Normal) Activity Basal gangliaThalamus STNGPiTC DBS exc. input

29. DBS off Basal gangliaThalamus PD: DBS off

30. PD: DBS on DBS on ThalamusBasal ganglia

31. DBS off Basal ganglia Thalamus PD: DBS on  off

32. Data-driven computational study We now consider signal obtained from single-unit GPi recordings from: control (normal) monkeys parkinsonian (MPTP) monkeys without DBS parkinsonian monkeys under sub-therapeutic STN-DBS parkinsonian monkeys under therapeutic STN-DBS

33. Inhibitory signal s i GP i spike time TC voltage Excitatory signal V (mV) A B C D time (msec) PD without DBS sub-therapeutic DBS therapeutic DBS control

34. periodic input Poisson input EST error index EST = elevated spiking time of GPi signal Normal PD w/o DBS sub-DBS therapeutic DBS #bad + #misses #exc. inputs error index = small: low firing rate medium: bursting large: high tonic firing

35. Collaborators Charles Wilson Jonathan Rubin Yixin Guo Cameron McIntyre Jerold Vitek Janet Best Choongseok Park