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Basal Ganglia BASAL GANGLIA • Involved in the control of movement • Dysfunction associated with Parkinson’s and Huntington’s disease • Site of surgical procedures -- Deep Brain Stimulation (DBS) STN Deep Brain Stimulation (DBS) QuickTime™ and a decompressor are needed to see this picture. QuickTime™ and a decompressor are needed to see this picture. Parkinson’s disease associated with: Loss of dopamine: Parkinson’s disease associated with changes in firing patterns. Some neurons within basal ganglia exhibit: • Increased synchronization • Increased bursting activity 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. 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, tremorlike rhythms and irregular, uncorrelated activity? • Mechanism underlying DBS? GPe Striatum STN GPi Cortex inh exc Thalamus MODEL STN NEURON Based on Experiments (Bevan and Wilson) Firing Properties of STN Cells Experiment Model Firing Properties of STN/GPE Neurons STN Post Inhibitory Rebound GPE Firing Profiles STN / GPe NETWORK STRIATUM Can this network exhibit both irregular and correlated activity (same architecture, different parameters) ? QuickTime™ and a YUV420 codec decompressor are needed to see this picture. Irregular firing QuickTime™ and a YUV420 codec decompressor are needed to see this picture. Clustering When does the network exhibit irregular or correlated activity? Irregular firing • 10 STN & GPe cells • Sparse, structured coupling I PCA Input to striatum GPe STN inhibition Clustering Analysis of Irregular Firing Consider a Periodically Forced GPe Cell: Outline of Analysis: GPe STN • Fast/Slow Analysis of GPe Cell • Phase-Response Curve for GPe Cell • Construct a 1-D Map MODEL GPe NEURON We consider Ca as a slow variable. GPe bifurcation diagram stable periodic orbits Saddle-node of limit cycles Hopf unstable fixed pts bifurcation Stable fixed pts Dynamics Reduce to a Single Equation for the Slow Variable Good Approximation: - lS cell silent Ca’ = VGPe Ca lA cell active A one-dimensional map Linear Approximation of Map π(t) Slope -lS / lA TA TGPe - TSTN Slope 1 TSTN-TS π(t) = TGPe > TSTN TGPe = period of an isolated, bursting, GPe cell. TSTN = interval between STN spikes TS = GPe silent phase TA = GPe active phase TSTN t + TGPe - TSTN TSTN - TGPe < t ≤ TSTN -TS (λs/λA)(TSTN - t) TSTN - TS < t ≤ TSTN Tent map predicts: λS < λA : number of spikes per burst is nearly λS > λA : number of spikes per burst may vary chaotically constant Numerically Computed Map TGPe > TSTN TGPe < TSTN Poincare Section Remark: This analysis does a very good job in predicting when irregular activity arises in larger networks. STN 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? 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? How Does Input From BG Effect Thalamic Ability to Relay Excitatory Input? Normal ??? Parkinson Thalamus DBS Basal Ganglia ExcitatoryInput Irregular (Normal) Activity Basal ganglia STN DBS GPi Thalamus TC exc. input PD: DBS off Basal ganglia DBS off Thalamus PD: DBS on Basal ganglia DBS on Thalamus PD: DBS on off Basal ganglia DBS off Thalamus 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 control V (mV) A TC voltage Excitatory signal sub-therapeutic DBS V (mV) C therapeutic DBS V (mV) D Inhibitory signal si GPi spike time V (mV) B PD without DBS time (msec) EST Poisson input error index error index periodic input Normal PD w/o DBS sub-DBS therapeutic DBS EST error index = #bad + #misses #exc. inputs EST = elevated spiking time of GPi signal small: low firing rate medium: bursting large: high tonic firing Collaborators Charles Wilson Jonathan Rubin Yixin Guo Cameron McIntyre Jerold Vitek Janet Best Choongseok Park