Workshop 3: Disease
On the Therapeutic Mechanisms of Deep Brain Stimulation for Parkinson's Disease: Annihilation or Restoration?Sridevi Sarma
Sridevi Sarma's lecture on the Therapeutic Mechanisms of Deep Brain Stimulation for Parkinson's Disease: Annihilation or Restoration?
A seizure represents an extreme deviation from normal brain activity. In this talk, we will consider some characteristics of the seizure as observed across spatial and temporal scales in human patients. We will focus specifically on changes in the rhythmic voltage activity, and consider techniques to characterize these changes. We will also discuss a mathematical model consistent with the stereotyped dynamics observed at seizure termination, and use this model to propose what happens dynamically when a seizure fails to self- terminate.
Despite decades of research, the biochemical and neurophysiological causes of depression remain unknown. Furthermore, although selective serotonin reuptake inhibitors (SSRIs) block the reuptake of serotonin and alleviate depression in some patients, it is not clear how or why they work. Mathematical models of serotonin synthesis, release, and reuptake can shed light on the control mechanisms of the serotonin system and suggest hypotheses about the action of SSRIs. We will discuss two of the standard hypotheses and propose a new hypothesis.
Parkinson?s disease has been traditionally thought of as a dopaminergic disease in which cells of the substantia nigra pars compacta (SNc) die. However, accumulating evidence implies an important role for the serotonergic system in Parkinson?s disease in general and in physiological responses to levodopa therapy, the first line of treatment. We use a mathematical model to investigate the consequences of levodopa therapy on the serotonergic system and on the pulsatile release of dopamine (DA) from dopaminergic and serotonergic terminals in the striatum.
We will also ask, and propose an answer to, the question of what serotonin is doing in the striatum anyway?
Ionic concentrations fluctuate significantly during seizures. Substantial increase of extracellular K+ is found during electrically- or pharmacologically-induced paroxysmal activity, along with increase of intracellular Na+. These changes of the ionic concentrations trigger various homeostasis mechanisms such as glial uptake and Na+/K+ ATPase. While Na+/K+ ATPase is one of the most studied proteins, its role in epilepsy remains unclear. Using computational model of in vivo epileptiform activity, we found that increase of intracellular Na+ during epileptiforms leads to significant activation of Na+/K+ ATPase; this increase mediates hyperpolarizing current by Na+/K+ pump that contributes to termination of seizure and postictal depression state. Deficiencies of the Na+/K+ ATPase promote continuous epileptiform activity. In terms of dynamics, the mechanism underlying the smooth transition is due to a safe bifurcation of a homoclinic orbit of a saddle-node equilibrium state terminating the quiescence period of bursting. Overall, our study demonstrated a complex role played by Na+/K+ ATPase in developing of epileptiform activity and may suggest new targets for antiepileptic drugs.
Motor symptoms of Parkinson's disease have been associated with the synchronized oscillatory activity in the cortico-basal ganglia-thalamic circuits. Here we will present our observations of the patterns of synchronized activity obtained through simultaneous intraoperative recordings of spikes and LFP in the basal ganglia and cortical EEG in parkinsonian patients. We discuss the temporal patterning of the observed synchronized patterning. We show how the synchronization of EEG in motor and prefrontal areas (which can be obtained noninvasively) is predictive of the spike-LFP synchrony in subthalamic nucleus. We also consider the observed phenomena within the framework of mathematical models of cortico-basal ganglia circuits.
Uri Eden's lecture on tracking dynamic rhythms in the spiking of STN neurons using point process methods.