title: Brain (Hyper)Excitability Revealed by Optimal Electrical Stimulation of GABAergic Interneurons.
abstract: Neurological disorders are often characterized by an excessive and prolonged imbalance between neural excitatory and inhibitory processes. An ubiquitous finding among these disorders is the disrupted function of inhibitory GABAergic interneurons.
  
  
  
  The objective is to propose a novel stimulation procedure able to evaluate the efficacy of inhibition imposed by GABAergic interneurons onto pyramidal cells from evoked responses observed in local field potentials (LFPs).
  
  
  
  Using a computational modeling approach combined with in vivo and in vitro electrophysiological recordings, we analyzed the impact of electrical extracellular, local, bipolar stimulation (ELBS) on brain tissue. We implemented the ELBS effects in a neuronal population model in which we can tune the excitation-inhibition ratio and we investigated stimulation-related parameters. Computer simulations led to sharp predictions regarding: i) the shape of evoked responses as observed in local field potentials, ii) the type of cells (pyramidal neurons and interneurons) contributing to these field responses and iii) the optimal tuning of stimulation parameters (intensity and frequency) to evoke meaningful responses. These predictions were tested in vivo (mouse). Neurobiological mechanisms were assessed in vitro (hippocampal slices).
  
  
  
  Appropriately-tuned ELBS allows for preferential activation of GABAergic interneurons. A quantitative neural network excitability index (NNEI) is proposed. It is computed from stimulation-induced responses as reflected in local field potentials. NNEI was used in four patients with focal epilepsy. Results show that it can readily reveal hyperexcitable brain regions.
  
  
  
  Well-tuned ELBS and NNEI can be used to locally probe brain regions and quantify the (hyper)excitability of the underlying brain tissue.
authors: INSERM U1099, LTSI, Rennes, France; Université de Rennes 1, LTSI, Rennes, France. Electronic address: fabrice.wendling@univ-rennes1.fr.
authors: F
authors: F
authors: Wendling
authors: Brain Research Institute, Zurich, Switzerland.
authors: U
authors: U
authors: Gerber
authors: Université de Rennes 1, LTSI, Rennes, France.
authors: D
authors: D
authors: Cosandier-Rimele
authors: Neurology Department, Functional Explorations Department, Epilepsy Surgery Unit, CHU, Rennes, France.
authors: A
authors: A
authors: Nica
authors: INSERM U1099, LTSI, Rennes, France; Université de Rennes 1, LTSI, Rennes, France.
authors: J
authors: J
authors: De Montigny
authors: Brain Research Institute, Zurich, Switzerland.
authors: O
authors: O
authors: Raineteau
authors: Foundation of Epilepsy Institutions of the Netherlands (SEIN), Heemstede, The Netherlands.
authors: S
authors: S
authors: Kalitzin
authors: Center of Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, The Netherlands.
authors: F
authors: F
authors: Lopes da Silva
authors: INSERM U1099, LTSI, Rennes, France; Université de Rennes 1, LTSI, Rennes, France.
authors: P
authors: P
authors: Benquet
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000502:physiology*; D004558:Electric Stimulation / Q000379:methods*; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology*; D006801:Humans; D007395:Interneurons / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D055815:Young Adult
keywords: Computational model; Depth-EEG; Electrical; Epilepsy; Excitability; Extracellular bipolar direct stimulation; GABAergic interneuron; In vitro; In vivo; Local field potential; Neuronal network; Neurostimulation