The Neuroscientist 1–14 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1073858415591964 nro.sagepub.com Hypothesis Introduction Based on clinical similarities between deep brain stimula- tion (DBS) at high frequencies (HFS; above 100 Hz) and radiofrequency lesions in patients with Parkinson’s dis- ease (PD), tremor, and dystonia, this technique was ini- tially suggested to induce a “functional inhibition” of the stimulated target (Benabid and others 1987). Supporting this theory, studies have shown that subthalamic nucleus (STN), globus pallidus internus (GPi), or thalamic HFS suppressed firing of neuronal populations surrounding the stimulation electrode (Anderson and others 2006; Boraud and others 1996; Filali and others 2004; Hamani and others 2010; Kiss and others 2002; Meissner and oth- ers 2005). In addition to this well-documented “target inhibition,” HFS has also been shown to increase electri- cal activity in nearby axonal projections (Hamani and Temel 2012; Hashimoto and others 2003; Johnson and others 2008; Miocinovic and others 2006). This mecha- nism would explain how DBS modulates activity in brain structures projecting to or receiving projections from the stimulated region. Though both theories are currently well accepted, it is becoming clear that the paradoxical dissociation “local inhibition” and “distant excitation” is far more complex than initially thought (Johnson and others 2008). For example, multiple neurotransmitter systems may be influenced by DBS (Fig. 1) (Hamani and Temel 2012). In addition, normal cell firing is substituted by stimulation- induced tonic high-frequency patterns that may ulti- mately “jam” the normal communication between structures. Despite the excitation of axonal pathways, both an increase in GABAergic tone and the jamming of circuits after HFS could lead to a reduction in neuronal 591964NRO XX X 10.1177/1073858415591964The NeuroscientistFlorence and others research-article 2015 1 Division of Functional Neurosurgery, Department of Neurology, Hospital das Clínicas, School of Medicine of the University of São Paulo, São Paulo, SP, Brazil 2 Department of Radiology and Oncology, School of Medicine of the University of São Paulo, São Paulo, SP, Brazil 3 Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada 4 Behavioural Neurobiology Laboratory and the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Corresponding Author: Clement Hamani, Centre for Addiction and Mental Health, 250 College Street, Room 270A, Toronto, Ontario, Canada M5T 1R8. Email: Clement.Hamani@camh.ca Deep Brain Stimulation: More Complex than the Inhibition of Cells and Excitation of Fibers Gerson Florence 1,2 , Koichi Sameshima 2 , Erich T. Fonoff 1 , and Clement Hamani 3,4 Abstract High-frequency deep brain stimulation (DBS) is an effective treatment for some movement disorders. Though mechanisms underlying DBS are still unclear, commonly accepted theories include a “functional inhibition” of neuronal cell bodies and the excitation of axonal projections near the electrodes. It is becoming clear, however, that the paradoxical dissociation “local inhibition” and “distant excitation” is far more complex than initially thought. Despite an initial increase in neuronal activity following stimulation, cells are often unable to maintain normal ionic concentrations, particularly those of sodium and potassium. Based on currently available evidence, we proposed an alternative hypothesis. Increased extracellular concentrations of potassium during DBS may change the dynamics of both cells and axons, contributing not only to the intermittent excitation and inhibition of these elements but also to interrupt abnormal pathological activity. In this article, we review mechanisms through which high extracellular potassium may mediate some of the effects of DBS. Keywords deep brain stimulation, Parkinson’s disease, potassium, depolarization block, axon, neuron by guest on July 7, 2015 nro.sagepub.com Downloaded from