Interfacing basal ganglia models and Parkinson’s disease phenomenology: How can we translate the findings of electrophysiological studies from research to clinic Matteo Bologna a,⇑ , Maja Kojovic b,c a Neuromed Institute (IRCCS), Pozzilli (IS), Italy b Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, UK c Department of Neurology, University of Ljubljana, Slovenia article info Article history: Available online 23 June 2012 Keywords: Parkinson’s disease Basal ganglia Electrophysiology Transcranial magnetic stimulation abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non- motor symptoms. There are several models both of basal ganglia (BG) function and their dysfunction in PD. Degeneration of the nigrostriatal dopaminergic pathway is the key pathological feature of PD, lead- ing to classical motor symptoms, such as bradykinesia and rigidity. A dysfunction of structures other than BG, including cerebellum and brainstem, may be involved in the generation of tremor and axial symp- toms, while the degeneration of non-dopaminergic neurotransmitter systems is a likely contributing fac- tor of non-motor symptoms. BG models provide hypotheses testable by electrophysiological research in humans. In PD patients with implanted deep brain stimulators, activity from BG nuclei, i.e. the subtha- lamic nucleus the internal pallidal segment, and from the peduncolopontine nucleus may be directly recorded using depth electrodes. Non-invasive electrophysiological techniques allow the investigation of dysfunctional BG through interconnections with motor cortical areas, brainstem and spinal structures. Electrophysiological studies have revealed functional abnormalities at every level of the central nervous systems, including BG nuclei, motor cortex, cerebellum, brainstem and spinal cord. Despite the progress in electrophysiological characterization of PD, with particular advances in understanding the role of path- ological BG oscillatory activity in generating bradykinesia, there is still a large gap in understanding the pathophysiological relevance of other electrophysiological findings in PD. Better insight into the relation- ship between electrophysiological abnormalities and motor and non-motor symptoms in PD is likely to have important clinical implications. Ó 2012 Elsevier GmbH. All rights reserved. Introduction Parkinson’s disease (PD) is a progressive neurodegenerative dis- order characterized by a variety of motor and non-motor symp- toms [1]. Among the motor symptoms, bradykinesia and rigidity can be readily reversed by L-dopa administration or deep brain stimulation (DBS), suggesting that they are directly caused by dopaminergic deficit and basal ganglia (BG) dysfunction. By con- trast, tremor, axial symptoms and most of the non-motor symp- toms of PD, are not fully L-dopa responsive, suggesting that a deficiency of other neurotransmitters and/or dysfunction of struc- tures other than BG have a role in generating these symptoms. Fi- nally, some symptoms of PD are related to dopaminergic replacement, such as L-dopa induced dyskinesias (LIDs) and im- pulse control disorders (ICD) [2]. There are a number of anatomical and functional models of the BG and several models of BG dysfunction in PD. According to the influential anatomical model of Alexander and DeLong, the BG are viewed as components of parallel and segregated circuits that sub- serve motor, cognitive and limbic functions [3,4]. The striatum is the main input structure of the BG and it is connected to the BG out- put nuclei, i.e. the internal pallidal segment (GPi) and the substantia nigra pars reticulata through the so called ‘‘direct’’ and ‘‘indirect’’ pathways [3,4]. According to the firing rate model, striatal dopa- mine deficit leads to decreased activation of the direct pathway and increased activation of the indirect pathway, resulting in a net increased activation of the inhibitory BG output. This in turn leads to an increased inhibition of thalamic nuclei and intercon- nected cortical areas and brainstem structures [3,4]. The firing rate model also predicts that LIDs result from reduced neuronal firing in the GPi due to release of the inhibitory external pallidum (GPe) and 2210-5336/$ - see front matter Ó 2012 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.baga.2012.05.007 Abbreviations: BG, basal ganglia; CNS, central nervous system; CSP, cortical silent period; DBS, deep brain stimulation; EEG, electroencephalography; GPe, external pallidal segment; GPi, internal pallidal segment; ICD, impulse control disorders; LIDs, L-dopa induced dyskinesias; PAS, paired associative stimulation; PD, parkinson disease; PPN, peduncolopontine nucleus; STN, subthalamic nucleus; TBS, theta burst stimulation; TMS, transcranial magnetic stimulation. ⇑ Corresponding author. Address: Neuromed Institute (IRCCS), Via Atinense, 18, 86077 Pozzilli (IS), Italy. Tel./fax: +39 0649914700. E-mail address: matteo.bologna@uniroma1.it (M. Bologna). Basal Ganglia 2 (2012) 189–193 Contents lists available at SciVerse ScienceDirect Basal Ganglia journal homepage: www.elsevier.com/locate/baga