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ARTICLES: R. Hilker, J. Voges, T. Weber, L. W. Kracht, J. Roggendorf, S. Baudrexel, M. Hoevels, V. Sturm, and W. D. Heiss STN-DBS activates the target area in Parkinson disease Neurology 2008; 0: 01.wnl.0000312380.01852.77v1 [Abstract]

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STN-DBS activates the target area in Parkinson disease

Erwin B. Montgomery Jr. MD   (9 December 2008)

Reply from the author

Ruediger Hilker   (9 December 2008)

STN-DBS activates the target area in Parkinson disease 9 December 2008
Erwin B. Montgomery Jr. MD, University of Wisconsin-Madison H6/538 CSC, 600 Highland Ave., Madison, WI, 53792 Send Correspondence to journal: Re: STN-DBS activates the target area in Parkinson disease montgomery{at}neurology.wisc.edu Erwin B. Montgomery Jr. MD	Hilker et al. provide important neurometabolic imaging evidence that subthalamic (STN) Deep Brain Stimulation (DBS) does not inhibit the stimulated target and drives activity in downstream structures reflecting increased synaptic input to the downstream structures. [1] These findings are consistent with neuronal action potentials recorded in non-human primates and in humans in response to STN and globus pallidus internal segment (GPi) DBS. [2] However, the authors narrow the regions of interest to the STN and globus pallidus (GP) which belies the more widespread propagation of neuronal activities throughout the entire basal ganglia-thalamic-cortical (BG-Th-Ctx) system in response to DBS. This includes antidromic activation of cortical neurons projecting to STN and antidromic activation of ventrolateral (VL) thalamic neurons which assuredly orthodromically activates motor cortical neurons during GPi DBS. [2] Furthermore, these effects are propagated to the striatum and globus pallidus external segment. [2] A narrow focus could cause a preoccupation with the local effects of DBS which has characterized the majority of research. This may neglect investigation of a systems-wide effect which may better explain why DBS of nearly every structure in the BG-Th-Ctx system is effective to some degree. The exception is DBS of the putamen which has not been attempted. The article and the accompanying editorial did not sufficiently emphasize the important implication of the results. [1,3] Their evidence of increased GP activity and by others more specific to GPi [2] demonstrate that a Parkinson pathophysiology causally related to increased GPi activity is not tenable [4] although this notion still exists. Furthermore, the derivative theory of basal ganglia physiology where the GPi serves to inhibit unwanted movements, the Focused Attention/Action Selection theory, is also no longer tenable. [4] If the role of GPi activity is to suppress movements, then STN and GPi DBS should worsen bradykineisa rather than improve it. Hypotheses about how increased and regularized activity in the BG-Th- Ctx system improves function have gone beyond the vague notion of “jamming” and include overwriting of misinformation to no information and to resonance application of the signal-to-noise ratio in the BG-Th-Ctx system. [2] There is an important caveat to neurometabolic imaging. There is evidence that antidromic activation does not increase metabolic markers while orthodromic activation does. [5] As antidromic activations may play a large role in the DBS therapeutic mechanisms of action, this role may not be detected by neurometabolic imaging. [2] References 1. Hilker R, Voges J, Weber T et al. STN-DBS activates the target area in Parkinson disease: An FDG-PET study. Neurology 2008;71:708-713. 2. Montgomery EBJ, T. GJ. Mechanisms of action of Deep Brain Stimulation (DBS). Neuroscience and Biobehavioral Reviews 2008;32:388–407. 3. Martin WRW, Wieler M. Subthalamic nucleus stimulation in Parkinson disease: exciting or depressing? Neurology 2008;71:704-705. 4. Montgomery EBJ. Basal ganglia physiology and pathophysiology: a reappraisal. Parkinsonism and Related Disorders 2007;13:455-465. 5. Logothetis NK. The ins and outs of fMRI signals. Nature Neuroscience 2007:1230-1232. Disclosures: Research grant from Medtronic Neuromodulation Inc. Consultant to Advanced Neuromodulation Systems.
Reply from the author 9 December 2008
Ruediger Hilker, Department of Neurology, Goethe University Schleusenweg 2-16, 60528 Frankfurt, Germany Send Correspondence to journal: Re: Reply from the author hillker{at}med.uni-frankfurt.de Ruediger Hilker	We thank Dr. Montgomery for his comments on our paper. We wish to respond as follows: 1. We fully agree that a comprehensive way to investigate the effects of deep brain stimulation (DBS) on the human brain is a network-based analysis of neuronal activity changes free from prejudices due to a priori region selection. However, we believe that the investigation of stimulation effects on the local target and directly related projection sites as described in our paper is an important first step in the understanding of DBS primary mechanism of action and constitutes the base for further network analyses. This does not mean that we neglect the value of voxel-based functional imaging approaches which allow to investigate the entire brain and which have already been published by us and several other groups. [1,6-8] 2. Since the local FDG uptake is primarily determined by the afferent trans-synaptic input, we argued in the discussion section that the increased PET signal in the globus pallidus (GP) most likely results from antidromic activation of STN-GP fibers by DBS. However, this does not essentially imply an increased neuronal activity of GP neurons because the net effect of trans-synaptic processes on GP neuron firing rates are not known and not directly accessible to the PET technique. Independent from these considerations, we agree with Montgomery that the role of GP activity in the pathophysiology of hyper- and hypokinetic movement disorders is conflicting and not well explained by current models of basal ganglia functioning. 3. It is surely correct that the term “neuronal jamming” is not more than a vivid description of DBS effects on neuronal activity and, therefore, somewhat global, vague and oversimplifying. However, limitations of manuscript length did not allow us to go into deeper discussion of this detail. 4. We demonstrated that FDG PET is able to detect strong local and remote metabolic activation of neurons by STN stimulation which most likely results from antidromic fiber excitation in several brain regions. [1,8] As Logothetis pointed out, an increase of metabolic activity is mostly dependent on the activation of presynaptic axon terminals where the highest density of respiratory chain enzymes can be found. [5] Thus, we are convinced that antidromic trans-synaptic processing of DBS-modulated neuronal activity involves these terminals and leads, possibly among other factors, to the observed PET changes. References 6. Asanuma K, Tang C, Ma Y, et al. Network modulation in the treatment of Parkinson's disease. Brain 2006;129:2667-2678. 7. Campbell MC, Karimi M, Weaver PM, et al. Neural correlates of STN DBS-induced cognitive variability in Parkinson disease. Neuropsychologia 2008;46:3162-3169. 8. Hilker R, Voges J, Weisenbach S, et al. Subthalamic Nucleus Stimulation Restores Glucose Metabolism in Associative and Limbic Cortices and in Cerebellum: Evidence from a FDG-PET Study in Advanced Parkinson's Disease. J Cereb Blood Flow Metab 2004;24:7-16. Disclosure: The authors report no disclosures.