Cortically Evoked Responses ofHuman Pallidal Neurons

Regarding Nishibayashi et al,1 a description of human pal-lidal neuronal responses to cortical stimulation, there are 2sets of concerns. First, the latencies of 22 ms are far longerthan reported elsewhere in laboratory animals, as noted bythe authors. Their explanation of longer conduction timesbased on larger human brain sizes is improbable. Theirlatencies are far longer than those reported in human studiesas well. Thalamic neuronal responses latencies to globus pal-lidus interna (GPi) deep brain stimulation (DBS) are approx-imately 3.5 ms.2 Reese et al3 reported latencies of GPineuronal responses to subthalamic nucleus (STN) DBS rang-ing from 0.265 to 1.0 ms.3 Further, STN DBS cortical-evoked potentials to single pulses demonstrate latencies ofmuch less than the 22 ms. The observations by Baker et al4

are particularly relevant, as the evoked potentials reflect an-tidromic activation of the cortical projections to the STNand thus reflect at least conduction velocities of some of thecomponents that Nishibayashi et al1 posited as mediatingthe pallidal neuronal responses.The range of latencies of GPi responses to STN DBS in

the study by Reese et al3 is much faster than antidromicresponses described above. Stimulus artifact could obscureearlier extracellular antidromic potentials in the other stud-ies; however, intracellular recordings in cortical neurons toSTN stimulation show latencies on the order of 2 6 0.5 msin the rodent.5 Rather, the response reported by Reese et al3

probably represents reentrant activities from DBS pulses ear-lier than the immediately preceding DBS pulse. The actuallatencies probably ranged from n*5.6 þ 0.265 ms to n*5.6þ 1 ms, where n is some integer and 5.6 ms is the intersti-mulus interval of 180 pps DBS. This is relevant, as theresponses described by Nishibayashi et al1 could reflect laterreentrant activity in the basal ganglia-thalamic-cortical sys-tem, which is very different from the presumption of anopen-loop feed-forward mechanism by Nishibayashi et al.1

The second concern relates to the attribution of the se-quential changes in neuronal activities to excitation, then in-hibition and then excitation from which they inferred asequence of orthodromic influences. This is an unwarrantedconclusion as there are alternatives that cannot be excludedbased on the data presented. These alternatives include re-fractory periods reducing neuronal activity following excita-tion and a post–refractory period of increased excitabilityproducing increased neuronal activity following the reduc-tion.2 At the least, alternatives should be considered.

Erwin Montgomery, Jr., MD*Department of Neurology, University of Alabama

at Birmingham, Birmingham, Alabama, USA*E-mail: emontgom@uab.edu

References1. Nishibayashi H, Ogura M, Kakishita K, et al. Cortically evoked

responses of human pallidal neurons recorded during stereotacticneurosurgery. Mov Disord 2011;26:469–476.

2. Montgomery EB, Jr. Effects of GPi Stimulation on Human ThalamicNeuronal Activity. Clin Neurophysiol 2006;117:2691–2702.

3. Reese R, Leblois A, Steigerwald F, et al. Subthalamic deep brainstimulation increases pallidal firing rate and regularity. Exp Neurol2011;229:517–521.

4. Baker K, Montgomery JrEB, Rezai AR, Burgess R, Luders HO. Sub-thalamic nucleus deep brain stimulus evoked potentials: physiologyand therapeutic implications. Mov Disord 2002;17:969–983.

5. Li S, Arbuthnott GW, Jutras1 MJ, Goldberg JA, Jaeger D. ResonantAntidromic Cortical Circuit Activation as a Consequence of High-Frequency Subthalamic Deep-Brain Stimulation. J Neurophysiol2007;98:3525–3537.

Reply: Cortically Evoked Responses ofHuman Pallidal Neurons

We thank Montgomery for his valuable comments on ourarticle.1 His first concern was that the latencies of corticallyevoked early excitation in the external (GPe) and internal(GPi) segments of the human globus pallidus (22 ms) werefar longer than those reported in animal and human studies.We have already discussed several reasons for the longerlatencies including the larger human brain size.1 Here, wewould like to add more details. Cortical stimulation inducessimilar triphasic responses that include early excitation, inhi-bition, and late excitation in the GPe and GPi of mice,2 rats,marmosets, and macaque monkeys.3 We plotted the latenciesof early excitation and inhibition in these animals2,3 and inhumans1 against their brain sizes (distances between the an-terior and posterior commissures), shown in Figure 1. Theobtained graph indicates a linear relationship between thelatencies and brain sizes (r2 ¼ 0.99, P < .01), suggestingthat the larger brain size in humans can well explain the lon-ger latencies. The early excitation in the GPe/GPi is consid-ered to be mediated by the cortico-subthalamo (STN)-GPe/GPi pathway.3 Janssen et al recently reported that the stimu-lation of the human primary motor cortex induced excita-tion in the STN at a latency of 10–50 ms,4 supporting ourstudy. We have also discussed other possibilities including

------------------------------------------------------------Relevant conflicts of interest/financial disclosures: Nothing to report.

Full financial disclosures and author roles may be found in the onlineversion of this article.

Published online 12 October 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23886

------------------------------------------------------------Relevant conflicts of interest/financial disclosures: Nothing to report.

Full financial disclosures and author roles may be found in the onlineversion of this article.

Published online 27 September 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23885

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different stimulus methods (cortical surface disk electrodesin our human study vs intracortical wire electrodes in animalstudies) and pathological changes associated with Parkin-son’s disease.1

Montgomery also pointed out that the cortically evokedinhibition and late excitation could be caused by refractoryperiods following early excitation and increased excitabilityafter refractory periods, respectively. However, this is lessprobable because GPe/GPi neurons are capable of high-fre-quency repetitive firing (up to 200–300 Hz) and have shortrefractory periods. Combined with a number of non-humanprimate studies,3,5 we can safely consider that these sequen-tial responses are evoked through different basal gangliapathways. Local injection of a glutamatergic blocker intothe STN attenuated the early excitation in the GPe/GPi with-out any effects on subsequent inhibition,3 GABAergicblocker injection into the GPi attenuated the inhibition inthe GPi without affecting early and late excitation,5 andGABAergic blocker injection into the GPe diminished thelate excitation in the GPi.5 Thus, cortically evoked early ex-citation, inhibition, and late excitation in the GPe/GPi aremediated by the cortico-STN-GPe/GPi, cortico-striato-GPe/GPi, and cortico-striato-GPe-STN-GPe/GPi pathways,respectively.

Hiroki Nishibayashi, MD, PhD,1*

Atsushi Nambu, MD, PhD,2

Yoshihisa Tachibana, DDS, PhD,2

and Toru Itakura, MD, PhD1

1Department of Neurological Surgery, WakayamaMedical University, Wakayama, Japan*E-mail: hirokin@wakayama-med.ac.jp

2Division of System Neurophysiology, NationalInstitute for Physiological Sciences and

Department of Physiological Sciences, GraduateUniversity for Advanced Studies, Okazaki, Japan

References1. Nishibayashi H, Ogura M, Kakishita K, et al. Cortically evoked

responses of human pallidal neurons recorded during stereotacticneurosurgery. Mov Disord. 2011;26:469–476.

2. Chiken S, Shashidharan P, Nambu A. Cortically evoked long-lastinginhibition of pallidal neurons in a transgenic mouse model of dysto-nia. J Neurosci. 2008;28:13967–13977.

3. Nambu A, Tokuno H, Hamada I, et al. Excitatory cortical inputs topallidal neurons via the subthalamic nucleus in the monkey. J Neu-rophysiol. 2000;84:289–300.

4. Janssen M, Zwartjes D, Temel Y, et al. Subthalamic responses tomotor cortex stimulation: selective targeting of the subthalamicmotor area. Society for Neuroscience, 2010, Program 459.11.

5. Tachibana Y, Kita H, Chiken S, Takada M, Nambu A. Motor corti-cal control of internal pallidal activity through glutamatergic andGABAergic inputs in awake monkeys. Eur J Neurosci. 2008;27:238–253.

Rapidly Progressing Diffuse LewyBody Disease

Among 83 patients with autopsy-confirmed diffuse Lewybody disease (DLBD), Gaig et al1 found 6 cases with rapiddisease progress (mean duration, 9 months), clinically pre-senting with delirium or dementia in 3 cases each. All pre-sented visual hallucinations, with parkinsonism occurring in4 and myoclonus in 3. Clinical diagnosis was Lewy bodydisorder and probable Creutzfeldt–Jakob disease (CJD) in 3cases each. Neuropathology revealed neocortical-diffusepathology in 4 cases and limbic (transitional) Lewy body–type pathology (LBP) in 2 cases. Five brains had additionalAlzheimer disease (AD)–type pathology, with Braak stagesranging from II to VI. PrP immunohistochemistry was nega-tive in all cases. Four had concomitant mild amyloid angiop-athy, and 1 small-vessel pathology. Hence, neuropathologystudies did not identify any particular feature that could dif-ferentiate rapidly progressive DLBD from classical forms ofthe disease. These data can be confirmed by personal studiesin 90 patients with autopsy-confirmed DLBD observed inthe collection of the Institute of Clinical Neurobiology,Vienna, Austria. We found 9 cases (8 women, 1 man; agerange, 64–88 years; mean, 74.2 years), with a durationof disease from onset of symptoms to death between 3 and16 months (mean, 10.7 months), compared with classicalcases, with a disease duration between 2 and 26 years(mean, 8.1 year). The clinical diagnosis in the rapidly pro-gressing cases was Parkinson’s disease dementia in 8 andprobable CJD in 1. Seven patients presented visual

------------------------------------------------------------Kurt A. Jellinger and Johannes Attems contributed equally to this article.

*Correspondence to: Kurt A. Jellinger, Institute of Clinical Neurobiology,Vienna, Austria; kurt.jellinger@univie.ac.at

Funding agencies: Research related to this article was partly funded bythe Society for Support of Research in Experimental Neurology, Vienna,Austria.

Relevant conflicts of interest/financial disclosures: Nothing to report.

Full financial disclosures and author roles may be found in the onlineversion of this article.

Published online 28 October 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23976

L E T T E R S : P U B L I S H E D A R T I C L E S

FIG. 1. Latencies of cortically evoked early excitation and inhibition inGPe and GPi neurons of mice,2 rats (Chiken et al, personal communi-cation, used with their permission), marmosets (Koketsu et al, perso-nal communication, used with their permission), macaque monkeys,3

and humans1 are plotted against distances between the anterior andposterior commissures (AC-PC).

2584 Movement Disorders, Vol. 26, No. 14, 2011

hallucinations or illusions, early dementia occurred in 5, par-kinsonism in all, and myoclonus in 2. Neuropathologyrevealed limbic (transitional) LBP in 8 and diffuse-neocorti-cal LBP in 1, corresponding to Lewy body Braak stages Vand VI.2 No unusual or atypical findings regarding extensionand severity of LBP were detected. All brains had additionalAD-type pathology, with Braak stages ranging from II to V(stage II, n ¼ 3; stage IV, n ¼ 4; stages III and V, n ¼ 1each). Six brains had concomitant mild (n ¼ 4) to severe (n¼ 2) amyloid angiopathy, and 3 had a lacunar state in thebasal ganglia and/or white matter, which did not differ fromconcomitant lesions in DLBD cases with longer disease dura-tion. PrP immunohistochemistry was negative in all cases;gene studies were not performed.In conclusion, these and the data from the Barcelona

group1 confirm that DLBD with and without additionalAD and other concomitant pathologies may cause rapid PDand dementia progression, in about 7%–10% of autopsy-confirmed DLBD cases neuropathology showing no particu-lar features that could differentiate rapidly progressing fromclassical forms of DLBD.

Kurt A. Jellinger, MD1* and Johannes Attems, MD2

1Institute of Clinical Neurobiology,Vienna, Austria

2Institute for Ageing and Health,Newcastle University, Wolfson Research Center

Campus for Ageing and Vitality,Newcastle upon Tyne, United Kingdom

References1. Gaig C, Valldeoriola F, Gelpi E, et al. Rapidly progressive diffuse

Lewy body disease. Mov Disord. 2011;26:1316–1323.

2. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, BraakE. Staging of brain pathology related to sporadic Parkinson’s dis-ease. Neurobiol Aging. 2003;24:197–211.

Reply: Rapidly Progressing DiffuseLewy Body Disease

We thank Professor Jellinger and Dr. Attems for their in-terest in our article in which we report 6 patients withpathologically proven diffuse Lewy body disease (DLBD)presenting clinically with rapidly progressive dementia or de-lirium leading to death in fewer than 18 months.1 These 6

------------------------------------------------------------*Correspondence to: Carles Gaig, Neurology Service, Hospital Clınic ofBarcelona, Barcelona, Spain; cgaig@clinic.ub.es

Funding agencies: This work was supported in part by the Centro deInvestigacion Biomedica en Red sobre EnfermedadesNeurodegenerativas (CIBERNED).

Relevant conflicts of interest/financial disclosures: Nothing to report.

Full financial disclosures and author roles may be found in the onlineversion of this article.

Published online in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/mds.23981

L E T T E R S : P U B L I S H E D A R T I C L E S

patients were identified among 83 patients with DLBD fromthe Neurological Tissue Bank Hospital Clınic–Universitat ofBarcelona. In 36 of them the clinical diagnosis was Parkin-son’s disease (PD)—25 of them with dementia—and in theremaining 47 patients, the clinical picture was consistentwith that of dementia with Lewy bodies. None of the 36 PDcases presented a rapidly progressive course. We appreciatethe observations provided by Professor Jellinger and Dr.Attems, which confirm and extend the findings reported inour article. Among 90 patients with pathologically provenDLBD from the collection of the Institute of Clinical Neuro-biology, Vienna, Professor Jellinger and Dr. Attems identi-fied 9 cases with a rapidly progressing clinical course.2

Interestingly, and in contrast to our findings, the clinical di-agnosis was PD with dementia in 8 of these 9 patients, indi-cating that a rapid progression of DLBD can also occur inpatients presenting clinically as PD. In fact, there arereported in the literature patients with a long-lasting historyof PD who develop rapidly progressive dementia and showpathological changes at postmortem typical of DLBD.3 Theauthors were also unable to identify any additional or specificpathologic feature in their rapidly progressing cases whencompared with cases with classical DLBD. Rapidly progres-sive DLBD may not be a rare condition, but the relativelyhigh frequency of rapidly progressing cases found in these 2series of pathologically proven DLBD (7% and 10%)1,2

should be interpreted with caution because brain bank–basedseries may be prone to referral bias for those atypical cases.Additional studies are needed to clarify the biological mecha-nism underlying this atypical presentation of DLBD.

Carles Gaig, MD, PhD,1,2* Francesc Valldeoriola, MD, PhD1

Ellen Gelpi, MD, PhD,2 Mario Ezquerra, PhD,1

Sara Llufriu, MD,1 Mariateresa Buongiorno, MD,1

Maria Jesus Rey, MD, PhD,2 Maria Jose Martı, MD, PhD,1

Francesc Graus, MD, PhD,1,2 and Eduardo Tolosa, MD, PhD1

1Neurology Service, Hospital Clınic of Barcelona,Barcelona, Spain

2Neurological Tissue Bank, Universitat ofBarcelona-Hospital Clınic Barcelona,

Spain Centro de Investigacion Biomedica en Redsobre Enfermedades Neurodegenerativas

(CIBERNED), Barcelona, Spain

References1. Gaig C, Valldeoriola F, Gelpi E, et al. Rapidly progressive diffuse

Lewy body disease. Mov Disord. 2011;26:1316–1323.

2. Jellinger KA, Attems J. Rapidly progressing diffuse Lewy body dis-ease. Mov Disord. 2011.

3. Momjian-Mayor I, Pizzolato GP, Burkhardt K, Landis T, CoeytauxA, Burkhard PR. Fulminant Lewy body disease. Mov Disord. 2006;21:1748–1751.

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