Dysosmia in PD (Parkinson’s Disease) may result from changes in the olfactory apparatus or in structures involved in olfactory perception. Previous work1,2 has suggested that deep brain stimulation (DBS) pa-tients have improved odor discrimination in stimulation-on/medication-off state in comparison to their own scores in a stimulation-off/medication-off state. What remains unclear is whether it is the ON state itself or an effect of stimulation that leads to improved olfaction. In this study we evaluate dysosmia in two PD cohorts in the ON state, those treated with medication alone and those treated with medication and DBS.
A prospective study geared at improving predictive value of olfactory testing with a battery of psychological tests enrolled 45 PD patients and 44 controls. Of the PD patients, 9 had bilateral STN (subthalamic nucleus) DBS and 36 were medically treated. Subset analysis of PD patients with and without DBS placement revealed no difference in apathy or depression. DBS patients had better olfaction on UPSIT (Univ of Pennsylvania Smell Identification Test) (p
This study provides further data that DBS patients have improved ol-faction. It also provides preliminary evidence that DBS with medica-tion improves dysosmia to a greater extent than medication alone. This may result from indirect stimulation of olfactory processing cen-ters or changes in olfactory circuitry metabolism

Burrows, Anthony M

Dundamadappa, Sathish Kumar

King, Jean

Linton Peters, Mary

Novak, Peter

Pilitsis, Julie G.

Ravin, Paula

Swearer, Joan

English

eScholarship@UMMS

Neurological Bulletin Volume 2 Issue 1 Article 1 December 2010 DBS-implanted Parkinson's Disease Patients Show Better Olfaction Than Those Treated Medically Mary Linton Peters University of Massachusetts Medical School Paula Ravin University of Massachusetts Medical School Peter Novak University of Massachusetts Medical School Anthony M. Burrows University of Massachusetts Medical School Joan Swearer University of Massachusetts Medical School See next page for additional authors Follow this and additional works at: https://escholarship.umassmed.edu/neurol_bull Recommended Citation Linton Peters M, Ravin P, Novak P, Burrows AM, Swearer J, King J, Dundamadappa SK, Pilitsis JG. DBS-implanted Parkinson's Disease Patients Show Better Olfaction Than Those Treated Medically. Neurological Bulletin 2010;2:1-6, http://dx.doi.org/10.7191/neurol_bull.2010.1016 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Neurological Bulletin by an authorized administrator of eScholarship@UMMS. For more information, please contact Lisa.Palmer@umassmed.edu. DBS-implanted Parkinson's Disease Patients Show Better Olfaction Than Those Treated Medically Authors Mary Linton Peters, Paula Ravin, Peter Novak, Anthony M. Burrows, Joan Swearer, Jean King, Sathish Kumar Dundamadappa, and Julie G. Pilitsis This article is available in Neurological Bulletin: https://escholarship.umassmed.edu/neurol_bull/vol2/iss1/1 Neurol. Bull. 2: 1-6, 2010 doi:10.7191/neurol_bull.2010.1016   Abstract  Dysosmia in PD (Parkinson’s Disease) may result from changes in the olfactory apparatus or in structures involved in olfactory perception. Previous work1,2 has suggested that deep brain stimulation (DBS) pa-tients have improved odor discrimination in stimulation-on/medication-off state in comparison to their own scores in a stimulation-off/medication-off state.  What remains unclear is whether it is the ON state itself or an effect of stimulation that leads to improved olfaction. In this study we evaluate dysosmia in two PD cohorts in the ON state, those treated with medication alone and those treated with medication and DBS.   A prospective study geared at improving predictive value of olfactory testing with a battery of psychological tests enrolled 45 PD patients and 44 controls.  Of the PD patients, 9 had bilateral STN (subthalamic nucleus) DBS and 36 were medically treated. Subset analysis of PD patients with and without DBS placement revealed no difference in ap-athy or depression.  DBS patients had better olfaction on UPSIT (Univ of Pennsylvania Smell Identification Test)  (p<0.05).  No difference was noted in disease severity, gender, smoking status, medication dosing, use of dopamine agonists, or maximal olfactory sulcus depth on MRI.  DBS patients were significantly younger, however inter-group differences in UPSIT scores exceeded those seen in our control cohort with similar ages.   This study provides further data that DBS patients have improved ol-faction.  It also provides preliminary evidence that DBS with medica-tion improves dysosmia to a greater extent than medication alone.  This may result from indirect stimulation of olfactory processing cen-ters or changes in olfactory circuitry metabolism.    DBS-implanted Parkinson's Disease Patients Show Better Olfaction Than Those  Treated Medically  Mary Linton Peters, Paula Ravin, Peter Novak,  Anthony M. Burrows, Joan Swearer, Jean King,  Sathish Kumar Dundamadappa, and Julie G. Pilitsis  Department of Surgery, Division of Neurosurgery University of Massachusetts Medical School, Worcester, MA  Correspondence to Julie Pilitsis: julie.pilitsis@umassmemorial.org  Keywords: Parkinson’s Disease, olfaction, deep brain stimulation 1 http://escholarship.umassmed.edu/neurol_bull Linton Peters et al.: DBS-implanted Parkinson's Disease PatientsNeurol. Bull. 2: 1-6, 2010 doi:10.7191/neurol_bull.2010.1016  Introduction  Deep brain stimulation (DBS) is used in the treatment of Parkinson’s Disease (PD), and has been shown to improve motor symptoms to a greater extent than optimal medical ther-apy in selected patients.3  In addition to mo-tor symptoms, PD is characterized by a set of autonomic, cognitive, and emotional non-motor symptoms.  Olfaction is lost early in the disease process of idiopathic PD.  A 2006 practice parameter statement regarding the diagnosis of PD concluded that olfaction testing could help to differentiate new-onset idiopathic PD from other Parkinsonian syn-dromes.4,5  Our study was designed to test several sur-veys of non-motor symptoms of PD for their potential as diagnostics in an office-based setting.  The University of Pennsylvania Smell Identification Test (UPSIT)6 differs from other olfactory tests because of its abil-ity to be self-administered and its everyday relevance.  It is a 40-question forced choice scratch-and-sniff test in which fewer than 18 correct answers indicates anosmia.  Among the 45 PD patients recruited for the study, nine had received bilateral subthalamic nu-cleus (STN) deep brain stimulation.  This analysis investigates the difference in non-motor symptoms, particularly olfaction, be-tween patients treated medically and those treated with medical therapy combined  with DBS.   Methods  After obtaining permission from the Institu-tional Review Board, subjects were recruited from the neurology, surgery, and otolaryn-gology clinics at U Mass University Hospital and provided written informed consent.  All subjects were free of cognitive impairment and of ongoing respiratory infections.  Pa-tients were determined by their treating neu-rologist to have a diagnosis of idiopathic PD7 of Hoehn and Yahr stage 1-3, and to be free of confounding psychiatric disorders.  Con-trols were determined by their treating physi-cian to be free of PD and psychiatric disor-ders.  Within the patient group, 9 subjects had bilateral DBS placement in the STN.  Subjects completed four surveys: UPSIT,6 the Beck Depression Inventory (BDI),8 the Apathy Evaluation Scale – Self-administered version (AES),9 and the UK Parkinson’s Dis-ease Society non-motor symptoms assess-ment questionnaire (PDS).10  All surveys were self-administered in writing following written instructions.  A research assistant was available to answer questions if necessary.  Olfaction re-testing was performed with 5 of the 9 DBS patients in a stimulator-off/medication-on state.  During these tests, the DBS stimulators were off for a minimum of 30 minutes.  Medication use was not varied.  Comparisons were analyzed with chi-square,  2 Table 1 DBS  (n=9) Medically treated (n=36) p-value Age 61   (55-68) 71   (53-88) 0.01 Hoehn and Yahr Stage 2.83   (2-3) 2.44   (1-3) 0.07 Age at Disease Onset* 46 63 0.003 Duration of Disease* 15 8 0.002 % Female 33 % 22 % 0.49 Current Smokers 0 % 6 %   Past Smokers 22 % 31 %              * Disease onset information is not available for 9 study participants  Linton Peters et al.: DBS-implanted Parkinson's Disease PatientsNeurol. Bull. 2: 1-6, 2010 doi:10.7191/neurol_bull.2010.1016   t-test, logistic regression, and linear regres-sion calculations performed in Microsoft Ex-cel (Microsoft Corp, version 11) and STATA (StataCorp, version 10); p< 0.05 was consid-ered statistically significant.  Results  All four of the tested surveys were shown to be significantly better in the age-matched control group without PD than the PD dis-ease group.  Olfaction in particular was shown to be significantly poorer in the PD group, and to have sufficient predictive value to be useful as a diagnostic tool (results not shown).  Within the PD group, 9 patients had received bilateral STN DBS (Table 1).  The DBS pa-tients were younger than the medically treat-ed group (average age 61 vs. 71), and had more severe disease (Hoehn and Yahr stage 2.83 vs. 2.44).  The DBS patients also demonstrated an earlier age of disease onset and longer disease duration.    The DBS group showed significantly im-proved olfaction (mean 19.1 ± 6.7) compared  to the medically-treated group (mean 14.5 ± 5.5, p < 0.05) (Figure 1).  In contrast, the DBS group showed more general non-motor symptoms (mean 13.0 ± 4.2) compared to the medically-treated group (mean 8.9 ± 5.7, p =  3   Figure 1 (on left):  Olfaction in DBS and Medically-Treated PD Patients  Figure 2 (on right):  PDS Score in DBS and Medically-Treated PD Patients  0510152025303540UPSIT ScoreDBS Medical 051015202530PDS Non-Motor ScoreDBS Medical Linton Peters et al.: DBS-implanted Parkinson's Disease PatientsNeurol. Bull. 2: 1-6, 2010 doi:10.7191/neurol_bull.2010.1016   0.05) (Figure 2).  The other two surveys, of depression and apathy, were not significantly different between the two groups.  Logistic regression yielded olfaction odds ratio of 1.13 (1.00-1.29, p = 0.04) and a non-motor odds ratio of 1.14 (0.99 – 1.32, p = 0.05).  Further analysis was conducted to assess the impact of demographic variability on olfacto-ry and non-motor systems testing.  Linear regression conducted on the results using both age and gender as dependent variables yielded an r-squared effect size of 15%.    We created age and gender matched groups by selecting only those patients between the ages of 50 and 69 with Hoehn and Yahr scores of 2.5 or above (Table 2).  In these similar groups, the differences in olfaction and non-motor symptoms remained signifi-cant (olfaction p < 0.05, non-motor p = 0.05).  We then investigated the role of stimulation in olfactory processing by retesting 5 of the 9 DBS patients in a stimulator-off/medication-on state.  As a group, their olfaction was the same.    Conclusions  There are a number of reasons why olfaction may be different between the DBS/medication and medication alone cohorts.  In   part, the difference between our two groups may be a result of changes in metabolism either in the striatum, other basal ganglia are-as, or potentially in other regions of the brain.  Changes in metabolism in the striatum and thalamus in PD is complex and involves alterations in receptor availability as well as neurotransmitter processing.11  Studies in rats with 6-hydroxydopamine lesioning have shown a number of changes in metabolism with prolonged high frequency stimulation (HFS), including normalization of COX lev-els in the substantia nigra with HFS.12  In the same model, Cytochrome oxidase I mRNA levels in cortical regions have also shown to normalize following HFS.13  HFS has thus been implicated in altered transcription and signaling in both cortex and basal ganglia.  It is plausible that long term HFS stimulation could similarly affect regions associated with olfaction including the amygdala and olfacto-ry nucleus.    Alternatively, the improvement in olfaction with DBS may be due to indirect stimulation of olfaction processing centers.  A recent study using 18-fluorodeoxyglucose PET in PD patients with DBS has shown that nor-malized resting cerebral metabolic rates of glucose increase with DBS around the elec-trode, as well as in the center of the STN and the globus pallidus.14  Furthermore, a recent study in a rat model of PD suggests that cor-4              Table 2 DBS subset (n=8) Medically treated  subset (n=11) Age 62   (55-68) 63   (53-68) Hoehn and Yahr Stage 2.94   (2.5-3) 2.77   (2.5-3) % Female 38 % 27 % Linton Peters et al.: DBS-implanted Parkinson's Disease PatientsNeurol. Bull. 2: 1-6, 2010 doi:10.7191/neurol_bull.2010.1016   Our study is inherently limited by its small size.  The DBS group is smaller, and there are demographic differences in age and gen-der.  Olfaction is known to degrade with age, and the DBS group is younger than the medi-cally-treated group.18  Olfaction is also known to differ by gender, as women typi-cally have increased UPSIT scores.18  We attempted to address this difference both through linear regression analysis and crea-tion of an age and gender matched subset, but neither approach excludes the possibility of an underlying confounding factor.  In ad-dition, our study population exhibited a broad range of disease duration, which could be linked to severity of both motor and non-motor symptoms.     In conclusion, we believe that this study pro-vides preliminary evidence that patients with DBS have better olfaction than patients treat-ed medically.  This stands in contrast to other non-motor symptoms that are worse in the DBS patients.    References  1. Guo X, Gao G, Wang X, et al.  Effects of bilateral deep brain stimulation of the subthalamic nucleus on olfactory func-tion in Parkinson’s disease patients. Ste-reotact Funct Neurosurg 2008;86:237-244. 2. Hummel T, Jahnke U, Sommer U, Reich-mann H, Müller A.  Olfactory function in patients with idiopathic Parkinson’s dis-ease: effects of deep brain stimulation in the subthalamic nucleus.  J Neural Transm 2005;112:669-676. 3. Weaver FM, Follett K, Stern M, et al.  Bi-lateral deep brain stimulation vs best med-ical therapy for patients with advanced Parkinson disease: a randomized con-trolled trial.  JAMA 2009;301:63-73. 4. Suchowersky O, Reich S, Perlmutter J, tical electrical activity can be altered by STN HFS,15 providing evidence that DBS affects brain circuitry locally and globally.  Thus, stimulation may potentially have an effect on thalamocortical circuits involved in pro-cessing olfaction signals.  Olfaction in a sub-set of the DBS cohort was the same in the stimulation-off/medication-on state as the stimulation-on/medication-on state.  This may suggest that olfactory circuit stimulation has a longer response time than thirty minutes. Prior studies have suggested that differences observed in olfaction may be re-lated to the cognitive processing of olfaction as opposed to the physical detection of odors.1,2    Finally, the possibility remains that these dif-ferences may reflect an epiphenomenon.  This study is limited in that it is a small sam-ple with confounding variables.  We have attempted to investigate several of these po-tential confounding factors.  First we exam-ined the role of dopaminergic therapy.  Pre-vious studies have shown that the use of do-pamine agonists has not been shown to corre-late to olfaction.16  We confirmed this result in our subset.  In this study, the DBS group did have a higher average use of dopamine agonists, however most of this difference was due to a single outlier with very signifi-cant dosing.  The remainder of the group is comparable to those treated solely with med-ical therapy.  The DBS group had an earlier disease onset, which may indicate a genetic component to their disease state.  There is evidence that young-onset PD patients dis-play similar non-motor symptoms to later-onset patients but have worsened olfaction. Parkin gene mutation associated disease demonstrates fewer non-motor symptoms, including olfaction.17  As our DBS group showed increased non-motor symptoms in the context of improved olfaction, this does not seem consistent with either early-onset disease or parkin gene-associated disease.  5 Linton Peters et al.: DBS-implanted Parkinson's Disease PatientsNeurol. Bull. 2: 1-6, 2010 doi:10.7191/neurol_bull.2010.1016   Zesiewicz T, Gronseth G, Weiner WJ.  Practice Parameter: diagnosis and progno-sis of new onset Parkinson disease (an evi-dence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.  Neurology 2006;66:968-975. 5. McKinnon JH, Demaerschalk BM, Cavi-ness JN, Wellik KE, Adler CH, Winger-chuk DM.  Sniffing out Parkinson disease:  can olfactory testing differentiate parkin-sonian disorders?  Neurologist 2007;13:382-385. 6. Doty RL, Shaman P, Kimmelman CP, Dann MS.  University of Pennsylvania Smell Identification Test: a rapid quantita-tive olfactory function test for the clinic.  Laryngoscope 1984;94:176-178. 7. Gelb DJ, Oliver E, Gilman S.  Diagnostic criteria for Parkinson disease.  Arch Neu-rol 1999;56:33-39.  8. Beck AT.  An inventory for measuring depression.  Arch Gen Psychiatry 1961;4:561-71. 9. Marin RS, Biedrzycki RC, Firinciogullari S.  Reliability and validity of the Apathy Evaluation Scale.  Psychiatry Res 1991;38:143-162. 10. Chaudhuri KR, Martinez-Martin P, Schapira AH, et al.  International multi-center pilot study of the first comprehen-sive self-completed nonmotor symptoms questionnaire for Parkinson’s disease:  The NMSQuest study.  Mov Disord 2006;21:916-923. 11. Smith Y, Villalba R.  Striatal and ex-trastriatal dopamine in the basal ganglia: An overview of its anatomical organiza-tion in normal and Parkinsonian brains.  Mov Disord 2008;23:S534-S547. 12. Vlamings R, Visser-Vandewalle V, Kozan R, Kaplan S, Steinbusch HW, Temel Y.  Bilateral high frequency stimu-lation of the subthalamic nucleus normal-izes COX activity in the substantia nigra of Parkinsonian rats.  Brain Res 2009;1288:143-148. 13. Oueslati A, Sgambato-Faure V, Melon C, et al.  High frequency stimulation of the subthalamic nucleus potentiates L-DOPA-induced neurochemical changes in the stri-atum in a rat model of Parkinson’s Dis-ease.  J Neurosci 2007;27:2377-2386.  14. 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. 15. Lehmkuhle MJ, Bhangoo SS, Kipke DR. The electrocorticogram signal can be modulated with deep brain stimulation of the subthalamic nucleus in the hemipar-kinsonian rat.  J Neurophysiol 2009;102:1811-1820. 16. Simuni T, Lyons KE, Pahwa R, et al.  Treatment of early Parkinson’s disease.  Part 2.  Eur Neurol 2009;61:206-215. 17. Kägi G, Klein C, Wood NW, et al.  Nonmotor symptoms in Parkin gene-related parkinsonism.  Mov Disord 2010;25:1279-1284. 18. Ship JA, Weiffenbach JM.  Age, gender, medical treatment, and medication effects on smell identification.  J Gerontol 1993;48:M26-32.    Disclosure:  the authors report no conflicts of interest.  Acknowledgement:  thanks to the Neurology, Neuro-surgery, and Otolaryngology clinics at U Mass Memo-rial for their assistance with this project.  Supported in part by the Worcester Biomedical Re-search Foundation (to J.P.) and by the Clinical and Translational Research Pathway of the University of Massachusetts Medical School (to M.P.)  All content in Neurological Bulletin, unless otherwise noted, is licensed under a Creative Commons  Attribution-Noncommercial-Share Alike License  http://creativecommons.org/licenses/by-nc-sa/3.0/ (ISSN 1942-4043)  6 Linton Peters et al.: DBS-implanted Parkinson's Disease Patients

DBS-implanted Parkinson\u27s Disease Patients Show Better Olfaction Than Those Treated Medically

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DBS-implanted Parkinson\u27s Disease Patients Show Better Olfaction Than Those Treated Medically

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