Join Us | Latest Articles | Contact

Journal Home


Editorial Board


Recent Articles


Submit to this journal


Special Issues


Current issue

International Journal of Neurology and Neurotherapy





DOI: 10.23937/2378-3001/1/1/1001



Deep Brain Stimulation Frequency Modulation in Parkinson's Disease - One Size May Not Fit All

Ritesh A Ramdhani*



Movement Disorders Division, Icahn School of Medicine at Mount Sinai, New York, USA


*Corresponding author: Ritesh A Ramdhani, MD, Movement Disorders Division, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, First Floor, New York, NY 10029, USA, Tel: 212-241-5607, Fax: 212-241-3656, E-mail: Ritesh.Ramdhani@mssm.edu
Int J Neurol Neurother, IJNN-1-001, (Volume 1, Issue 1), Editorial; ISSN: 2378-3001
Received: September 06, 2014 | Accepted: September 09, 2014 | Published: September 11, 2014
Citation: Ramdhani RA (2014) Deep Brain Stimulation Frequency Modulation in Parkinson's Disease - One Size May Not Fit All. Int J Neurol Neurother 1:001e. 10.23937/2378-3001/1/1/1001
Copyright: ©2014 Ramdhani RA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Deep Brain Stimulation (DBS) is an effective therapeutic modality for patients with Parkinson's Disease who have developed complications from longstanding levodopa such as dyskinesias and motor fluctuations. It produces robust responses to segmental symptoms (ie, bradykinesia, tremor, rigidity) while attenuating involuntary dyskinetic movements and smoothing out 'on' and 'off' period cycling. The subthalamic nucleus and the globus pallidus internaare widely accepted surgical targets for stimulation therapy, with STN more commonly used, though superiority has not been established [1-4].

Long-term outcome studies reveal sustained stable responses to rigidity, tremor, motor fluctuations, and dyskinesias among patients with bilateral DBS, mostly STN based [3,5-7]. Bradykinesia improvement also persisted but trended upwards as time went on, though remaining below preoperative baseline. Axial symptoms such as gait, postural stability, freezing of gait, and speech oftentimes transiently responded to stimulation and continued to deteriorate over time. Despite many of the DBS outcome studies having been conducted in patients with short disease duration, Merola and colleagues [8] described the development of progressive axial symptoms in patients treated with STN-DBS with more than 20 years disease duration. These symptoms globally lose any levodopa responsiveness and the synergism of stimulation ON/medication ON condition wanes as well, underscoring the likely contribution of non-dopaminergic systems in their phenotype.


High Frequency Stimulation (HFS) and Temporal Pattern Effects

The hypodopaminergic state changes the integrity of the intrinsic, tonic neuronal activity in the basal gangliaproducing excessive synchronous neuronal activity in the beta frequency (13-30Hz) [9], hence the reduction in beta oscillations observed with dopamine replacement therapy [10]. This excessive beta synchrony is associated with increasedcortical phase-amplitude coupling between the STN and cortex [11]. HFS-DBS mediates neuronal activity through excitatory or inhibitory changes but also influences the pattern and rates of neuronal firing- regularizing increased burst activity and simultaneously suppressing synchronized oscillations [12-15]. In addition, DBS reversibly reduces the strength of the cortical phase-amplitude coupling [11].

Suppression of beta oscillations has been related to improved motor performance, specifically bradykinesia and rigidity, and reaction time [16,17] in Parkinson's patients. Interestingly, rest tremor response does not seem to be linked to attenuation of beta oscillations suggesting a differential role of the cerebellar network its pathophysiology. Mounting evidence suggests that the frequency of deep brain stimulation governs much of the therapeutic gain through attenuation of the pathological activity and regularization of neuronal activity. Suppression ofbeta oscillatory activity in the STN is achieved at 130Hz or 185Hz and in the GPi at >70Hz [12,13,18,19]. In addition to the frequency, the therapeutic effect may also depend on the pattern of stimulation with worsening of tremor and UPDRS motor scores observed when the pattern is irregular [20]. Bridno et al. 2012 [21] showed that pauses in the stimulation pattern rather than temporally non-regular DBS produces deleterious motor effects. Bradykinesia and tremor improved above 50Hz with a ceiling effect reached between 130-185Hz, highlighting the parallel clinical correlation produced with continuous HFS [22]. Worsening of these symptoms occurred when cycling settings [23] were used, supporting the notion that disrupted, non-regular stimulation at a neuronal level, whether generated from an externalized system or internalized neurostimulator, parallels similar clinical outcomes.


The Paradox of Low FrequencyStimulation (LFS)

Low Frequency Stimulation, on the other hand, tendsnot to only worsen motor symptoms such as akinesia and tremor [24,25], but fails to override pathological oscillations [14]. It has been posited that this is attributed to the long interpulse intervals failing to mask intrinsic activity and/or facilitate rebound burst activity in the target nuclei [14]. However, a recent study testing hand opening and closing in PD patients, using an instrumented glove at multiple frequencies (low and high) did not find worsening of bradykinesia at low frequencies in a drug naive state with Total Electrical Energy Delivered (TEED) kept constant, thus challenging the prevailing view that LFS is inefficacious [26].

Furthermore, several studiesprobed the therapeutic effects of low frequency (60 - 80Hz) for gait disorders [27-30] among advanced PD patients with severe axial and gait disturbance, which are often refractory to HFS-DBS and L-Dopa. The results have been conflictingand likely related to differences in methodology. For example, two blinded studies examined changes in gait and axial symptoms on a cohort of advanced PD patients and showed contrary results. In the first study, the authorsreported sustained clinical gait benefit in 13 patients over 8 months on 60Hz frequency withTEEDcontrolled and ventral contacts utilized in 10 of the 13 patients [27]. In the second study, Sidiropolous et al.[28], while not controlling fully for TEED, reported no benefits of frequency < 80Hz in 45 patients. In addition, a partially blinded study by Richhi and colleagues [29], showed transient benefits in axial symptoms at 80Hz frequencywhile controlled for TEED, with majority of stimulation flowing through dorsal contacts used in 10 of 11 patients. Khoo et al [31]. revealed that the optimal contacts for 60Hz DBS were located ventrally and that the randomized, double blinded, prospective crossover comparison between 60-Hz and 130Hz yielded a better response of axial symptoms to 60Hz frequency. Interestingly, the analyses were done in the ON dopaminergic medication state, but were not controlled for TEED.

Though the efficacy of low frequency stimulation of the STN remains undetermined, the suggestion that ventral lead contacts as well as the ON-medication state are important forefficacy for this type of stimulationrequire further investigation. In parallel, Moro and colleagues [32] showed that stimulating the pedunculopontine nucleus (PPN), which lies caudal to the STN, at 25Hz in advanced PD patients with axial dysfunction and freezing improves their gait. Steffani et al [33] demonstrated further synergism between STN(HFS)-PPN(LFS) in the ON-medication state with improvement of axial symptomsproduced beyond that of stimulating either target individually. In addition, Weiss and colleagues [34] reported reduced freezing with simultaneous stimulation of STN and SNr at 125Hz from the same DBS lead. These studies underscore the concept of different targetshaving their own unique intrinsic pathologic activitybeing modulated by different frequencies to produce similar clinical outcomes. This potentially implicates the mechanistic theory of resonance interactions among various nested, oscillating circuits subserving motor functions [35]. Biochemical studies reveal that such resonance can impact the inhibitory or excitatory status of the target nucleus based on the type of frequency modulation being delivered [36].

Frequency-dependent modulation has also been reported to ameliorate involuntary movements such as dyskinesias [37] and improve intelligibility of PD patients with dysarthropneumophonia [38] through low frequency STN stimulation. But, frequency modulation is not restricted to the STN, as there is extensive experience described with pallidal (GPi)stimulation in treating primary dystoniawith high frequency (130-185hz) [39-43] and low frequency (60Hz) [44,45] stimulation. Interestingly, bradykinetic movements (ie, micrographia, hypomimia) and hypokinetic gait with freezinghave been reported as adverse effects of HFS in a number of case series [46-49]. Schrader and colleagues [49] reported an incidence of 8.5% of a new gait disorder among 71 patients with dystonia who underwent DBS. Ventral contacts seemed to be related to the development of this hypokinetic state. Reduction in frequency improved bradykinetic movements among a cohort of cranial-segmental dystonia patients that developed gait disorder on HFS, but the majority experienced a worsening of dystonia symptoms [46]. There have been no reports to date of hypokinesia in dystonia patients treated with LFS from the outset.


Conclusion

Despite the wide spread use of HFS in treating Parkinson's motor symptoms,evidence of low frequency stimulation efficacy, whether in the STN, PPN, or GPi, cannot be overlooked. It speaks to the likelihood that pathological neuronal synchrony and oscillatory patterns are not the only unique entities in the disease state, but are features of altered large networks [50,51] that may have differential responses at various nodes based on the frequency of stimulation delivered. Further studies will need to investigate the role clinical (i.e., age, disease duration, phenotype), surgical targeting, and genetics have in frequency modulation efficacy and how that relates to the network changes being derived from a growing body of large scale electrophysiological and neuroimaging evidence.


References
  1. Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP (2005) Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol 62: 554-560.

  2. Follett KA, Weaver FM, Stern M, Hur K, Harris CL, et al. (2010) Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease. N Engl J Med 362: 2077-2091.

  3. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, et al. (2003) Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 349: 1925-1934.

  4. Odekerken VJ, van Laar T, Staal MJ, Mosch A, Hoffmann CF, et al. (2013) Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial. Lancet Neurol 12: 37-44.

  5. Castrioto A, Lozano AM, Poon YY, Lang AE, Fallis M, et al. (2011) Ten-year outcome of subthalamic stimulation in Parkinson disease: a blinded evaluation. Arch Neurol 68: 1550-1556.

  6. Fasano A, Romito LM, Daniele A, Piano C, Zinno M, et al. (2010) Motor and cognitive outcome in patients with Parkinson's disease 8 years after subthalamic implants. Brain 133: 2664-2676.

  7. Schupbach WM, Chastan N, Welter ML, Houeto JL, Mesnage V, et al. (2005) Stimulation of the subthalamic nucleus in Parkinson's disease: a 5 year follow up. J Neurol Neurosurg Psychiatry 76: 1640-1644.

  8. Merola A, Zibetti M, Angrisano S, Rizzi L, Ricchi V, et al. (2011) Parkinson's disease progression at 30 years: a study of subthalamic deep brain-stimulated patients. Brain 134: 2074-2084.

  9. Hammond C, Bergman H, Brown P (2007) Pathological synchronization in Parkinson's disease: networks, models and treatments. Trends Neurosci 30: 357-364.

  10. Brown P, Oliviero A, Mazzone P, Insola A, Tonali P, et al. (2001) Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson's disease. J Neurosci 21: 1033-1038.

  11. de Hemptinne C, Ryapolova-Webb ES, Air EL, Garcia PA, Miller KJ, et al. (2013) Exaggerated phase-amplitude coupling in the primary motor cortex in Parkinson disease. Proc Natl Acad Sci U S A 110: 4780-4785.

  12. Brown P, Mazzone P, Oliviero A, Altibrandi MG, Pilato F, et al. (2004) Effects of stimulation of the subthalamic area on oscillatory pallidal activity in Parkinson's disease. Exp Neurol 188: 480-490.

  13. Wingeier B, Tcheng T, Koop MM, Hill BC, Heit G, et al. (2006) Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease. Exp Neurol 197: 244-251.

  14. Birdno MJ, Grill WM (2008) Mechanisms of deep brain stimulation in movement disorders as revealed by changes in stimulus frequency. Neurotherapeutics 5: 14-25.

  15. Dorval AD, Kuncel AM, Birdno MJ, Turner DA, Grill WM (2010) Deep brain stimulation alleviates parkinsonian bradykinesia by regularizing pallidal activity. J Neurophysiol 104: 911-921.

  16. Kuhn AA, Kupsch A, Schneider GH, Brown P (2006) Reduction in subthalamic 8-35 Hz oscillatory activity correlates with clinical improvement in Parkinson's disease. Eur J Neurosci 23: 1956-1960.

  17. Kuhn AA, Kempf F, Brucke C, Gaynor Doyle L, Martinez-Torres I, et al. (2008) High-frequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson's disease in parallel with improvement in motor performance. J Neurosci 28: 6165-6173.

  18. Birdno MJ, Cooper SE, Rezai AR, Grill WM (2007) Pulse-to-pulse changes in the frequency of deep brain stimulation affect tremor and modeled neuronal activity. J Neurophysiol 98: 1675-1684.

  19. Kuhn AA, Fogelson N, Limousin PD, Hariz MI, Kupsch A, et al. (2009) Frequency-specific effects of stimulation of the subthalamic area in treated Parkinson's disease patients. Neuroreport 20: 975-978.

  20. Hess CW, Vaillancourt DE, Okun MS (2013) The temporal pattern of stimulation may be important to the mechanism of deep brain stimulation. Exp Neurol 247: 296-302.

  21. Birdno MJ, Kuncel AM, Dorval AD, Turner DA, Gross RE, et al. (2012) Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation. J Neurophysiol 107: 364-383.

  22. Moro E, Esselink RJ, Xie J, Hommel M, Benabid AL, et al. (2002) The impact on Parkinson's disease of electrical parameter settings in STN stimulation. Neurology 59: 706-713.

  23. Montgomery EB Jr (2005) Effect of subthalamic nucleus stimulation patterns on motor performance in Parkinson's disease. Parkinsonism Relat Disord 11: 167-171.

  24. Timmermann L, Wojtecki L, Gross J, Lehrke R, Voges J, et al. (2004) Ten-Hertz stimulation of subthalamic nucleus deteriorates motor symptoms in Parkinson's disease. Mov Disord 19: 1328-1333

  25. Chen CC, Lin WY, Chan HL, Hsu YT, Tu PH, et al. (2011) Stimulation of the subthalamic region at 20 Hz slows the development of grip force in Parkinson's disease. Exp Neurol 231: 91-96.

  26. Huang H, Watts RL, Montgomery EB Jr (2014) Effects of deep brain stimulation frequency on bradykinesia of Parkinson's disease. Mov Disord 29: 203-206.

  27. Moreau C, Defebvre L, Destee A, Bleuse S, Clement F, et al. (2008) STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 71: 80-84.

  28. Sidiropoulos C, Walsh R, Meaney C, Poon YY, Fallis M, et al. (2013) Low-frequency subthalamic nucleus deep brain stimulation for axial symptoms in advanced Parkinson's disease. J Neurol 260: 2306-2311.

  29. Ricchi V, Zibetti M, Angrisano S, Merola A, Arduino N, et al. (2012) Transient effects of 80 Hz stimulation on gait in STN DBS treated PD patients: a 15 months follow-up study. Brain Stimul 5: 388-392.

  30. Brozova H, Barnaure I, Alterman RL, Tagliati M (2009) STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 72: 770.

  31. Khoo HM, Kishima H, Hosomi K, Maruo T, Tani N, et al. (2014) Low-frequency subthalamic nucleus stimulation in Parkinson's disease: a randomized clinical trial. Mov Disord 29: 270-274.

  32. Moro E, Hamani C, Poon YY, Al-Khairallah T, Dostrovsky JO, et al. (2010) Unilateral pedunculopontine stimulation improves falls in Parkinson's disease. Brain 133: 215-224.

  33. Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, et al. (2007) Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain 130: 1596-1607.

  34. Weiss D, Walach M, Meisner C, Fritz M, Scholten M, et al. (2013) Nigral stimulation for resistant axial motor impairment in Parkinson's disease? A randomized controlled trial. Brain 136: 2098-2108.

  35. Montgomery EB Jr, Gale JT (2008) Mechanisms of action of deep brain stimulation(DBS) . Neurosci Biobehav Rev 32: 388-407.

  36. Aravamuthan BR, Muthusamy KA, Stein JF, Aziz TZ, Johansen-Berg H (2007) Topography of cortical and subcortical connections of the human pedunculopontine and subthalamic nuclei. Neuroimage 37: 694-705.

  37. Merola A, Zibetti M, Artusi CA, Rizzi L, Angrisano S, et al. (2013) 80 Hz versus 130 Hz subthalamic nucleus deep brain stimulation: effects on involuntary movements. Parkinsonism Relat Disord 19: 453-456.

  38. Moreau C, Pennel-Ployart O, Pinto S, Plachez A, Annic A, et al. (2011) Modulation of dysarthropneumophonia by low-frequency STN DBS in advanced Parkinson's disease. Mov Disord 26: 659-663.

  39. Kupsch A, Benecke R, Muller J, Trottenberg T, Schneider GH, et al. (2006) Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 355: 1978-1990.

  40. Coubes P, Cif L, El Fertit H, Hemm S, Vayssiere N, et al. (2004) Electrical stimulation of the globus pallidus internus in patients with primary generalized dystonia: long-term results. J Neurosurg 101: 189-194.

  41. Starr PA, Turner RS, Rau G, Lindsey N, Heath S, et al. (2006) Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes. J Neurosurg 104: 488-501.

  42. Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Benabid AL, et al. (2005) Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 352: 459-467.

  43. Yianni J, Bain P, Giladi N, Auca M, Gregory R, et al. (2003) Globus pallidus internus deep brain stimulation for dystonic conditions: a prospective audit. Mov Disord 18: 436-442.

  44. Alterman RL, Miravite J, Weisz D, Shils JL, Bressman SB, et al. (2007) Sixty hertz pallidal deep brain stimulation for primary torsion dystonia. Neurology 69: 681-688.

  45. Goto S, Mita S, Ushio Y (2002) Bilateral pallidal stimulation for cervical dystonia. An optimal paradigm from our experiences. Stereotact Funct Neurosurg 79: 221-227.

  46. Berman BD, Starr PA, Marks WJ Jr, Ostrem JL (2009) Induction of bradykinesia with pallidal deep brain stimulation in patients with cranial-cervical dystonia. Stereotact Funct Neurosurg 87: 37-44.

  47. Zauber SE, Watson N, Comella CL, Bakay RA, Metman LV (2009) Stimulation-induced parkinsonism after posteroventral deep brain stimulation of the globus pallidus internus for craniocervical dystonia. J Neurosurg 110: 229-233.

  48. Tisch S, Zrinzo L, Limousin P, Bhatia KP, Quinn N, et al. (2007) Effect of electrode contact location on clinical efficacy of pallidal deep brain stimulation in primary generalised dystonia. J Neurol Neurosurg Psychiatry 78: 1314-1319.

  49. Schrader C, Capelle HH, Kinfe TM, Blahak C, Bazner H, et al. (2011) GPi-DBS may induce a hypokinetic gait disorder with freezing of gait in patients with dystonia. Neurology 77: 483-488.

  50. Montgomery EB Jr (2007) Basal ganglia physiology and pathophysiology: a reappraisal. Parkinsonism Relat Disord 13: 455-465.

  51. McIntyre CC, Hahn PJ (2010) Network perspectives on the mechanisms of deep brain stimulation. Neurobiol Dis 38: 329-337.

International Journal of Anesthetics and Anesthesiology (ISSN: 2377-4630)
International Journal of Blood Research and Disorders   (ISSN: 2469-5696)
International Journal of Brain Disorders and Treatment (ISSN: 2469-5866)
International Journal of Cancer and Clinical Research (ISSN: 2378-3419)
International Journal of Clinical Cardiology (ISSN: 2469-5696)
Journal of Clinical Gastroenterology and Treatment (ISSN: 2469-584X)
Clinical Medical Reviews and Case Reports (ISSN: 2378-3656)
Journal of Dermatology Research and Therapy (ISSN: 2469-5750)
International Journal of Diabetes and Clinical Research (ISSN: 2377-3634)
Journal of Family Medicine and Disease Prevention (ISSN: 2469-5793)
Journal of Genetics and Genome Research (ISSN: 2378-3648)
Journal of Geriatric Medicine and Gerontology (ISSN: 2469-5858)
International Journal of Immunology and Immunotherapy (ISSN: 2378-3672)
International Journal of Medical Nano Research (ISSN: 2378-3664)
International Journal of Neurology and Neurotherapy (ISSN: 2378-3001)
International Archives of Nursing and Health Care (ISSN: 2469-5823)
International Journal of Ophthalmology and Clinical Research (ISSN: 2378-346X)
International Journal of Oral and Dental Health (ISSN: 2469-5734)
International Journal of Pathology and Clinical Research (ISSN: 2469-5807)
International Journal of Pediatric Research (ISSN: 2469-5769)
International Journal of Respiratory and Pulmonary Medicine (ISSN: 2378-3516)
Journal of Rheumatic Diseases and Treatment (ISSN: 2469-5726)
International Journal of Sports and Exercise Medicine (ISSN: 2469-5718)
International Journal of Stem Cell Research & Therapy (ISSN: 2469-570X)
International Journal of Surgery Research and Practice (ISSN: 2378-3397)
Trauma Cases and Reviews (ISSN: 2469-5777)
International Archives of Urology and Complications (ISSN: 2469-5742)
International Journal of Virology and AIDS (ISSN: 2469-567X)
More Journals

Contact Us

ClinMed International Library | Science Resource Online LLC
3511 Silverside Road, Suite 105, Wilmington, DE 19810, USA
Email: contact@clinmedlib.org
 

Feedback

Get Email alerts
 
Creative Commons License
Open Access
by ClinMed International Library is licensed under a Creative Commons Attribution 4.0 International License based on a work at https://clinmedjournals.org/.
Copyright © 2017 ClinMed International Library. All Rights Reserved.