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GrantApplication Form

Please complete the following form for IETF grant applications. This form and all the attachments belowmust be combined into one document before submiiting electronically. Crant iuUmissions will not beaccepted otherwise.

Attachments Required]. Specific aims of the proposal (1 page maximum).2' Rationale of the pr-oposal and reievance to essential tremor (1-2 pages maximum).3. Preliminary data, if available should be incorporated into the Ratibnile/Relevance section. preliminary

data are. not required for a proposal. However, if preliminary data are referred to in the proposil rationate,or have been used to formulate the hypotheses tb be tested, such information must be'forinall/ pieienteOin this section.

4. Research methods and procedures (1-2 pages maximum).5. Anticipated results (half-page maximum).6. Detailed budget and justification (1 page maximum).7' Biographic sketch of.principal investigator and all piofessional personnel participating in the project_ (standard NIH format, including biosketch and other support). - -.-'-'r8' Copies of relevant abstracts and/or articles that have bbbn fublished, are in press, or have been

submitted for publication.9. Completed conflict of interest questionnaire.

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Postal Code: f/ ST)S Icountry: C4N4 O8 E-mail address: * /, *{. ,rr/-Phone: tZL.&qV -f9 o o,%*Vtt 6 rax: H6-Oo3- +{All grant-applicants acknowledge that the Board of Directors of the IETF is the only entity authorized to award grants onbehalf of the IETF and the amounts of and occasions for awarding such grants, it iny irialf be awarded at alt, jrritt uewholly within the sole and exclusive discretion of said Board and iis judgirent .nrff UL nnrl and conclusive and not subjectto review for any reason judicial or otherwise.

PO Box 14005 | Lenexa, Kansas 66285-4005 I USA | 888.387.3667 (tollfree) | 913.341.3880 (locat) | essentialtremor.org

IETF - WD Hutchison Feb 2015 requesting $25,000

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Beta and Tremor-Related Oscillations in the Motor Thalamus of Essential Tremor Patients as Signals for Closed Loop DBS

1. Specific aims of proposal The proposed study will examine beta oscillations (13-30 Hz) in the motor thalamus of essential tremor (ET) patients and will test the hypothesis that the beta rhythm plays a role in the suppression of tremor. Microelectrode recordings of the ventral thalamus will be collected during intraoperative mapping procedures for deep brain stimulation (DBS) surgery. Since our data indicates closed loop stimulation based on sensing beta activity alone is contraindicated for tremor control we wish to explore central 3 - 7 Hz oscillation amplitude as the trigger for stimulation. The second hypothesis is that sensing tremor rhythm is effective for tremor control and but sensing beta rhythm is not. The project will consist of four studies:

a. A retrospective study using archived microelectrode recordings of the motor thalamus of essential tremor and pain patients. Beta oscillatory power in LFP and spike trains will be measured and mapped to the ventral thalamus according to the reconstructed microelectrode track. Beta oscillatory power will be measured in the ET group and compared to beta power in the pain patient group.

b. The relationship between the severity of ET and beta oscillatory power will be assessed by examining the correlation between clinical tremor scores and beta power in the motor thalamus. The data set from the above retrospective study will also be used for this study.

c. A prospective study of ET and pain patients examining beta activity during rest and tremor (ET only). Microelectrode recordings of the motor thalamus will be collected from upcoming DBS cases and neuronal activity in the beta band will be examined during rest and during tremor episodes. Pain patients will serve as controls for this study.

d. An intraoperative study of the effect of closed loop microstimulation on tremor. Using dual microelectrodes we will microstimulate with one microelectrode and record the effect on a nearby thalamic cell with the other ‘sentinel’ electrode while monitoring the effect on tremor reduction or arrest. Using online power spectrum we will generate triggers based on the amplitude of the oscillations to initiate microstimulation trains (200 Hz continuous, 2 sec, or 130 Hz for 3 sec) through one electrode while monitoring the effects on the other electrode.


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2. Rationale of proposal and relevance to ET

Essential tremor (ET) is one of the most common movement disorders but its precise origin and etiology remain unknown. Our group has examined tremor and beta oscillations in the subthalamic nucleus1 and globus pallidus2 of Parkinson’s disease patients, but more recently we have noted significant beta oscillations in motor thalamus of ET patients. Our aims are to further characterize the extent and prevalence of beta oscillation in the motor thalamus of ET and control pain patients in order to correlate this to ET severity. One long standing electrophysiological model is that oscillations in the olivo-cerebellar system give rise to action tremor. The inferior olive is a brainstem structure with climbing fibre input to cerebellar Purkinje cells which also receive the parallel fibre input from granule cell. Inferior olive neurons have gap junctions that allow synchronous oscillatory activity to be generated and propagated into cerebellar cortex. The Purkinje cells in turn inhibit the deep nuclei such as the dentate which then project to the motor thalamus. It is known that animals treated with harmaline develop peripheral tremor which is accompanied by tremor-frequency oscillations in the inferior olive3 and cerebellum.4

The electrophysiological model maintains that ET is caused by aberrant neural synchronization within an otherwise healthy network. There is ample evidence that the motor thalamus as well as other motor areas such as the inferior olive3, cerebellum4, motor cortex5 and the basal ganglia6 are capable of producing rhythmic discharges at tremor frequencies. However, of all these motor areas, the ventral intermediate (Vim) nucleus of the thalamus has tremor frequency oscillations in spike and local field potential (LFP) recordings that are the most strongly coherent with limb tremor7. Furthermore, microstimulation with high frequency trains (50 – 100 uA, 200 Hz, 1 – 3 sec) in the motor thalamus is capable of producing tremor reduction or arrest which appear to be associated with interruption of oscillatory thalamic activity (see Fig 1). The success of surgical interventions in the Vim (ablative or deep brain stimulation) is likely due to the abolition of tremor frequency oscillations.8

Although there is consistent data that central network oscillations lead to the manifestation of essential tremor, it is not yet clear how this rhythm emerges. An emerging concept in the pathogenesis of ET is a loss of inhibition in motor nuclei. For example, some research has shown that there is a loss of GABA receptors in the dentate nucleus in ET that inversely correlates with disease duration9, 10. In fact, lesions of the GABAergic cerebello-olivary pathway lead to the emergence of tremor symptoms in the arm and leg of post-ischemic patients11. Treatment with inhibitory drugs such as propranolol – a frequently used beta-blocker that reduces membrane excitability – is particularly effective against ET12. Indeed, a common pharmacological approach is the administration of positive GABA allosteric modulators such as benzodiazepines and barbiturates12, 14. The GABAmimetic drug gabapentin is also effective in tremor reduction15. Ethanol, which has long been known to ease essential tremor16, is a potent depressant that enhances GABA- and glycine-mediated currents17. It is increasingly evident that the beta frequency is associated with inhibitory states of the motor system. For example, benzodiazepines and barbiturates - agents that increase GABA-


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mediated currents and reduce tremor – all produce an increase in beta oscillations in the motor system18. Muthukumaraswamy et al.19 have shown that increasing endogenous GABA in healthy subjects results in enhanced beta oscillation throughout the motor cortex. This is consistent with Rodolfo Llinas’s observations of inferior olive neurons20 switching from the low beta (~12 Hz) to the theta rhythm in response to depolarization of the cell membrane. Studies from our group 2 have demonstrated the co-occurrence of tremor- and beta-oscillatory cells within neuronal populations of the subthalamic nucleus in long samples of data. In our data collected from motor thalamus to date (see Fig 2.), and looking more closely at the dynamics of the two rhythms with shorter segments, it is clear that the beta rhythm disappears some time before the tremor rhythm appears in thalamus which is then followed shortly after that by the emergence of tremor in the limbs.

There is currently much interest in closed loop DBS systems that titrate the stimulation amplitude and/or parameters based on the beta power or amplitude (see Little, 201321). This remarkable development was driven by the observations of several groups that implicate beta oscillations as a causative factor in akinesia and bradykinesia characteristic of Parkinson’s’ disease patients. It seems clear from the data shown in Fig 2 (also confirmed for STN in unpublished observations) that in the case of Vim DBS for tremor that such a device running on 15 – 25 Hz would be ON when the limb is at rest when it is not needed and then OFF just at a time when it would be needed for tremor control. Thus these closed loop devices may (or may not) be suitable only for PD patients and may not be indicated for ET patients. The work proposed here is to gain proof of principle based on neurophysiological observations in the thalamus for a closed loop DBS device specifically designed for ET patients that would optimize tremor control and prevent unnecessary excess stimulation and further maximize battery life and ultimately quality of life for ET patients. 3. Research methods and procedures:

a.) General methods Using dual microelectrodes, physiologic exploration of the thalamus will be carried out

during intraoperative mapping procedures prior to the insertion of the DBS electrode. The stereotactic coordinates of the anterior commissure (AC) and posterior commissure (PC) will be determined by 1.5 T magnetic resonance imaging and used to estimate the location of the ventral thalamic nuclear group based on the 14.5 mm sagittal map of the standard atlas of Schaltenbrand and Wahren (1977), reformatted by computer to conform to each patient’s specific AC-PC length. The tentative X-target in Vim is 14.5 mm lateral to midline or 11mm lateral to the wall of III ventricle, Y is 5mm anterior to PC and Z is on the AC-PC line. Physiologic identification of the motor (Vop/Vim) and sensory (Vc) nuclei of the ventral thalamus will be performed using single-unit and LFP recordings (10-30 Hz bandpass) obtained from two microelectrodes (about 25 μm tip length, axes 600 μm apart, about 0.2-MΩ impedance at 1,000 Hz) that traverse the thalamus in an anterodorsal to ventroposterior direction. The first site in the progression of the track where microelectrode stimulation (200 Hz, 5μA - 100μA) induces paresthesia will be considered the anterior border of the ventral caudal nucleus. Tracks will be reconstructed based on normalizing the track to zero as the anterior border of Vc, and using the corrected sagittal map, movement-related cells found along the track superior and anterior to this sensory border will be classified as Vim if they fall within the region outlined on the corrected atlas template.

Recording segments with well-defined spike signals (signal-to-noise ratio of 2:1 or higher) will be selected for offline analysis. Single-unit activity will be discriminated using


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template-matching tools in Spike2 (Cambridge Electronic Design, UK). Spike times and LFP data from Spike2 will be imported into MATLAB (version 6.5, The MathWorks, Natick, MA) for spectral and cross-correlation analyses. The power spectra of single-unit and LFP signals will be calculated using the discrete Fourier transform (Halliday et al. 1995) and significant neuronal oscillations will be detected through shuffling of spike trains (Rivlin-Etzion et al. 2006). For power density comparisons, individual spike spectrograms with significant oscillatory peaks will be averaged per track and the area under the significant peak will approximated according to the “integral over a finite interval” method described by Challis and Kitney (1991)

𝑃(𝜔1,𝜔2) = � 𝑃(𝜔)𝑑𝜔𝜔2

𝜔1

where P(ω) is the power spectrum and ω are the limits of the frequency interval.

b.) Localization of Beta Oscillations in the Ventral Thalamus of ET and Pain Patients: Retrospective Study

Archived microelectrode recordings of the ventral thalamus of 20 ET and 20 Pain patients will be analyzed for spike and LFP oscillatory activity in the beta band. Recording segments during which the patients had their limbs at rest will be isolated according to the accelerometer or EMG signal. Ventral thalamic beta power will be mapped with respect to the anterior border of Vc according to the mapping procedures described in 3 a.). Similar methods will be used for the archived intraoperative observations used to reconstruct and normalize the microelectrode tracks with respect to Vc border. Beta power in the ET patient group will be compared to that of the pain group. The relationship between the severity of ET and beta power will be examined by relating beta power to the tremor score of the patients prior to surgery.

c.) Beta oscillations during rest and tremor: Prospective Study

Microelectrode recordings will be obtained from 10 ET and 10 pain patients in forthcoming DBS cases. Spike and LFP activity will be recorded simultaneously with accelerometry while the patients are performing the following four motor tasks:

• Condition 1 - with the limbs at rest, recorded for 30 seconds

• Condition 2 - during maintenance of a posture that induces tremor in the particular patient often with the limb positioned in front of the face and/or holding a bottle partly filled with coloured fluid (250g), 30 seconds

d.) Microstimulation: High Frequency Stimulation (HFS) trains triggered on neuronal tremor and beta band oscillatory signals

We will perform microstimulation with one electrode and observe the effects on tremor reduction while recording the local response in thalamus with the sentinel electrode using the following two stimulation protocols and a third closed loop feedback protocol

1. High Frequency Stimulation (HFS) - Four 2-second trains of 200Hz stimulation with 8 second recovery time between each train


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2. Theta Burst Protocol (TBP) - Four 20 second trains, each consisting of 10 bursts of four 200 Hz pulses, with each burst separated by 200 ms (i.e at 5 Hz). The recovery time between each train will be 8 seconds.

3. Closed loop feedback Protocol – Using the Active cursor mode in spike 2 we will general two feedback signals from the motor thalamus by filtering the LFP signal at 3 – 7 Hz for a tremor signal and from 15 -25 Hz for the beta signal. The active cursor mode with take the average value of each continuous LFP signal over a moving 0.5 sec window and write each to value to two new memory channels that will show the ongoing amplitude of each of the tremor and the beta signal. Once a pre-determined tremor and β frequency thresholds are surpassed, a script running also in Spike2 will generate a pulse output from the DAC output to an external electrically isolated stimulator unit to initiate a train at 200 Hz for 2 sec (or we can used 130Hz for 3 sec – an “industry standard” stimulation frequency which yields clinical benefit). The development of the software and hardware components will be made with played-back spike and LFP data of previously recorded data to simulate real time experiments. When optimized we will go ahead with real time trials. The stimulation will be delivered to one of the two microelectrodes and the result will continue to be measured on the other electrode although a time out for the 2 or 3 sec will be used to block feedback during the train delivery. When the delivery of the high-frequency stimulation to the VIM produces tremor reduction or tremor arrest, the system will no longer sense oscillatory activity and will stay switched OFF. In these initial experiments we will set the threshold high to see the tremor fluctuate as stimulation comes ON and OFF. We expect that with the limb at rest and no tremor present the stimulator will not deliver pulses, however when the patient initiates a specific posture that exacerbates the tremor the stimulation will activate.

4. Anticipated results a. We expect that the motor thalamus of ET patients at rest will have less ongoing

beta activity in comparison to the pain group. b. We expect that patients with more severe tremor scores will have less ongoing

beta activity at rest. c. We expect that beta oscillations will diminish in ET during the tremor-inducing

posture and will yield to the tremor rhythm. In pain patients with no tremor, we expect that the beta oscillations will be sustained during the same posture.

d. Closed loop feedback based on monitoring LFPs in the 3 – 7 Hz range will be highly effective in controlling essential tremor. Feedback based on 15 – 25 Hz range will be ineffective, activating when the limb is at rest and deactivating during episodes when tremor is present.

The proposed study will refine current systems for closed loop DBS systems based on a solid knowledge of the driving signals, and will develop a more valid and realistic system based on tremor oscillations in thalamus. This should be most beneficial for patients with essential tremor.


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5.Detailed budget and justification

Please be advised that the balance that exceeds the maximum grant offered by IETF ($25,000) may be supplemented by Medtronic Inc.

a. Stipend for graduate student from the Physiology Department $25,800 b. Software licenses (Sigmaplot, Coreldraw, Matlab) $200 c. Microelectrodes (48 pieces) $560

Total $26,560

Item a. The Department Of Physiology at the University of Toronto requires a financial plan for taking graduate students and the PI has to guarantee the term of the salary. The graduate student, Mr. Diellor Basha, has been working in the field on and off for some 4years and has a manuscript published in Exp Neurol regarding thalamic beta oscillations (see attached reprint). I have enclosed a reference letter from the new stereotactic functional surgeon at Toronto Western Hospital supporting Mr.Basa’s background and qualifications. I am also currently supervising a graduate student from the Institute for Biomedical Engineering at U of T that is initiating aspects of this work for his PhD, in which I have provided guidance. He can work on software and hardware issues. Item b. Two metal microtargeting electrodes (Frederick Haer Company) will be used for each recording session and discarded after surgery. Our proposed study consists of 20 such recording sessions (10 ET and 10 pain), requiring a total of 40 microelectrodes. Eight extra electrodes will be kept as backup in case of damaged or malfunctioning electrodes. Item c: Software licences through University of Toronto are an inexpensive alternative to purchasing the programs outright. Sigmaplot and Coreldraw are used for graphics and Matlab is used for analysis of local field potential data with wavelets as well as fixed routines for doing statistics on cell firing histograms.


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6. Biographic sketch of principal investigator and all professional personnel participating in the project (standard NIH format, including biosketch and other support).

BIOGRAPHICAL SKETCH – Feb 2015

NAME POSITION TITLE

HUTCHISON, William Duncan Associate Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION DEGREE(if applicable) YEAR(S) FIELD OF STUDY

U. of Toronto, (Trinity), Ontario, Canada B.Sc. 1979-83 Biology Specialist

U. of Toronto, Ontario, Canada M.Sc. 1984-86 Pharmacology

Australian National University, Canberra Ph.D. 1986-89 Neuroscience

U. of Würzburg, Germany Post-doctoral 1989-91 Neurophysiology

U. of Toronto, Dept. Physiology Post-doctoral 1991-95 Neurophysiology

RESEARCH AND PROFESSIONAL EXPERIENCE:

Alexander von Humboldt Stiftung Postdoctoral Award (1989-91), Postdoctoral Fellow of Parkinson Foundation of Canada (1992-94). Assistant Professor of Surgery (Division of Neurosurgery), University of Toronto (1996 - present) and Research Scientist of the Toronto Hospital Research Institute (Division of Neurosurgery). Adjunct Professor, University of Waterloo, Systems and Design Engineering (2005-2008)

PRIZES AND HONORS:

Academic “M” and Ontario Scholar (1979); University of Toronto Open Fellowship (1985); Addiction Research Foundation PhD Scholarship (1986, declined); Australian National University PhD Scholarship (1986-1989); Alexander von Humboldt Stiftung Postdoctoral Research Scholarship (1989-91); Parkinson Foundation of Canada Postdoctoral Fellow (1992-1996). Best Poster Presentation Prize at Movement Disorders Meeting NYC, October (1998) “Coherent relation of pallidal tremor cells and rest tremor” Best poster UHN Research day, TWRI Research Day, Program in Neuroscience Research Day “Pallidal DBS influences both reflexive and voluntary saccades in Huntington’s disease”


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RESEARCH PROJECTS ONGOING OR COMPLETED DURING THE LAST YEARS

1. “Neurophysiological studies of subthalamic nucleus” JO Dostrovsky, WD. Hutchison, AM Lozano ($94,850/yr, 2004-2009) CIHR

2. “Pathological oscillations in human basal ganglia” PI Hutchison WD, Co-PI’s Dostrovsky JO, Hodaie M, Lozano AM. Pilot project $42, 000 Jul 06 – Jul 07 Park Soc Canada

3. “Dopamine and synaptic plasticity in human substantia nigra pars reticulata” PI Hutchison WD, Co-PI’s Dostrovsky JO, Hodaie M, Lozano AM. $495, 000 Oct 2009 – Oct 2014 CIHR

4. “Activity-dependent synaptic plasticity in globus pallidus of dystonia patients” ” PI Hutchison WD, Co-PI’s Dostrovsky JO, Hodaie M, Lozano AM. $60, 000 Oct 10 – Oct 12 Dystonia Medical Research F’n

5. “Synaptic plasticity and deep brain stimulation action” PI Hutchison WD. June 2010-2012 Medtronic

SELECTED PUBLICATIONS: Peer-reviewed research papers:

1. Hutchison WD, Lozano AM, Dostrovsky JO, Davis KD, Kiss ZHT: Differential neuronal activity in segments of globus pallidus in Parkinson's disease patients. Neuroreport 1994: 5: pp 1533-1537.

2. Hutchison WD, Lozano AM, Kiss ZHT, Lang AE, Dostrovsky JO: Identification and characterization of neurons with tremor-frequency activity in human globus pallidus. Experimental Brain Research 1996: 113: pp 557-563.

3. Hutchison WD, Levy R, Lozano AM, Lang AE, Dostrovsky JO: Effects of apomorphine on globus pallidus neurons in parkinsonian patients. Annals of Neurology 1997: 42: pp 767-775.

4. Lang AE, Lozano AM, Montgomery E, Duff J, Tasker RR, Hutchison WD: Posteroventral medial pallidotomy in advanced Parkinsons disease. New England Journal of Medicine 1997: 337: pp 1036-1042.

5. Hutchison WD, Allan RJ, Opitz H, Levy R, Dostrovsky JO, Lozano AE: Neurophysiologic identification of subthalamic nucleus in surgery for Parkinson’s disease. Annals of Neurology 1998: 44: pp 622-628.

6. Gross RE, Lombardi WJ, Hutchison WD, Narula S, Saint-Cyr JA, Dostrovsky JO, Tasker RR, Lang AE, Lozano AM: Variability in lesion location after microelectrode-guided pallidotomy for Parkinson's disease: anatomical, physiological and technical factros that determine lesion distribution. J.Neurosurg. 1999: 90: pp 468-77.

7. Hutchison WD, Davis KD, Lozano AM, Tasker RR, Dostrovsky JO: Pain-related neurons in human cingulate cortex. Nature Neuroscience 1999: 2: pp 403-405.

8. Levy R, Hutchison WD, Lozano AM, Dostrovsky JO: High-frequency synchronization of neuronal activity in the subthalamic nucleus of parkinsonian patients with limb tremor. J. Neurosciences 2000: 20: pp 7766-7775.

9. Levy R, Lang AE, Dostrovsky JO, Pahapill P, Romas J, Saint-Cyr J, Hutchison WD, Lozano AM: Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms. Brain 2001: 124: pp 2105-2118.

10. Levy R, Ashby P, Hutchison WD, Lozano AM, Lang AE, Dostrovsky JO: Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease. Brain 2001: 125: pp 1196-1209.

11. Levy R, Hutchison WD, Lozano AM, Dostrovsky JO: Synchronized neuronal discharge in the basal ganglia of Parkinsonian patients is limited to oscillatory activity. Journal of Neurosciences 2002: 22: pp 2855-2861.


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12. Levy R, Ashby P, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO: Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease. Brain 2002: 125: pp 1196-1209.

13. Abosch A, Hutchison WD, Saint-Cyr JA, Dostrovsky JO, Lozano AM: Movement-related neurons of the subthalamic nucleus in patients with Parkinson disease. Jouranl of Neurosurgery 2002: 97: pp 1167-72.

14. Saint-Cyr JA, Hoque T, Pereira LCM, Dostrovsky JO, Hutchison WD, Mikulis DM, Abosch A, Sime E, Lang AE, Lozano AM: MRI localization of clinically effective stimulating electrodes in the human subthalamic nucleus. J Neurosurg 2002: 97: pp 1152-1166.

15. Hutchison WD, Lang AE, Levy R, Dostrovsky JO, Lozano AM: Pallidal neuronal activity: implications for models of dystonia. Annals of Neurology 2003: 53

16. Macmillan M, Dostrovsky JO, Lozano AM, Hutchison WD: Involvement of human thalamic neurons in internally and externally generated movements. J. Neurophysiol 2004; 91: 1085-1090

17. Fawcett AP, Dostrovsky JO, Lozano AM, Hutchison WD. Eye movement-related responses of neurons in human subthalamic nucleus. Exp Brain Res. 2005 Apr;162(3):357-65.

18. Fawcett AP, Moro E, Lang AE, Lozano AM, Hutchison WD. Pallidal deep brain stimulation influences both reflexive and voluntary saccades in Huntington's disease. Mov Disord. 2005 Mar;20(3):371-7.

19. Hung SW, Hamani C, Lozano AM, Poon YY, Piboolnurak P, Miyasaki JM, Lang AE, Dostrovsky JO, Hutchison WD, Moro E. Long-term outcome of bilateral pallidal deep brain stimulation for primary cervical dystonia. Neurology. 2007 68(6):457-9.

20. Tang JK, Mahant N, Cunic D, Chen R, Moro E, Lang AE, Lozano AM, Hutchison WD, Dostrovsky JO. Changes in cortical and pallidal oscillatory activity during the execution of a sensory trick in patients with cervical dystonia. Exp Neurol. 2007 Apr;204(2):845-8.

21. Levy R, Lozano AM, Hutchison WD, Dostrovsky JO. Dual microelectrode technique for deep brain stereotactic surgery in humans. Neurosurgery. 2007 Apr;60(4 Suppl 2):277-83; discussion 283-4.

22. Piboolnurak P, Lang AE, Lozano AM, Miyasaki JM, Saint-Cyr JA, Poon YY, Hutchison WD, Dostrovsky JO, Moro E. Levodopa response in long-term bilateral subthalamic stimulation for Parkinson's disease. Mov Disord. 2007 May 15;22(7):990-7.

23. Tang JK, Moro E, Mahant N, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO. Neuronal firing rates and patterns in the globus pallidus internus of patients with cervical dystonia differ from those with Parkinson's disease. J Neurophysiol. 2007 Aug;98(2):720-9.

24. Prescott IA, Dostrovsky JO, Moro E, Hodaie M, Lozano AM, Hutchison WD. Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients. Brain. 2009: Dec 2:132: 285.

25. Prescott IA, Dostrovsky JO, Moro E, Hodaie M, Lozano AM, Hutchison WD. Reduced paired pulse depression in the basal ganglia of dystonia patients. Neurobiol Dis. 2013 Mar;51:214-21.

26. Alavi M, Dostrovsky JO, Hodaie M, Lozano AM, Hutchison WD. Spatial extent of β oscillatory activity in and between the subthalamic nucleus and substantia nigra pars reticulata of Parkinson's disease patients. Exp Neurol. 2013 Jul;245:60-71.

27. Fuller J, Prescott IA, Moro E, Toda H, Lozano A, Hutchison WD. Pallidal deep brain stimulation for a case of hemidystonia secondary to a striatal stroke. Stereotact Funct Neurosurg. 2013;91(3):190-7.

28. Yugeta A, Hutchison WD, Hamani C, Saha U, Lozano AM, Hodaie M, Moro E, Neagu B, Chen R. Modulation of Beta oscillations in the subthalamic nucleus with prosaccades and antisaccades in Parkinson's disease. J Neurosci. 2013 Apr 17;33(16):6895-904.

29. Liu LD, Prescott IA, Dostrovsky JO, Hodaie M, Lozano AM, Hutchison WD. Frequency-dependent effects of electrical stimulation in the globus pallidus of dystonia patients. J Neurophysiol. 2012 Jul;108(1):5-17.


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30. Torres CV, Moro E, Lopez-Rios AL, Hodaie M, Chen R, Laxton AW, Hutchison WD, Dostrovsky JO, Lozano AM. Deep brain stimulation of the ventral intermediate nucleus of the thalamus for tremor in patients with multiple sclerosis. Neurosurgery. 2010 Sep;67(3):646-51; discussion 651.

6.Copies of relevant abstracts and/or articles that have been published, are in press, or have been submitted for publication.

Basa D, Hodaie M, Lozano AM, Dostrovsky JO, Hutchison WD. Beta and gamma local field potential oscillations in the motor thalamus of essential tremor, Parkinson’s disease and pain. Poster session presented at Neuroscience 2011. Annual Conference of the Society for Neuroscience; 2011 Nov 12-16; Washington, DC

Abstract: The basal ganglia of Parkinson’s disease (PD) patients show a significant increase in beta-band (11-30Hz) oscillatory activity in neuronal firing and local field potentials (LFPs) which has been suggested to underlie the antikinetic symptoms of the disease. Gamma band oscillations have been termed “prokinetic” and associated with movement generation. However, Paradiso et al. (2004) demonstrated the occurrence of beta oscillations (12-30 Hz) in LFPs recorded from DBS contacts in the thalamus of essential tremor (ET) patients that lack akinesia and rigidity and our previous study (Kane et al 2009) suggested that theta band activity was increased in ET patients compared to pain and multiple sclerosis patients. In order to investigate whether beta oscillations are specific to a disease state such as PD, our study compared thalamic oscillatory activity in ET, PD and chronic pain patients. Furthermore, the relationship between LFP oscillations and the firing pattern of thalamic neurons was examined. Using dual microelectrodes, a total of 11 recordings were obtained during intraoperative mapping procedures in patients undergoing DBS implantation surgery of the thalamus. A total of 7 pairs of neuronal recordings were obtained from 2 ET patients, 3 pairs from PD and 3 from a chronic deafferentation pain case (amputated arm). Well-defined spikes were then isolated in Spike2 and subsequent spectral analysis of the firing activity as well as LFP activity was analyzed in MATLAB via discrete Fourier transform procedures. Our preliminary results confirm the occurrence of beta-LFP (16-23 Hz) in the thalamus of ET patients, as observed by Paradiso et al. Furthermore, beta oscillatory activity was found in the thalamus of the PD patients (25-30 Hz) and pain patient, whereas gamma activity (38-40 Hz) was only observed in the chronic pain case . All LFP oscillations occurred coherently across both recording electrodes. In addition to LFP oscillations, our analyses demonstrate the presence of regular beta oscillatory activity in the thalamic spike trains of ET, PD and chronic pain patients. In accordance with their respective LFPs, spike trains exhibited rhythmic firing in the beta range for ET and PD thalami whereas gamma oscillatory firing was additionally observed in the chronic pain case. Spike-triggered averages (STAs) obtained from the above data show that thalamic spikes are phase-dependent and occurred on the negative phase of their respective oscillations. These preliminary results suggest that beta and gamma oscillations may not be specific to an akinetic or prokinetic basal ganglia state, and can occur in other disease states such as essential tremor and deafferentation pain.


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1. Alavi M, Dostrovsky JO, Hodaie M, Lozano AM, Hutchison WD. Spatial extent of beta

oscillatory activity in and between the subthalamic nucleus and substantia nigra pars reticulata of Parkinson's disease patients. Exp Neurol 2013; 245: 60-71.

2. Kane A, Hutchison WD, Hodaie M, Lozano AM, Dostrovsky JO. Enhanced synchronization of thalamic theta band local field potentials in patients with essential tremor. Exp Neurol 2009; 217: 171-176.

3. Weinberger M, Hutchison WD, Alavi M et al. Oscillatory activity in the globus pallidus internus: comparison between Parkinson's disease and dystonia. Clin Neurophysiol 2012; 123:358-368.

4. Weinberger M, Hutchison WD, Lozano AM, Hodaie M, Dostrovsky JO. Increased gamma

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http://www.ncbi.nlm.nih.gov/pubmed/23852650


Figure 1. High frequency microstimulation in the motor thalamus of an ET patient produces tremor arrest and abolishes the tremor rhythm of the motor thalamic neuron.


Figure 2. Spike power spectrogram showing the modulation of beta-oscillatory spikes during non-tremulous movement and during a tremor episode. Beta activity is sustained while the patient is at rest but desynchronized with passive flexion-extension of the related limb. The beta desynchronization occurs at the onset of movement and not prior to it. The bottom trace shows the spontaneous emergence of tremor in a PD patient and the concomitant replacement of the beta rhythm with tremor frequency.

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