Tandem DBS for Parkinson's Disease: A Pilot Study Utilizing STN/GPi + Hypothalamic Stimulation
Phase: NA
Conditions: Parkinson's Disease, Deep Brain Stimulation
Sponsor: Mayo Clinic

 
 
Uitti et al - 1 -  
January 15, 2020 Version 4 
 
Title of Project 
 
Tandem DBS for Parkinson’s Disease: A Pilot Study Utilizing STN/GPi + 
hypothalamic stimulation  
 
DESCRIPTION 
 
With progression of symptoms, patients with Parkinson’s disease (PD) frequently 
develop significant disability despite optimal medical therapy. Surgical treatments, 
such as subthalamic or globus pallidal-deep brain stimulation (DBS), offer some 
benefit for selected patients.  However, a large percentage of patients subsequently 
develop dementia. 
Preliminary studies have identified stimulation of the hypothalamus/fornix as 
potentially useful in improving cognitive functioning acutely and there are 
theoretical reasons why such stimulation may lead to neurogenesis and potentially 
obviate future cognitive decline/dementia. 
 
We propose a pilot study of dual hemispheric stimulation of the subthalamic 
nucleus (STN) and fornix/hypothalamus in 12 PD patients experiencing motor 
disability despite optimal medical therapy, who would otherwise be undergoing 
STN-DBS.  These individuals may also have mild cognitive impairment.  The study 
will include measures of motor and cognitive function.  
 
 
PERFORMANCE SITES 
 
Mayo Clinic, Jacksonville, FL 
 
KEY PERSONNEL 
 
Ryan J. Uitti, MD 
             PI 
Robert E. Wharen, Jr., MD      Co-PI 
John A. Lucas, PhD  
Co-investigator 
 
Amy Grassle, RN 
Nurse Coordinator 
Audrey Strongosky, BA          Research Coordinator  
 
Ryan J. Uitti, MD  PI 
Dr. Uitti will oversee the project, selecting patients for entry into the study, insuring 
optimization of medical therapy, participating in electrophysiological and clinical 
guidance of stimulator lead placement in the operating room, regulating stimulators 
and directing follow-up evaluation and care for all patients.  He will perform initial 
UPDRS scoring in every patient evaluation.  He is a fellowship-trained movement 
disorder specialist who has functioned in this capacity in studies concerning both 

 
 
Uitti et al - 2 -  
lesioning and stimulation procedures.  He has provided neurological assistance 
intraoperatively for Dr. Wharen for nearly every patient undergoing movement 
disorders surgery at Mayo Clinic in Jacksonville. 
 
Robert E. Wharen, Jr., MD,  Co-PI 
Dr. Wharen will perform all surgery in study patients and pre- and post-surgical 
evaluations.  He will determine the radiological target in every patient and 
determine the utility of electrophysiological and clinical guidance on the basis of 
eventual lead location site.  He was the first neurosurgeon to perform MR-
electrophysiological-guided movement disorder surgery at the Mayo Clinic and has 
performed every deep brain stimulation procedure carried out at Mayo Clinic in 
Jacksonville (in conjunction with Dr. Uitti). 
 
John A. Lucas, PhD 
Dr. Lucas, neuropsychology consultant, will oversee collection and interpretation of 
all neurobehavioral data, including quality of life information.  He has served in this 
capacity in previous studies with Drs. Uitti and Wharen. 
 
Amy Grassle, RN 
Amy Grassle is Dr. Uitti’s research nurse coordinator.  She will coordinate logistics 
for the study, including pre- and post-surgical evaluations.  She will perform 
nursing duties during each surgery.  She will collect and record data during every 
patient evaluation.  She will assist with IRB compliance and clinical data 
compilation.   
Audrey Strongosky, BA 
Audrey Strongosky is a clinical research coordinator with the Movement Disorders 
Group.  She will be responsible for IRB documentation and will assist in managing 
data, data entry into the computerized database, scheduling of patient’s visits 
 

 
 
Uitti et al - 3 -  
Background 
 
Tandem Deep Brain Stimulation for Parkinson’s Disease  
 
Abstract 
 
Deep brain stimulation (DBS) targets for Parkinson's disease have been limited to 
neuronal regions wherein lesions have produced beneficial effects.  Improvements in 
imaging allow placement in small and novel targets.  Additionally, due to the ability of 
impulse generators to accommodate multiple electrodes, simultaneous stimulation in 
multiple neuronal regions is possible. 
 
Given that the two most disabling clinical features of Parkinson's disease, namely 
postural instability and dementia, have evaded effective treatment, consideration for new 
structural targets is warranted.  Characteristics of dementia in parkinsonism include 
progressive deficits in attention and executive function.  Additionally, many patients 
experience pronounced variability in cognition with profound fluctuations/variability in 
attention and alertness.  
Anecdotal and initial trial reports concerning DBS to the fornix/hypothalamus have been 
associated with improvement in memory function and reductions in expected cognitive 
decline in patients with early Alzheimer’s disease.  The fornix constitutes the major 
inflow and output pathway from the hippocampus and medial temporal lobe. 
I hypothesize that tandem DBS, targeting the STN/GPi and fornix/hypothalamus and/or 
hippocampus may have a positive impact on improving cognitive function and/or 
reducing risk for subsequent dementia with Lewy bodies/Parkinson dementia.  Such 
targets also pose potential negative ramifications.  Nevertheless, given the tremendous 
disability produced by dementia, new structural targets require systematic study.  
 
 
Tandem Deep Brain Stimulation for Parkinson’s Disease 
 
Deep brain stimulation (DBS) targets for Parkinson's disease (PD) have been limited to 
neuronal regions wherein lesions have produced beneficial effects.  Every DBS target 
routinely employed at international centers: ventral intermediate nucleus of the thalamus, 
subthalamic nucleus, or globus pallidus internus, have been historically lesioned with 
documentation of ensuing motor benefit.  The positive ramifications have included 
predominantly improvement in motor function and functional “on” time.  Patients 
undergoing surgery have been highly selected; PD patients with depression and dementia 
have consistently been avoided as surgical candidates [1]. 
 
While most series of DBS surgery for PD patients find minimal changes in cognition 
within the first year following surgery, longitudinal series subsequently document that 
cognitive decline and dementia are still commonplace.  Additionally, most DBS series 
have avoided operating on elderly PD patients who are at most risk for dementia.  We 

 
 
Uitti et al - 4 -  
have suggested for some time that unilateral STN-DBS be routinely employed (as 
opposed to immediate bilateral surgery) in PD, as it may be therapeutically effective and 
carry fewer cognitive complications, particularly in elderly patients [2]. 
 
Most long-term follow-up indicate that speech, axial motor features and cognitive decline 
frequently become apparent in PD patients receiving DBS [3].  Studies examining 
specific cognitive outcomes more than two years after surgery indicate that the majority 
of STN-DBS patients demonstrate significant declines in nonverbal memory, semantic 
fluency, and processing speed, with the same percentage converting to dementia as those 
PD who were not surgical patients [4].  Hence, there is no evidence to suggest that current 
DBS targets, even employed in a selected, non-demented, non-depressed cohort, 
subsequently minimize the risk for future dementia. 
 
In summary, currently available pharmacological and surgical therapies do not 
consistently, effectively ameliorate balance and cognitive decline/dementia or reduce 
their risk, and frequently exacerbate these problems in the short-term. 
 
Dementia and Parkinson’s disease 
Dementia in Parkinson’s disease (PD) represents the most frequent, eventually disabling 
feature of this common neurodegenerative disorder.  It also is a strong predictor of 
survival [5].  
Parkinson dementia/dementia with Lewy bodies represents the second most common 
form of disabling dementia.  Characteristics of dementia in parkinsonism include 
progressive dementia with deficits in attention and executive function [6].  Recurrent, 
complex visual hallucinations frequently occur and may be accompanied by REM sleep 
behavior disorder (concurrently or prior to development of other features).   Additionally, 
many patients experience pronounced variability in cognition with profound 
fluctuations/variability in attention and alertness. Fluctuations in cognitive functioning 
and deficits in attention and executive function, often without prominent memory 
impairment, is a core feature of dementia with Lewy bodies [6], and occurs particularly in 
early stages.  Such variability is a hallmark of dementia with Lewy bodies that 
differentiates this form of cognitive decline from Alzheimer’s disease and aging [7]. 
 
Unfortunately, the two most common disabling clinical features of PD, namely postural 
instability leading to falls and dementia have evaded effective treatment.  Additionally, 
these features are increasingly common in aging PD patients, precisely the demographic 
who are avoided by most centers performing DBS surgery.   
 
Could DBS potentially impact cognitive decline/dementia in PD? 
 
DBS with high-frequency stimulation of the limbic circuitry, namely the anterior thalamic 
nuclei, demonstrates neurogenesis of neurons in the dentate gyrus of the hippocampus, a 
component of the limbic circuit. 
 

 
 
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The ability to produce adult hippocampal neurogenesis has also been associated with 
effective antidepressant treatments.  Studies in mice have demonstrated that stimulation 
of the ATN may produce increases in neural progenitors in the dentate gyrus of the same 
variety that can be stimulated by fluoxetine and physical exercise [8].  This suggests that 
ATN stimulation might be useful for limbic circuitry activation and influence on 
cognition and mood.  While most clinical studies in PD patients do not suggest that 
cognition is negatively impacted by DBS per se, this may also be possible.  DBS of the 
anterior thalamus at high current has shown the ability to impair memory in rat animal 
models [9]. 
 
An anecdotal report concerning DBS in the fornix and hypothalamus in a patient being 
treated for obesity included descriptions of impressive memory enhancement [10].  While 
on the operating table, this patient was able to provide detailed memory recollections 
from 30 years previous.  Subsequent evaluation disclosed that there were EEG effects in 
the hippocampal formation and medical temporal lobe in conjunction with high-intensity 
stimulation (3-5 V, 60-microsecond pw, 130 Hz).  Additionally, performance on 
neuropsychological testing after chronic hypothalamic stimulation demonstrated 
improvements in attention, verbal learning (short- and long-delay recall) and spatial 
associative learning.  This testing suggested that hypothalamic stimulation induced 
enhanced recollection in the memory process.  The mechanism thought to be responsible 
was driving activity of the hippocampal memory circuit through stimulation of the fornix.  
The fornix represents the major axonal bundle from the hippocampus and medial 
temporal lobe.  Lesions in the fornix are also well known to produce memory deficits in 
humans.  In contrast in this instance, apparent driving of activity in the ipsilateral medial 
temporal lobe to unilateral hypothalamic stimulation (“on” state), was associated with 
increased memory ability. 
 
A subsequent trial has ensued examining the impact of DBS on memory circuits in 
Alzheimer’s disease (AD) [11].  This trial recruited six patients with early AD.  All had 
Clinical Dementia Rating scores of 0.5 or 1.0 [12] and scores between 15-26 on the Mini 
Mental State Examination (MMSE)[13].  Each were implanted bilaterally in the vertical 
portion of the fornix within the hypothalamus.  Assessments with the Alzheimer’s 
Disease Assessment Scale, Cognitive Subscale (ADAS-Cog)[14] took place at baseline 
and 6 and 12-months post-operatively.  After 6 months of stimulation, 4 of 6 patients 
showed improvement, with lowering of 1.3-4.0 points in the ADAS-Cog scores.  This 
magnitude compares favorably to the reported impact of donepezil in mild cognitive 
impairment, which is 0.5 points [15]. 
 
After 12 months, one patient had 4.4 points lower than baseline, 2 patients a 2-point 
increase, 1 patient a 5-point increase, and 2 patients >5 point increases.  The expected 
change in the cohort of 6 was: 2 patients had less than expected increases, 1 more, and 3 
within the expected range.  Interestingly the patient with the greatest improvement 
experienced the most vivid experiential experience with stimulation during surgery, as 
had been the case with the original anectodal patient reported.  Functional imaging carried 
out in this trial also suggested that fornix/hypothalamic-DBS produced changes in the 

 
 
Uitti et al - 6 -  
cognitive and limbic brain areas (improved glucose metabolism), were the basis for 
observed changes in some of the AD patients.  These authors also suggest that DBS may 
drive greater delivery of neurotrophin brain-derived neurotrophic factor and influence 
neurogenesis in the diseased hippocampus. 
 
Hypothesis: Tandem DBS for PD 
 
Given that 1) the most disabling and common negative consequence of PD is dementia 
for which there is no means to avoid or beneficial treatment, and 2) there is some 
evidence that DBS can potentially safely impact upon memory, I suggest that tandem 
DBS, namely targeting both STN (or GPi) and the fornix/hypothalamus and/or 
hippocampus may improve both motor and cognitive function (immediate and future).  
As such, tandem DBS with STN/GPI + fornix/hypothalamus for PD patients should be 
considered for systematic study. 
DBS of the fornix/hypothalamus and/or hippocampus may have a positive impact on 
cognitive function and/or reducing risk for subsequent dementia with Lewy 
bodies/Parkinson dementia. 
Potential studies could include PD patients with: 
• normal cognition 
• mild cognitive impairment 
• mild dementia 
Studies with patients who have normal cognition could determine if DBS of the 
fornix/hypothalamus had any impact on the natural course of the disorder and likelihood 
of subsequent development of dementia.  Studies engaging patients with cognitive 
dysfunction could test whether DBS of the fornix/hypothalamus was capable of providing 
symptomatic improvement through improved alertness, attention, memory and other 
performance metrics.  
Logistical Possibilities 
 
Originally, impulse generators for deep brain stimulation electrodes accommodated only 
single quadric-polar brain electrodes.  Consequently, deep brain stimulation was 
necessarily constrained by the lack of pulse generator flexibility.  Currently available 
impulse generators readily accept multiple brain electrodes.  Therefore, it is logistically 
possible to consider utilizing multiple brain electrodes simultaneously.  The studies 
suggested would require at least two electrodes to be placed in one cerebral hemisphere 
(one for motor improvement and one for potential cognitive implications).  Trials would 
need to include designs to determine the impact of DBS in targets considered singly (e.g. 
STN or fornix/hypothalamus) and in combination (e.g. STN and fornix/hypothalamus). 
 
I propose controlled studies implanting PD patients who are otherwise undergoing 
unilateral DBS-GPi or DBS-STN with a unilateral DBS electrode with stimulation to the 

 
 
Uitti et al - 7 -  
fornix/hypothalamus region, i.e. tandem DBS.  Such patients would receive a single IPG, 
as would otherwise be required for such surgery.  Patients subsequently undergoing 
second-sided surgery for motor parkinsonism would concurrently also receive a second 
electrode with stimulation for the fornix/hypothalamus.  Stimulation to the 
fornix/hypothalamus would be accomplished with either the same rate/frequency as for 
the unilateral basal ganglia structure or utilize 3.0-3.5 V with a frequency of 130 Hz and 
pulse width of 90 microseconds. 
Neuropsychological studies and dementia status immediately prior to and years post-
operatively would form the primary outcome measure for these tandem DBS 
studies.  Historical results, with single hemispheric electrodes (either unilateral or 
bilateral) could serve as potential comparative data for secondary analyses. 
MRI scans will be completed for serial hippocampal volume measures.  Scans will be 
evaluated by Erik Middlebrooks, MD. 
Pathological studies of brain from patients at death would subsequently help to determine 
the nature of results, including ability to ascertain whether neurogenesis or other 
mechanism might be associated with fornix/hypothalamus-DBS/tandem DBS. 
Summary 
DBS utilizing “traditional motor targets” for PD patients has provided improvement in 
functional “on” time and reduced tremor compared to standard medical therapy.  
However, subsequent risk for cognitive decline/dementia remains and development of 
these features leads to early disability and death.  Potential improvements in cognitive 
function and neurogenesis are conceivable with tandem DBS targeting STN/GPi and the 
fornix/hypothalamus and should now be considered for systematic study in PD. 
References 
[1]  Lang AE, Houeto J-L, Krack P, Kubu C, Lyons KE, Moro E, et al. Deep brain 
stimulation: preoperative issues. Movement Disorders 2006;21:S171-96. 
 
[2] Slowinski JL, Putzke JD, Uitti RJ, Lucas JA, Turk MF, Kall BA, et al. Unilateral deep 
brain stimulation of the subthalamic nucleus for Parkinson disease. J Neurosurg 
2007;106:626-32. 
 
[3]  Fasano A, Romito LM, Daniele A, Piano C, Zinno M, Bentivoglio AR, et al. Motor 
and cognitive outcome in patients with Parkinson’s disease 8 years after subthalamic 
implants. Brain 2010;133:2664-76. 
  
[4] William AE, Arzola GM, Strutt AM, Simpson R, Jankovic J, York MK. Cognitive 
outcome and reliable change indices two years following bilateral subthalamic nucleus 
deep brain stimulation. Parkinsonism & Rel Disord 2011;17:321-7.   
[5]  Uitti RJ, Ahlskog JE, Maraganore DM, Muenter MD, Atkinson EJ, Cha RH et al. 
Levodopa therapy and survival in idiopathic Parkinson’s disease – Olmsted county 
project. Neurology 1993;43:1918-26.    

 
 
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[6] McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, et al. Diagnosis 
and management of dementia with Lewy bodies – Third report of the DLB consortium. 
Neurology 2005;65:1863-72.   
 
[7]  Ferman TJ, Smith GE, Boeve BF, Ivnik RJ, Petersen RC, Knopman D, et al. DLB 
fluctuations- specific features that reliably differentiate DLB from AD and normal aging. 
Neurology 2004;62:181-7. 
 
[8] Encinas JM, Hamani C, Lozano AM, Enikolopov G. Neurogenic hippocampal targets 
of deep brain stimulation. J Comp Neurol 2011;519:6-20.   
 
[9] Hamani C, Dubiela FP, Soares JCK, Shin D, Bittencourt S, Covolan L, et al. Anterior 
thalamus deep brain stimulation at high current impairs memory in rats. Experimental 
Neurol 2010;225:154-62. 
 
[10]  Hamani C, McAndrews MP, Cohn M, Oh M, Zumsteg D, Shapiro CM, et al. 
Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann 
Neurol 2008;63:119-23.   
 
[11] Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, et 
al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. 
Ann Neurol 2010;68:521-34. 
 
[12]  Morris JC. The clinical dementia rating (CDR): current version and scoring rules. 
Neurology 1992;43:2412b-4b. 
 
[13] Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”: a practical method for 
grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98. 
 
[14] RosenWG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J 
Psychiatry 1984;41:1356-64. 
 
[15]  Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Farris S, et al. 
Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 
2005;352:2379-88.  
 
Acknowledgments 
RJU is partially supported by the NIH/NINDS P50-NS072187 and NIH/NINDS 
NS057567, research funding from Advanced Neuromodulation Systems, Inc./St. Jude 
Medical, and a gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF 
#90052031/PAU #90052). 
 
 
 

 
 
Uitti et al - 9 -  
 
RESEARCH DESIGN AND METHODS 
 
Experimental Subjects 
Inclusion/Exclusion Criteria 
 
All patients will be enrolled from the practice of the primary investigator.  It is 
anticipated that PD patients eligible for this study will range from 40-80 years and will 
have been symptomatic with parkinsonism for 7-20 years.   
 
The study will include PD patients in whom optimal medical therapy has failed to 
relieve the patient from significant disability owing to parkinsonism.  PD will be 
diagnosed by the principal investigator on the basis of the presence of at least 2 of 3 
cardinal features of parkinsonism (resting tremor, rigidity, and bradykinesia) without 
known cause.  Patients with prominent and early dysautonomia or ataxia or downgaze 
palsy or pyramidal signs will be excluded.  Response to levodopa should be specified as 
more than minimal (reductions in UPDRS motor scoring of 20% or greater when “off” 
scores are compared to “on” scores during the drug motor response profile) and as 
sustained (e.g. for at least five years).  
 
All patients will have responsivity to levodopa (as defined by UPDRS changes 
above).  Common causes for significant disability will be intractable tremor, levodopa-
induced dyskinesias and other motor fluctuations.  Optimal medical therapy will consist 
of appropriate use of levodopa and at least one dopamine agonist under the direction of 
the principal investigator.  Common causes for significant disability will be motor 
fluctuations, levodopa-induced dyskinesias, intractable tremor, other motor disability 
including gait disturbances.  Individuals with normal or mild cognitive impairment as a 
diagnosis following neuropsychological study will be eligible for the study. 
Exclusionary criteria will include clinically significant dementia (MMSE <23), 
Hoehn & Yahr [Hoehn, 1967 #1839] stage I or V disease, other significant neurological 
or psychiatric disease, previous pallidotomy or thalamotomy, previous placement of other 
implantable devices, and secondary parkinsonism (non-idiopathic parkinsonism).  
Patients with the aforementioned characteristics (without exclusionary criterion) are 
defined as surgical candidates.   
 
The study will seek to include women and members of minority groups.   
 
The principal investigator will discuss the study with surgical candidates.  Patients 
will not incur any financial charges or responsibility relating to this study. 
Consent for participation in this study will be sought and obtained by the primary 
investigator and study coordinator.  The information provided to prospective subjects will 
include the details regarding each surgical procedure and the risks inherent with surgery 
(as listed below) will be that included on the IRB-approved consent form with consent 
being documented by written or econsent signature of the patient.  
 

 
 
Uitti et al - 10 -  
Potential risks for participation in this study include death, stroke, hemiparesis, 
and visual field deficits, and all other risks related to stereotactic brain surgery.  The 
likelihood of such occurrences is generally reported to be approximately 2%.  At our 
institution there have been no such serious adverse events in the >100 procedures 
performed during the past 2 years.  Should patients expect greater improvement than 
obtained they may experience depression and frustration with outcome.  Patients in this 
study would by definition have failed to experience significant relief of parkinsonism 
despite best medical therapy.  Alternatives to treatment in this study would include no 
additional treatment or other surgery, such as pallidotomy, thalamotomy, and 
subthalamotomy (significant additional risk for bilateral procedures). 
 
The risks to subjects are reasonable in relation to the anticipated benefits to 
subjects as these patients have no predictably successful alternatives and would be 
expected to continue to decline functionally without treatment. 
 
Patient-related data will remain confidential, with only numerical patient 
identification numbers being placed on data collection sheets.  In the event of adverse 
effects to the subjects, patients would be cared for, including all appropriate specialty out-
patient and in-patient care at Mayo Clinic in FL.  Any unexpected or untoward outcomes 
encountered in this study would be reported to the IRB.  Clinical data will be obtained 
both for research purpose and for clinical care as indicated.  The medical record will be 
recorded in the Mayo Clinic electronic record.  Data exclusive to this study will not be 
recorded in the Mayo Clinic electronic record but will be stored on paper record before 
being transcribed into electronic computer record form. 
  
Surgical Technique 
 
Surgical implantation of DBS leads will be carried out employing techniques 
previously reported (Uitti, Wharen et al. 1997) (Wharen, Uitti et al. 1996) as described 
below.  Patients will have antiparkinsonian medication withheld for 12-48 hours prior to 
surgery.  During this time, patients will be constantly accompanied by a caregiver to 
insure their safety.    
 
After application of a stereotactic headframe under IV sedation in the operating 
room to maximize patient comfort, MR imaging is performed using a 1.5-T magnet 
(General Electric, Milwaukee, WI).  The MRI scanner in our facility is located adjacent to 
the operating room.  Images are acquired using a 3-D volumetric spoiled GRASS 
sequence in the sagittal and axial planes. The sagittal acquistion is a 2 cm volume of 1 
mm thick contiguous slices obtained in 3 minutes.  This sequence will be used to define 
the anterior (AC) and posterior (PC) commissures.  The second acquisition uses an 
identical sequence in the axial plane consisting of a 12 cm volume of 1mm thick 
contiguous slices obtained in 10 minutes.  This sequence will be used to construct 
multiplanar (axial, sagittal, and coronal) viewing of the target point and trajectory.  Axial 
images are used because this data is least vulnerable to any magnetic distortion.  
Additionally, a directly acquired axial fast spin echo inversion recovery sequence 

 
 
Uitti et al - 11 -  
(T1=200, TR=2200, TE=24, slice thickness=2mm) is obtained.  This sequence is used to 
construct coronal images for direct visualization of the subthalamic nucleus (STN) and 
substantia nigra (SN).  Targeting of the fornix/hypothalamus will take place utilizing the 
same computer software/imaging. 
 
MR accuracy is verified by weekly quality assurance evaluations of the MR 
magnet using stereotactic phantoms.  MR data is transferred over a network directly to the 
stereotactic planning computer in the OR computer room.  The COMPASS software is 
used to define the AC and PC, the AC-PC line, and its midpoint.   
 
The initial target is chosen using standard coordinates for the STN (3 mm 
posterior, 4 mm inferior, and 12 mm lateral to the midpoint of the AC-PC line).  Final 
anatomic target adjustments are made based on correlation with the visualization of both 
SN and STN on the T2 weighted coronal images. A trajectory is chosen to include the 
target site, the midpoint of the AC-PC line and to avoid the lateral ventricles. 
 
Microelectrode recording (MER) is then performed to verify the borders of the 
STN.  STN has a characteristic electrophysiological activity that may be recognized by 
the discharge pattern within high background noise.  The background noise diminishes 
distinctly at the inferior border of the STN into the SNR.  Single units are recorded, both 
in the STN and SNR.  In STN, cells fire with high activity (50-60 Hz), the spikes being 
almost symmetrical.  They may respond to passive movements of the limbs with an 
increased firing rate.  Cells in SNR typically produce larger potentials with slower firing 
rates (15-20Hz) and are irregular.  They may be less likely to vary with limb movement.  
The medial and lateral borders of the STN formed by the lemniscal and corticospinal 
fibers respectively are identified by microstimulation-evoked sensory and motor 
responses.  The MERs are again correlated to the tri-planar MR anatomy in the 
COMPASS software to assist in verification of the borders of the STN.  We will perform 
MER using 1-5 microelectrodes placed simultaneously with our linear array (separated 3 
mm apart center-to-center) aligned with the long axis of the STN as judged by its location 
immediately superior to SNR. 
 
Microstimulation (0.5-5 uA, 130 Hz, 60usec pulse width) is carried out over the 
length of the STN to determine clinical response based on measurement of rigidity at the 
contralateral wrist to passive movement, as well as bradykinesia.  Additionally, increasing 
microstimulation-induced side effects (such as paresthesias, vertigo, diplopia, eye 
deviation, etc.) are determined at each level.  The final target will be determined by 
selecting the microelectrode track with the largest inferior-superior span of STN 
recording, the optimal clinical response in terms of reduction of rigidity and the highest 
threshold for side effects (particularly eye deviation and diplopia). 
 
After the final STN target is selected, a Medtronic or Boston Scientific multipolar 
electrode is stereotactically placed at the target site and macroelectrode stimulation is 
performed.  Adjustments in the final electrode placement are made based upon clinical 
response of parkinsonian symptoms and sensory and motor thresholds, selecting the 

 
 
Uitti et al - 12 -  
location that provides the greatest reduction in parkinsonian signs without significant side 
effects. 
 
The initial electrode will be placed on the appropriate side contralateral to the 
most severe symptoms, or the dominant hand.  If stimulation demonstrates improvement 
in parkinsonian symptoms at acceptable thresholds, the electrode will be secured in the 
burr hold and placed in a subgaleal pocket.  Immediately thereafter, the hypothalamic 
electrode will be placed, with similar stimulation being employed to confirm proper 
placement. 
 
 
Both hemispheric electrodes will subsequently be joined to extension leads which 
will be connected to an ipsilateral IPG placed in an infraclavicular superficial location. 
 
Follow-Up 
 
All patients will be seen preoperatively and at, 3, , 12, , 24months, and yearly 
intervals in order to adjust medications and stimulation parameters optimally. MRI 
scanning will be completed at baseline, and at yearly  follow up visits. During year 4 and 
5 a member of the study team will call the patient to see if they require additional 
evaluations. 
Evaluations will be performed as outlined in the Summary – Evaluation Protocol 
table. 
 
We will attempt to optimize the use of antiparkinsonian medications following 
surgery in conjunction with DBS parameters.  Patients will be seen up to daily within the 
first week post-operatively for such adjustments and for suture removal. 
 
Data Handling 
 
Data obtained from all evaluations will be recorded on electronic data sheets or  in 
Epic by the principal investigator (R. Uitti) and study coordinator (A. Grassle);  
 
Brain Bank Registry 
 
 
Clinicopathological studies in individuals who have undergone BSUBSTIM may 
be extremely informative and every attempt will be made to obtain autopsy in the unlikely 
event of death during the study.  All patients in the study will be strongly encouraged to 
participate in the registry although this participation is not mandatory. 

 
 
Uitti et al - 13 -  
 
Motor Function Testing 
 
Evaluations 
 
Patients’ motor function will be evaluated pre-operatively and at, 312, 24months, 
and yearly thereafter with quantitative outcome measures, employing standardized motor 
rating scales as have been previously reported by the investigators. (Uitti, Wharen et al. 
1997)  Changes in motor function of both sides of the body will be quantitated. Gait 
assessments may be videotaped if patient agrees, but it is not required. 
 
Motor Function Testing – Drug and Stimulation Profile 
 
During all post-operative visitspatients will be seen “ON” stimulation and “ON” 
medication. Time of last dose of antiparkinsonian medication will be collected. 
 
The following motor function testing battery consists of: modified UPDRS, 
modified Hoehn & Yahr (Hoehn and Yahr 1967) scoring. 
 
 
The motor function tests will be scored  while patient is adhering to normal 
medication schedule and optimal “on” DBS settings.   
 
Neuropsychological testing 
 
A short test of mental status utilizing the Kokmen test will be completed on patients at 3 
month follow up.  The full neuropsychological test battery (see below) will be 
administered at baseline, and at yearly follow-up evaluations. Per normal clinical care 
  Testing will take place annually (within 6-month windows of the exact date). 
 
Post-operative testing will be completed with the patient in an “ON” setting.  
 
Assessment and Statistical Analyses 
 
The primary method of assessing treatment effects will be paired t-tests at the 
various post-operative intervals. 
 
The primary efficacy parameters are neuropsychological battery scores over time 
in comparison with pre-operative scoring. 
 
Secondary efficacy parameters will include UPDRS scoring (motor and activity of 
daily living subscores).   
 
The primary endpoints will be the change in neuropsychological scoring from 
baseline to 12 and 36 months, expressed as a percentage change from baseline 
(employing “on”/”on” post-operative status versus “on” pre-operative values.  Two-sided 
two-sample t-tests will compare post-operative changes to pre-operative data. Such 

 
 
Uitti et al - 14 -  
comparisons will take place when the full contingent of patients are accrued and have 
completed such assessments.   
 
The effect of stimulation on cognitive functioning and mood state will be assessed 
using t-tests for dependent samples to compare performance on neuropsychological tests 
and POMS scores in the “on” and “off” condition at each follow-up evaluation.  Changes 
in cognitive functioning, mood, and HRQOL from presurgical baseline will be analyzed 
using repeated-measures ANOVAs, with neuropsychological test scores as the DV and 
time of testing as the repeated measure. Demographic variables and measures of social 
support and locus of control will be entered into analyses of covariance whenever 
appropriate.  
 
Hierarchical multiple regression analyses will be used to determine the 
relationship between presurgical psychosocial and neuropsychological variables and 
postsurgical outcome, as measured by HRQOL. 
 
 

 
 
Uitti et al - 15 -  
 
 
References 
Benedict, R.H.B., Schretlen, D., Groninger, L., & Brandt, J. (1998).  Hopkins Verbal 
Learning Test - Revised:  Normative data and analysis of inter-form and test-retest 
reliability.  The Clinical Neuropsychologist, 12,  43-55. 
 
Benton AL, Hamsher KD: Multilingual aphasia examination. Iowa City, AJA 
Associates:1983 
 
Benton, A.L., Hamsher, K. deS., Varney, N., and Spreen, O. (1983). Contributions to 
Neuropsychological Assessment.  New York:  Oxford University Press. 
 
Collerton, D. Burn, I. McKeith and J. O’Brien, Systematic review and meta-analysis 
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Crowell, T.A. Luis, CA, Cox, DE, Mullan, M. Neuropsychological comparison of 
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TX: The Psychological Corporation. 
  
 
Summary – Evaluation/Data Collection Protocol 
 
 
Pre-
op 
Post 
-op 
3 
mo 
12 
mo 
24 
mo 
 36 
mo 
Yr 4 
YR5 
Entry criteria 
x 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
Medications 
x 
x 
x 
x 
x 
x 
 
 
Lead Implant Data 
 
x 
 
 
 
 
 
 
Settings 
 
 
x 
x 
x 
x 
 
 
Therapy side effects 
 
x 
x 
x 
x 
x 
 
 
System complications 
 
x 
x 
x 
x 
x 
 
 
Physician evaluation 
x 
x 
x 
x 
x 
x 
 
 
Drug profile motor 
function testing: 
 
 
 
 
 
 
 
 
motor rating scale 
x 
 
 
x 
x 
x 
 
 
MRI Imaging 
x 
 
 
x 
x 
x 
 
 
Memory testing 
x 
 
x 
x 
x 
x 
 
 
Videotaping  
x 
 
x 
x 
x 
x 
 
 
Questionnaires 
x 
 
x 
x 
x 
x 
 
 
Brain bank registry 
x 
 
 
 
 
 
 
 
Phone follow-up 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Uitti et al - 17 -  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Uitti et al - 18 -  
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Benton, A.L., Hamsher, K. deS., Varney, N., and Spreen, O. (1983). Contributions to 
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Uitti et al - 21 -  
Summary required by Mayo IRB: 
 
Tandem DBS for Parkinson’s Disease: A Pilot Study 
 
Summary  
 
Hypothesis 
 
STN and hypothalamic nucleus deep brain stimulation (Tandem DBS) is a safe 
and effective method for minimizing motor and cognitive dysfunction in disabling 
Parkinson’s disease. 
 
Basic study plan 
 
This is a prospective study of Parkinson’s disease outcome following a deep brain 
stimulation procedure.  Twelve Parkinson’s disease patients, with significant disability 
despite optimal medical therapy, will undergo stereotactic placement of unilateral deep 
brain stimulation electrodes (Medtronic 3387 electrode) into the subthalamic nucleus or 
GPi AND the hypothalamus/fornix during a single surgical procedure (Tandem DBS).  A 
single, dual implantable pulse generator will be placed to control both DBS leads.  
Patients will be evaluated pre- and post-operatively (at, 3, 12, , 24months 36-months (and 
yearly thereafter)  with quantitative outcome measures.  The study will include measures 
of motor function, speech, neurobehavior, socioeconomic impact and quality of life. 
 
Statistical method/rationale 
 
The primary method of assessing treatment effects will be paired t-tests at the 
various post-operative intervals. 
 
The primary efficacy parameters are neuropsychological scoring.  Secondary 
measures are UPDRS scoring (motor and activity of daily living subscores) and changes 
in hippocampal volume as measured on MR imaging.   
 
Scientific basis or justification 
 
Parkinson’s disease is a common neurodegenerative disorder with no treatment 
that definitively alters the natural progression of the condition.  With progression of 
symptoms, patients with Parkinson’s disease (PD) frequently develop significant 
disability despite optimal medical therapy. This study is designed to test a new 
technology for the treatment of severe PD. 
 
Currently available surgical treatments, such as pallidotomy, GPi-DBS, and STN-
DBS, offer some benefit for selected patients but do not influence cognitive dysfunction.  
Reports concerning cognitive benefit have documented potential improvement with 

 
 
Uitti et al - 22 -  
placement of DBS electrodes and stimulation in the fornix/hypothalamus in normal and 
patients with mild Alzheimer’s disease. 
 
We propose a pilot study of tandem DBS in 12 PD patients experiencing disability 
despite optimal medical therapy.  The subthalamic nucleus and substantia nigra reticulata 
are crucial output nuclei in the cortico-basal ganglia-thalamic anatomy in which abnormal 
physiological activity have been described in animal models of parkinsonism and 
confirmed in human PD.  DBS of STN bilaterally has been shown to ameliorate 
parkinsonism in both settings.  The substantia nigra reticulata is an output nucleus that 
shares neurophysiological function with the internal segment of the globus pallidus or 
medial pallidum.  Lesioning or DBS of the medial pallidum have both been shown to 
improve parkinsonism in animal models and human parkinsonism.  We believe that DBS 
of both STN and hypothalamus would prove optimal in terms of reducing both 
parkinsonian and cognitive signs and symptoms. 
 
Our surgical technique (MRI-microelectrode-guided procedure) allows for the 
implantation of bihemispheric DBS leads and pulse generator within the space of 3 hours.   
 
Inclusion/exclusion criteria 
 
Inclusion criteria 
 
All patients will be enrolled from the practice of the primary investigator.  It is anticipated 
that PD patients eligible for this study will range from 40-80 years and will have been 
symptomatic with parkinsonism for 7-20 years.   
 
The study will include PD patients in whom optimal medical therapy has failed to relieve 
the patient from significant disability owing to parkinsonism.  PD will be diagnosed by 
the principal investigator on the basis of the presence of at least 2 of 3 cardinal features of 
parkinsonism (resting tremor, rigidity, and bradykinesia) without known cause.  Patients 
with prominent and early dysautonomia or ataxia or downgaze palsy or pyramidal signs 
will be excluded.  Response to levodopa should be specified as more than minimal 
(reductions in UPDRS motor scoring of 20% or greater when “off” scores are compared 
to “on” scores during the drug motor response profile) and as sustained (e.g. for at least 
five years). 
 
All patients will have responsivity to levodopa (as defined by UPDRS changes above).  
Common causes for significant disability will be intractable tremor, levodopa-induced 
dyskinesias and other motor fluctuations.  Optimal medical therapy will consist of 
appropriate use of levodopa and at least one dopamine agonist under the direction of the 
principal investigator.   
 
Exclusionary criteria  
 
• clinically significant dementia (MMSE <23) 

 
 
Uitti et al - 23 -  
• Hoehn & Yahr (Hoehn and Yahr 1967) stage V disease 
• other significant neurological or psychiatric disease 
• previous pallidotomy or thalamotomy 
• previous placement of other implantable devices 
• secondary parkinsonism (non-idiopathic parkinsonism) 
• inability to travel to Jacksonville for post-operative study visits 
• women who are not post-menopausal 
 
 
 
Monetary considerations 
 
We are requesting provision from Medtronics of twelve (12) 3387 DBS leads and 
extensions.  We may also utilize Boston Scientific electrodes as clinically indicated.  
Reimbursement for the procedure will be requested from patient medical insurance 
carriers.  Mayo Clinic in FL will absorb all costs associated with the study (physician 
time and clinic visits). Additional funding has been obtained to cover the costs associated 
with MRI scanning.