Transcript JacobsR_AdvancesintheTreatmentofPD

Advances in the Treatment of Parkinson’s
Disease
Rennie U. Jacobs, MHS, LOTR, CHT
What do you know about Parkinson’s
Disease?
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What are the cardinal symptoms?
Where is the damage in the brain?
What neurotransmitter is lacking?
How quickly does it progress?
What type of neurologist/neurosurgeon treats PD?
What can therapist’s do to help?
Basal Ganglia – Actually Nuclei (5)
•Caudate
•Putamen
•Globus Pallidus
•Lateral segment
•Medial segment
•Subthalamic nucleus
•Substantia Nigra
•Pars compacta
•Pars reticulata
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Basal Ganglia
Subcortical
Extrapyramidal
Deep within the cerebral hemispheres, deep
to white matter
No outputs to LMN
Essentially a feedback loop as a result of
parallel circuits w/ the cerebral cortex by
way of the thalamus
“Smooths” behavior by influencing cerebral
cortex through assisting in action selection
Function primarily through disinhibition
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Neurotransmitter Specificity
Efferent Axons
GABA (-)
GABA (-)
GABA (-)
GABA (-)
Dopamine (+)
GABA (-)
Glutamate (+)
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Nolte, 19.1
Damage to the Basal Ganglia
Movement disorders:
Hypokinetic
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Parkinson’s disease (loss of dopanergic neurons in SNc)
Parkinsonisms
Hyperkinetic
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Hemiballism (loss of subthalamic nucleus)
Tics/Tourette’s (smaller BG on one side, usually left)
Huntington’s Chorea (atrophy of caudate and putamen)
Tardive dyskinesia (overmedication with antipsychotic/antidopanergic
drugs)
Direct vs. Indirect Pathways
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DIRECT PATHWAY: facilitates behavior
Net effect:
Increased
activity of the
thalamus and
subsequent
excitation of
cerebral cortex
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INDIRECT PATHWAY: suppresses behavior
Net effect:
Decreased
activity of the
thalamus and
subsequent
suppression of
cortical
activity
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Parkinson’s Disease
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Parkinson’s Disease (PD)
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Progressive and debilitating
affects 1 in 100 people (1%) over age 60
It is suggested that at least 1 million people in the
US suffer from PD, mean age onset of symptoms is
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First characterized extensively by James Parkinson
in 1817
Primarily ideopathic
Possible causes of Parkinsonism: genetics (younger
patients), environmental toxins (MPTP), and head
trauma (pugilistic Parkinson disease)
Pathophysiology
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Loss of dopaminergic neurons in substantia nigra
compacta
Decreased nigrostriatal projections
Increased activity of “indirect pathway”
http://neurophilosophy.wordpress.com/2006/07/05/dopamine-receptor-agonist-stimulates-neurogenesis-leads-tofunctional-recovery-in-parkinsonian-rats/
PD Symptoms – Vary in severity
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Cardinal symptoms:
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Rigidity
Resting tremors
Akinesia and Bradykinesia
Loss of postural reflexes > instability
Diagnosis of PD
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No tests available to diagnose PD
Symptom presentation are hallmarks of disease
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2 or more
Often begin unilaterally then progress to bilateral,
asymmetry common
Responsiveness to Parkinson’s medications used as
evidence of disease
Can be misdiagnosed as medication induced PD,
essential tremor, normal pressure hydrocephalus,
progressive supranuclear palsy
Unified Parkinson’s Disease Rating Scale UPDRS
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Unified and accepted mechanism for following the
progression of PD
Part I - Mentation, behavior, and mood
Part II - Activities of daily life (ADLs)
Part III – Motor
Part IV – Hoenh and Yahr scoring of severity (0-5)
Part V - Schwab & England Activities of Daily Living
Scale
“OFF – ON Challenge”
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Treatment of PD
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Medications
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Dopamine Replacement Therapies
Dopamaine agonists
MAO-B inhibitors – prolong effects of dopamine
Surgeries
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Ablative surgery
 Pallidotomy (GPi)
 Thalamotomy (ventral intermediate nucleus)
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Deep brain stimulation
 Gpi
 STN – sensorimotor portion (dorsolateral)
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Deep Brain Stimulation (DBS)
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high-frequency electrical stimulation of specific brain
targets
Shuts down activity at the site
Mimics the effect of a lesion without the need for
destroying brain tissue
Advantages:
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Doesn’t require making a destructive lesion
Can be performed bilaterally with relative safety
Stimulation parameters can be adjusted postoperatively to improve
efficacy, reduce adverse effects, and to adapt to the progression of
the disease
Reversible, therefore doesn’t preclude the use of possible future
therapies for PD
STN General Topography – DBS Target
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Challenges to DBS
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Direct visualization of nuclei difficult
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Cho et al. found superiority of using 7-T MR imaging
(compared to 1.5- and 3-T), enabling authors to visualize STN
and GPi on T2-weighted images.
Lack of visualization makes targeting nucleus difficult
Once in nucleus, difficult to determine where you are and
what the ideal placement of the electrode will be
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How Can We Utilize
Neurophysiological Data to Better
Describe STN?
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Is There a Homunculus?
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Presence of a sensorimotor map would better guide
surgical procedures, theoretically resulting in better
outcomes
Primate studies have described the presence of a
somatopic map in the motor territory of the primate
STN
Several groups have performed human studies and
developed a proposed map, however there is opportunity
and need for more rigorous, exact correlations
statistically.
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How Can We Utilize Neurophysiological
Data to Better Describe STN?
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Specific Aim: Test the hypothesis that that the human STN has
an organization similar to that in normal monkey, and that with
disease progression, surviving cells develop enlarging receptive fields
as a compensatory mechanism with resultant “blurring” of regional
distinctions within the nucleus.
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Significance: The suggestion of a homunculus has guided surgical
procedures in the past. This current study has great potential in
contributing fundamental understanding of the individual
variation in the mapping characteristics between patients as
the disease progresses. We aim to clear an area of ambiguity in
the neurosurgery literature by using statistical analysis to
describe the sensorimotor representation in the human STN
of patients with PD, as well as determine if there is a scale of
despecification with the progression of the disease. Results
from this study may have immediate effect on surgical practices
worldwide.
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Human Studies
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Romanelli P; Heit G; Hill BC; Kraus A;
Hastie T; Brontë-Stewart HM (2004)
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Microelectrode Recording Revealing a Somatotopic Body Map in the
Subthalamic Nucleus in Humans with Parkinson Disease
Journal of Neurosurgery, Vol. 100 (4), pp. 611-8.
Retrospective review of intraoperative electrophysiological data
Used velocity sensors to record joint motions
Although some single neuronal responses were observed, recordings were
primarily from more than one cell, or “unit recordings”
Position and type of each unit’s response was recorded on scaled graph
paper > transcribed on clear film
Film overlaid on scaled parasagittal plane map of target region to compare
the physiological data with atlas
This constituted their electrophysiological spatial map
Analysis of the spatial relationships b/w STN units w/ UE and LE
somatosensory driving showed leg-related units located medially and
ventrally to arm-related units
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Theodosopoulos PV; Marks WJ Jr; Christine
C; Starr PA (2003)
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Locations of Movement-Related Cells in the Human Subthalamic Nucleus in
Parkinson’s Disease
Movement Disorders, Vol. 18(7), 791-798.
Utilized single microelectrode penetrations (range 1-7, mean 3.8)
Cells were considered movement-related if they exhibited modulation of the
cell discharge during passive movements
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15 procedures analyzed
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Audible alterations synchronous with the movement
Presence of at least seven movement-related cells distributed among at least three tracks
Selected microelectrode tracks were localized on the STN referencing the
Schaltenbrand and Wahren human brain atlas and post-op visualization of the
DBS lead MRI
Statisical analyses were performed to determine if arm-related and leg-related
cells had different distributions
Proportion of leg cells over arm cells in medial half of nucleus (Fischer’s twotailed exact test)
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Rodriguez-Oroz MC; Rodriguez M; Guridi J; Mewes
K; Chockkman V; Vitek J; DeLong MR; Obeso JA.
(2001)
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The Subthalamic Nucleus in Parkinson’s Disease: Somatotopic Organization and
Physiological Characteristics
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Brain,Vol. 124, 1777-1790.
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EMG activity of tibialis anterior and extensor carpi radialis recorded
simultanteously with neuronal recordings
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Neurons with sensorimotor responses noted intra-operatively and relative
position in the tract was noted using x and z coordinates (mediolateral (x) and
dorsoventral (z))
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DBS lead placement on post-op MRI was used as objective reference
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From medial to lateral, proportion of neurons responding to movement of leg
decreased, while arm increased
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77% of arm cells were in lateral planes (>12mm)
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51% of leg cells were medial to 12mm plane
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Abosch A; Hutchinson WD; Saint-Cyr JA;
Dostrovsky JO; Lozano AM. (2002)
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Movement-Related Neurons of the Subthalamic Nucleus in Patients with
Parkinson Disease
J Neurosurg, Vol 97, 1167-1172.
Intraoperatively, cells were tested for response to passive motion
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Reproducible , audible change in firing rate
Recorded and time-locked to the movement of the specific joint
Electrophysiological data retrospectively collected from microelectrode
recordings
Analysis of receptive fields obtained along individual electrode tracks through
the STN did not reveal any consistent pattern of somatotopic organization
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Experimental Design
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IRB Approval, Patient Selection, Consent
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IRB approval received 9/2009 (#7320)
Patients undergoing DBS to STN for relief of
symptoms related to PD meet criteria for study
To date, 6 patients enrolled in study and properly
consented
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4 bilateral
2 unilateral
Microelectrode Data
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MicroGuide™ System (Alpha Omega Company,
Alpharetta, Georgia, US)
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Microelectrodes are connected to the
recording tower, which collects and
stores data from 1-5 channels
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Measurement of Joint Position – Electronic
Goniometers
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PASCO® PASPORT goniometer sensors and probes
PASCO ® PowerLink
Collects angle, velocity, acceleration at each joint
Capable of writing data to text files for further analyses
Range
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Accuracy
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<1% of measurement
Sampling Rate
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0 – 340° (-170° to +170°)
100Hz
All needed equipment
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~$1000
Data Collection - Methods
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Patient is brought to OR
Electronic goniometers are attached to patient and input to an instrument hub
(PASCO Powerlink, PASCO, Roseville, California, US)
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Contralateral elbow, hip, and knee (e.g. DBS to right brain, goniometers on left limbs)
Data Collection - Methods
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A digital adapter is wired from a Data Acquisition Board (DAQ) digital output
to the PASCO Powerlink
Microelectrode activity wired directly from splitters sending duplicate data to
the Micro-Guide System an the DAQ board
Both PASCO Powerlink and DAQ board are connected to a single research
laptop via USB
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Data Collection - Methods
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Neurosurgeon preps patient for microelectrode recording
Software capable of collecting joint motion data and microelectrode data are
started
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Data Collection - Methods
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Neurophysiologist begins advancing the microelectrodes through the brain
Data are taken beginning 15 mm above what is expected to be the bottom of
the STN based on trajectory planning
At each 0.5 mm, the research assistant passively moves the patient’s elbow, hip,
and knee separately in both flexion and extension
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Data Collection - Methods
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Recordings are continued in 0.5 mm increments until the cellular activity
indicates that all 5 microelectrodes have passed completely through the STN
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Response more indicative of substantia nigra or white matter
Software is stopped, and all data are saved for post-surgery conversion
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Research Equipment and Flow of Data
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Establishment of a Single Chronological
Frame of Reference - ClockSynch
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Visual Basic .NET (VB.NET) program
Created by Tyler Moore, BS, LSUHSC School of Medicine
Collects microelectrode data at 25 kHz via a Data
Acquisition Board (USB-6212 DAQ Board, National
Instruments, Austin, TX)
Sends random digital pulses to PASCO software via
PASCO Powerlink
Data is stored in binary file during surgery
Post-operatively, ClockSynch capable of converting binary
files to tab-delimited text files
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Preliminary Results
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Preliminary Results - Spatial Atlas of STN
Depth of 10.5
Depth of 3.5
Depth of 1.5
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Preliminary Results - Spatial Atlas of STN
Depth of 10.5
Depth of 3.5
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Statistical Analysis – Sensorimotor
Representation of STN
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MATLAB R2009a
Ted Weyand, PhD, LSUHSC
Data files were reduced to a more maneagable size by
converting ascii files to 16 bit binary format
Data were then subject to a Gaussian filter to smooth the data
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Take the absolute value of all points
Averaged every 5 data points to begin smoothing filter
Data divided into epochs that are considered signal if
exceeding 2.5 sdu
Resulting data then subject to Boolean logic
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>threshold = 1
<threshold = 0
Statistical Analysis
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Final product: Data reduced and displayed at a lower
resolution (10Hz) to match goniometer data
Excess of 2.5 sdus considered an “event”
Greater than 5-10 degrees of change of motion
considered “event”, event expanded to cover 500 ms
Chi-square analysis done to test for goodness of fit
between cell activity and goniometer data.
Results used to generate a 3-dimensional map of motorrelated activity in space
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3-Dimensional Map
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Future Research
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Future Research
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Spatial atlas –
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This spatial matrix can be further developed in such a way that
a trainee can select target and entry points of their own
choosing and perform virtual microelectrode recording along
the resulting trajectory, allowing for practice outside of the
clinical and time constraints of the operating room and
improved learning.
This simulation tool has implications to assist surgeons in
trajectory mapping, surgical procedure, and discrimination of
cellular activity.
Future Research
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Sensorimotor Representation –
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ideally would like single cell analysis but signal:noise ratio
typically not high enough
Looking at cross-correlation across electrode sites
Storage of activity patterns for analysis to better understand
potential prognosis, with a better understanding of how lack of
dopamine alters endogenous activity patterns.
Therapist’s Role
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Therapist’s Role
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Advocate for your clients pre-operatively
Assist w/ client education re: disease process, as well as
medical management options
Perform outcome measures to determine gains made
from surgery
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What do you know about Parkinson’s
Disease?
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What are the cardinal symptoms?
Where is the damage in the brain?
What neurotransmitter is lacking?
How quickly does it progress?
What type of neurologist/neurosurgeon treats PD?
What can therapist’s do to help?
Questions????
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Thank You!
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