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Cerebrospinal fluid norepinephrine reductions in man after degeneration and electrical stimulation of the caudate nucleus.

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Cerebrospinal Fluid Norepinephrine
Reductions in Man after Degeneration
and Electrical Stirnulati& of
the Caudate Nucleus
James H. Wood, MD, Michael G. Ziegler, MD, C . Raymond Lake, MD, PhD,
Ira Shoulson, MD, Benjamin R. Brooks, M D , and John M. Van Buren, M D , P h D
Lumbar cerebrospinal fluid (CSF) norepinephrine concentrations determined by radioenzymatic assay in 9 patients
with caudate atrophy associated with Huntington’s disease were lower ( p < 0.02)than those i n 9 age- and sex-matched
control patients.
Preoperative lumbar CSF norepinephrine concentrations were determined in 5 patients undergoing stereotaxic
thalamotomy. No significant alterations in prestimulation lumbar CSF norepinephrine levels were recorded 12
days after electrode installation and thalamic coagulation. Lumbar CSF norepinephrine concentrations were reduced
( p < 0.03), however, 1 2 hours following intermittent selective electrical stimulation of the caudate nucleus.
These data suggest that noradrenergic pathways in man are ( 1 ) impaired in Huntington’s disease and (2) inhibited
by direct caudate stimulation.
Wood JH, Ziegler MG, Lake CR, et al: Cerebrospinal fluid norepinephrine reductions in man after
degeneration and electrical stimulation of the caudate nucleus. A n n Neurol 1:94-99, 1977
Attempts to ameliorate the characteristic choreic
symptoms of Huntington’s disease by blocking
dopaminergic transmission [ 11 or compensating for
choline acetylase [2, 31, serotonin [4-61, and gammaaminobutyric acid (GABA) [ 71 deficiencies have
yielded limited or n o benefit. To date, the role of
noradrenergic pathways in the pathophysiology of
Huntington’s disease has not been determined. The
first segment of our study evaluates cerebrospinal
fluid (CSF) norepinephrine reductions in patients
with Huntington’s disease and caudate atrophy.
Neuronal degeneration within the caudate nucleus
is a consistent finding in autopsy material from patients with Huntington’s disease [8], and loss of caudate function might contribute to the symptoms of this
disorder. Reasoning from recent successes with cerebellar stimulation in epileptic patients with cerebellar
atrophy [9- 111, extrinsic stimulation of the remaining
intact caudate neurons might then compensate for the
pathological reduction in caudate function secondary
to atrophic changes. In accordance with such a
hypothesis, caudate stimulation would be expected to
result in evoked neurotransmitter alterations that
would oppose those noted in patients with caudate
atrophy. Incorporating depth electrodes capable of
selective stimulation at precise intervals along the
shaft [ 121 and recently developed methods for accurate determination of norepinephrine levels in human
CSF [13, 141, the second segment of this study
evaluates the response of CSF norepinephrine concentrations to electrical stimulation of the human
caudate nucleus.
A preliminary abstract concerning this investigation
has been published [14a].
From the Surgical Neurology, Medical Neurology, and Clinical
Neurosciences Branches, National Institute of Neurological and
Communicative Disorders and Stroke, and the Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
Accepted for publication July 2 7 , 1776.
Materials and Methods
The caudate atrophy study included 9 patients with the
clinical diagnosis of Huntington’s disease and a mean age of
53 * 2 (SEM) years (Table 1). Caudate atrophy was verified
by computerized axial tomography (Fig 1) in 2 patients and
by autopsy examination in a third patient with Huntington’s
disease. For comparison, we studied 9 age- and sex-matched
control patients with myasthenia gravis, peripheral
neuropathies excluding clinical autonomic involvement,
vascular malformations without subarachnoid hemorrhage,
intrasellar nonsecreting pituitary adenoma, or mild spinal
Address reprint requests to Dr Wood, Division of Neurosurgery,
The University of Pennsylvania School of Medicine, 3400 Spruce
St, Philadelphia, PA 19104.
Table I . Clinical and Laborirtory Data on Patients with Huntington's Disease and Control Patient.{
No., Age,
and Sex
1. 40, M
2. 46, M
3. 50, M
4. 52, F
5. 53, M
6. 53, M
7. 54, M
8. 61, M
9. 64, M
53 ? 2"
CSF Norepinephrine
Conccntrations (urrlml)
Huntington's disease
Huntington's disease
Huntington's disease
Huntington's disease
Huntington's disease
Huntington's disease
Huntington's disease
Huntington's disease
Huntington's disease
171 i 18"
No., Age,
and Sex
10. 38, M
11. 47, M
12. 47, M
13. 51, F
14. 51, M
15. 53, M
16. 55, M
17. 67, M
18. 67, M
5 3 i- ?a
CSF Norepinephrine
Concentrations (pglml)
Pituitary adenoma
Spinal cord AVM
Neuropath y
Occipital AVM
Neuropath y
Myasthenia gravis
Spond y losis
Myasthenia gravis
2 34
239 ? 17h
"No significant difference in mean age between patients with Huntington's disease and control patients.
'Significant reductions ( p < 0.02, two-tailed Student t-test) in cerebrospinal fluid norepinephrine levels i n patients with Huntington's disease
compared with control patients.
arreriovenous malformation; SEM
standard error about rhe meaii
Fig I . Computerized axial tomograms, without contrust
enhancement, of (A) control Putient 10 with intrasellar
pituitary adenoma and iB) choreic Patient 8 with Battened
caudate nucleus (arrows), cortical atrophy, and ex fi'acuo
ven triular enlargement ,
Wood et al: CSF Norepinephrine and Caudate Nucleus
spondylosis (Table 1).The mean age of the control patients
was 53 2 3 years.
The caudate stimulation study [12] included 1 patient
with intractable thalamic pain following evacuation of a left
thalamocapsular hematoma, 1 patient with right hemiparkinsonism, 1 patient with spasmodic torticollis and retrocollis, and 2 patients with dystonia musculorum deformans
(Table 2). Their mean age was 38 & 8 gears.
O n admission, all patients were placed on a low
monoamine diet and medications were discontinued. All
oral intake and physical activity were avoided during the 18
hours preceding each lumbar puncture. Lumbar punctures
were performed in the lateral decubitus position at 3 PM on
both the patients with Huntington’s disease and the control
patients and at 3 AM on the patients in the stimulation study.
A t lumbar puncture, a 4 ml aliquot of CSF was collected in a
tube containing 10 mg of ascorbic acid after 15 ml of CSF
had drained from the spinal needle. This sampling technique
was intended to promote CSF circulation from the ventricular outlets to the lumbar sac. After collection, CSF samples
were placed on ice for less than 30 minutes before storage at
-70°C [13]. The norepinephrine content of each CSF sample was determined by a radioenzymatic assay technique
[13, 141 and reported in picograms per milliliter.
Among the 5 patients involved in the stimulation study,
lumbar CSF samples were obtained prior to thalamotomy.
At operation, ventricular landmarks were established by
pressure ventriculography [ 151. Using a previously described procedure [16], the coagulating tips of the depth
electrodes were inserted stereotaxically i n t o the nuclei
medialis centralis of the patient with thalamic pain and into
the nuclei ventralis intermedius of the 4 patients with
abnormal movements (Fig 2). The flexible electrode shafts,
containing stimulating contacts at 5.0 mm intervals (Fig 3 ) ,
passed chrough che caudate nucleus. Detailed descriptions
of these coagulating depth electrodes have been presented
previously [ 121. After incremenral coagulation of the
thalamic targets [17, 181, the electrode shafts were attached
to the scalp using small nylon clamps [191 prior to the
patient’s return to the ward. All patients received prophylactic antibiotics.
Cerebrospinal fluid samples were collected 1 2 days after
the installation of electrodes and coagulation of thalamic
targets in order to evaluate the contribution made by the
surgical procedure to CSF alterations observed after caudate
stimulation. After the electrode position was verified by
calibrated radiography, those contact points along the electrode shaft within the caudate nucleus were stimulated at
15-second intervals for 10 minutes using biphasic 8 to 10
mA, peak-to-peak, 2.5 msec square waves at 60 Hz frequency. The final postoperative CSF samples from these
patients were obtained 12 hours following caudate stimulation to allow the ventricular fluid to diffuse to the lumbar
CSF according to normal circulation patterns 1201. Thereafter, the respective thalamic targets were recoagulated prior
to electrode removal.
Unpaired and paired Student’s two-tailed t-tests were
used to estimate the significance of results i n the caudate
atrophy and caudate stimulation studies, respectively.
T h e m e a n CSF n o r e p i n e p h r i n e concentration of 17 1
? 18 pg/ml i n t h e 9 patients with H u n t i n g t o n ’ s disease
and caudate atrophy was lower than t h e 239 +- 17
pg/ml (p < 0.02) i n t h e 9 age- a n d sex-matched c o n t r o l
patients (see T a b l e 1).
The m e a n CSF n o r e p i n e p h r i n e concentration i n t h e
Table 2.Clinzral aiid Lboratorj Data o n PutzentJ i n Caudate hrflrleus S t ~ m u f a t m Stady
No., Age,
and Sex
19. 16, M
20. 27, M
21. 38, F
22. 45, M
23. 63, F
Thalamic pain
Right hemiparkinsonism
38 ? 8
CSF Norepinephrine
Concentrations before
Electrode Insertion
CSF Norepinephrine
Concentrations 12
Days after Electrode
Insertion (t.g/ml)
CSF Norepinephrine
Concentrations 12 Hours
after Caudate Nucleus
Stimulation (pg/ml)
42 7
. . .
48 2
455 -+ 30”
327 t 27“.h
aSignificant reductions (/I < 0.01, two-tailed paired Student t-test) in cerebrospinal fluid norepinephrine levels after caudatc stimulation
compared with preoperative CSF norepinephrine concentrations.
”Significant reductions (I<: 0.03) in CSF norepinephrine levels after caudate stirnulation compared with postnpcrativc, prestimulation CST;
norepinephrine concentrations.
standard error about the mean.
96 Annals of Neurology
Vol 1 No 1 January 19-7
Fig 2. Caldwellposteroanteriorand lateralskull radiographs of
Patient 23 after thalamotomy. Coagulating tip ofjexible depth
electrode is located within left thalamus. Arrows indicate
stimulating points along electrode shaft passing through IeJt
caudate nucleus.
F i g 3. Coagulating depth electvode u i t h stimulating contucts a t
5.0 mrn intervals along jexible shuft.
mencia and chorea [ 8 , 2 11. At necropsy, atrophy with
cell loss is noted in the caudate nucleus, the putamen,
and the third, fifth, and sixth layers of the cerebral
cortex [21]. In addition, degeneration has been noted
in the cerebellum [22] and ventrolateral thalamus
[23]. As opposed to Parkinson’s disease, the dorsal
compact zone of the substantia nigra is intact, but
some neuronal loss may be noted in the ventral reticular zone [24].The degenerative changes noted in our
autopsied patients with Huntington’s disease were in
accordance with these pathological findings. Caudate
flattening, cortical atrophy, and ex vacuo ventricular
enlargement were verified using computerized axial
tomography in 2 patients with the clinical diagnosis of
Huntington’s disease.
Neurochemical analysis of postmortem brain material from patients with Huntington,s disease has revealed reductions in the concentration of dopamine
and of its major metabolite, homovanillic acid, in the
caudate nucleus [25]. Both GABA and homocarnosine, a related dipeptide, were found to be decreased in the substantia nigra, putamen-globus pallidus, and caudate nucleus [26]. Reductions in the
steady-state levels of homovanillic acid [27, 281 and
GABA [29] have been reported in the lumbar CSF of
patients with Huntington’s disease. Brain neurochemical alterations may therefore be reflected by changes
in lumbar CSF. Increasing CSF norepinephrine concentrations have been noted in successive lumbar CSF
aliquots collected from patients with Huntington’s
disease [ 131. This increasing CSF norepinephrine
concentration plateaus after 12 ml of CSF has been
drained. and remains constant in later aliquots [30].
The CSF norepinephrine may either reflect brain
norepinephrine content or be derived from noradrenergic terminals in the spinal cord whose cell bodies
are located in a brainstem region such as the locus
ceruleus [30, 311.
5 patients in the caudate stimulation study was 455 t
30 p d m l preoperatively and 477 & 58 p d m l 12 days
after electrode installation and thalamic coagulation.
Thus, the stereotaxic procedure did not contribute
significantly to the stimulation-evoked alterations in
CSF norepinephrine. Twelve hours after caudate
stimulation, the mean CSF norepinephrine concentration was 327 5 27 p$ml and was lower than either the
preoperative (p < 0.01) or postoperative prestimulation mean level (p < 0.03) (see Table 2).
Huntington’s disease, a degenerative brain disorder of
early o r middle adult life, is inherited as an autosomal
dominant trait with complete penetrance. The disease
follows a relentlessly progressive course, with death
occurring 12 to 15 years following the onset of de-
Wood et al: CSF Norepinephrine and Caudate Nucleus
Galvanic skin reflexes [32] and vasoconstrictor reflexes 132, 331 evoked in the cat’s paw by radial nerve
stimulation are decreased in amplitude by electrical
stimulation of the caudate nucleus. Clonidine, a centrally acting hypotensive agent, depresses brainstem
sympathetic outflow [34]and norepinephrine concentrations [351. Recent communications [351 suggest
that the caudate nuclei modulate the blood pressure
centers in the brainstem and hypothalamus and play a
role in the postural regulation of blood pressure. The
finding of decreased levels of CSF norepinephrine
among our patients with Huntington’s disease may
have clinical significance with respect to recent reports of central autonomic and vasoregulatory dysfunction in choreic patients [36, 371.
The report of exogenous norepinephrine release
into ventricular perfusates during electrical stimulation of rhe cat caudate nucleus [38] does not suggest
that endogenous norepinephrine is released by caudate stimulation. Evidence indicates that norepinephrine does not play a major role in interneuronal
transmission within the caudate nucleus. Dopamine-/3-hydroxylase, a necessary enzyme for the synthesis of norepinephrine, is not present in the
caudate nucleus [39], and caudate norepinephrine
concentrations are minimal [40]. Therefore, norepinephrine alterations induced by caudate stimulation would have to be secondary to synaptic events
distant to the caudate nucleus. Regardless of the
source of CSF norepinephrine, our findings imply that
further depression of noradrenergic activity by extrinsic electrical stimulation of the caudate nucleus should
not be expected to benefit patients with Huntington’s
The authors are grateful to Dr William F. Caveness of the Laboratory of Experimental Neurology, National Institute of Neurological and Communicative Disorders and Stroke, National Institures
of Health, for sponsorship of this paper, and to Dr Mahlon R.
DeLong of the Department of Neurology, The Johns Hopkins
Hospital, for his valuable suggestions. In addirion, we are indebted
to Shane W. Potter, George J. Palmer, Randall Ryan, Steve
Hookanson, and John Mann for their technical assistance.
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Wood et al: CSF Norepinephrine and Caudate Nucleus
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