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Dexamethasone and local cerebral glucose utilization in freeze-traumatized rat brain.

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Dexamethasone and h c a l
Cerebral Glucose Utilization in
Freeze-Traumatized Rat Brain
H. M. Pappius, PhD
Local cerebral glucose utilization (LCGU) was studied using the 14C-deoxyglucosemethod in dexamethasonetreated rats with focal cortical freezing lesions. Widespread depression of LCGU, which developed with time after
the lesion in untreated animals, was significantly diminished by dexamethasone (0.25 mg/kg/day) started either 6 to
18 hours before or 4 or 2 4 hours after the lesion. The effect of dexamethasone was most striking in cortical areas of the
traumatized hemisphere, where the depression was most profound in untreated animals. Thus, three days after the
lesion, average LCGU in these regions was 47% and 72% of normal in untreated and pretreated rats, respectively.
Dexamethasone also affected LCGU bilaterally in subcortical structures and in white matter. The results suggest
that dexamethasone modified the widespread depression in functional state of the rat brain that developed in response to injury. Since the spatial distribution and time course of the observed changes in LCGU did not parallel
those of cerebral edema, these effects of dexamethasone do not appear to be mediated by effects on the edematous
process.
Pappius HM: Dexamethasone and local cerebral glucose utilization in freeze-traumatized rat brain.
Ann Neurol 12:157-162, 1982
Materials and Methods
Freezing lesions standardized to produce superficial focal
cortical injury in the rat were made in the left parietal region of halothane-anesthetized male Sprague-Dawley rats
(weight, 280 to 320 gm) by applying a freezing probe
(-50°C) for 5 seconds through a 4 x 4 mm opening in the
skull. After the lesion was made, the wound was sutured
and the animals were allowed to awaken.
Dexamethasone (Decadron phosphate; Merck Sharp &
Dohme, Kirkland, Que), 0.25 mg per kilogram of body
weight per day in two divided doses, was given starting 6 to
18 hours before the lesion in pretreated animals and 4 or
24 hours after the lesion in posttreated animals. This regi-
men was continued until the animal was killed. In one
group of posttreated animals the dose was increased to 2.5
rndkglday. Animals without lesions that were not treated
with dexamethasone or that were given dexamethasone for
two or four days served as “normal” and “dexamethasone”
controls, respectively.
‘‘C-Deoxyglucose studies were carried out in awake rats
at specified times (4 hours to five days) after the lesion was
made. Evans blue dye (2%; 0.35 ml per rat) was injected
intravenously before the start of the deoxyglucose study to
determine the state of the blood-brain barrier at each time
period following the lesion.
The physiological state of the awake animals was assessed
by monitoring arterial blood pressure and rectal temperature and by measuring blood gases prior to and during the
deoxyglucose study. Values obtained for these variables in
15 normal animals before the start of the deoxyglucose
studies were (average -+ SEM): mean arterial blood pressure, 121 -+ 3 mm Hg; rectal temperature, 37 t 0.1”C;
arterial oxygen tension, 77 -+ 1 mm Hg; arterial carbon
dioxide tehsion, 32 ? 1 mm Hg; and pH, 7.43 2 0.1; the
values remained in this range till the end of the experiment.
The rats with cortical lesions, whether treated with dexamethasone or not, were in a similar physiological state.
However, all dexamethasone-treated rats had significantly
higher blood glucose levels than the normal or lesioned
From the Department of Experimental Neurochemistry, Montreal
Neurological Institute, and the Department of Neurology and
Neurosurgery, McGill University, Montreal, Que, Canada.
Address reprint requests to Dr Pappius, Department of Experimental Neurochemistry, Montreal Neurological Institute, 3801
University St, Montreal, Que, Canada H3A 2B4.
Unilateral focal freezing lesions have been found to
depress local cerebral glucose utilization (LCGU) in
all areas of rat cortex in the traumatized hemisphere
and to reduce it to a lesser extent in the contralateral
hemisphere [4].Some depression in LCGU has also
been noted bilaterally in subcortical structures and in
the white matter. The metabolic depression was not
associated with a diminished blood supply. The present investigation shows that dexamethasone, given
either before or after the lesion, ameliorates these
effects of trauma in rat brain.
Received Aug 28, 1981, and in revised form Oct 27. Accepted for
publication Nov 7, 1981.
0364-5 134/82/080157-06$01.25 @ 1981 by the American Neurological Association
157
Table I . Locdl Cerebral Glucose Utilization in Selected Areas of Traumatized Rat Brain after Pretreatment with Dexumethasonea
Time Lapse following Freezing Lesion
1 Day
N o Lesion
Brain Site
Lesioned hemisphere
Cortical areas
Visual
Sensorimotor
Olfactory
Subcortical structures
Superior colliculus
Lateral thalamus
Brainstem structures
Inferior colliculus
Lateral lemniscus
White matter
Corpus callosurn
Internal capsule
Hemisphere contralateral t o lesion
Cortical areas
Visual
Sensorimotor
Olfactory
Subcortical structures
Superior colliculus
Lateral thalamus
White matter
Corpus callosum
Internal capsule
Not
Treated
(N = 1 5 )
Treated
(N = 8 )
94
102
106
:+
94 t 4
102 t 5
94 t 5
59 t 7 h
7 3 L 9h
72 8h
*
*
_t
3
4
3
96 t 5*
105
3d
94 i 4'
44 t 2 h
45 t 3*
57 t 2h
66 t 3*
78 5 5 d
90 ? 4d
80
:+
2
99 + 2
82 t 6
100 t 5
62 r 4b
70 t 7h
82 t 3"
86 2'
65 t 4h
6 4 2 3h
68 t 3
83 4*
5
5
162 i 7
96 t 6
164 t 15
90 t 7
41 t 2
36 2
36 t 2
31 ? 2
24 t 3h
23
2h
33 t I d
31 t 2"
82 t 8
94 t 6
82 ab
101 5
107 t 5
97 t 4
166
93
:+
.t_
:+
*
Not
Treated
(N = 5 )
3 Days
*
*
Pretreated
(N = 7 )
172 ? 7
99 t 5
*
Not
Treated
(N = 7 )
Pretreated
(N = 6 )
166 t 11
98 t 7
*
130 * 5"
88 * 4
27 t 1''
24 t 2h
31 % 3
28 i 3
86 t 3
95 t 4
88 t 2'
82 t 4
99 6
94 t 6
*
66 t 5 b
90 L 8
84 ? 3"
99 t 3
69 t S h
88 t 4'
73 ? 4
94 t 6
25 t 3b
24 & S h
35 t 2"
31 -t 2"
30 t l b
26 t 2h
34 2
28 t 4
*
aValues are in pm01/100 &mi.,
mean ? standard error. Numbers of animals are given in parentheses. Dexamethasone dosage: 0.25
mdkglday .
Statistical significance: different from normal at: 'p < 0.01; 'p < 0.05; different from corresponding untreated at: 9 < 0.01; p < 0.05.
untreated animals. The respective figures (average -C SEM)
were 173 ? 5 mgldl (51 rats), 128 t 5 (15 rats), and 132
? 8 (21 rats).
Plasma glucose concentration was measured by means of
a YSI glucose analyzer (Model 23A, Yellow Springs Instrument Company, Yellow Springs, OH) and plasma 14Cdeoxygltlcose content was determined in a liquid scintillation counter (Model SL32, Intertechnique, Plaisir, France),
with calibrated ''C-toluene (New England Nuclear Corp,
Boston, MA) used for internal standardization. Blood gases
were determined with a micro blood gas analyzer (Model
175, Corning, Boston, MA).
Local Cerebral Glucose Utilization
Local cerebral glucose utilization was determined by the
14C-deoxyglucosemethod of Sokoloff et al [ l l ]as originally described. Briefly, polyethylene catheters were
placed in a femoral artery and vein under light halothane
anesthesia. The animals were then immobilized from the
waist down by means of a loose-fitting plaster cast, and
were allowed to recover from the anesthesia for 3 to 4
hours. In animals studied 4 hours after injury, the catheters
were placed immediately after the lesion was made.
158 Annals of Neurology Vol 12 No 2
August 1982
A pulse of about 40 pCi of 2-deoxy-~-(l-I4C) glucose
(specific activity, 50 to 56 pcilmmol; New England Nuclear) was injected via the venous catheter. Timed arterial
sampling for assay of ''C-deoxyglucose and glucose concentration in plasma was started at the time of the injection
and continued for 45 minutes, at which point the animals
were killed by decapitation. The brain was immediately
removed, frozen in Freon 12, chilled to - 5 5°C over a liquid nitrogen bath, and stored at -80°C until sectioned.
Brain sections were cut 20 p thick in a cryostat (American
Optical Company, Buffalo, NY) at -22°C. Autoradiographs were made from the dried sections, and local tissue
concentrations of I4C were determined from the optical
densities of 33 specific anatomical structures and of appropriately calibrated 14C-rnethyl methacrylate standards
(New England Nuclear) included in each of the autoradiographs. The densitometric measurements were made with a
Photovolt Densitometer (Model 52, Photovolt Corp, New
York, NY) equipped with a 0.1 mm aperture. Final values
for LCGU were calculated as previously described [ 111
using a PDP-12 computer (Digital Equipment Corp,
Maynard, MA) and a program modified from that kindly
provided by Dr L. Sokoloff.
Table 2. Local Cerebral Glucose Utilization Thvee Days after Lesion in Selected Areas
of Traumatized Rat Brain with Different Regimens of Dexamethasone Treatmenta
Brain Site
Lesio ned hemisphere
Cortical areas
Auditory
Parietalb
Frontal
Subcortical structures
Substantia nigra
Caudate nucleus
White matter
Corpus callosum
Internal capsule
Hemisphere contralateral to lesion
Cortical areas
Auditory
Parietal
Frontal
Subcortical structures
Substantia nigra
Caudate nucleus
White matter
Corpus callosum
Internal capsule
Pooled
Controls
( N = 23)
Lesioned,
Not Treated
(N = 7 )
Pretreated,
0.25 mg
(N = 6 )
Posttreated
4 hr,
0.25 mg
(N = 3 )
134 ? 3
98 t 2
96 t 3
53 t 3"
4 9 ? 2"
45 t 2'
97 t 7'
7 9 ? 6"
79t6"
102 t 17'
80 t 12'
. . .
53 t 2
95 t 3
4 4 t 2'
67 t 4"
49 t 3
80 t 6
55
85
39 2 2
34 t 2
27 ? 1'
24 t 2'
31 ? 1
28 t 3
122 ? 4"
91 t 5
82 t 4"
118t 4
90 t 4
91 t 2
47 t 2
81 t 3"
30 +- 1*
2 6 ? 2"
24 hr,
0.25 mg
(N = 4 )
24 hr,
2.5 mg
(N = 6 )
88 t 16'
7 4 t 9'
7 4 -t 14f
7 4 t 8'
66 t
57 ? 5'
4
3
48 ? 4
82 t 5'
49
89
41 t 2"
33 ? 1'
39 t 2'
33 t 4'
40 -c 3'
29 t 1
7
7
116t 8
89 t 6
83 t 7
107 2 3
79 t 4
81 -t 6
51 t 3
85 t 4
52 t 5
94 t 2
50 t 2
84 ? 2
51 2 4
86 -t 7
34 2 2
28 ? 4
36 t le
31 ? 1
37 i 3
33 2 3
34
3
29 2 2
125
91
?
2
?
?
. . .
2
?
4
8f
*
aValues are pmol/lOO gmlmin, mean 2 standard error. Dexamethasone dosage (kg/day) is indicated for each treated group. Numbers of
animals are given in parentheses.
bSite of freezing lesion.
Statistical significance: different from pooled controls (normal and dexamethasone treated) at: 'p < 0.01; 'p < 0.05; different from corresponding untreated at: 'p < 0.01; 'p < 0.05.
Local Cerebral Blood Flow
Local cerebral blood flow (LCBF) was measured by means
of the ''C-iodoantipyrine autoradiographic technique described by Sakurada et al [8]in dexamethasone-pretreated
animals three days following a freezing lesion as well as in
normal and lesioned untreated animals. The tracer, 4iodo-(N-methyl 14C)antipyrine (specific activity, 50 to 6 0
mCi/mmol), was obtained from the New England Nuclear
Corporation.
Results
Effects of Pretreatment w i t h Dexamethasone
on L C G U i n Traumatized Brain
In normal rats, dexamethasone had no effect o n
LCGU when given for 36 hours (4 animals) or 78
hours (4 animals). T h e results for these two groups
are pooled in Table 1.
As shown previously [ 4 ] ,LCGU was profoundly
decreased in many areas of focally traumatized rat
brain. Results presented in Tables 1 and 2 and Figures 1 and 2 show that this effect of trauma was
significantly diminished by pretreatment with dexa-
methasone. To avoid duplication, different individual structures were selected to illustrate typical results of pretreatment with dexamethasone with time
after lesion (Table 1) and of different treatment
schedules (Table 2). Results for all structures studied,
expressed as percent of normal for each structure, are
averaged in Figure 1.
In all cortical areas of the lesioned hemisphere, the
effect of dexamethasone pretreatment was highly
statistically significant both o n e and three days after
the lesion (see Table 1). The increase in LCGU on
the side of the lesion was sufficiently pronounced to
abolish the side to side differences invariably recognizable on inspection of the autoradiographs from
untreated animals (Fig 2). At the same time, dexamethasone had no obvious effect on the size and
appearance of the lesion area, which varied somewhat
from animal to animal but was comparable in the untreated and pretreated groups as a whole both on the
autoradiographs and with respect to Evans blue
staining. In the contralateral hemisphere one day
after the lesion, LCGU in all areas of the cortex was
Pappius: Steroids and Cerebral Glucose Utilization 159
lpsilateralto Lesion
Subcartical Structures
(12)
Cortical Areas
(6)
Brain Stem Structures
(5)
OUntreated
Dexarnethasonepre treated,
0 25mglKglday
Dexamethasonepost treated, 4hrs.O 25mg/Kg/day
Dexarnethasonepost treated, 24hrs. 0.25mglKglday
t Dexarnethasonepost treated, 24hrs. 2.5 mQlKglday
Contralateralto Lesion
120r
E
7oc
vlw
4o
Superiorcolliculus
Substantla nigra
MedialQeniculate
Oenlategyrus
An1 nlppocampus
LateralQeniculate
Amygdala
Laleral Thalamus
HabenJla
Hypotllalamus
Globur pallidus
Caudate
Cachlear nucleus
Vestibular nucIeus
superior olive
Laterallemnlcus
lnter~orCOI~~CUIUS
--Auditory
Parietal
Sensory motor
Frontal
Olfactory
0
1
3
5
0
1
3
5
0
1
3
5
l i m e After Lesion (Days)
F i g 1 . Effect of dexamethasone on focal c-erebrulglucose utilization in traumatized rat brain as percentage of normal. Areas
averaged for each group as listed.
higher in the pretreated than in the untreated animals, but the individual differences were not statistically significant. However, when expressed as a percentage of normal and averaged for the six cortical
areas, the difference between untreated ( 8 5 k 2%)
and pretreated (103 i 2%) rats was highly significant (average k SEM;p < 0.01) (see Fig 1). Three
days after the lesion there was no difference between treated and untreated animals in LCGU in
cortical areas in the hemisphere contralateral to the
lesion.
The depression of LCGU seen in subcortical and
white matter structures in both hemispheres was invariably diminished by dexamethasone pretreatment.
This effect was statistically significant in all individual
structures of the traumatized hemisphere and in most
of them in the contralateral hemisphere one day after
the lesion (see Table 1). In both hemispheres, the
effect in subcortical structures three days after the
lesion was significant when expressed as percentage
of normal (untreated and pretreated, respectively:
lesioned hemisphere, 76 k 29% and 88
196,
p < 0.01; contralateral hemisphere, 86 5 1% and 91
k l % , p < 0.01) (see Tables 1 and 2, Fig 1).
Dexamethasone pretreatment had essentially no
effect on the normal levels of LCGU in brainstem
structures of traumatized brain except for a slight depression noted bilaterally three and five days after the
lesion (see Table 1, Fig 1).
*
160 Annals of Neurology
Vol 12 No 2
August 1982
F i g 2. 14C-Deoxyglucoseautoradiographs at selected anatomical locations i n rat brain. (A)Normal. ( B ) Three days following production of a freezing lesion i n an untreated animal:
note obvious decrease i n optical density in cortical areas of the
traumatized hemisphere. (C) Three days after a freezing lesion
i n animals pretreated with dexamethusone: note that side to
side differenceJ are no longer visible.
Effects of Different Regimens
of Dexamethasone Treatment
Results summarized in Table 2 and Figure 1 show
that dexamethasone (0.25 mg/kg/day), given starting
4 or 2 4 hours after the lesion was made and continued until the end of the experimental period, diminished the depression in LCGU of traumatized
brain to a degree comparable to that found when the
drug was started before the lesion. The effect of
posttreatment started at 4 hours was not fully developed one day after the lesion (see Fig 1). However, three days after the lesion the results in the
three groups that received dexamethasone at a dosage of 0.25 mg/kg/day did not differ from each other,
while all showed similar differences from the untreated group (see Table 2, Fig 1).
A higher dose of dexamethasone (2.5 mg/kg/day)
started 2 4 hours after the lesion was made did not
further improve LCGU of traumatized brain. In cortical areas and brainstem structures LCGU was relatively depressed, an effect not seen when the higher
dose was given to control animals for a comparable
period (data not shown).
Table 3. Efject of Dexamethasone on Local Cerebral Blood Flow
in Selected Structures of Traumatized Rat Brain Three Days after Lesion"
Brain Site
Cortical areas
Visual
Parietalb
Sensorimotor
Subcortical structures
Superior colliculus
Lateral thalamus
Globus pallidus
Caudate nucleus
Brainstem structures
Inferior colliculus
Lateral lemniscus
White matter
Corpus callosum
Internal capsule
No Lesion
(N = 5)
Untreated
Hemisphere (N = 7)
Left
Right
1 3 8 * 11
158 2 19
1 3 6 t 11
187 5 42
174 5 25
170 2 37
210 30
194 27
172 t 23
122 t
129 t
76 t
128 +-
142 2
128 2
77 4
199 2
15
19
5
27
148
160 t
77
174
222 23
163 +- 18
301
177
5
32
12
299
189
37 2 4
42 t 3
46
45
5
5
3
43
45
11
13
7
10
*
2
2
Pretreated
Hemisphere (N = 5 )
Left
Right
*
*
* 14
11
*5
* 20
155 t 11
179 t 13
187 25
159 5 11
193 8
199 t 13
5
91
171
140*
180
89 2
173 k
263
182
14
*
144 * 9
171 * 20
2
2
5
21
+-
29
267 t 12
186 t 16
2
5
42 2
44 t 1
* 13
*3
*
*
* 17
2
5
18
* 17
40 t 1
43 2
*
"Values are m1/100 gm/rnin, mean 2 standard error. Numbers of animals are given in parentheses. Dexamethasone was started 6 hours
before the lesion and continued until the animal was killed.
bSite of freezing lesion in left hemisphere.
Effect of Dexamethasone on LCBF
i n Traumatized Brain
Table 3 presents LCBF values for selected structures
of traumatized rat brain with and without dexamethasone pretreatment. As shown previously [4],
three days after injury hyperemia was widespread in
traumatized brain, more pronounced in the hemisphere contralateral to the lesion. Dexamethasone
pretreatment had no significant effect on the
hyperemia, although in some structures blood flow
was marginally reduced toward normal from the level
in untreated animals.
Discussion
It has generally been accepted that edema is a major
factor underlying functional disturbances associated
with injury to cerebral tissues. Almost all efforts to
develop rational therapy for neurological complications resulting from trauma to the brain have been
directed at modifying the edematous process, while
putative beneficial effects of various treatment modalities, for example, steroids, have been ascribed to
their action on cerebral edema (e.g., [ 5 , 71). Results
of experimental studies designed to demonstrate effects of steroids on cerebral edema have been contradictory [2, 121.
Our earlier studies in the cat [6] showed limited
effects of the steroid dexamethasone on the degree
of edema that developed in response to a standard
freezing lesion: a decrease of about 30% two days
after the lesion, while differences between untreated
and treated animals one or three days after the
trauma were smaller and statistically not significant.
Furthermore, there was no correlation between the
effects of dexamethasone treatment on the edema
and its effects on the considerable electroencephalographic abnormalities in traumatized brain. We
suggested at the time that injury to the brain may
induce functional disturbances by mechanisms not
related to the development of cerebral edema. This
was borne out by a recent demonstration of depression of LCGU in many areas of focally traumatized
rat brain [4].In view of the usual coupling of cerebral
metabolism and cerebral function [ 101, these results
were interpreted as reflecting widespread functional
disturbances in the affected regions. Since there were
both spatial and time-course discrepancies between
changes in LCGU and the development of edema,
the edematous process did not appear to be primarily
involved in the metabolic, and hence functional, consequences of injury.
The present results show that dexamethasone,
given either before or after the lesion, largely reverses the changes in LCGU induced by trauma,
suggesting that functional disturbances in traumatized brain are modified by steroid treatment. The
effects of dexamethasone were not limited to the
traumatized hemisphere to which edema is restricted
in this model, nor was their time course such as to
indicate that they were mediated by effects on
edema.
What processes are involved in inducing widespread functional disturbances as a consequence of
focal injury to the cortex is not known. The mechanism of action of steroids also remains unexplained.
The size and appearance of the lesion was not affected by dexamethasone treatment in the present
studies, in agreement with earlier evidence that
Pappius: Steroids and Cerebral Glucose Utilization 161
localized injury was not modified by steroid treatment [ 2 , 61. Although protective effects of steroids
on cortical microcirculation within the first 2 hours of
cold injury have been reported 173, LCBF was not
normalized in the traumatized brain at the peak of
the dexamethasone effect on LCGU (three days
after lesion). Thus, uncoupling between cerebral
metabolism and cerebral blood flow demonstrated in
thermally traumatized brain [4] persisted in the
treated animals, and changes in blood flow cannot account for the clear-cut and unequivocal effects of
dexamethasone on glucose utilization. Further studies are required to determine if previously postulated mechanisms of action of steroids are involved,
for example, effects on electrolyte metabolism [ 2 ] ,
on stability of lysosomal membranes and cell membranes in general [2], or on pathological free radical
reactions [ 11. The possibility of more specific and direct effects on neuronal function must be considered,
as glucocorticosteroids have been shown to affect
protein synthesis and neurotransmitter metabolism
in brain [ 3 ] .
Supported in part by Grant MT-3021 from the Medical Research
Council of Canada and by the Donner Canadian Foundation.
Preliminary results of these studies were presented at the International Ernst Reuter Symposium on Brain Edema, Berlin, Sept
12-15, 1979.
I am indebted to Hanna Szylinger, Michael McHugh, Ralph Dadoun, Claudine Isaacs, and Izabella Latawiec for skilled and enthusiastic technical assistance.
162 Annals of Neurology Vol 12 No 2
August 1982
References
1. Demopoulos HB, Milvy P, Kakari S,Ransohoff J: Molecular
aspects of membrane structure in cerebral edema. In Reulen
HJ, Schurmann K (eds): Steroids and Brain Edema. Berlin/
HeidelberglNew York, Springer-Verlag, 1972, pp 29-39
2. Katzman R, Pappius HM: Brain Electrolytes and Fluid
Metabolism. Baltimore, Williams & Wilkins, 1973
3. McEwen BS, Davis PG, Parsons B, Pfaff DW: The brain as a
target for steroid hormone action. Annu Rev Neurosci
2165-112, 1979
4. Pappius HM: Local cerebral glucose utilization in thermally
traumatized rat brain. Ann Neurol 9:484-491, 1981
5. Pappius HM, Feindel W (eds): Dynamics of Brain Edema.
Berlin/Heidelberg/New York, Springer-Verlag, 1976
6. Pappius HM, McCann WP: Effects of steroids on cerebral
edema in cats. Arch Neurol 20:207-2 16, 1969
7. Reulen HJ: Schurmann K (eds): Steroids and Brain Edema.
Berlin/Heidelberg/New York, Springer-Verlag, 1972
8. Sakurada 0, Kennedy C, Jehle J, Brown JD, Carbin GL,
Sokoloff L Measurement of local cerebral blood flow with
iodo (I%) antipyrine. Am J Physiol 234:H59-H66, 1978
9. Soejima T, Yamamoto L, Meyer E, Feindel W, Hodge CP:
Protective effects of steroids on the corticomicrocirculation
injured by cold. J Neurosurg 51:188-200, 1979
10. Sokoloff L: Relation between physiological function and
energy metabolism in the central nervous system. J
Neurochem 29:13-26, 1977
11. Sokoloff L, Reivich M, Kennedy C, Des Rosiers M H , Patlak
CS, Pettigrew KD, Sakurada 0, Shinohara M: The (I%)deoxyglucose method for the measurement of local cerebral
glucose utilization: theory, procedure, and normal values in
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cerebral edema from cranial impact in the cat. J Neurosurg
48:220-227, 1978
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