Dias Chis Is

Diaschisis
DM Feeney and JC Baron

Stroke 1986;17;817-830
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Diaschisis
DENNIS M. FEENEY, P H . D . , AND JEAN-CLAUDE BARON,
A BETTER UNDERSTANDING of the mechanisms

of spontaneous recovery following stroke may provide
insight into achieving clinical interventive measures to
accelerate and enhance post-stroke recovery. This
progress review focuses on one such mechanism, Von
Monakow's controversial and often misunderstood
From Service Hospitalier Frederic Joliot, CEA, Department de Biologie 91406 Orsay, and Departments of Psychology and Physiology,
The University of New Mexico, Albuquerque, New Mxico, 87131
This article was written while Dennis M. Feeney, Ph.D. was an
INSERM Senior Research Fellow at the Service Hospitalier Frederic
Joliot.
Address correspondence to: Jean-Claude Baron, M.D., Service Hospitalier Frederic Joliot, CEA, Department de Biologie, 91406 Orsay,
France.
Received July 16, 1986; accepted August 4, 1986.
M.D.
theory of diaschisis.1 Although the extensive literature

on recovery of stroke function is notreviewed,2"10selected studies and theoretical issues potentially related
to diaschisis are discussed.
Diaschisis is but one of several general theories of
recovery of function which classically include: a) vicariation-the taking over of functions of the damaged
area byregionsnot originally involved in the performance of lost behavior, b) redundancy-recovery based
upon uninjured neurons that normally contribute to
that behavior, i.e. the distribution of a function
throughout the cerebral cortex, c) behavioral substitution-the learning of new behavioral strategies to compensate for the deficit, d) recovery from diaschisis-the
temporary functional "shock" or deactivation of intact
brain regions remote from but connected to the area of
818
STROKE
primary injury. These older theories of recovery, although quite different from recent objective observations of sprouting or denervation supersensitivity proposed to mediate recovery of function, are not
mutually exclusive. The unspecified mechanisms for
the alleviation of diaschisis could involve the growth
of new axon terminals or the multiplication of postsynaptic receptors.
While changes in neuronal function are common to
all of these theories, recovery of function is clearly a
multifactorial process including: the resolution of extracellular and/or intracellular edema; reestablishment
of cerebral blood flow (CBF) in "penumbral" areas
after ischemic stroke or subarchnoid hemorrhage-related vasospasm; and restitution of tissue function after
intracerebral hemorrhage (mass effect). Interventions
to promote these events may directly improve clinical
outcome by reducing the extent of initial damage.
Thus, acknowledging the many different approaches
to recovery after brain injury,5'n-8 this review will discuss only diaschisis.
Although the term diaschisis has often been used
loosely, few publications5' " l2 adhere to Von Monakow's original description written in German,1 language barriers having contributed to the confusion and
debates.1J~15 Diaschisis (from the Greek meaning
"shocked throughout") has been simplistically described as the cerebral counterpart of spinal shock.
Recent experimental, neurophysiological and metabolic data support the initial interpretation of spinal
shock as due to the loss of descending facilitory activity producing a transient loss of spinal reflexes below
the level of cord transection. Because the brain circuitry is relatively more complex than that of the spinal
cord, understanding the mechanisms underlying cerebral diaschisis will be more difficult.
In the 1870's, Brown-Sequard, the most notable
predecessor to the concept of diaschisis, described remote effects of focal brain damage ("actions at a distance"). He proposed that brain lesions produced excitatory and inhibitory effects causing disruption of
function in regions distant from the site of damage.5
Von Monakow, developing these ideas more fully,
introduced the term diaschisis to describe "abolition of
excitability" and "functional standstill". His theory of
diaschisis, which excluded previously held concepts of
irritation and active neural inhibition, was necessarily
dependent upon the interpretation of functional brain
organization. In contrast to the discrete localization of
cortical function held by many of his contemporaries,
Von Monakow noted:1 "The generally accepted theory
according to which aphasia, agnosia, apraxis, etc., are
due to destruction of narrowly circumscribed appropriate praxia, gnosia, and phasia centres, must be finally
discarded on the basis of more recent clinical and anatomical studies. It is just in the case of these focal
symptoms that the concept of complicated dynamic
disorders in the whole cortex becomes indispensible."
Von Monakow's perspective of "distribution of nervous function along several sections of the medullar
tube" (neuroaxis), was "Jacksonian" in nature.
VOL 17, No
5, SEPTEMBER-OCTOBER
1986
Von Monakow emphasized 4 important aspects of

diaschisis:
1) Damage to one brain area can, by loss of excitation, produce cessation of function in regions adjacent
to, or remote from but connected to the primary site of
damage. "The physiological process upon which the
local initial symptoms are based, may be regarded as a
shock confined to distinct nervous structures which
have to be defined more precisely from the anatomical
point of view. The local character (dependent upon the
site of the lesion), the closer content, and also the
manner of compensation for impairment of innervation, endows this shock with a special position, and
makes it seem justified to classify it separately from
other forms of shock. For this type of shock I shall use
the term diaschisis. Consequently, diaschisis represents an 'interruption of function' appearing in most
cases quite suddenly (this applies to all other types of
shock as well) and concerning certain widely ramified
fields of function, which originate from a local lesion
but have their points of impact not in the whole cortex
(corona radiata, etc.) like apoplectic shock but only at
points where fibers coming from the injured area enter
into primarily intact grey matter of the whole central
nervous system."1
Although, Von Monakow usually reserved the term
diaschisis for sudden onset of some symptoms, he also
proposed a "slowly creeping diaschisis"12 for which
recent experimental evidence has lent credence.16
2) Diaschisis was a clinical diagnosis whose presumptive mechanism was loss of excitation to intact
regions rather than neural inhibition:
"In other words, massive lesions of commissural
fibres in the left hemisphere will interrupt dynamically
the points of entry and exit of fibers in the cortex of the
right hemisphere, which will impair a number of more
complicated nervous processes (apraxia, aphasia, agnosia)."1
3) Diaschisis "undergoes gradual regression in well
defined phases" such that resolution will parallel resumption of function in areas of diaschisis. With the
recent neuroscientific focus on potential repair mechanisms following brain damage, Von Monakow's concept of a Darwinian struggle between diaschisis and an
active repair process by unspecified restorative mechanisms, is indeed insightful:
"Any injury suffered by the brain substance will lead
(as for lesions in any other organ) to a struggle for the
preservation of the disrupted nervous function, and the
central nervous system is always (although not always
to the same degree) prepared for such a struggle; . . .
The final result of this struggle (schism) will vary for
each given area of the brain depending on the number
and distribution of battling forces . . . and this is why
the residual symptoms (pure sequels of the defect) will
rarely be the same in different individuals."1
An exception to the general rule of the transient state
of diaschisis, is "diaschisis protractiva" wherein the
cerebral shock cannot be spontaneously compensated
for by active repair mechanisms."115
4) The "wave of diaschisis" follows neuroanatomi-
DIASCHISIS/Fee/iey and Baron
cal pathways apreading from the site of injury. Von

Monakow refers to three types of diaschisis, illustrating their spread through classical fiber paths:1
a) Diaschisis cortico-spinalis progression of
functional depression from a motor cortex injury to the
spinal cord along pyramidal tract fibers.
b) Diaschisis commissuralis functional contralateral cortical depression via axons of the corpus collosum following injury to the cortex of one hemisphere.
c) Diaschisis associativa intracortical fiber-mediated depression of function in intact cortical areas
neighboring the locus of injury.
Von Monakow proposed that three types of diaschisis usually occur simultaneously, but one form may
predominate depending upon the "injured connections" and the degree of cortical development in the
species under study.
Only during the last three decades have methodologies been developed for the scientific investigation of
diaschisis. Additionally the concept of chemical neurotransmission has been accepted and the antiquated
terms "shock" and "functional standstill" have no direct counterpart in modern neurophysiology. Investigations of the theory of diaschisis have recently used
two approaches: 1) the study of remote effects of lesions on such variables as spontaneous or evoked electrophysiological activity, neurotransmitter levels, synaptic receptors and CBF and metabolism; 2) the
manipulation of recovery of a particular behavioral
symptom after brain injury.
Although alterations of neurotransmitters, sprouting
of new neuronal processes, and changes in cerebral
metabolism occur simultaneously at sites distant from
actual injury, and bearing in mind that various interventions can influence behavioral recovery, causal effects are difficult to substantiate. For example, the
concept of pharmacological restoration of behavioral
deficits following brain injury17' " assumes that drugs
which cannot be acting upon lost neurons exert their
effects upon intact systems rendered nonfunctional by
the primary lesion.
More convincing would be a demonstration of the
correlation of pharmacological manipulation of symptoms with alterations of physiological markers of the
remote effects of lesions.19 Unfortunately, because of
the multiple (and many unknown) drug effects in injured brain, and lack of a strict relationship between
structure (or neurotransmitter) and a single behavioral
function, it is difficult to firmly ascertain the etiologic
mechanisms of manipulated recovery.
The separation of causal and beneficial effects from
those only correlated with recovery of function (epiphenomena), demands an interdisciplinary study of
behavior and neurophysiology. Deleterious changes
following CNS lesions may also occur, e.g. neuronal
sprouting after spinal damage may produce spasticity.20 In the injured brain, establishment of aberrant
connections may impede rather than facilitate recovery.2I> n Because of these complexities there are few
unequivocal experiments supporting any of the theo-
819
ries of recovery of function.

In the last decade, tomographic and autoradiographic technological advances have accelerated the study of
remote functional effects of stroke. There has been
repeated confirmation23 of the original observation that
changes in structurally normal brain neuronal function
are attended by proportional and parallel changes in the
cerebral oxygen metabolic rate (CMRO2), glucose utilization (CMRGlu) and because of the so called
coupling phenomena CBF. This relationship is
maintained in the brain as a whole, regionally, and
even at the local level. Most early studies of diaschisis
wererestrictedto stroke patients, were limited in their
interpretation of the location and extent of the lesion.
In contrast recent localization of pathology based upon
radiologic technical advances in computerized tomography (CT) and magnetic resonance imaging (MRI),
provide more accurate localization of pathology.
Experimental Studies of Diaschisis
Spinal Cord
As discussed above, the term diaschisis can be considered analogous to spinal shock, and is used by some
clinicians in this context only. Supporting the classic
interpretation that spinal shock is due to the loss of
descending excitatory input is the report of immediate
alpha motor neuron hyperpolarization after cooling
and rewarming, respectively at higher cord levels.24
Post-cord transection measurements of glucose utilization using 14C-deoxyglucose (2DG) in the monkey have
recently indicated more complex and widespread effects appearing in many segments above and below the
level of the injury.23 Increased CMRGlu in some lamina was interpreted as a loss of tonic descending inhibition, and while reminiscent of diaschisis, the loss of
active neural inhibition was not included in Von Monakow's theory. The observation of hypermetabolic lamina adjacent to hypometabolic lamina after cord transection suggest caution in the interpretation of data,
especially negative results, when measures from large
regions of neuropil are combined.
Brainstem Lesions
Since a vast number of pathways interconnect brainstem, diencephalic and telencephalic neuronal aggregates, a brainstem vascular lesion might be expected to
exert transynaptic effects at many distant loci. In
stroke patients, brainstem lesions inducing stupor or
coma are associated with diminution of supratentorial
perfusion and metabolism roughly correlating with
both the state of arousal and altered EEG patterns.26
Conversely, patients with severe brainstem stroke resulting in total paralysis but normal arousal ("locked-in
syndrome"), have normal CBF.27
The classic work demonstrating coma in the cerveau
isole" preparation was interpreted as a remote effect of
the diffusely projecting mesencephalic reticular formation altering forebrain function.28 Although the critical
involvement of the mesencephalic region in the regulation of wakefulness has long been accepted, recent
work has focused on the complex interactions of di-
820
STROKE
verse nuclei within this region, and has utilized strategically placed lesions.
In the rat, large unilateral lesions interrupting most
of the brainstem-forebrain pathways resulted in
marked ipsilateral decreases in CMRGlu in cortical
and subcortical gray matter.29 Destruction of the rostral
reticular formation in stages30firston one side and then
after some time period, the contralateral side, did not
produce enduring coma. This attenuated effect was
interpreted as lesions performed in sequence producing less diaschisis. Lesions done in stages may be
likened to slowly growing tumors which produce less
symptomatology than acute lesions of the same magnitude. This effect of the Jacksonian "momentum" of a
lesion or "slowly creeping diaschisis" is still poorly
understood.
Experimental animal studies have examined
changes in forebrain metabolism after stereotaxic lesions of specific brainstem nuclei. Electrolytic lesions
of the rat raphe serotonergic somata resulted in moderate depression of CMRGlu in other brainstem nuclei
and the hippocampal dentate gyms without altering
metabolism in other forebrain regions.31 Unilateral lesions of the locus coeruleus (LC) reportedly caused
either very moderate or no change in cerebral metabolism. Glucose utilization was markedly reduced in the
ipsilateral cerebral cortex and latero-ventral thalamus
(by 10% and 15% respectively)32 or unchanged.2933
Cortical resting metabolic rates measured using the
histochemical stain alpha-glycerophosphate dehydrogenase (a-GPDH) were unchanged.19 In contrast, the
depression of a-GPDH in the entire ipsilateral cortex
following focal cortical injury34 is exaggerated by lesions of the LC.19 This data is compatible with the
hypothesis that the LC "modulates" activity of other
systems.35
In the rat, 6-hydroxydopamine-induced substantia
nigra lesions have simulated the dopamine (DA) deafferentation of Parkinson's disease. Resulting physiologic changes include mildly deceased CMRGlu in the
ipsilateral frontal cortex, not reversed by administration of DA agonists, mild ipsilateral strial metabolic
depression and marked hypermetabolism in the ipsilateral habenula and globus pallidus. These latter effects,
in contrast to the frontal cortex hypometabolism, are
alleviated by apomorphine or L-Dopa. These metabolic changes, which are associated with ipsilateral
DA postsynaptic hypersensitivity and behavioral abnormalities, are not found in animals showing spontaneous recovery of function.29' 3*~38 Although these studies satisfy most of die criteria for diaschisis they are
rarely discussed in this framework. That the target
structure of the substantia nigra shows only a mild
metabolic depression despite the almost total DA deafferentation may result from the sparing of the nonDA afferents constituting the major inputs to the striatum. There may be no presently detectable direct
metabolic counterpart to the presumptive primary neural abnormality of Parkinson's Disease i.e. the loss of
nigro-striatal input. Transneuronal hyperactivity resulting from loss of tonic inhibition, reflected by in-
VOL 17, No
1986
creased pallidal glucose utilization following substantia nigra lesions, can occur after brain injury and
incorporating this concept is essential to present-day
revision of the theory of diaschisis.
hi summary, remote supratentorial functional effects of brainstem reticular and nigro-striatal lesions
have been clearly demonstrated using cerebral metabolic measurements. Transient, transynaptic effects
secondary to lesions of either of these anatomically and
physiologically unique systems could potentially be
considered diaschisis.
Thalamus
The thalamus constitutes a major relay and integrative nuclear cluster, including the sensory, motor, limbic systems, as well as the ascending brainstem reticular formation. Thus, interruption of neuronal function
such as occurs in thalamic stroke, can give rise to a
constellation of different clinical expressions including
sensory loss, ataxis, speech alterations (thalamic aphasia), visual-spatial deficits, global or selective amnesia, hemi-inattention (neglect), psychomotor retardation, akinetic mutism, thalamic dementia and possibly
coma. Apart from designated functional roles of the
ventrobasal complex and geniculate bodies, precise
clinico-anatomic correlations of other thalamic nuclei
are lacking. However, selected human studies (including sterotaxic thalamotomy) have suggested the dominant ventral-lateral and intralaminar nuclei play a significant role in the mechanisms of attention. Lesions of
the left or right medio-dorsal nucleus may produce
verbal and visual amnesia respectively, while bilateral
lesions may result in global amnesia or dementia.40'41
Some of these thalamic injury syndromes have also
been reproduced in nonhuman primates.42
In view of the dense thalamocortical projections, it
has been speculated that these behavioral consequences of thalamic damage result from cortical dysfunction after loss of these important cortical afferents
perhaps a loss of cortical "activation."43-44 Some
particular patterns of symptoms may only reflect "specialized cortical functions." This could be interpreted
as a diaschisis, since such effects would be remote
from the lesion and recovery is often remarkable after
thalamic stroke even when initial symptoms are severe.
Electrophysiological data from both human and animal experimentation shows that there is marked ipsilateral cortical EEG slowing following unilateral lesions in many of the "non-sensory" thalamic nuclei,
particularly the intralaminar, medio-dorsal, ventralanterior and the reticular nuclei.45"" These effects,
which depending on the size of the lesion last for
weeks or longer, reportedly affect the entire ipsilateral
cortical mantle. Lesions of a "specific" projection nucleus, such as the ventral-posterior-lateral nucleus may
notresultin EEG slowing or die effects are restricted to
the somatosensory cortical projection area.45' ** Unilateral lesions of the rostral pole of the thalamus (anterior-ventral and reticular nuclei) in the cat, depressed
both seizure activity and sleep spindles over the ipsilat-
DIASCHISIS/Feert<ry ond Baron
eral cortical hemisphere without attenuating cortical

evoked responses. This suppression of cortical circuitry involved in the generation of synchronous discharge
without reducing cortical excitability can be considered a selective remote cortical effect of injury to the
anterior thalamus. But whether the mechanism of this
effect is intrathalamic or a disruption of the diffuse
cortical projection system is unclear.49 A similar depression of synchronous discharge, ipsilateral alpha
rhythm blockade, has been described following unilateral stroke involving these nuclei.50
Positron emission tomography (PET) and single
photon emission computerized tomography (SPECT)
studies of patients with recent ischemic or hemorrhagic
unilateral thalamic stroke, have clearly demonstrated
matched reductions in ipsilateral cortical perfusion,
CMRO 2 and CMRGlu involving the entire ipsilateral
cortical mantle. *"51"5* Although correlations between
distribution and severity of cortical metabolic depression, the particular thalamic nuclei involved and clinical symptoms are indeterminate, studies suggest an
association between the degree of cortical hypometabolism and behavior deficits.40'52 Additionally, there is
a significant trend between recovery of cortical metabolism and clinical improvement.4050"56
Experiments involving thalamic lesions in rats show
some correspondence with this human data. After unilateral electrolytic lesions of the ventro-medial nucleus
of the thalamus, there is an ipsilateral reduction of
cortical metabolic rate directly proportional in severity
to the size of the thalamic lesion.57
Since cerebral energy metabolism essentially reflects sodium pump activity58"60 and hence the density
of pre- and postsynaptic events, the cortical metabolic
depression after pure thalamic lesions may involve any
number of factors including: 1) anterograde Wallerian
degeneration of thalamo-cortical terminals; 2) retrograde degeneration of cortico-thalamic neurons secondary to lesions of their thalamic terminals; 3) transynaptic degeneration of cortical neurons secondary- to
loss of thalamic afferents; 4) reduced functional activity of cortical neurons (without degeneration) after a
loss of thalamic input.40 Metabolic depression invoked
by the first two mechanisms, rather than an index of
diaschisis, is a simple manifestation of direct injury to
neurons. The latter two mechanisms involving transynaptic processes capable of recovery, could qualify
as physiologic measures of diaschisis. The disproportionate magnitude of cortical metabolic depression
after thalamic lesions, relative to the density of thalamo-cortical projections, makes the anterograde degeneration a tenuous explanation.61 Retrograde degeneration of cortico-thalamic neurons and cortical
transynaptic neuronal death is rare, if not absent, in the
adult mammalian brain.62 A loss of dendritic spines
from cortical neurons does occur after deafferentation 63 ' w but has not been reported following thalamocortical disconnection. Electron microscopic studies
are needed to determine any potential association of
metabolic disturbances with morphological changes
(such as dendritic spine atrophy) that would reflect
821
postsynaptic membrane adaptation to alterations of

thalamic input. 63 ' M The trend for recovery from cortical hypometabolism seen after thalamic stroke would
be consistent with this view. Alternatively, the diffuse
cortical hypometabolism subsequent to thalamic lesions may result from a non-specific process of "deactivation." Other postulated mechanisms for the accommodation to loss of thalamic input to the cortex include
collateral sprouting or postsynaptic receptor supersensitivity. The observations of cortical hypometabolism
after thalamic injury are somewhat similar to those
seen in the rat visual cortex following enucleation, or
the somatosensory cortex after the removal of whiskers.16' 66 Recovery of synaptic density in the deafferented dentate gyrus in the rat follows a roughly similar
time course to that of metabolic recovery in peripheral
deafferentation models. 67
Thalamic lesions in animals and humans induce
mild contralateral cortical metabolic depression.40' " 57
This very transient effect may occur via second-order
corpus callosum connections57 and represent a transcallosal diaschisis. Hypometabolism of the ipsilateral
basal ganglia has also been reported following thalamic stroke55 and experimental lesions,57 and is likely
mediated via the extensive thalamo-striatal projections. Bilateral metabolic depression in other subcortical structures has also been described following experimental unilateral thalamic ventromedial nuclear
lesions.57
Stria turn
Data regarding the remote functional effects of striatal lesions are sparse. The effects of experimentally
induced caudate lesions in animals were mild, transient and not reproducible by similar putamenal lesions.45' "* Of the few anecdotal reports of patients with
stroke involving the striatum, none were "pure," but
also involved adjacent internal capsule and hence possibly thalamo-cortical fibers. In these cases, mild
metabolic depression affecting the entire ipsilateral
cortical mantle and thalamus, has been described.53' M'68"70 These cortical effects may be secondary to degeneration of cortico-striate fibers rather
than diaschisis.
Unilateral striatal lesions in the rat, using the neurotoxin kainic acid (which presumably spares the tract
fibers)71"73 has no apparent effect on ipsilateral cortical
metabolism.72 However, the increased CMRGlu in the
ipsilateral globus pallidus and substantia nigra (pars
reticulata) presumably reflects a GABA-mediated
transynaptic loss of inhibition blocked by pretreatment
with systemically administered muscimol.74
Cholinergic System Lesions
The cholinergic system has received considerable
attention following the demonstration of the role of
hippocampal and cortical cholinergic projections in
memory and cognition, as well as in the pathogenesis
of Alzheimer's disease. Unilateral lesions of the nucleus basalis of Meynert (NBM) or the septohippocampal
pathway in rats suppresses cholinergic function in the
822
STROKE
deafferented ipsilateral structures as well as reducing

cortical EEG, while bilateral lesions cause learning
and memory deficits.73 Recovery of function resulting
from collateral sprouting of surviving cholinergic neurons, has been observed.76 Neurotoxin-induced lesions
of NBM also depress ipsilateral CMRGlu as early as 3
days after surgery, maximal in the primary frontal cortex projection area with recovery between 7 and 30
days.76"79 Whereas recovery of hippocampal hypometabolism induced by medial septal lesions occurs by 3
months, that produced by complete destruction of the
fimbria-fornix and cingulate cortex persists for longer
than 6 months postinjury.80 That these metabolic effects of lesions result from cholinergic deafferentation
was clearly demonstrated by 1) high linear correlations
between percent reduction in CMRGlu and measures
of acetylcholinesterase (AChE) and 2) the striking and
parallel recovery of both AChE and CMRGlu resulting
from cholinergic grafts six months following cholinergic deafferentation.80 Administration of oxotremorine,
a cholinergic agonist, and atropine, a cholinergic antagonist, is associated with respective improvement
and deterioration in the behavioral and metabolic responses to injury.81
These models of cholinergic deafferentation satisfy
criteria for diaschisis by providing evidence for an
association between synaptic functional alterations and
behavioral deficits, strengthened by the parallel response of these measures to pharmacological manipulations. While there is no spontaneous recovery after
severe cholinergic deafferentation, a favorable reaction to pharmacological manipulations or grafting suggests that this model is an example of "diaschisis protactiva."
The use of CBF, SPECT, and PET techniques in
Alzheimer's disease patients has demonstrated a preferential parieto-temporo-occipital association cortex
metabolic depression;82 this is likely not the result of
innominato-cortical cholinergic deafferentation because of the different anatomic, namely prefrontal,
cortical innervation by the cholinergic system.83 Progressive supranuclear palsy, a degenerative disorder
affecting the basal ganglia and most brainstem ascending systems, is marked in some patients by an intellectual impairment termed "subcortical dementia," reminiscent of prefrontal lobe damage. While the prefrontal
cortex is pathologically intact, PET studies have revealed a marked metabolic depression corresponding
to the behavioral deficits.84 This prefrontal hypometabolism is thought to result from loss of several afferent
systems to this cortical area, including the cholinergic
projections.84 The pattern of symptoms and the PET
data can be considered an example of "slowly creeping
diaschisis" and suggests that replacement of the failing
neurotransmitter(s) may improve the intellectual deficit in this disorder.
White Matter Lesions
Animal white matter lesions made just beneath the
cortical surface (undercutting), result in marked EEG
slowing.46 In contrast, electrolytic lesions of the posterior limb of the internal capsule produce inconsistent,
VOL. 17, No
1986
transient effects.43 In humans, "pure" white matter lesions are difficult to confirm, and small infringements
on neighboring grey matter (e.g. thalamus, pallidum)
contributing to the lesions' manifestations, may go
undetected by present imaging techniques. Physiological observations in deep hemispheric syndromes have
included; 1) lack of the normal sensorimotor cortex
cerebral blood flow activation during contralateral
hand movements in patients with capsulo-thalamic infarcts;83 2) reduced CMRGlu in cortical and thalamic
regions ipsilateral to caudate and internal capsule lacunar lesions;69 3) reduction in precentral and central
cortical blood flow ipsilateral to internal capsule infarcts.86'" Other studies of smaller white matter lesions have shown no cortical metabolic impairments.88' w Taken together, these observations suggest
that damage to the thalamus itself or to thalamo-cortical fibers is necessary for development of behavioral
symptoms and cortical hypometabolism.87"90
Lesions of the optic radiations reportedly induce
ipsilateral metabolic depression in the deafferented visual cortices.68'TO'""M Patients studied weeks after the
onset of lateral homonomous hemianopia still exhibit
this visual cortex depression.92 The discrepancy between the transient metabolic effects of enucleation16
and the lasting metabolic depression following optic
radiation lesions, although possibly species specific,
more likely results from the different points of interruption of this multiple relay circuit.
Transcallosal Diaschisis
Kempinsky's experimental contributions to the
study of diaschisis should not be overlooked.94"97 He
primarily studied electrophysiological responses contralateral to unilateral cortical lesions produced by diverse methods (ablation, electric cautery, vascular ligation, and freezing). However there are some
shortcomings which limit intrepretation of his data
which include possible variations in the depth of etherinduced anesthesia, lack of quantification of evoke
potential and EEG data, and the absence of histological
verification of prior corpus callosum section done in
some cats. In none of the animals with the callosal
section was a depression of evoke potentials observed,
however some of the cats with large lesions did show
EEG amplitude reduction contralateral to the cortical
injuries. Despite these factors, Kempinsky interpreted
his data as strong support for Von Monakow's theory
of diaschisis.
Although it is tempting to invoke a mechanism of
transcallosal diaschisis for the commonly reported
CBF depression contralateral to a stroke, such studies
areflawedby confounding variables prior to or following the acute event.55-98"107 Such factors include chronic hypertension, previous cerebral infarction, large
vessel occlusion and "steal" phenomenon, increased
intracranial pressure, transtentorial herniation, drug
effects, and changes in PaCO2, hematocrit, and arterial
blood pressure. The effect of these variables on cortical function, contralateral to a stroke, as measured by
CBF, CMR02, or CMRGlu is unknown.
Animal experiments circumvent some of these confounding variables in the human studies. In models of
and Baron
focal cerebral ischemia there are reportedly variable

decreases in contralateral CBF and CMRGlu post-arterial occlusion108""7 some refuting"4 and others supporting116 the concept of transcallosal diaschisis.
Not recognized by Von Monakow was the loss of
neuronal function in intact brain depleted of neurotransmitter because of a shift from synthesis of transmitters to proteins for repair by remote injured neurons
innervating these areas." 8 ' " 9 The LC is one candidate
for such an effect119 because of its diffuse intracortical
projections, as small cortical lesions may cause transient retrograde reactions with resulting widespread
alterations of noradrenergic (NE) transmission in several CNS regions.
Experimentally induced right middle cerebral artery
territory ischemia has been shown to effect transcallosal physiologic changes remote from the site of injury.120"123 There is widespread reduction of neurotransmitter levels from brainstem neurons, as well as
behavioral hyperactivity. The postulated association
between post-right hemisphere cortical injury evoked
hyperactivity and depressed NE levels in intact regions
is supported by the blockade of hyperactivity by daily
administration of the NE uptake blocker desmethylimipramine at doses not affecting activity in sham-operated controls.121 It is quite likely that other neurotransmitters including DA,124"12* serotonin128 and
GAB A,129' 13 whose levels also change in intact brain
remote from cerebral ischemia, contribute to the clinical profile. As emphasized by Robinson and Bloom121:
" . . the idea of stroke as a local injury producing its
effect by disruption of local mechanisms of function is
inadequate conceptually and misleading clinically
. . . " They suggest that the mood depression often
occurring following stroke may be a manifestation of
such remote pathophysiological events rather than a
psychological reaction to disability.
Functional Effects in the Ipsilateral Cortex
Initial and delayed neurologic functional improvement following cortical stroke has been viewed in
terms of recovery from a state of diaschisis, i.e. a
partially reversible functional depression of the cortical area surrounding a site of necrotic damage. However, confirmation of this mechanism is difficult as electrophysiological activity, CBF, and metabolism may
be disrupted within an ischemic penumbra beyond the
boundaries of the infarct.131 Human PET studies of
CBF and CMRO 2 have demonstrated the frequent occurrence of the "misery-perfusion" syndrome over
morphologically intact cortical regions in the first 2-4
days following stroke, a situation of hemodynamic
failure that occasionally persists into a chronic stage. I32
Depressed cortical functions ipsilateral to cortical
stroke may, in addition to the ischemic process per se,
result from a constellation of factors including tissue
edema, increased intracranial pressure with or without
brainstem compression, diffusion of toxic waste products from the necrotic core, and selective neuronal cell
death without necrosis. Furthermore, the extension of
ischemic necrosis to subcortical white matter may isolate the overlying cortex from its afferent input and
823
sever efferent axons. This "undercutting" process can

produce depressed cortical function based on the previously discussed mechanisms other than a diaschisis.
Finally, a spread of necrosis to subcortical nuclei may
depress the functional activity of the cortex. As in the
case of transcallosal diaschisis, the study of post-infarct intracortical diaschisis is difficult but experimental cortical lesions, albeit not free of all confounding
variables, offer a more controllable data base.
Animal studies have correlated behavioral disabilities (e.g. reaching for food with the appropriate limb)
and a depression in sensory evoked potentials recorded
in tissue adjacent to small electrolytic lesions placed in
the motor cortex. Normalization of the evoked potentials in intact cortex adjacent to the lesions paralleled
recovery of behavior.133-134 In contrast, enhancement
of evoked responses recorded in intact cortex adjacent
to small cortical lacerations has been reported,135 possibly heralding post-traumatic epilepsy.136 A diffuse reduction in ipsilateral hemispheric oxidative metabolism measured by enzymatic a-GPDH histochemical
staining has been described following focal cortical
trauma.34 Reduced monoamine neurotransmitter levels
in cortex remote from but ipsilateral to the injury have
been reported also.120"126' m Intracortical diaschisis has
been a postulated mechanism for the depressed cortical
perfusion surrounding an area of infarction in aphasic
stroke patients.137 The advent of the PET scan has
made it possible to discriminate between primary
metabolic depression and primary hypoperfusion.
Matched decreases in CBF and metabolism ipsilateral
to cortical infarction have been reported.33'M'm- m-139
Such reduction of CBF and CMRO 2 beyond infarct
boundaries has been reported in patients,140"142 and animals143 with chronic occlusion of either the internal
carotid or middle cerebral artery (MCA). Widespread
depression of early I-Isopropyl-ioto-amphetamine uptake involving almost the entire cortical mantle ipsilateral to chronic MCA territory infarction has also been
observed with SPECT, even in the absence of an arterial occlusion at angiography.144 Selective cortical cell
death without tissue necrosis could cause this metabolic depression; it occurs experimentally in penumbral
areas,143'143 but appears rare in humans.l46> l47 Available
metabolic data from experimental cortical ablation or
freeze-lesions 19 ' l16 ' ll7 ' l48 " 130 suggest that intracortical
diaschisis is of minor importance, perhaps because
maintainence of a functional cortex depends on many
afferents other than those from the cortical lesion site.
Functional Effects in the Subcortex
Patients with primarily cortical stroke have shown
definitive ipsilateral thalamic and/or basal ganglia
metabolic depression occurring within hours, but also
found years later, in PET study.33'68--139'l31"133 Putative clinical correlates of these remote metabolic effects include verbal memory deficits without aphasia
associated with left thalamic hypometabolism and motor speech deficits related to reduced left caudate nucleus CMRGlu.31'154 Thalamic medial-dorsal and/or
ventral basal nuclear complex glucose hypometabolism ipsilateral to unilateral anterior or posterior corti-
824
STROKE
cal lesions, has been reported.148"150'l53'156 While these

thalamic hypometabolic responses to cortical ablation
predominantly reflect retrograde degeneration, some
may represent a diaschisis mediated by transynaptic
actions either from cortico-thalamic or intrathalamic
pathways.
Reduced striatal CMRGlu, although occurring less
consistently than in the thalamus, has been reported
following unilateral ablations of the ipsilateral frontal
cortex.116148"150155 Additionally modulations of the
striatal neurotransmitters DA, glutamate, and GABA
have been reported following such lesions.127128157
Frontal lobe ablation-induced neglect is associated
with the remote metabolic effects in monkeys.150 The
analysis of the metabolic changes after frontal ablation
following prolongation of the neglect syndrome by
diazepam,158 could clarify any causal relation between
the metabolic and behavioral changes. Interestingly,
transneuronal glucose hypermetabolism has been observed in the pallidum ipsilateral to a frontal ablation in
rats,149 but not monkeys.150'l55 The remote effects of
unilateral frontal cortex lesions on cerebral metabolism have been quantitatively examined using cytocrome oxidase histochemistry in the rat.159 The latter
investigation has shown that injury produces a bilateral
hypometabolism in the pallidum and several other extrapyramidal structures; an effect reversed by amphetamine. These findings are possibly related to this
drug's acceleration of recovery from hemiplegia discussed below.
Electrophysiological data from the hippocampus
after cortical lesions has been cited as evidence against
diaschisis. l6 Dendritic field potentials evoked by stimulation of the monosynaptic hippocampal-commissural pathway were recorded before and after unilateral
lesions of the ipsilateral entorhinal cortex. The absence
of postlesion evoked response changes was interpreted
as an absence of diaschisis. This study has been critiqued by others13 and hippocampal CMRGlu measurement have indicated a depression of function following
simular entorhinal lesions.1*1-l62
A number of diencephalic and brainstem nuclei other than thalamus and basal ganglia exhibit metabolic
changes following experimental cortical ablation. The
time course, neurochemical and behavioral correlations of these remote metabolic effects are not known.
The affected nuclei show no clear histologic neuronal
degeneration to account for the metabolic changes.
The metabolic depression found in the ipsilateral pontine nuclei in monkeys'55 may reflect degenerating
cortical pontine terminals, transynaptic depression of
activity (degeneration of excitatory corticofugal afferents) or both. Conversely, changes in metabolism and
neurotransmitter levels seen in the region of the LC
ipsilateral to frontal cortex lesions,19-l20"127 have been
interpreted as a retrograde reaction of the neuronal
soma after damage to one or more of its cortical axonal
branches. Finally, the hypometabolism seen in the ipsilateral red nucleus,19-149'159 subthalamic nucleus149-159
and substantia nigra after frontal cortex lesions155 may,
in part, represent transneuronal effects secondary to
disruption of a motor circuit.
VOL 17, No
1986
Pharmacological Studies of an Animal Model of

Hemiplegia
In an attempt to explain the mechanisms of hemiplegia following motor cortex damage, Von Monakow
described "diaschisis cortico-spinalis", a reversible
functional depression of remote intact structures. Experimental pharmacologic manipulations in hemiplegic animals have been shown to accelerate recovery
while also affecting cerebral metabolism and neurotransmitter release at a site remote from the primary
lesion. Unilateral sensorimotor cortex ablation in the
rat produced pronounced but transient contralateral
hemiplegia evident on the beam-walking task. Amphetamine, administered in moderate doses was combined with the beam-walking experience. A single administration of the drug one day post-operatively
enhanced recovery compared to saline controls and the
beneficial effects endured and were maintained long
after the drug was metabolized. In animals given amphetamine and kept in a small cage to prevent ballistic
movements during intoxication, no promotion of recovery was observed indicating the necessity to combine drug and experience. Haloperidol blocked this
treatment effect and when given alone in a single dose,
also markedly retarded recovery, implicating the catecholamines (CA) inrecoveryof function.'" This effect
has been replicated in the cat whose more severe
hemiplegia responds favorably to delayed (10 days
post-surgery) multiple but spaced administrations of
amphetamine combined with beam-walking experience.164
The mechanism of these effects is uncertain but
diaschisis has been suggested to explain the rapid behavioral improvements produced by this pharmacologic treatment plus behavioral experience.19 Alternative
interpretations include: the reversal of lesion-induced
input or depleted neurotransmitter, longterm potentiation,63-165-l66 and behavioral substitution. A CA-related
diaschisis is supported by the observations that single
infusions of NE,167 or systemic administration of the
amphetamine analogs phentermine168 or phenolpropanolamine,169 combined with experience also promote
recovery from hemiplegia. The DA agonist apomorphine and the DA uptake-blocker methylphenidate do
not promote recovery from hemiplegia in this model.170- m Further biochemical support for CA-related
diaschisis is the observation in post-operative treated
animals of increased NE turnover in the ipsilateral LC
(whose neurons project to forebrain and cerebellum172)
and the cerebellum contralateral to the cortical lesion
compared to saline treated controls. Such changes
could indicate a treatment-induced alleviated or compensated "crossed cerebellar diaschisis" which has
been associated with supratentorial stroke discussed
below. Metabolic studies in this model suggest a
diaschisis as there is a widespread depression of 2DG
utilization especially prominent in the ipsilateral red
nucleus and LC following unilateral sensorimotor
cortex lesions.19 Paralleling the pharmacological manipulation of behavioral recovery is the respective improvement or worsening of post-surgical hypometabolism by amphetamine and haloperidol.19 However,
DIASCHISIS/Feenry "<* Baron
since these CNS metabolic effects are diffuse, delineation of anatomically selective effects is necessary before a specific structural correlate of treatment-accelerated functional recovery can be established.
Crossed Cerebellar Diaschlsis
Cerebellar hemisphere hypometabolism contralateral to supratentorial infarction was first described by
Baron et al using PET and the steady-state oxygen-15
method.173"175 This phenomenon has since been reported in about 50% of patients with stroke and those with
supratentorial neoplasms, studied by tomographic
mapping of perfusion CMRO 2 , CMRGlu, or I-iodoamphetamine uptake.53' " 107 ' 139 ' '"176"185
Significant contralateral cerebellar hypometabolism
(CCH) has been observed in patients with isolated lesions of the frontal cortex, 5 5 ' l 7 6 ' m parietal cortex, 107179183
thalamic
and
basal
ganglia
areas 53 ' m - l77 ' m-183 and internal capsule.89 The CCH is
most prominent with large lesions involving two or
three cerebral lobes, or after smaller lesions destroying
most of the internal capsule at the level of the basal
ganglia. The size and location of the lesion rather than
severity of hemiparesis appear to be the best predictors
of CCH in stroke patients. Additionally, CCH has been
seen in patients with pure motor hemiparesis related to
an internal capsule lacune, 8889 as well as in patients
with large infaxcts and no hemiparesis176' m-179, but not
in hemiparetic patients with a presumed pontine lacune.
Interruption of the cerebro-cerebellar loop is
thought to be the most likely mechanism of this remote
transneuronal metabolic depression.174'175 Its frequent
association with frontal and parietal cortical lesions
the origin of the cortico-pontine fiber tract186"188 fits this
hypothesis. Since cortico-pontine projections provide
predominantly excitatory input to the contralateral
cerebellar granule cells,189' l9 damage to this system
could "deactivate" the contralateral cerebellum, hence
the term "crossed cerebellar diaschisis."173'll* Although CCH was not specifically studied, experiments
in monkeys'49'191 have shown ipsilateral pontine nuclei
hypometabolism after cortical ablation. CCH has been
difficult to observe in rats 19 ' l49 ' l59 ' "" m presumably
because the cerebro-cerebellar loop is well developed
only in primates.186
In conflict with the theoretical interpretation of CCH
as a diaschisis are examples where CCH persists or
even worsens post-infarction. 53107176177179181 Furthermore, CCH may develop in association with slowly growing supratentorial tumors,178-183 indicating that
acute brain injury is not essential for its development.
Thus, two essential criteria for a diaschisis, namely
sudden onset and a transient response are lacking in
CCH. While other examples of slowly developing
diaschisis have been discussed, the lack of CCH reversibility is a major theoretical problem. Other possible explanations include anterograde transneuronal degeneration, known to occasionally develop years after
adult-onset supratentorial stroke.193' l94 Since dendritic
alterations as early as 2-3 days after deafferentation
have been described, 195196 the acutely detectable
825
CCH177 might represent early metabolic responses expected to preceed irreversible morphological alterations .179 The lack of recovery of CCH and its apparent
progression to degeneration sharply contrast with the
other examples of transynaptic depression discussed
above. Nevertheless, recovery of CCH has actually
been reported in a few stroke patients175'177-179 suggesting that this process is not necessarily inescapable.
While the mechanisms for recovery are unclear, they
may represent a link between reversible diaschisis and
irreversible degeneration.179
As yet, there is no well established clinical expression of CCH. In a recent study of seven patients with
pure internal capsular infarcts, no obvious association
between CCH and ipsilateral limb ataxia was found.89
Thus, until large scale prospective studies are undertaken, the phenomenon of CCH, although the most
consistent evidence of transneuronal functional depression in humans, will remain poorly understood in
terms of pathophysiology, clinical correlations and
therapeutic implications.
In addition to effects on the contralateral cerebellum, supratentorial lesions may result in a mild, less
profound metabolic depression in the ipsilateral cerebellum. 5 5 1 0 7 1 7 6 1 7 8 This observation has been challenged179 because of the lack of an adequately matched
control group with respect to age and vascular risk
factors, as well as a nonhomogeneous study group.
Furthermore, its reported association with impaired
consciousness,107 suggests a role for supratentorial
edema and herniation.
Concussion
Experimental data suggest that the sequelae of cerebral concussion may reflect midbrain muscarinic cholinergic hyperactivity.197 Supporting this theory is the
reproduction in cats of transient behavioral and EEG
changes mimicking concussion following acetylcholine agonist (carbachol) infusion. An increased 2DG
utilization in cholinergic neurons remote from the site
of trauma was observed in a concussion model. Such a
cholinergic pathological hyperactivity may act upon
other intact systems to produce symptoms of concussion. These findings are compatible with the theory of
diaschisis if it is modified to incorporate disruptive
hyperactivity as well as loss of facilitatory input from
damaged areas.
Permanent Diaschisis
Schneider15 first conceptualized a permanent
diaschisis, "diaschisis protractiva," to explain the surgical alleviation of the hemianopsia contralateral to
posterior cortical ablation in cats.198 Animals with
longstanding loss of orienting responses to stimuli in
the visual field contralateral to a large unilateral posterior cortex ablation recovered after a lesion of the contralateral superior colliculus or intercollicular commissure. The subcortical lesions were thought to abolish a
pathological intercollicular tonic inhibition resulting
from the unilateral cortical ablation.198'199 Another possible example of permanent diaschisis is the amphetamine plus visual experience restoration of depth perception after bilateral visual cortex ablation in cats.200
826
STROKE
This effect is blocked by haloperidol adding further

support for a role of CA in a diaschisis. Preliminary
cytochrome oxidase histochemistry indicates that this
treatment also reverses the hypometabolism in the superior colliculi which follows visual cortex lesions.201
Therapeutic Implications
A recent double-blind pilot investigation suggests
that the animal data on the treatment of hemiplegia
may be applicable to human stroke.202 Eight patients
with stable motor deficits studied within ten days of
their first stroke, were randomly assigned to treatment
or control groups. Motor performance was objectively
scored prior to, and 24 hours following a single oral
administration of either 10 mg of d-amphetamine sulfate or a vitamin placebo. Intensive physical therapy of
the aifected limbs was provided for all patients following drug or placebo, to induce the necessary relevant
experience as determined from the animal studies. A
statistically significant improvement in motor scores
over pretreatment values was seen in all patients receiving amphetamine plus physical therapy, compared
with lack of improvement in the control group. Other
drugs with non-specific, potential therapeutic effects
on diaschisis include naloxone, piracetam, and GM1
ganglioside.
Haloperidol and alpha-noradrenergic antagonists
have been reported to retard recovery in aphasic stroke
patients.203 Recovery can be accurately predicted using
a mathematical model based on the test results of the
Porch Index of Communicative Ability.204' ^ Patients
on alpha-blockers, in contrast to those on betablockers or no medication, showed a significant retardation of recovery as compared with the predicted recovery. The transient reinstatement or enhancement of
post-stroke neurological deficits by CNS depressants
such as benzodiazepines,138 phenytoin,206, or anesthetic agents suggests that recovered neuronal function, in
contrast to normal function, is much more vulnerable
to disruption by pharmacological agents.
Concluding Comments
Kempinsky proposed97 "essential criteria" for
diaschisis including 1) a circumscribed injury, 2) a
neuronal basis for the depressive effects, 3) its occurence at a distance from the injury, 4) identification of
the fiber tract involved, and 5) a reversible process.
The above criteria still appear valid. Regarding distance from injury, at least one synapse must exist between the lesion and the target structure that is in the
proposed state of diaschisis. A synapse lying within
the target structure could potentially reflect only presynaptic events or direct reactions to axonal injury,
thereby confounding interpretation of the data. Reversibility is a necessary requirement in order to exclude the direct effects of the primary injury; however,
in the case of permenant diaschisis, its demonstration
would require surgical or pharmacological interventions.
Ideally, in a modern conception of diaschisis the
physiological indices of this phenomenon should correlate with a behavioral symptom, and both should
VOL 17, No
1986
parallel improvement with time and response to manipulations. With prolonged lack of normal afferent
input or function, diaschisis may result in morphologic
alterations. The disruption of function in the target
structure may result from a loss of either excitation or
inhibition. In cases of low afferent input activity or in
the presence of numerous other inputs to the target
structure, diaschisis may not occur. Conversely, if the
lesioned area constitutes the sole or major input to the
target structure, a readily detectable diaschisis must
occur. Diverse mechanisms, possibly including repair
processes such as sprouting and/or denervation supersensitivity, could allow the target structure to accomodate for the loss of input from the lesioned area.
While none of the experiments discussed in this
review completely satisfy all the criteria for diaschisis,
they do provide persuasive evidence for certain aspects
of the theory. Only if this concept stimulates future
work which provides some understanding of recovery
of function will such a general theory of reaction to
brain injury prove worthwhile.
Acknowledgments
We wish to express our gratitude to Elise Scott and Dr. Irene
Meissner for assistance in the preparation of this manuscript.
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Diaschisis

DM Feeney and JC Baron

Subscriptions: Information about subscribing to Stroke is online at

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RED BLOOD CELL DISORDERS AND STROKE/Gro/ta et al

A BETTER UNDERSTANDING of the mechanisms

theory of diaschisis.1 Although the extensive literature

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Von Monakow emphasized 4 important aspects of

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DIASCHISIS/Fee/iey and Baron

cal pathways apreading from the site of injury. Von

ries of recovery of function.

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DIASCHISIS/Feert<ry ond Baron

eral cortical hemisphere without attenuating cortical

postsynaptic membrane adaptation to alterations of

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deafferented ipsilateral structures as well as reducing

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focal cerebral ischemia there are reportedly variable

sever efferent axons. This "undercutting" process can

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cal lesions, has been reported.148"150'l53'156 While these

Pharmacological Studies of an Animal Model of

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DIASCHISIS/Feenry "<* Baron

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This effect is blocked by haloperidol adding further

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DIASCHISIS/FeevMry and Baron

on cortical electroencephalogram in cats. Arch Neurol Psychiat

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septal nuclei. Brain Res 50: 241-264, 1973

ME, Kuhl DE: Comparison of glucose metabolism, X-ray CT and

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DIASCHISIS/Fee/wry and Baron

effect of unilateral cerebral infarction on cerebral blood flow and

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Downloaded from stroke.ahajournals.org at VA MED CTR BOISE on February 28, 2009

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