Dias Chis Is

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DM Feeney and JC Baron Diaschisis

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RED BLOOD CELL DISORDERS AND STROKE/Gro/ta et al 817

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DiaschisisDENNIS M. FEENEY, P H . D . , AND JEAN-CLAUDE BARON, M.D.

A BETTER UNDERSTANDING of the mechanismsof spontaneous recovery following stroke may provideinsight into achieving clinical interventive measures toaccelerate and enhance post-stroke recovery. Thisprogress review focuses on one such mechanism, VonMonakow's controversial and often misunderstood

From Service Hospitalier Frederic Joliot, CEA, Department de Bio-logie 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 anINSERM Senior Research Fellow at the Service Hospitalier FredericJoliot.

Address correspondence to: Jean-Claude Baron, M.D., Service Hos-pitalier Frederic Joliot, CEA, Department de Biologie, 91406 Orsay,France.

Received July 16, 1986; accepted August 4, 1986.

theory of diaschisis.1 Although the extensive literatureon recovery of stroke function is not reviewed,2"10 se-lected studies and theoretical issues potentially relatedto diaschisis are discussed.

Diaschisis is but one of several general theories ofrecovery of function which classically include: a) vi-cariation-the taking over of functions of the damagedarea by regions not originally involved in the perform-ance of lost behavior, b) redundancy-recovery basedupon uninjured neurons that normally contribute tothat behavior, i.e. the distribution of a functionthroughout the cerebral cortex, c) behavioral substitu-tion-the learning of new behavioral strategies to com-pensate for the deficit, d) recovery from diaschisis-thetemporary functional "shock" or deactivation of intactbrain regions remote from but connected to the area of



818 STROKE VOL 17, No 5, SEPTEMBER-OCTOBER 1986

primary injury. These older theories of recovery, al-though quite different from recent objective observa-tions of sprouting or denervation supersensitivity pro-posed to mediate recovery of function, are notmutually exclusive. The unspecified mechanisms forthe alleviation of diaschisis could involve the growthof new axon terminals or the multiplication of postsyn-aptic receptors.

While changes in neuronal function are common toall of these theories, recovery of function is clearly amultifactorial process including: the resolution of ex-tracellular and/or intracellular edema; reestablishmentof cerebral blood flow (CBF) in "penumbral" areasafter ischemic stroke or subarchnoid hemorrhage-relat-ed vasospasm; and restitution of tissue function afterintracerebral hemorrhage (mass effect). Interventionsto promote these events may directly improve clinicaloutcome by reducing the extent of initial damage.Thus, acknowledging the many different approachesto recovery after brain injury,5'n-8 this review will dis-cuss only diaschisis.

Although the term diaschisis has often been usedloosely, few publications5' "•l2 adhere to Von Mona-kow's original description written in German,1 lan-guage barriers having contributed to the confusion anddebates.1J~15 Diaschisis (from the Greek meaning"shocked throughout") has been simplistically de-scribed as the cerebral counterpart of spinal shock.Recent experimental, neurophysiological and meta-bolic data support the initial interpretation of spinalshock as due to the loss of descending facilitory activ-ity producing a transient loss of spinal reflexes belowthe level of cord transection. Because the brain circuit-ry is relatively more complex than that of the spinalcord, understanding the mechanisms underlying cere-bral diaschisis will be more difficult.

In the 1870's, Brown-Sequard, the most notablepredecessor to the concept of diaschisis, described re-mote effects of focal brain damage ("actions at a dis-tance"). He proposed that brain lesions produced ex-citatory and inhibitory effects causing disruption offunction in regions distant from the site of damage.5

Von Monakow, developing these ideas more fully,introduced the term diaschisis to describe "abolition ofexcitability" and "functional standstill". His theory ofdiaschisis, which excluded previously held concepts ofirritation and active neural inhibition, was necessarilydependent upon the interpretation of functional brainorganization. In contrast to the discrete localization ofcortical function held by many of his contemporaries,Von Monakow noted:1 "The generally accepted theoryaccording to which aphasia, agnosia, apraxis, etc., aredue to destruction of narrowly circumscribed appropri-ate praxia, gnosia, and phasia centres, must be finallydiscarded on the basis of more recent clinical and ana-tomical studies. It is just in the case of these focalsymptoms that the concept of complicated dynamicdisorders in the whole cortex becomes indispensible."Von Monakow's perspective of "distribution of ner-vous function along several sections of the medullartube" (neuroaxis), was "Jacksonian" in nature.

Von Monakow emphasized 4 important aspects ofdiaschisis:

1) Damage to one brain area can, by loss of excita-tion, produce cessation of function in regions adjacentto, or remote from but connected to the primary site ofdamage. "The physiological process upon which thelocal initial symptoms are based, may be regarded as ashock confined to distinct nervous structures whichhave to be defined more precisely from the anatomicalpoint of view. The local character (dependent upon thesite of the lesion), the closer content, and also themanner of compensation for impairment of innerva-tion, endows this shock with a special position, andmakes it seem justified to classify it separately fromother forms of shock. For this type of shock I shall usethe term diaschisis. Consequently, diaschisis repre-sents an 'interruption of function' appearing in mostcases quite suddenly (this applies to all other types ofshock as well) and concerning certain widely ramifiedfields of function, which originate from a local lesionbut have their points of impact not in the whole cortex(corona radiata, etc.) like apoplectic shock but only atpoints where fibers coming from the injured area enterinto primarily intact grey matter of the whole centralnervous system."1

Although, Von Monakow usually reserved the termdiaschisis for sudden onset of some symptoms, he alsoproposed a "slowly creeping diaschisis"12 for whichrecent experimental evidence has lent credence.16

2) Diaschisis was a clinical diagnosis whose pre-sumptive mechanism was loss of excitation to intactregions rather than neural inhibition:

"In other words, massive lesions of commissuralfibres in the left hemisphere will interrupt dynamicallythe points of entry and exit of fibers in the cortex of theright hemisphere, which will impair a number of morecomplicated nervous processes (apraxia, aphasia, ag-nosia)."1

3) Diaschisis "undergoes gradual regression in welldefined phases" such that resolution will parallel re-sumption of function in areas of diaschisis. With therecent neuroscientific focus on potential repair mecha-nisms following brain damage, Von Monakow's con-cept of a Darwinian struggle between diaschisis and anactive repair process by unspecified restorative mecha-nisms, is indeed insightful:

"Any injury suffered by the brain substance will lead(as for lesions in any other organ) to a struggle for thepreservation of the disrupted nervous function, and thecentral nervous system is always (although not alwaysto the same degree) prepared for such a struggle; . . .The final result of this struggle (schism) will vary foreach given area of the brain depending on the numberand distribution of battling forces . . . and this is whythe residual symptoms (pure sequels of the defect) willrarely be the same in different individuals."1

An exception to the general rule of the transient stateof diaschisis, is "diaschisis protractiva" wherein thecerebral shock cannot be spontaneously compensatedfor by active repair mechanisms."115

4) The "wave of diaschisis" follows neuroanatomi-



DIASCHISIS/Fee/iey and Baron 819

cal pathways apreading from the site of injury. VonMonakow refers to three types of diaschisis, illustrat-ing their spread through classical fiber paths:1

a) Diaschisis cortico-spinalis — progression offunctional depression from a motor cortex injury to thespinal cord along pyramidal tract fibers.

b) Diaschisis commissuralis — functional contra-lateral cortical depression via axons of the corpus col-losum following injury to the cortex of one hemi-sphere.

c) Diaschisis associativa — intracortical fiber-medi-ated depression of function in intact cortical areasneighboring the locus of injury.

Von Monakow proposed that three types of diaschi-sis usually occur simultaneously, but one form maypredominate depending upon the "injured connec-tions" and the degree of cortical development in thespecies under study.

Only during the last three decades have methodolo-gies been developed for the scientific investigation ofdiaschisis. Additionally the concept of chemical neu-rotransmission has been accepted and the antiquatedterms "shock" and "functional standstill" have no di-rect counterpart in modern neurophysiology. Investi-gations of the theory of diaschisis have recently usedtwo approaches: 1) the study of remote effects of le-sions on such variables as spontaneous or evoked elec-trophysiological activity, neurotransmitter levels, syn-aptic receptors and CBF and metabolism; 2) themanipulation of recovery of a particular behavioralsymptom after brain injury.

Although alterations of neurotransmitters, sproutingof new neuronal processes, and changes in cerebralmetabolism occur simultaneously at sites distant fromactual injury, and bearing in mind that various inter-ventions can influence behavioral recovery, causal ef-fects are difficult to substantiate. For example, theconcept of pharmacological restoration of behavioraldeficits following brain injury17' " assumes that drugswhich cannot be acting upon lost neurons exert theireffects upon intact systems rendered nonfunctional bythe primary lesion.

More convincing would be a demonstration of thecorrelation of pharmacological manipulation of symp-toms with alterations of physiological markers of theremote effects of lesions.19 Unfortunately, because ofthe multiple (and many unknown) drug effects in in-jured brain, and lack of a strict relationship betweenstructure (or neurotransmitter) and a single behavioralfunction, it is difficult to firmly ascertain the etiologicmechanisms of manipulated recovery.

The separation of causal and beneficial effects fromthose only correlated with recovery of function (epi-phenomena), demands an interdisciplinary study ofbehavior and neurophysiology. Deleterious changesfollowing CNS lesions may also occur, e.g. neuronalsprouting after spinal damage may produce spastic-ity.20 In the injured brain, establishment of aberrantconnections may impede rather than facilitate recov-ery. 2I> n Because of these complexities there are fewunequivocal experiments supporting any of the theo-

ries of recovery of function.In the last decade, tomographic and autoradiograph-

ic technological advances have accelerated the study ofremote functional effects of stroke. There has beenrepeated confirmation23 of the original observation thatchanges in structurally normal brain neuronal functionare attended by proportional and parallel changes in thecerebral oxygen metabolic rate (CMRO2), glucose util-ization (CMRGlu) and — because of the so calledcoupling phenomena — CBF. This relationship ismaintained in the brain as a whole, regionally, andeven at the local level. Most early studies of diaschisiswere restricted to stroke patients, were limited in theirinterpretation of the location and extent of the lesion.In contrast recent localization of pathology based uponradiologic technical advances in computerized tomog-raphy (CT) and magnetic resonance imaging (MRI),provide more accurate localization of pathology.

Experimental Studies of DiaschisisSpinal Cord

As discussed above, the term diaschisis can be con-sidered analogous to spinal shock, and is used by someclinicians in this context only. Supporting the classicinterpretation that spinal shock is due to the loss ofdescending excitatory input is the report of immediatealpha motor neuron hyperpolarization after coolingand rewarming, respectively at higher cord levels.24

Post-cord transection measurements of glucose utiliza-tion using 14C-deoxyglucose (2DG) in the monkey haverecently indicated more complex and widespread ef-fects appearing in many segments above and below thelevel of the injury.23 Increased CMRGlu in some lam-ina was interpreted as a loss of tonic descending inhibi-tion, and while reminiscent of diaschisis, the loss ofactive neural inhibition was not included in Von Mona-kow's theory. The observation of hypermetabolic lam-ina adjacent to hypometabolic lamina after cord tran-section suggest caution in the interpretation of data,especially negative results, when measures from largeregions of neuropil are combined.

Brainstem LesionsSince a vast number of pathways interconnect brain-

stem, diencephalic and telencephalic neuronal aggre-gates, a brainstem vascular lesion might be expected toexert transynaptic effects at many distant loci. Instroke patients, brainstem lesions inducing stupor orcoma are associated with diminution of supratentorialperfusion and metabolism roughly correlating withboth the state of arousal and altered EEG patterns.26

Conversely, patients with severe brainstem stroke re-sulting in total paralysis but normal arousal ("locked-insyndrome"), have normal CBF.27

The classic work demonstrating coma in the cerveauisole" preparation was interpreted as a remote effect ofthe diffusely projecting mesencephalic reticular forma-tion altering forebrain function.28 Although the criticalinvolvement of the mesencephalic region in the regula-tion of wakefulness has long been accepted, recentwork has focused on the complex interactions of di-




verse nuclei within this region, and has utilized strate-gically placed lesions.

In the rat, large unilateral lesions interrupting mostof the brainstem-forebrain pathways resulted inmarked ipsilateral decreases in CMRGlu in corticaland subcortical gray matter.29 Destruction of the rostralreticular formation in stages30 first on one side and thenafter some time period, the contralateral side, did notproduce enduring coma. This attenuated effect wasinterpreted as lesions performed in sequence produc-ing less diaschisis. Lesions done in stages may belikened to slowly growing tumors which produce lesssymptomatology than acute lesions of the same magni-tude. This effect of the Jacksonian "momentum" of alesion or "slowly creeping diaschisis" is still poorlyunderstood.

Experimental animal studies have examinedchanges in forebrain metabolism after stereotaxic le-sions of specific brainstem nuclei. Electrolytic lesionsof the rat raphe serotonergic somata resulted in moder-ate depression of CMRGlu in other brainstem nucleiand the hippocampal dentate gyms without alteringmetabolism in other forebrain regions.31 Unilateral le-sions of the locus coeruleus (LC) reportedly causedeither very moderate or no change in cerebral metabo-lism. Glucose utilization was markedly reduced in theipsilateral cerebral cortex and latero-ventral thalamus(by 10% and 15% respectively)32 or unchanged.2933

Cortical resting metabolic rates measured using thehistochemical stain alpha-glycerophosphate dehydro-genase (a-GPDH) were unchanged.19 In contrast, thedepression of a-GPDH in the entire ipsilateral cortexfollowing focal cortical injury34 is exaggerated by le-sions of the LC.19 This data is compatible with thehypothesis that the LC "modulates" activity of othersystems.35

In the rat, 6-hydroxydopamine-induced substantianigra lesions have simulated the dopamine (DA) deaf-ferentation of Parkinson's disease. Resulting physio-logic changes include mildly deceased CMRGlu in theipsilateral frontal cortex, not reversed by administra-tion of DA agonists, mild ipsilateral strial metabolicdepression and marked hypermetabolism in the ipsilat-eral habenula and globus pallidus. These latter effects,in contrast to the frontal cortex hypometabolism, arealleviated by apomorphine or L-Dopa. These meta-bolic changes, which are associated with ipsilateralDA postsynaptic hypersensitivity and behavioral ab-normalities, are not found in animals showing sponta-neous recovery of function.29' 3*~38 Although these stud-ies satisfy most of die criteria for diaschisis they arerarely discussed in this framework. That the targetstructure of the substantia nigra shows only a mildmetabolic depression despite the almost total DA de-afferentation may result from the sparing of the non-DA afferents constituting the major inputs to the stria-tum. There may be no presently detectable directmetabolic counterpart to the presumptive primary neu-ral abnormality of Parkinson's Disease i.e. the loss ofnigro-striatal input. Transneuronal hyperactivity re-sulting from loss of tonic inhibition, reflected by in-

creased pallidal glucose utilization following substan-tia nigra lesions, can occur after brain injury — andincorporating this concept is essential to present-dayrevision of the theory of diaschisis.

hi summary, remote supratentorial functional ef-fects of brainstem reticular and nigro-striatal lesionshave been clearly demonstrated using cerebral meta-bolic measurements. Transient, transynaptic effectssecondary to lesions of either of these anatomically andphysiologically unique systems could potentially beconsidered diaschisis.

Thalamus

The thalamus constitutes a major relay and integra-tive nuclear cluster, including the sensory, motor, lim-bic systems, as well as the ascending brainstem reticu-lar formation. Thus, interruption of neuronal functionsuch as occurs in thalamic stroke, can give rise to aconstellation of different clinical expressions includingsensory loss, ataxis, speech alterations (thalamic apha-sia), visual-spatial deficits, global or selective amne-sia, hemi-inattention (neglect), psychomotor retarda-tion, akinetic mutism, thalamic dementia and possiblycoma. Apart from designated functional roles of theventrobasal complex and geniculate bodies, preciseclinico-anatomic correlations of other thalamic nucleiare lacking. However, selected human studies (includ-ing sterotaxic thalamotomy) have suggested the domi-nant ventral-lateral and intralaminar nuclei play a sig-nificant role in the mechanisms of attention. Lesions ofthe left or right medio-dorsal nucleus may produceverbal and visual amnesia respectively, while bilaterallesions may result in global amnesia or dementia.40'41

Some of these thalamic injury syndromes have alsobeen reproduced in nonhuman primates.42

In view of the dense thalamocortical projections, ithas been speculated that these behavioral conse-quences of thalamic damage result from cortical dys-function after loss of these important cortical afferents— perhaps a loss of cortical "activation."43-44 Someparticular patterns of symptoms may only reflect "spe-cialized cortical functions." This could be interpretedas a diaschisis, since such effects would be remotefrom the lesion and recovery is often remarkable afterthalamic stroke even when initial symptoms are se-vere.

Electrophysiological data from both human and ani-mal experimentation shows that there is marked ipsi-lateral cortical EEG slowing following unilateral le-sions in many of the "non-sensory" thalamic nuclei,particularly the intralaminar, medio-dorsal, ventral-anterior and the reticular nuclei.45"" These effects,which depending on the size of the lesion last forweeks or longer, reportedly affect the entire ipsilateralcortical mantle. Lesions of a "specific" projection nu-cleus, such as the ventral-posterior-lateral nucleus maynot result in EEG slowing or die effects are restricted tothe somatosensory cortical projection area.45' ** Unilat-eral lesions of the rostral pole of the thalamus (anteri-or-ventral and reticular nuclei) in the cat, depressedboth seizure activity and sleep spindles over the ipsilat-



DIASCHISIS/Feert<ry ond Baron 821

eral cortical hemisphere without attenuating corticalevoked responses. This suppression of cortical circuit-ry involved in the generation of synchronous dischargewithout reducing cortical excitability can be consid-ered a selective remote cortical effect of injury to theanterior thalamus. But whether the mechanism of thiseffect is intrathalamic or a disruption of the diffusecortical projection system is unclear.49 A similar de-pression of synchronous discharge, ipsilateral alpharhythm blockade, has been described following unilat-eral stroke involving these nuclei.50

Positron emission tomography (PET) and singlephoton emission computerized tomography (SPECT)studies of patients with recent ischemic or hemorrhagicunilateral thalamic stroke, have clearly demonstratedmatched reductions in ipsilateral cortical perfusion,CMRO2 and CMRGlu involving the entire ipsilateralcortical mantle. *"•51"5* Although correlations betweendistribution and severity of cortical metabolic depres-sion, the particular thalamic nuclei involved and clini-cal symptoms are indeterminate, studies suggest anassociation between the degree of cortical hypometab-olism and behavior deficits.40'52 Additionally, there isa significant trend between recovery of cortical metab-olism and clinical improvement.4050"56

Experiments involving thalamic lesions in rats showsome correspondence with this human data. After uni-lateral electrolytic lesions of the ventro-medial nucleusof the thalamus, there is an ipsilateral reduction ofcortical metabolic rate directly proportional in severityto the size of the thalamic lesion.57

Since cerebral energy metabolism essentially re-flects sodium pump activity58"60 and hence the densityof pre- and postsynaptic events, the cortical metabolicdepression after pure thalamic lesions may involve anynumber of factors including: 1) anterograde Walleriandegeneration of thalamo-cortical terminals; 2) retro-grade degeneration of cortico-thalamic neurons secon-dary to lesions of their thalamic terminals; 3) transyn-aptic degeneration of cortical neurons secondary- toloss of thalamic afferents; 4) reduced functional activ-ity of cortical neurons (without degeneration) after aloss of thalamic input.40 Metabolic depression invokedby the first two mechanisms, rather than an index ofdiaschisis, is a simple manifestation of direct injury toneurons. The latter two mechanisms involving tran-synaptic processes capable of recovery, could qualifyas physiologic measures of diaschisis. The dispropor-tionate magnitude of cortical metabolic depressionafter thalamic lesions, relative to the density of thal-amo-cortical projections, makes the anterograde de-generation a tenuous explanation.61 Retrograde degen-eration of cortico-thalamic neurons and corticaltransynaptic neuronal death is rare, if not absent, in theadult mammalian brain.62 A loss of dendritic spinesfrom cortical neurons does occur after deafferenta-tion63'w but has not been reported following thalamo-cortical disconnection. Electron microscopic studiesare needed to determine any potential association ofmetabolic disturbances with morphological changes(such as dendritic spine atrophy) that would reflect

postsynaptic membrane adaptation to alterations ofthalamic input.63'M The trend for recovery from corti-cal hypometabolism seen after thalamic stroke wouldbe consistent with this view. Alternatively, the diffusecortical hypometabolism subsequent to thalamic le-sions may result from a non-specific process of "deac-tivation." Other postulated mechanisms for the accom-modation to loss of thalamic input to the cortex includecollateral sprouting or postsynaptic receptor supersen-sitivity. The observations of cortical hypometabolismafter thalamic injury are somewhat similar to thoseseen in the rat visual cortex following enucleation, orthe somatosensory cortex after the removal of whis-kers.16' 66 Recovery of synaptic density in the deaffer-ented dentate gyrus in the rat follows a roughly similartime course to that of metabolic recovery in peripheraldeafferentation models.67

Thalamic lesions in animals and humans inducemild contralateral cortical metabolic depression.40' "•57

This very transient effect may occur via second-ordercorpus callosum connections57 and represent a trans-callosal diaschisis. Hypometabolism of the ipsilateralbasal ganglia has also been reported following thalam-ic stroke55 and experimental lesions,57 and is likelymediated via the extensive thalamo-striatal projec-tions. Bilateral metabolic depression in other subcorti-cal structures has also been described following ex-perimental unilateral thalamic ventromedial nuclearlesions.57

Stria turnData regarding the remote functional effects of stria-

tal lesions are sparse. The effects of experimentallyinduced caudate lesions in animals were mild, tran-sient and not reproducible by similar putamenal le-sions.45' "* Of the few anecdotal reports of patients withstroke involving the striatum, none were "pure," butalso involved adjacent internal capsule and hence pos-sibly thalamo-cortical fibers. In these cases, mildmetabolic depression affecting the entire ipsilateralcortical mantle and thalamus, has been de-scribed.53' M'68"70 These cortical effects may be secon-dary to degeneration of cortico-striate fibers ratherthan diaschisis.

Unilateral striatal lesions in the rat, using the neuro-toxin kainic acid (which presumably spares the tractfibers)71"73 has no apparent effect on ipsilateral corticalmetabolism.72 However, the increased CMRGlu in theipsilateral globus pallidus and substantia nigra (parsreticulata) presumably reflects a GABA-mediatedtransynaptic loss of inhibition blocked by pretreatmentwith systemically administered muscimol.74

Cholinergic System LesionsThe cholinergic system has received considerable

attention following the demonstration of the role ofhippocampal and cortical cholinergic projections inmemory and cognition, as well as in the pathogenesisof Alzheimer's disease. Unilateral lesions of the nucle-us basalis of Meynert (NBM) or the septohippocampalpathway in rats suppresses cholinergic function in the



822 STROKE VOL. 17, No 5, SEPTEMBER-OCTOBER 1986

deafferented ipsilateral structures as well as reducingcortical EEG, while bilateral lesions cause learningand memory deficits.73 Recovery of function resultingfrom collateral sprouting of surviving cholinergic neu-rons, has been observed.76 Neurotoxin-induced lesionsof NBM also depress ipsilateral CMRGlu as early as 3days after surgery, maximal in the primary frontal cor-tex projection area with recovery between 7 and 30days.76"79 Whereas recovery of hippocampal hypome-tabolism induced by medial septal lesions occurs by 3months, that produced by complete destruction of thefimbria-fornix and cingulate cortex persists for longerthan 6 months postinjury.80 That these metabolic ef-fects of lesions result from cholinergic deafferentationwas clearly demonstrated by 1) high linear correlationsbetween percent reduction in CMRGlu and measuresof acetylcholinesterase (AChE) and 2) the striking andparallel recovery of both AChE and CMRGlu resultingfrom cholinergic grafts six months following choliner-gic deafferentation.80 Administration of oxotremorine,a cholinergic agonist, and atropine, a cholinergic an-tagonist, is associated with respective improvementand deterioration in the behavioral and metabolic re-sponses to injury.81

These models of cholinergic deafferentation satisfycriteria for diaschisis by providing evidence for anassociation between synaptic functional alterations andbehavioral deficits, strengthened by the parallel re-sponse of these measures to pharmacological manipu-lations. While there is no spontaneous recovery aftersevere cholinergic deafferentation, a favorable reac-tion to pharmacological manipulations or grafting sug-gests that this model is an example of "diaschisis pro-tactiva."

The use of CBF, SPECT, and PET techniques inAlzheimer's disease patients has demonstrated a pref-erential parieto-temporo-occipital association cortexmetabolic depression;82 this is likely not the result ofinnominato-cortical cholinergic deafferentation be-cause of the different anatomic, namely prefrontal,cortical innervation by the cholinergic system.83 Pro-gressive supranuclear palsy, a degenerative disorderaffecting the basal ganglia and most brainstem ascend-ing systems, is marked in some patients by an intellec-tual impairment termed "subcortical dementia," remi-niscent of prefrontal lobe damage. While the prefrontalcortex is pathologically intact, PET studies have re-vealed a marked metabolic depression correspondingto the behavioral deficits.84 This prefrontal hypometab-olism is thought to result from loss of several afferentsystems to this cortical area, including the cholinergicprojections.84 The pattern of symptoms and the PETdata can be considered an example of "slowly creepingdiaschisis" and suggests that replacement of the failingneurotransmitter(s) may improve the intellectual defi-cit in this disorder.

White Matter LesionsAnimal white matter lesions made just beneath the

cortical surface (undercutting), result in marked EEGslowing.46 In contrast, electrolytic lesions of the poste-rior limb of the internal capsule produce inconsistent,

transient effects.43 In humans, "pure" white matter le-sions are difficult to confirm, and small infringementson neighboring grey matter (e.g. thalamus, pallidum)contributing to the lesions' manifestations, may goundetected by present imaging techniques. Physiologi-cal observations in deep hemispheric syndromes haveincluded; 1) lack of the normal sensorimotor cortexcerebral blood flow activation during contralateralhand movements in patients with capsulo-thalamic in-farcts;83 2) reduced CMRGlu in cortical and thalamicregions ipsilateral to caudate and internal capsule lacu-nar lesions;69 3) reduction in precentral and centralcortical blood flow ipsilateral to internal capsule in-farcts.86'" Other studies of smaller white matter le-sions have shown no cortical metabolic impair-ments.88' w Taken together, these observations suggestthat damage to the thalamus itself or to thalamo-corti-cal fibers is necessary for development of behavioralsymptoms and cortical hypometabolism.87"90

Lesions of the optic radiations reportedly induceipsilateral metabolic depression in the deafferented vi-sual cortices.68'TO'""M Patients studied weeks after theonset of lateral homonomous hemianopia still exhibitthis visual cortex depression.92 The discrepancy be-tween the transient metabolic effects of enucleation16

and the lasting metabolic depression following opticradiation lesions, although possibly species specific,more likely results from the different points of inter-ruption of this multiple relay circuit.

Transcallosal DiaschisisKempinsky's experimental contributions to the

study of diaschisis should not be overlooked.94"97 Heprimarily studied electrophysiological responses con-tralateral to unilateral cortical lesions produced by di-verse methods (ablation, electric cautery, vascular li-gation, and freezing). However there are someshortcomings which limit intrepretation of his datawhich include possible variations in the depth of ether-induced anesthesia, lack of quantification of evokepotential and EEG data, and the absence of histologicalverification of prior corpus callosum section done insome cats. In none of the animals with the callosalsection was a depression of evoke potentials observed,however some of the cats with large lesions did showEEG amplitude reduction contralateral to the corticalinjuries. Despite these factors, Kempinsky interpretedhis data as strong support for Von Monakow's theoryof diaschisis.

Although it is tempting to invoke a mechanism oftranscallosal diaschisis for the commonly reportedCBF depression contralateral to a stroke, such studiesare flawed by confounding variables prior to or follow-ing the acute event.55-98"107 Such factors include chron-ic hypertension, previous cerebral infarction, largevessel occlusion and "steal" phenomenon, increasedintracranial pressure, transtentorial herniation, drugeffects, and changes in PaCO2, hematocrit, and arterialblood pressure. The effect of these variables on corti-cal function, contralateral to a stroke, as measured byCBF, CMR02, or CMRGlu is unknown.

Animal experiments circumvent some of these con-founding variables in the human studies. In models of



and Baron 823

focal cerebral ischemia there are reportedly variabledecreases in contralateral CBF and CMRGlu post-arte-rial occlusion108""7 some refuting"4 and others support-ing116 the concept of transcallosal diaschisis.

Not recognized by Von Monakow was the loss ofneuronal function in intact brain depleted of neuro-transmitter because of a shift from synthesis of trans-mitters to proteins for repair by remote injured neuronsinnervating these areas."8' "9 The LC is one candidatefor such an effect119 because of its diffuse intracorticalprojections, as small cortical lesions may cause tran-sient retrograde reactions with resulting widespreadalterations of noradrenergic (NE) transmission in sev-eral CNS regions.

Experimentally induced right middle cerebral arteryterritory ischemia has been shown to effect transcallo-sal physiologic changes remote from the site of in-jury.120"123 There is widespread reduction of neuro-transmitter levels from brainstem neurons, as well asbehavioral hyperactivity. The postulated associationbetween post-right hemisphere cortical injury evokedhyperactivity and depressed NE levels in intact regionsis supported by the blockade of hyperactivity by dailyadministration of the NE uptake blocker desmethyl-imipramine at doses not affecting activity in sham-op-erated controls.121 It is quite likely that other neuro-transmitters including DA,124"12* serotonin128 andGAB A,129' 13° whose levels also change in intact brainremote from cerebral ischemia, contribute to the clini-cal profile. As emphasized by Robinson and Bloom121:" . . the idea of stroke as a local injury producing itseffect by disruption of local mechanisms of function isinadequate conceptually and misleading clinically. . . " They suggest that the mood depression oftenoccurring following stroke may be a manifestation ofsuch remote pathophysiological events rather than apsychological reaction to disability.

Functional Effects in the Ipsilateral CortexInitial and delayed neurologic functional improve-

ment following cortical stroke has been viewed interms of recovery from a state of diaschisis, i.e. apartially reversible functional depression of the corti-cal area surrounding a site of necrotic damage. Howev-er, confirmation of this mechanism is difficult as elec-trophysiological activity, CBF, and metabolism maybe disrupted within an ischemic penumbra beyond theboundaries of the infarct.131 Human PET studies ofCBF and CMRO2 have demonstrated the frequent oc-currence of the "misery-perfusion" syndrome overmorphologically intact cortical regions in the first 2-4days following stroke, a situation of hemodynamicfailure that occasionally persists into a chronic stage.I32

Depressed cortical functions ipsilateral to corticalstroke may, in addition to the ischemic process per se,result from a constellation of factors including tissueedema, increased intracranial pressure with or withoutbrainstem compression, diffusion of toxic waste prod-ucts from the necrotic core, and selective neuronal celldeath without necrosis. Furthermore, the extension ofischemic necrosis to subcortical white matter may iso-late the overlying cortex from its afferent input and

sever efferent axons. This "undercutting" process canproduce depressed cortical function based on the pre-viously discussed mechanisms other than a diaschisis.Finally, a spread of necrosis to subcortical nuclei maydepress the functional activity of the cortex. As in thecase of transcallosal diaschisis, the study of post-in-farct intracortical diaschisis is difficult but experimen-tal cortical lesions, albeit not free of all confoundingvariables, offer a more controllable data base.

Animal studies have correlated behavioral disabil-ities (e.g. reaching for food with the appropriate limb)and a depression in sensory evoked potentials recordedin tissue adjacent to small electrolytic lesions placed inthe motor cortex. Normalization of the evoked poten-tials in intact cortex adjacent to the lesions paralleledrecovery of behavior.133-134 In contrast, enhancementof evoked responses recorded in intact cortex adjacentto small cortical lacerations has been reported,135 possi-bly heralding post-traumatic epilepsy.136 A diffuse re-duction in ipsilateral hemispheric oxidative metabo-lism measured by enzymatic a-GPDH histochemicalstaining has been described following focal corticaltrauma.34 Reduced monoamine neurotransmitter levelsin cortex remote from but ipsilateral to the injury havebeen reported also.120"126' m Intracortical diaschisis hasbeen a postulated mechanism for the depressed corticalperfusion surrounding an area of infarction in aphasicstroke patients.137 The advent of the PET scan hasmade it possible to discriminate between primarymetabolic depression and primary hypoperfusion.Matched decreases in CBF and metabolism ipsilateralto cortical infarction have been reported.33'M'm- m-139

Such reduction of CBF and CMRO2 beyond infarctboundaries has been reported in patients,140"142 and ani-mals143 with chronic occlusion of either the internalcarotid or middle cerebral artery (MCA). Widespreaddepression of early I-Isopropyl-ioto-amphetamine up-take involving almost the entire cortical mantle ipsilat-eral to chronic MCA territory infarction has also beenobserved with SPECT, even in the absence of an arteri-al occlusion at angiography.144 Selective cortical celldeath without tissue necrosis could cause this metabol-ic depression; it occurs experimentally in penumbralareas,143'143 but appears rare in humans.l46> l47 Availablemetabolic data from experimental cortical ablation orfreeze-lesions19'l16'll7'l48"130 suggest that intracorticaldiaschisis is of minor importance, perhaps becausemaintainence of a functional cortex depends on manyafferents other than those from the cortical lesion site.

Functional Effects in the SubcortexPatients with primarily cortical stroke have shown

definitive ipsilateral thalamic and/or basal gangliametabolic depression occurring within hours, but alsofound years later, in PET study.33'68-™-139'l31"133 Puta-tive clinical correlates of these remote metabolic ef-fects include verbal memory deficits without aphasiaassociated with left thalamic hypometabolism and mo-tor speech deficits related to reduced left caudate nu-cleus CMRGlu.31'154 Thalamic medial-dorsal and/orventral basal nuclear complex glucose hypometabo-lism ipsilateral to unilateral anterior or posterior corti-




cal lesions, has been reported.148"150'l53'156 While thesethalamic hypometabolic responses to cortical ablationpredominantly reflect retrograde degeneration, somemay represent a diaschisis mediated by transynapticactions either from cortico-thalamic or intrathalamicpathways.

Reduced striatal CMRGlu, although occurring lessconsistently than in the thalamus, has been reportedfollowing unilateral ablations of the ipsilateral frontalcortex.116148"150155 Additionally modulations of thestriatal neurotransmitters DA, glutamate, and GABAhave been reported following such lesions.127128157

Frontal lobe ablation-induced neglect is associatedwith the remote metabolic effects in monkeys.150 Theanalysis of the metabolic changes after frontal ablationfollowing prolongation of the neglect syndrome bydiazepam,158 could clarify any causal relation betweenthe metabolic and behavioral changes. Interestingly,transneuronal glucose hypermetabolism has been ob-served in the pallidum ipsilateral to a frontal ablation inrats,149 but not monkeys.150'l55 The remote effects ofunilateral frontal cortex lesions on cerebral metabo-lism have been quantitatively examined using cyto-crome oxidase histochemistry in the rat.159 The latterinvestigation has shown that injury produces a bilateralhypometabolism in the pallidum and several other ex-trapyramidal structures; an effect reversed by amphet-amine. These findings are possibly related to thisdrug's acceleration of recovery from hemiplegia dis-cussed below.

Electrophysiological data from the hippocampusafter cortical lesions has been cited as evidence againstdiaschisis. l6° Dendritic field potentials evoked by stim-ulation of the monosynaptic hippocampal-commis-sural pathway were recorded before and after unilaterallesions of the ipsilateral entorhinal cortex. The absenceof postlesion evoked response changes was interpretedas an absence of diaschisis. This study has been cri-tiqued by others13 and hippocampal CMRGlu measure-ment have indicated a depression of function followingsimular entorhinal lesions.1*1-l62

A number of diencephalic and brainstem nuclei oth-er than thalamus and basal ganglia exhibit metabolicchanges following experimental cortical ablation. Thetime course, neurochemical and behavioral correla-tions of these remote metabolic effects are not known.The affected nuclei show no clear histologic neuronaldegeneration to account for the metabolic changes.The metabolic depression found in the ipsilateral pon-tine nuclei in monkeys'55 may reflect degeneratingcortical pontine terminals, transynaptic depression ofactivity (degeneration of excitatory corticofugal affer-ents) or both. Conversely, changes in metabolism andneurotransmitter levels seen in the region of the LCipsilateral to frontal cortex lesions,19-l20"127 have beeninterpreted as a retrograde reaction of the neuronalsoma after damage to one or more of its cortical axonalbranches. Finally, the hypometabolism seen in the ip-silateral red nucleus,19-149'159 subthalamic nucleus149-159

and substantia nigra after frontal cortex lesions155 may,in part, represent transneuronal effects secondary todisruption of a motor circuit.

Pharmacological Studies of an Animal Model ofHemiplegia

In an attempt to explain the mechanisms of hemiple-gia following motor cortex damage, Von Monakowdescribed "diaschisis cortico-spinalis", a reversiblefunctional depression of remote intact structures. Ex-perimental pharmacologic manipulations in hemiple-gic animals have been shown to accelerate recoverywhile also affecting cerebral metabolism and neuro-transmitter release at a site remote from the primarylesion. Unilateral sensorimotor cortex ablation in therat produced pronounced but transient contralateralhemiplegia evident on the beam-walking task. Am-phetamine, administered in moderate doses was com-bined with the beam-walking experience. A single ad-ministration of the drug one day post-operativelyenhanced recovery compared to saline controls and thebeneficial effects endured and were maintained longafter the drug was metabolized. In animals given am-phetamine and kept in a small cage to prevent ballisticmovements during intoxication, no promotion of re-covery was observed indicating the necessity to com-bine drug and experience. Haloperidol blocked thistreatment effect and when given alone in a single dose,also markedly retarded recovery, implicating the cate-cholamines (CA) in recovery of function.'" This effecthas been replicated in the cat whose more severehemiplegia responds favorably to delayed (10 dayspost-surgery) multiple but spaced administrations ofamphetamine combined with beam-walking ex-perience.164

The mechanism of these effects is uncertain butdiaschisis has been suggested to explain the rapid be-havioral improvements produced by this pharmacolog-ic treatment plus behavioral experience.19 Alternativeinterpretations include: the reversal of lesion-inducedinput or depleted neurotransmitter, longterm potentia-tion,63-165-l66 and behavioral substitution. A CA-relateddiaschisis is supported by the observations that singleinfusions of NE,167 or systemic administration of theamphetamine analogs phentermine168 or phenolpropan-olamine,169 combined with experience also promoterecovery from hemiplegia. The DA agonist apomor-phine and the DA uptake-blocker methylphenidate donot promote recovery from hemiplegia in this mod-el.170- m Further biochemical support for CA-relateddiaschisis is the observation in post-operative treatedanimals of increased NE turnover in the ipsilateral LC(whose neurons project to forebrain and cerebellum172)and the cerebellum contralateral to the cortical lesioncompared to saline treated controls. Such changescould indicate a treatment-induced alleviated or com-pensated "crossed cerebellar diaschisis" which hasbeen associated with supratentorial stroke discussedbelow. Metabolic studies in this model suggest adiaschisis as there is a widespread depression of 2DGutilization especially prominent in the ipsilateral rednucleus and LC following unilateral sensorimotorcortex lesions.19 Paralleling the pharmacological ma-nipulation of behavioral recovery is the respective im-provement or worsening of post-surgical hypometabo-lism by amphetamine and haloperidol.19 However,



DIASCHISIS/Feenry «"<* Baron 825

since these CNS metabolic effects are diffuse, delinea-tion of anatomically selective effects is necessary be-fore a specific structural correlate of treatment-acceler-ated functional recovery can be established.

Crossed Cerebellar DiaschlsisCerebellar hemisphere hypometabolism contralat-

eral to supratentorial infarction was first described byBaron et al using PET and the steady-state oxygen-15method.173"175 This phenomenon has since been report-ed in about 50% of patients with stroke and those withsupratentorial neoplasms, studied by tomographicmapping of perfusion CMRO2, CMRGlu, or I-iodoam-phetamine uptake.53' "•107'139' '"•176"185

Significant contralateral cerebellar hypometabolism(CCH) has been observed in patients with isolated le-sions of the frontal cortex,55 ' l76 'm parietal cor-tex,107179183 thalamic and basal gangliaareas53'm-l77' m-183 and internal capsule.89 The CCH ismost prominent with large lesions involving two orthree cerebral lobes, or after smaller lesions destroyingmost of the internal capsule at the level of the basalganglia. The size and location of the lesion rather thanseverity of hemiparesis appear to be the best predictorsof CCH in stroke patients. Additionally, CCH has beenseen in patients with pure motor hemiparesis related toan internal capsule lacune,8889 as well as in patientswith large infaxcts and no hemiparesis176' m-179, but notin hemiparetic patients with a presumed pontine la-cune.

Interruption of the cerebro-cerebellar loop isthought to be the most likely mechanism of this remotetransneuronal metabolic depression.174'175 Its frequentassociation with frontal and parietal cortical lesions —the origin of the cortico-pontine fiber tract186"188 fits thishypothesis. Since cortico-pontine projections providepredominantly excitatory input to the contralateralcerebellar granule cells,189' l9° damage to this systemcould "deactivate" the contralateral cerebellum, hencethe term "crossed cerebellar diaschisis."173'll* Al-though CCH was not specifically studied, experimentsin monkeys'49'191 have shown ipsilateral pontine nucleihypometabolism after cortical ablation. CCH has beendifficult to observe in rats19'l49'l59' ""• m presumablybecause the cerebro-cerebellar loop is well developedonly in primates.186

In conflict with the theoretical interpretation of CCHas a diaschisis are examples where CCH persists oreven worsens post-infarction.53107176177179181 Fur-thermore, CCH may develop in association with slow-ly growing supratentorial tumors,178-183 indicating thatacute brain injury is not essential for its development.Thus, two essential criteria for a diaschisis, namelysudden onset and a transient response are lacking inCCH. While other examples of slowly developingdiaschisis have been discussed, the lack of CCH re-versibility is a major theoretical problem. Other possi-ble explanations include anterograde transneuronal de-generation, known to occasionally develop years afteradult-onset supratentorial stroke.193' l94 Since dendriticalterations as early as 2-3 days after deafferentationhave been described,195196 the acutely detectable

CCH177 might represent early metabolic responses ex-pected to preceed irreversible morphological alter-ations .179 The lack of recovery of CCH and its apparentprogression to degeneration sharply contrast with theother examples of transynaptic depression discussedabove. Nevertheless, recovery of CCH has actuallybeen reported in a few stroke patients175'177-179 suggest-ing that this process is not necessarily inescapable.While the mechanisms for recovery are unclear, theymay represent a link between reversible diaschisis andirreversible degeneration.179

As yet, there is no well established clinical expres-sion of CCH. In a recent study of seven patients withpure internal capsular infarcts, no obvious associationbetween CCH and ipsilateral limb ataxia was found.89

Thus, until large scale prospective studies are under-taken, the phenomenon of CCH, although the mostconsistent evidence of transneuronal functional de-pression in humans, will remain poorly understood interms of pathophysiology, clinical correlations andtherapeutic implications.

In addition to effects on the contralateral cerebel-lum, supratentorial lesions may result in a mild, lessprofound metabolic depression in the ipsilateral cere-bellum.55107176178 This observation has been chal-lenged179 because of the lack of an adequately matchedcontrol group with respect to age and vascular riskfactors, as well as a nonhomogeneous study group.Furthermore, its reported association with impairedconsciousness,107 suggests a role for supratentorialedema and herniation.

ConcussionExperimental data suggest that the sequelae of cere-

bral concussion may reflect midbrain muscarinic cho-linergic hyperactivity.197 Supporting this theory is thereproduction in cats of transient behavioral and EEGchanges mimicking concussion following acetylcho-line agonist (carbachol) infusion. An increased 2DGutilization in cholinergic neurons remote from the siteof trauma was observed in a concussion model. Such acholinergic pathological hyperactivity may act uponother intact systems to produce symptoms of concus-sion. These findings are compatible with the theory ofdiaschisis if it is modified to incorporate disruptivehyperactivity as well as loss of facilitatory input fromdamaged areas.Permanent Diaschisis

Schneider15 first conceptualized a permanentdiaschisis, "diaschisis protractiva," to explain the sur-gical alleviation of the hemianopsia contralateral toposterior cortical ablation in cats.198 Animals withlongstanding loss of orienting responses to stimuli inthe visual field contralateral to a large unilateral poste-rior cortex ablation recovered after a lesion of the con-tralateral superior colliculus or intercollicular commis-sure. The subcortical lesions were thought to abolish apathological intercollicular tonic inhibition resultingfrom the unilateral cortical ablation.198'199 Another pos-sible example of permanent diaschisis is the amphet-amine plus visual experience restoration of depth per-ception after bilateral visual cortex ablation in cats.200




This effect is blocked by haloperidol adding furthersupport for a role of CA in a diaschisis. Preliminarycytochrome oxidase histochemistry indicates that thistreatment also reverses the hypometabolism in the su-perior colliculi which follows visual cortex lesions.201

Therapeutic ImplicationsA recent double-blind pilot investigation suggests

that the animal data on the treatment of hemiplegiamay be applicable to human stroke.202 Eight patientswith stable motor deficits studied within ten days oftheir first stroke, were randomly assigned to treatmentor control groups. Motor performance was objectivelyscored prior to, and 24 hours following a single oraladministration of either 10 mg of d-amphetamine sul-fate or a vitamin placebo. Intensive physical therapy ofthe aifected limbs was provided for all patients follow-ing drug or placebo, to induce the necessary relevantexperience as determined from the animal studies. Astatistically significant improvement in motor scoresover pretreatment values was seen in all patients re-ceiving amphetamine plus physical therapy, comparedwith lack of improvement in the control group. Otherdrugs with non-specific, potential therapeutic effectson diaschisis include naloxone, piracetam, and GM1ganglioside.

Haloperidol and alpha-noradrenergic antagonistshave been reported to retard recovery in aphasic strokepatients.203 Recovery can be accurately predicted usinga mathematical model based on the test results of thePorch Index of Communicative Ability.204' ^ Patientson alpha-blockers, in contrast to those on beta-blockers or no medication, showed a significant retar-dation of recovery as compared with the predicted re-covery. The transient reinstatement or enhancement ofpost-stroke neurological deficits by CNS depressantssuch as benzodiazepines,138 phenytoin,206, or anesthet-ic agents suggests that recovered neuronal function, incontrast to normal function, is much more vulnerableto disruption by pharmacological agents.

Concluding CommentsKempinsky proposed97 "essential criteria" for

diaschisis including 1) a circumscribed injury, 2) aneuronal basis for the depressive effects, 3) its occur-ence at a distance from the injury, 4) identification ofthe fiber tract involved, and 5) a reversible process.

The above criteria still appear valid. Regarding dis-tance from injury, at least one synapse must exist be-tween the lesion and the target structure that is in theproposed state of diaschisis. A synapse lying withinthe target structure could potentially reflect only pre-synaptic events or direct reactions to axonal injury,thereby confounding interpretation of the data. Re-versibility is a necessary requirement in order to ex-clude the direct effects of the primary injury; however,in the case of permenant diaschisis, its demonstrationwould require surgical or pharmacological interven-tions.

Ideally, in a modern conception of diaschisis thephysiological indices of this phenomenon should cor-relate with a behavioral symptom, and both should

parallel improvement with time and response to ma-nipulations. With prolonged lack of normal afferentinput or function, diaschisis may result in morphologicalterations. The disruption of function in the targetstructure may result from a loss of either excitation orinhibition. In cases of low afferent input activity or inthe presence of numerous other inputs to the targetstructure, diaschisis may not occur. Conversely, if thelesioned area constitutes the sole or major input to thetarget structure, a readily detectable diaschisis mustoccur. Diverse mechanisms, possibly including repairprocesses such as sprouting and/or denervation super-sensitivity, could allow the target structure to accomo-date for the loss of input from the lesioned area.

While none of the experiments discussed in thisreview completely satisfy all the criteria for diaschisis,they do provide persuasive evidence for certain aspectsof the theory. Only if this concept stimulates futurework which provides some understanding of recoveryof function will such a general theory of reaction tobrain injury prove worthwhile.

AcknowledgmentsWe wish to express our gratitude to Elise Scott and Dr. Irene

Meissner for assistance in the preparation of this manuscript.

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