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(Stroke. 1996;27:1105-1111.)
© 1996 American Heart Association, Inc.

Articles

Electrophysiological Transcortical Diaschisis After Cortical Photothrombosis in Rat Brain

Irmgard Buchkremer-Ratzmann, MSc; Matthias August, CandMed; Georg Hagemann, MD Otto W. Witte, MD

From the Neurologische Klinik, Heinrich-Heine-Universität, Düsseldorf, Germany.

Correspondence to Otto W. Witte, MD, Neurologische Klinik, Heinrich-Heine-Universität, Moorenstraße 5, 40225 Düsseldorf, Germany. E-mail witte@leukos.neurologie-uni-duesseldorf.de.

	Abstract

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Background and Purpose The severity of functional deficits after a cortical infarction often does not correlate with lesion size. The stroke may affect pathways connecting to distant brain regions and therefore may also alter the function of remote parts of the cortex. Remote changes in electric activity, blood flow, and metabolism are called diaschisis. In the present study we addressed the question of whether in brain areas contralateral to a photochemically induced cortical infarction alteration of excitability can be observed as an indication of the effects of diaschisis.

Methods We induced focal lesions in the sensory area at the border of the motor and occipital cortices by injecting the photosensitizing dye rose bengal and illuminating the skull stereotaxically. Seven days after induction of photothrombosis, electrophysiological recordings were obtained with standard methods from 400-µm-thick neocortical coronal slices. As an indication of inhibition we used a paired-pulse stimulus protocol and calculated a ratio of the amplitudes of the second versus the first excitatory postsynaptic potential.

Results In lesioned animals we found a significant increase of the ratio over a wide zone of the neocortex, both ipsilateral and contralateral, compared with unlesioned animals.

Conclusions Our results suggest that a neocortical infarction leads to hyperexcitability not only in its direct vicinity but also in the contralateral hemisphere. Such hyperexcitability may contribute to increased activation of contralateral brain areas and to functional reorganization after stroke.

Key Words: cerebral ischemia • diaschisis • rats • photothrombosis

	Introduction

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Von Monakow¹ coined the term diaschisis to describe remote effects after central nervous system injury such as cerebral infarction. Since then, several main types of diaschisis have been recognized: effects on the cerebral hemisphere ipsilateral to the lesion, termed diaschisis associativa by von Monakow; effects on the contralateral cerebellum, first described by Baron et al² as crossed cerebellar diaschisis; and effects on the contralateral hemisphere, which Andrews³ called transhemispheric diaschisis and which are the topic of this report.

According to the original description of von Monakow,¹ diaschisis is a usually transient alteration of brain function remote from the lesion. These alterations may involve resting blood flow, brain metabolism, and spontaneous or evoked electrophysiological activity of the brain.^{3 4 5} In humans, CBF has been reported to be decreased contralateral to the infarction, particularly in the mirror area, 7 to 14 days after inception of the lesion.^{6 7 8} In the following months this recovers. Animal studies have also revealed a decrease of contralateral blood flow that can be observed several hours after the insult and persists for several days.⁹ Likewise, cerebral metabolism was found to be decreased in the contralateral hemisphere of patients for several weeks.¹⁰ In contrast, the metabolic effects persisted for only 24 hours in a study that involved middle cerebral artery occlusion¹¹ and less than 5 days after photochemical cortical infarction.¹² In addition, a contralateral decrease of protein metabolism was found when investigated 72 hours after middle cerebral artery occlusion.¹³

In humans, systematic studies of contralateral electric cerebral activity are only available for the subacute and chronic phases of the lesion. At these times, bilateral slowing of the electroencephalographic recording has been observed occasionally.¹⁴ Two weeks after injury, the majority of patients showed an increase of the contralateral N22 component of somatosensory evoked potentials.^{15 16 17} In agreement with this, Hossmann et al¹⁸ found an increase of somatosensory evoked potential amplitudes in rat brain in the first 24 hours after middle cerebral artery occlusion. Studies concerning chronic alterations of brain electrophysiological activity in animal experiments are not yet available.

The aim of the present study was to investigate the chronic effects of a unilateral photothrombotic lesion on the electrophysiological properties of the contralateral brain.

	Materials and Methods

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The experiments were performed on a total of 30 male Wistar SPF strain rats (weight, 290 to 310 g). Twelve animals served as controls, and 18 underwent surgery for induction of photothrombosis. The 18 rats were anesthetized with halothane (2% during preparation and 1.5% to 1.7% during lesioning), and a catheter was inserted into the femoral vein. The rats were then placed in a stereotaxic frame. Focal lesions were induced in the sensory area Par1 at the border of the motor and occipital cortices. For this purpose the skin above the skull was opened, and a fiber-optic bundle (aperture, 1.5 mm) was positioned exactly 4 mm posterior to bregma and 4 mm lateral to midline. The illumination with the fiber-optic bundle, which mounted onto a light source (Schott KL 1500; heat filter, Schott KG 1.45x45, d=4.2; power rating, 300 W), lasted 20 minutes. During the first minute rose bengal (Aldrich Chemie; 1.3 mg/100 g body wt) was injected through the femoral catheter. During the illumination, rectal temperature was controlled and held constant at 37.0±0.2°C. Test measurements of cortex temperature during induction of thrombosis next to and beneath the illuminated area showed a moderate increase in cortex temperature of 1°C to 2°C. These measurements were performed after we opened the skull to insert the measurement instrument. The increase in temperature that can be expected with an intact skull should be considerably smaller. After induction of thrombosis, the catheter was removed, and the wounds were sutured. The animals were placed in a warm environment for approximately 30 minutes. Within this time they woke up and became responsive to light and noxious and acoustic stimuli; they were then returned to cages with free access to ground food and water for 6 to 7 days.

Electrophysiological recordings were obtained in unlesioned controls and on day 6 to 7 after surgery in lesioned animals. This time point was chosen because the infarct has then reached a stable volume and the brain water content has returned to control values.¹⁹ After ether anesthesia, the rats were decapitated, and the brain was rapidly removed (mean, 128±16 seconds). It was cut into coronal slices of 400 µm by a McIllwain tissue chopper. The slices were maintained in an interface recording chamber at 33°C and superfused with artificial cerebrospinal fluid containing (in mmol/L) NaCl 124, NaHCO₃ 26, KCl 5, CaCl₂ 2, MgSO₄ 2, NaHPO₄ 1.25, and glucose 10, equilibrated with carbogen (95% O₂ and 5% CO₂ to pH 7.4).

Field potentials were recorded by a glass capillary electrode placed in cortical layer II; the bipolar stimulation electrode was placed in layer VI beneath the recording electrode. Registrations were made in 0.5-mm steps ipsilateral and contralateral to the photothrombotic lesion, moving along the cortex down to the rhinal fissure (Figure). The registration sites in control animals were the same as in lesioned animals. A double-pulse stimulation protocol was applied to investigate paired-pulse inhibition (pulses of 50 microseconds per 5 to 40 V with intervals of 20 milliseconds). At each location a stimulation amplitude was chosen that yielded maximal fEPSP. A ratio of the responses of the first and second stimulus was calculated (Q=fEPSP₂/fEPSP₁). Values of Q smaller than 1 indicated that the second response was inhibited by the response to the first stimulus.

View larger version (21K): [in this window] [in a new window]   Figure 1. Top left, Schematic drawing of brain slice (bregma -3.8 mm; modified from Paxinos and Watson20 ). The lesion is indicated by an indentation. Positions of the stimulation electrode are marked by squares, those of the field potential electrode by circles. Numbers indicate the distance from midline in millimeters. Abbreviations indicate the cortical areas according to Paxinos and Watson20 : ec indicates corpus callosum; fi, fimbria hippocampi; HiF, hippocampal fissure; cg, cingulum; RSG, retrosplenial granular cortex; RSA, retrosplenial agranular cortex; Oc2, occipital cortex, area 2; DLG, dorsal lateral geniculate nucleus; Par1, parietal cortex, area 1; and Te1, temporal cortex, area 1. Field potential and stimulation electrodes were moved in parallel from the lesion border down to the rhinal fissure. Bottom left, Spatial profile of ratio of field potential amplitudes fEPSP2/fEPSP1. Mean and SEM values from recordings in control () and lesioned () animals are shown. Abscissa corresponds to positions indicated in the schematic drawing of the brain slice. Lesioning led to a significant increase in the ratio ipsilaterally (right panel) as well as contralaterally (left panel), indicating an increase in excitability. Right, typical extracellular recordings of response to paired-pulse stimulation. Top tracing is in unlesioned controls with a ratio of approximately 0.4; middle tracing is in lesioned animals with a ratio near 1; bottom tracing is in lesioned animals with multiple discharges.

For each position mean±SD values were computed. We used Student's t test (one way, type 0) for statistical analysis. A value of P<.01 was considered highly significant; a value of P<.05 indicated a significant difference between the two groups.

	Results

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Control animals did not show any morphological changes in brain tissue. In contrast, those animals that underwent photothrombosis had a well-demarcated necrotic brain area. In the electrophysiological studies the infarcted area had a diameter of 2.3±0.3 mm (mean±SD) measured from the brain slices in the recording chamber (n=35). The infarction extended through all cortical layers but did not affect subcortical structures.

We tested 21 slices from 12 control animals without a lesion. Throughout the neocortical area the paired pulses evoked two field potentials with amplitudes of the first fEPSP of 2.25±1.9 mV reflecting excitatory postsynaptic potentials. A typical extracellularly recorded field response after paired-pulse stimulation in unlesioned control animals is shown in the Figure (right panel, circles). The ratio of the second to the first fEPSP after double-pulse stimulation was rather constant (bottom left panel, circles) and indicated a paired-pulse inhibition at all investigated positions. Recordings of the left and the right hemispheres of the controls gave the same results and were pooled.

We examined 28 ipsilateral and 33 slices contralateral to the infarction from 17 and 18 animals, respectively. Within the lesion, electrophysiological responses could not be evoked. In slices from infarcted animals, the second fEPSP was larger than in slices from control animals and sometimes even larger than the first fEPSP. The amplitude of the first fEPSP in lesioned animals was 1.84±1.01 mV ipsilateral and 2.06±1.14 mV contralateral. A typical extracellularly recorded field response after paired-pulse stimulation in lesioned animals is shown in the Figure (right panel, squares). In the ipsilateral part of the neocortex we found a significant increase of the ratio of fEPSP₂ to fEPSP₁ beginning 1 to 2 mm lateral from the lesion border (positions 6.5, 7, 7.5, 8, and 9.5 mm, highly significant; positions 6, 8.5, and 9 mm, significant). A change of excitability was also found in the contralateral cortex. This was obvious not only in the area homotopic to the lesion but also in more lateral brain areas. These results were significant over wide zones of the neocortex (P.01 for positions 2, 3, 3.5, 4.5, 5, 6.5, and 7.5 mm; P.05 for positions 2.5, 4, 5.5, 7, and 8.5 mm).

In control and lesioned animals, double or multiple discharges were occasionally found in response to extracellular stimuli, but there were clear quantitative differences: in control animals these multiple discharges were observed in 4% and in lesioned animals in more than 30% of the recordings. A typical multiple discharge is shown in the lowest right panel of the Figure.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In this study we focused our interest on the hemisphere contralateral to a photothrombotic infarction. As a measure of excitability we recorded field potentials elicited by paired pulses. Paired-pulse inhibition obtained with the described method reflects the potency of GABAergic inhibition in the rat neocortex.^{21 22} The data presented show that excitability was altered not only in the hemisphere ipsilateral to the photothrombotic lesion but also in the contralateral hemisphere. Moreover, hyperexcitability was found in the area homotopic as well as lateral to the lesion.

For these investigations, small cortical lesions were produced by photothrombosis. As shown by Watson et al,²³ illumination through the skull after intravenous injection of the dye rose bengal produces platelet aggregation (photothrombosis) in small vessels. This lesion model has the advantage of being noninvasive and producing lesions with good reproducibility in terms of size and a sharp boundary between infarcted tissue and noninfarcted surrounding brain. Recent studies showed that photothrombosis produces pronounced changes of excitability of the ipsilateral cortex shown by recording of field potentials induced by double-pulse stimuli in vitro²⁴ and in vivo.²⁵ These changes could be detected between 1 and 60 days after the insult, with a progressive decrease of inhibition over the first 5 days and a subsequent though incomplete recovery. Intracellular in vitro studies that reported less negative resting membrane potential and smaller inhibitory postsynaptic potentials provide an explanation for the extracellularly observed hyperexcitability.²⁶ The reduced inhibition was associated with a decrease of GABA_A receptor expression.²⁵ Further investigations should clarify whether treatment with GABAergic drugs after photochemical lesioning can alter excitability. These long-lasting alterations of brain excitability contrast with the fast recovery of CBF and metabolism in the same model. Dietrich et al⁹ showed that local CBF is impaired after photothrombosis. In the acute phase CBF was depressed in the ipsilateral hemisphere, whereas the contralateral hemisphere was rather hyperemic. Five days after induction of thrombosis, both hemispheres showed decreased CBF compared with that in unlesioned controls. After 15 days CBF had returned to normal. Little change in contralateral glucose utilization has been reported 24 hours after induction of photothrombosis in the rat.^{12 27} In our laboratory we noted hypometabolism in the corresponding area contralateral to a photothrombotic lesion, which did not gain significance (M. Kraemer, personal communication). Reduced glucose metabolism reflects decreased transmitter release.²⁸ We can speculate that this decreased transmitter release leads to impairment of both excitation and inhibition.

Which mechanism can be responsible for the observed electrophysiological diaschisis? In previous studies concerning the decrease of inhibition in the hemisphere ipsilateral to an infarction, [K⁺] elevation and electroencephalographic suppression during CSD were discussed as causes of the alteration of inhibition.²⁴ The present data show that the change of excitability occurs not only on the side of the lesion but also at the contralateral hemisphere, where no CSD was observed. In further studies with the noncompetitive N-methyl-D-aspartate antagonist dizoclipine (MK-801), which prevents CSD, we investigated whether ipsilateral hyperexcitability can indeed be prevented by blocking CSD. The examination revealed that CSD blockade does not reduce increased excitability after photothrombotic infarction.²⁹ It is therefore highly unlikely that CSD alone is responsible for the described pathophysiology.

Humoral mechanisms are another possible cause of remote effects after infarction and the development of diaschisis. Cerebral infarction leads to a lack of oxygen, which in turn is followed by changes in neurotransmitter levels. This can be due to disordered neurotransmitter storage, uptake, and release.^{30 31} Subsequent to impaired neurotransmitter levels, several cascades, eg, the arachidonic acid cascade,³¹ are activated, which may contribute to the development of diaschisis. In addition, brain edema and increased intracranial pressure may contribute to neuronal impairment of excitability.^{33 34 35} However, in our model we found no signs of significant brain edema or increased intracranial pressure, and Evans blue experiments did not indicate a disruption of the blood-brain barrier in contralateral brain areas (G. Hagemann, M. Kraemer, D.W. Witte, unpublished observations, 1995).

One of the most obvious explanations for the observed electrophysiological diaschisis is deafferentation. As early as 1914 von Monakow¹ postulated that there must be severance of fiber tracts between the lesion and remote areas of functional depression and subsequent deafferentation. Andrews³ coined the term transhemispheric diaschisis as opposed to transcallosal diaschisis to stress that information transfer to the other cortical hemisphere can be accomplished on many different levels. However, by far the most direct connections from one hemisphere to the other occur through the corpus callosum.³⁶ CBF and evoked potential changes in the contralateral hemisphere in acute ischemia experiments seem to be dependent on an intact corpus callosum.^{37 38} Staining experiments have revealed that the hindlimb area and the parietal cortex 1, the site of infarction in this study, are sources of afferents to several other areas: the contralateral hindlimb, the contralateral parietal cortex 1, the ipsilateral cortex 2, and the ipsilateral motor cortex^{36 39} (only mentioned are afferents to neocortical areas). These dependent cortical areas correlate quite well with the brain regions that show an impaired excitability in our electrophysiological experiments. An analysis based on the stereotaxic atlas of Paxinos and Watson²⁰ indicated that ipsilaterally parietal areas 1 and 2 and contralaterally parietal area 1 and the homotopic areas of the lesion were afflicted. Erb and Povlishock⁴⁰ showed early GABAergic terminal loss with a prolonged recovery of 1 year after traumatic brain injury in the cat. Reduced GABA_A receptor binding was shown in our model.²⁵ These observations support the assumption that neuroanatomic changes are responsible for the reported hyperexcitability.

Changes in hyperexcitability are adaptive changes and therefore a measure of plasticity after stroke. In view of our observations of impaired excitability after neocortical infarction, one can discuss both a detrimental and a beneficial role of this hyperexcitability. Kotila and Waltimo⁴¹ reported that 14% of patients with ischemic brain infarction developed epilepsy, mostly generalized seizures; 20% of these patients had their first seizure within the first 2 weeks after stroke, and 60% developed epilepsy within the first 6 months. Jordan⁴² reported that nonconvulsive seizures occurred in 34% of neurology intensive care unit patients. The widespread alteration of inhibition may correlate with the occurrence of epilepsy after stroke. A rebalanced excitability may therefore be a sign of recovery from brain infarction. Glassman and Malamut^{43 44} reported a correlation between recovery of behavior and normalization of the evoked potentials in intact cortex adjacent to a lesion.

Schallert and Lindner⁴⁵ addressed the question of whether rescuing neurons from transsynaptic brain damage may be helpful, harmful, or neutral in recovery of function: Asymmetries in motor behavior after unilateral anteromedial cortex lesion are usually transient; with treatment by diazepam or phenobarbital, which enhance GABAergic inhibition, the functional asymmetries become more severe.^{46 47} This suggests that hyperexcitability counteracts the lesion-induced loss of function and may serve as an endogenous source of stimulation.

In humans, Weiller⁴⁸ reported that CBF is changed ipsilateral and contralateral to a motor cortex lesion during a defined task performance. Areas at rest showed a lower CBF in patients than in control subjects, whereas CBF was increased in cortical areas mainly in the undamaged hemisphere.⁴⁹ Chollet and Weiller⁵⁰ speculated that homologous regions compensate for the function of the damaged hemisphere or that activity is redistributed to areas adjacent to the lesion. An extension of the area that is activated with a certain motor task has also been observed in other experiments and has usually been interpreted as an indication of plasticity.^{51 52} In light of the present experiments, however, it cannot be excluded that such remote and altered activation patterns indicate a functional disturbance and hyperexcitability in these areas remote from the lesion itself. Thus, it is conceivable that such changes indicate adaptation and favor recovery; on the other hand, it is conceivable that they indicate hyperexcitability and impaired processing of incoming information. To resolve this ambiguity, behavioral studies correlated with these altered excitability patterns are necessary in both animals with cortical lesions and humans suffering from stroke.

	Selected Abbreviations and Acronyms

 

CBF = cerebral blood flow CSD = cerebral spreading depression fEPSP = field excitatory postsynaptic potential GABA = -aminobutyric acid

	Acknowledgments

 
This study was supported by Deutsche Forschungsgemeinschaft Wi830/4-2 and Janssen Research Foundation.

Received November 6, 1995; revision received February 13, 1996; accepted February 14, 1996.

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