Normal Hemisphere Research Articles

Functional magnetic resonance imaging of regional brain activity in patients with intracerebral gliomas: findings and implications for clinical management.

Functional magnetic resonance imaging (fMRI) was performed in seven patients harboring intracerebral gliomas proven by histological analysis using a noninvasive blood oxygen level-dependent technique based on the documented discrepancy between regional increases in blood flow and oxygen use in response to regional brain activation. We combined fMRI with conventional magnetic resonance imaging (MRI) during motor or language task activation experiments to investigate the potential usefulness of mapping regional brain activity as part of treatment planning in patients with intracerebral gliomas, in whom preservation of areas of functioning brain tissue is critical. Statistical fMRI maps were generated and directly mapped onto conventional MRI scans obtained at the same session. Of the five patients cooperative enough to remain motionless for the study and perform the task, the location of activation in the primary sensorimotor cortex on the side of the tumor was clearly displaced compared with that in the normal contralateral hemisphere in four patients. Four of the five tumors in these patients showed fMRI activation within the periphery of (or immediately adjacent to) areas of presumed tumor based on spin-echo MRI. In some patients with neurological deficit, the extent of activation was reduced on the side of the tumor as compared with the normal hemisphere. The supplemental motor area and the ipsilateral primary motor cortex were also reproducibly activated during motor tasks. We conclude that blood oxygen level-dependent fMRI can localize areas of cortical function in patients undergoing treatment planning for gliomas so that therapy can be directed away from regions of residual function. Our preliminary data suggest that functioning cortex within or adjacent to tumor margins can be demonstrated, which may correspond to partial preservation of clinical function. Our preliminary data also suggest that there may be a quantifiable difference on fMRI between activation in tumor-bearing cortex and activation in corresponding normal cortex in the contralateral hemisphere. We postulate that the magnitude of this difference may relate to the severity of patient deficit.

Evaluation of recombinant human basic fibroblast growth factor (rhbFGF) as a cerebroprotective agent using high speed MR imaging

The potential cerebroprotective effects of recombinant human basic fibroblast growth factor (rhbFGF) were evaluated in a feline model of acute cerebral ischemia using high-speed magnetic resonance imaging (MRI) in conjunction with immunohistology. The neuroprotective efficacy of three doses of rhbFGF was evaluated in a unilateral middle cerebral artery (MCA) occlusion/reperfusion model. Ten h following a 2 h period of MCA occlusion in control (vehicle-treated) animals, cerebral perfusion in the ischemic hemisphere was 58±17% of the contralateral normal hemisphere. Corresponding ischemic/normal perfusion ratios in rhbFGF-treated groups were not significantly different: 54±16% (14 μg/kg/h dose), 40±19% (42 μg/kg/h dose) and 75±8% (125 μg/kg/h dose). Triphenyltetrazolium chloride histopathological assessment demonstrated brain damage in vehicle-treated animals comprising 31±15% of the hemisphere; in rhbFGF-treated groups injury was not significantly different: 19±4% (14 μg/kg/h rhbFGF), 24±6% (42 μg/kg/h rhbFGF) and 16±10% (125 μg/kg/h rhbFGF). Immunohistochemical analysis of brain sections using glial fibrillary acidic protein (GFAP) revealed that in animals that showed marked perfusion deficits throughout the entire experiment (regardless of treatment), GFAP staining was elevated contralateral to the occlusion and absent ipsilaterally. While some tendency towards protection is found, particularly at higher doses of rhbFGF, it must be concluded that in the chosen stroke model and time interval, the doses used did not significantly improve reperfusion or confer significant cerebroprotective benefit. Non-invasive high-speed MRI was found to be useful for evaluation of putative cerebroprotective agents.

Ipsilateral motor response--is it an artefact?

The lack of information about the ipsilateral motor response to cortical stimulation prompted the present study. Motor evoked potentials (MEPs) in 60 patients with acute stroke were recorded bilaterally. The patients' ages ranged between 24 and 83 years; 45 were males. Intracerebral haemorrhage was present in 23 and infarction in 37 patients. In none of these patients was an ipsilateral response recorded from the hemiplegic side when a contralateral response was absent. On the non-hemiplegic side in all these patients an MEP was recorded on both contralateral and ipsilateral cortical stimulation. Unrecordable MEPs became recordable in 6 patients after 1-15 months of stroke. In these patients MEP latencies on ipsilateral cortical stimulation were either identical to that on contralateral stimulation (2 patients) or within the range of normal intraindividual variation. On the basis of these results, it is concluded that the ipsilateral motor response in our study may be due to cross stimulation of the normal hemisphere and not through the uncrossed motor pathways. Our results should be interpreted in the context of the stimulation conditions employed. Further studies are recommended using more focal stimulation to minimise the spread of current.

Ipsilateral motor response - is it an artefact?

The lack of information about the ipsilateral motor response to cortical stimulation prompted the present study. Motor evoked potentials (MEPs) in 60 patients with acute stroke were recorded bilaterally. The patients' ages ranged between 24 and 83 years; 45 were males. Intracerebral haemorrhage was present in 23 and infarction in 37 patients. In none of these patients was an ipsilateral response recorded from the hemiplegic side when a contralateral response was absent. One the non-hemiplegic side in all these patients an MEP was recorded on both contralateral and ipsilateral cortical stimulation. Unrecordable MEPs became recordable in 6 patients after 1-15 months of stroke. In these patients MEP latencies on ipsilateral cortical stimulation were either identical to that on contralateral stimulation(2 patients) or within the range of normal intraindividual variation. On the basis of these results, it is concluded that the ipsilaterl motor response in our study may be due to cross stimulation of the normal hemisphere and not through the uncrossed motor pathways. Our results should be interpreted in the context of the stimulation conditions employed. Further studies are recommended using more focal stimulation to minimise the spread of current.

Inferential abilities of normal and right hemisphere damaged adults

There were two aims of this study. The first was to compare indirect inferencing abilities by nine right hemisphere brain-damaged (RHD) adults with 18 matched normal controls. The second purpose was to determine the best condition in which to present information to the RHD individuals for the purpose of forming these inferences. Three conditions were evaluated: (1) Auditory-Only, (2) Orthographic-Only, and (3) Combined Auditory/Orthographic. It was hypothesized that right hemisphere damaged persons would perform most successfully when the materials (narrative paragraphs) were presented using the combined condition. Both groups performed significantly better in the combined Auditory/Orthographic condition. There were no significant differences in the performances of the RHD group as compared to the normal controls. This suggested that the RHD group did not exhibit an inference impairment on this type of linguistic task.

Increased sensitivity to ipsilateral cutaneous stimuli following transcranial magnetic stimulation of the parietal lobe.

Transcranial magnetic stimulation of the sensorimotor cortex results in decreased sensitivity of threshold electrical stimuli to fingers of the contralateral hand. It has been suggested that one factor contributing to neglect contralateral to a unilateral parietal lesion is a release of the normal hemisphere from reciprocal interhemispheric inhibition by the damaged hemisphere. Consistent with this account, the current study demonstrated that transcranial magnetic stimulation over the parietal cortex results in increased sensitivity to cutaneous stimulation ipsilateral to the stimulation. The likely mechanism is a transcranial magnetic stimulation-induced transient dysfunction of the ipsilateral parietal cortex that then results in disinhibition of the contralateral parietal cortex.

Assessment of cerebral pO2 by EPR oximetry in rodents: effects of anesthesia, ischemia, and breathing gas.

This report describes experiments designed to assess and illustrate the effectiveness of a new method for the measurement of cerebral interstitial pO2 in conscious rodents. It is based on the use of low frequency electron paramagnetic resonance (EPR) spectroscopy with lithium phthalocyanine as the oxygen sensitive probe. Magnetic resonance imaging was used to document placement of the probe in the brain, and to assess potential cerebral changes associated with the placement. The technique provided accurate and reproducible measurements of localized pO2 in the brains of conscious rodents under a variety of physiological conditions and for time periods of at least 2 weeks. Using this approach we quantitated the depressing effects on cerebral pO2 of three representative anesthetics, isoflurane, ketamine/xylazine, and sodium pentobarbital. The effects of changing the content of oxygen in the breathing gas was investigated and found to change the cerebral pO2. In experiments with gerbils, crystals of lithium phthalocyanine were implanted in each side of the brain and using a one-dimensional magnetic field gradient, simultaneous measurement of pO2 values from normal and ischemic (ischemia induced by unilateral ligation of a carotid artery) hemispheres of the brain were obtained. These results demonstrate that EPR oximetry with lithium phthalocyanine is a versatile and useful method in the measurement of cerebral pO2 under various physiological and pathophysiological conditions.

Three-Dimensional Image Analysis of Brain Glucose Metabolism-Blood Flow Uncoupling and its Electrophysiological Correlates in the Acute Ischemic Penumbra following Middle Cerebral Artery Occlusion

The relationship between local cerebral glucose utilization (LCMRglc) and local CBF (LCBF) is known to be disturbed in regions surrounding an acute focal ischemic lesion--areas that undergo repeated transient depolarizations. In this study, we evaluated the relationship between LCMRglc and LCBF in the acute focal ischemic penumbra to quantify metabolism-flow uncoupling, and we related these findings to local electrophysiological measurements. A novel strategy utilizing three-dimensional (3D) autoradiographic image averaging yielded group 3D reconstructions of LCBF, LCMRglc, and the CMR/CBF ratio. The distal right middle cerebral artery of Sprague-Dawley rats was occluded by laser-driven photothrombosis following administration of the photosensitizing dye rose bengal; this was coupled with permanent ipsilateral and 1-h contralateral common carotid artery occlusions. LCBF (n = 7) and LCMRglc (n = 7) were measured autoradiographically at 1.25 and 1.5-2 h postocclusion, respectively, in matched animal groups. Within the ischemic penumbra (defined as having LCBF of 20-40% of control or 0.23-0.47 ml g-1 min-1), LCMRglc showed a heterogeneous pattern with values ranging from near normal to markedly increased. The resulting CMRglc/CBF ratio in this zone was 234 +/- 100 mumol/100 ml (mean +/- SD), representing a severe degree of metabolism-flow dissociation when compared with the CMRglc/CBF ratio of 51.0 +/- 28.7 mumol/100 ml of the contralateral (normal) hemisphere. Metabolism-flow uncoupling was confined to the ipsilateral cortex and was most prominent at the anterior and posterior coronal poles of the ischemic lesion. In the frontoparietal penumbra, where marked uncoupling was observed, sustained deflections of the DC potential were recorded, which increased significantly in duration over the initial 65 min postocclusion. Both the heterogeneous pattern of LCMRglc and the widespread distribution of increased CMRglc/CBF ratio in the ischemic penumbra are thought to reflect the metabolic consequences of periinfarct depolarizations. Analysis of averaged 3D autoradiographic data sets provides a powerful means for assessing metabolism-flow uncoupling surrounding an ischemic focus.

Insulin reduction of cerebral infarction due to transient focal ischemia

✓ Insulin has recently been shown to ameliorate damage in models of global brain ischemia. To determine whether insulin is also neuroprotective in focal ischemia, 20 rats were given 2 to 3 IU/kg insulin and 10 did not receive treatment prior to normothermic transient middle cerebral artery occlusion for 2 hours at a blood pressure of 60 mm Hg. To further elucidate whether infarction volume is influenced by variations in blood glucose levels within the physiological range, blood glucose was raised in 10 of the insulin-treated animals to levels comparable with the untreated controls. At 1-week survival, damage was assessed using quantitative neuropathological examination of 25 coronal planes. It was found that preischemic insulin lowered the mean intraischemic blood glucose level from 8.4 ± 0.2 mM (µ ± standard error of the mean) in the control group to 3.4 ± 0.2 mM and reduced total damage (atrophy plus cortical and striatal necrosis), expressed as the percentage of the normal hemisphere, from a control of...

Insulin reduction of cerebral infarction due to transient focal ischemia.

Insulin has recently been shown to ameliorate damage in models of global brain ischemia. To determine whether insulin is also neuroprotective in focal ischemia, 20 rats were given 2 to 3 IU/kg insulin and 10 did not receive treatment prior to normothermic transient middle cerebral artery occlusion for 2 hours at a blood pressure of 60 mm Hg. To further elucidate whether infarction volume is influenced by variations in blood glucose levels within the physiological range, blood glucose was raised in 10 of the insulin-treated animals to levels comparable with the untreated controls. At 1-week survival, damage was assessed using quantitative neuropathological examination of 25 coronal planes. It was found that preischemic insulin lowered the mean intraischemic blood glucose level from 8.4 +/- 0.2 mM (mu +/- standard error of the mean) in the control group to 3.4 +/- 0.2 mM and reduced total damage (atrophy plus cortical and striatal necrosis), expressed as the percentage of the normal hemisphere, from a control of 28.5% +/- 2.9% to 14.5% +/- 1.6% (p < 0.005). Coadministration of glucose and insulin resulted in a mean intraischemic blood glucose level of 10.1 +/- 0.5 mM, with 27.0% +/- 2.4% total damage (p = 0.96, compared with control). Total ischemic damage showed an independent correlation with blood glucose levels (r = 0.67, p = 0.0018). The findings indicate that insulin benefits transient focal ischemia and that reducing the blood glucose from 8 to 9 mM to the low-normal range of 3 to 4 mM with insulin dramatically reduces subsequent infarction. The data suggest that the neuroprotective mechanism of insulin action in focal middle cerebral artery occlusion is mediated predominantly via alterations in blood glucose levels. In comparison to global ischemia, focal ischemia appears to show only a minor direct central nervous system effect of insulin. In clinical situations in which transient focal ischemia to the hemisphere can be anticipated, insulin-induced hypoglycemia of a mild degree may be beneficial.

Clinical application of diffusion-weighted magnetic resonance imaging to intracranial disorders.

Diffusion-weighted magnetic resonance imaging was performed to determine the changes in water diffusion and to investigate the detectability of diffusion anisotropy in patients with intracranial disorders. Diffusion maps of the apparent diffusion coefficient (ADC) were created of 19 patients with cerebral infarction, five with intracerebral hematoma, four with glioma, four with meningioma, four with hydrocephalus, and five with subdural hematoma. ADC was increased in chronic cerebral infarction and glioma, and decreased in acute cerebral infarction, meningioma, and the marginal area of glioma compared with the ADC of the normal gray matter. There was a significant difference in ADC between the marginal and internal areas of glioma. Increased ADC may be due to increased vasogenic edema in infarction and a lack of significant restriction of diffusion within glioma. Decreased ADC can be attributed to restricted diffusion caused by cytotoxic edema in infarction and the underlying histological pattern of densely packed tumor cells in glioma. Diffusion anisotropy of the internal capsule was less detectable in pathological than normal hemispheres. Diffusion anisotropy was less detectable in patients with hydrocephalus and subdural hematoma. Intracranial lesions were thought to have influenced the compression of the brain structures and cells, resulting in decreased diffusion. The measurement of ADC by diffusion-weighted magnetic resonance imaging has the potential for greater understanding of the biophysical changes in various intracranial disorders, including correct diagnosis of cerebral infraction, and histological diagnosis of brain tumor.

Widespread cerebral structural changes in patients with cortical dysgenesis and epilepsy.

Cerebral cortical dysgenesis (CD), as revealed by MRI is the second commonest cause of medically refractory chronic partial epilepsy. Surgical treatment is often disappointing in these cases. This has been attributed to the probable diffuse nature of the condition but proof of this in the human brain is lacking. We have quantitatively analysed MRI scans of 30 neurologically normal control subjects and 18 patients with CD, examining the regional distribution of grey and subcortical matter volumes. In 15 out of the 18 patients, we have demonstrated abnormalities of this distribution beyond the margins of the visualized lesion. Nine out of 10 patients with dysgenetic lesions visualized only in one hemisphere had volumetric abnormality in the apparently normal contralateral hemisphere. These abnormalities were not visible on reinspection of the MRI scans. Such abnormalities were not found in 10 patients with isolated hippocampal sclerosis (HS) although the history of generalized seizure activity and duration of epilepsy did not differ between the two groups of patients. Thus there is evidence for the existence of extensive structural disorganization outside visually identified focal lesions in the brains of patients with CD and chronic partial epilepsy. This disruption is not due to the effects of the epilepsy and must instead be associated with its cause. Possible mechanisms producing the abnormalities are discussed. The methodology described may be applied to other cortical diseases.

Abnormal laterality in schizophrenics and their parents

Previous studies found that schizophrenics do not show the normal right ear-left hemisphere perceptual advantage on language-related dichotic tests of lateralized cerebral function. We report evidence of a similar abnormality in non-schizophrenic parents of schizophrenic patients. Perceptual asymmetry was first measured with a dichotic word test which had previously yielded differences between schizophrenics and controls. The parents ( n=18) demonstrated a lower right ear advantage (REA) than controls ( n=10) ( p=0.05), but performed similarly to their schizophrenic offspring ( n=10). The same subjects were given two additional tests. Neutral words were paired with words of a positive emotional valence in one test, and with words of a negative emotional valence in the other. On these two tests, the parents were more similar to the controls than to their offspring with the schizophrenics demonstrating a lower REA than their parents ( p=0.005) on the negative test. These results suggest that schizophrenics and their parents have similar abnormalities in hemispheric activation at baseline only, but when listening to words with negative emotional valence, only the schizophrenics demonstrate a further decrease in left hemispheric activation.

EEG recordings in the course of recovery from stroke.

This study was designed to assess the value of quantified electroencephalography (EEG) in the follow-up of stroke and its possible correlation with other measures of recovery. EEGs were recorded over a period of 6 months in 34 patients with ischemic stroke in the middle cerebral artery territory who underwent spectral analysis. Two groups were formed: (1) 28 patients with a Barthel Index score of less than 60 at admission and (2) 6 patients with a Barthel score of over 60 and therefore with a much better prognosis. Ten recordings were made in each patient in the first group and at least three in the second group. Motor functions and activities of daily living (ADL) were assessed three times, on admission to the study and after 3 and 6 months. Quantified EEG was significantly abnormal in the affected hemisphere of the first group. Side and site were not relevant. Longitudinal recordings showed a significant improvement of the power spectrum in the first 3 months. Alpha mean weighted frequency of the injured hemisphere was always slower than that of the contralateral side. All patients improved in motor performance and ADL, with the greatest gain in the first 3 months. However, no correlation between quantified EEG and clinical testing was found. By looking at individual profiles, a frequent and unpredictable instability was seen in the "unaffected" hemisphere. In those who made the best recovery, the EEG spectrum became more symmetrical over the left and right hemispheres, an aspect that continued beyond the point of a good motor and ADL recovery. Quantified EEG undergoes early and subtle changes in the follow-up of stroke that can outlast clinical recovery. Routine evaluation for prognosis is not recommended because motor and ADL scales provide earlier and more accurate indicators. In contrast, quantified EEG can be useful for individual patients undergoing rehabilitation to monitor mechanisms of local repair and also to detect changes in the so-called normal hemisphere. It may reveal focal abnormalities that are undetected by coarse clinical evaluation and that call for appropriate neuropsychological testing.

Enhanced optical imaging of rat gliomas and tumor margins.

Current intraoperative methods used to maximize the extent of tumor removal are limited to intraoperative biopsies, ultrasound, and stereotactic volumetric resections. A new technique involving the optical imaging of an intravenously injected dye has the potential to localize tumors and their margins with a high degree of accuracy. In a rat glioma model, enhanced optical imaging was performed and indocyanine green was used as the contrast-enhancing agent. In all 22 animals, the peak optical change in the tumor was greater than in the ipsilateral brain around the tumor and the contralateral normal hemisphere. The clearance of the dye was significantly delayed to a greater extent in the tumor than in the brain around the tumor and the normal brain. After attempts were made at complete microscopic resection, enhanced optical imaging of the tumor margins and the histological samples demonstrated a specificity of 93% and a sensitivity of 89.5%. Enhanced optical imaging was capable of outlining the tumor even when the imaging was done through the cranium. The optical imaging of rat gliomas with a contrast-enhancing dye is able to differentiate between normal brain and tumor tissue both at the cortical surface and at the tumor margins. The application of these studies in an intraoperative clinical setting may allow for the more accurate determination of tumor margins and may increase the extent of tumor removal.

Developmental regulation of plasticity in cat somatosensory cortex.

1. The neocortical response to deprivation of somatic sensory input in young animals of different ages was compared with the same manipulation in adults. The response was measured through the use of 2-deoxyglucose (2DG) mapping. Although several features of the cortical response were similar in animals of all ages, the metabolic patterns evoked by somatic stimulation differed substantially from each other at all ages. 2. When adult cats receive a digit amputation and survive from 2 to 8 wk, the pattern of stimulus-evoked metabolic uptake expands dramatically in the somatosensory cortex contralateral to the deprived forepaw. Comparisons between the normal and experimental somatosensory cortices reveal that the distribution of activity on the experimental side was roughly an expanded version of the normal pattern. 3. Unilateral digit amputations of digit 2 were conducted on kittens 2, 4, or 6 wk old. They survived until 3-4 mo and then received a 2DG experiment, during which digit 3 was stimulated bilaterally. Evaluation of the evoked metabolic pattern indicated substantial differences from the activity elicited in adults undergoing identical manipulations. 4. The individual patches of activity that made up the metabolic pattern were similar in intensity in both hemispheres when the digit amputation was conducted at either 2, 4, or 6 wk. After a digit amputation at 2 wk, the patches were significantly narrower in the experimental hemisphere; after a digit amputation at 6 wk, the patches were significantly wider in the hemisphere receiving from the deprived forepaw. 5. Two-dimensional maps of 2DG uptake in areas 3b and 1 of the somatosensory cortex reveal that after a digit amputation at 2, 4, or 6 wk, the distribution of activity in the hemisphere receiving from the digit amputation was more dispersed and widespread than in the normal hemisphere. The dispersed pattern of uptake was not an expanded version of the normal pattern, but scattered over a wider region of somatosensory cortex. This observation is similar to the normal pattern of evoked activity seen in developing animals. 6. The total area of 2DG uptake in the somatosensory cortex contralateral to a digit amputation conducted at 2 or 4 wk was not greater than that in the normal hemisphere, even though it was more widespread. After a digit amputation at 6 wk, however, the area of evoked activity was greater in the experimental hemisphere but not of the magnitude as the same manipulation in an adult.(ABSTRACT TRUNCATED AT 400 WORDS)

Visual hemispheric dominance induced in split brain cats during development: a model of deficient interhemispheric transfer derived from physiological evidence in single visual cortex cells.

The effects of cancellation of both interhemispheric callosal transfer and interocular interactions, were studied in early monocularly deprived cats. The main purpose of this study was therefore to prove whether unilateral hemispheric dominance would result under these conditions and to what extent each hemisphere will be functionally independent. Secondly, we have attempted to establish such an experimental model physiologically, on the single cell level. Interhemispheric transfer was surgically canceled by sagittal transection of the corpus callosum. In addition, the ocular projections were separated by sagittal transection of the optic chiasm in the transbuccal approach. This condition had practically induced visual split brain condition in these cats. These manipulations were carried out concurrently with monocular deprivation (SBDK group) which was surgically done by eye closure during the critical period of development of the visual system. Thus, the hemisphere ipsilaterally to the visually deprived eye had developed under conditions of deficient visual experience while the hemisphere ipsilaterally to the normal eye had developed under conditions of unaltered visual experience. A group of cats (SBK) similarly operated but equally binocularly exposed during development was served as controls. In addition, adult cats similarly operated during adulthood either chronically or acutely were studied to evaluate the effects of interhemispheric and interocular separation. Other groups of cats were also studied for comparison, and included sham operated and normal adult cats. At adulthood, electrophysiological studies were done on these cats, in which action potentials were extracellularly recorded from single cells in the visual cortex (area 17-18 boundary) following anesthesia and paralysis. Stimulation was carried out manually and by a computer driven optical system, presenting on a tangent screen light bars at various spatial positions, orientations and directions. Receptive fields were thus mapped for all neurons and their dimensions and eccentricities were measured. The responsiveness, ocular dominance and other parameters were also studied for these cells. The results in the early deprived cats and in their controls, had shown a full separation between the two hemispheres, as reflected in the almost absolute ipsilateral eye responsiveness (> 97.0% cells). In comparison, in the sham operated and in the normal control cats only minor proportions of cells (13.0-18.7%) have been found as ipsilaterally and monocularly driven, showing almost full interhemispheric and interocular interaction. The main difference, however, in the results between the early monocularly deprived cats and their controls is that in the first group the two hemispheres were asymmetric concerning the amount of visual activation and in the second one they were very symmetric.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of angiogenesis in patients with cerebral ischemic stroke.

Stroke is one of the most common causes of mortality and morbidity in the Western world. It results from the occlusion of a cerebral artery followed by severe disturbances in blood supply through microvessels to brain tissue. Despite an extensive literature its pathophysiology is poorly understood, and this has severely impeded the logical development of therapy. Brains were obtained from 10 patients aged 46 to 85 years with survival times of 5 to 92 days after their stroke. Infarcted areas and representative control tissues from the contralateral uninvolved brain hemisphere were collected. Microvessel density was measured microscopically. A total of 6520 microvessels were scored in 10,801 areas. The level of activation of the endothelial cells was studied by immunohistochemistry using three monoclonal antibodies, viz, E-9, raised against activated endothelial cells; IG11, recognizing vascular cell adhesion molecule-1; and anti-proliferating cell nuclear antigen. Angiogenic activity in tissue extracts was examined using an in vivo chicken chorioallantoic membrane assay. There was a statistically significant increase in the number of microvessels (Wilcoxon log-rank test; P < or = .01) in 9 of 10 infarcted brain tissues when compared with their contralateral normal hemisphere. In these patients the higher blood vessel counts correlated with longer survival, as ascertained by Spearman's p analysis (P < .02). The number of microvessels filled with blood cells was significantly lower in the infarcted hemispheres (P < .01). In contrast, statistically significant increased numbers of empty microvessels occurred in infarcted tissues compared with the contralateral hemisphere. Monoclonal antibody E-9 reacted weakly with normal-brain vascular endothelial cells; anti-proliferating cell nuclear antigen and IG11 were virtually negative. All three antibodies strongly stained the blood vessels of stroke tissues. The stroke tissues contained angiogenic activity, as shown by the induction of new blood vessels in a chorioallantoic membrane assay. We have shown that stroke causes active angiogenesis that is more developed in the penumbra. Further experiments are needed to determine if this angiogenesis has beneficial effect.

Neonatal frontal cortical lesions in rats alter cortical structure and connectivity

Rats were given frontal cortical lesions at day 1 or 10 of life. Later, as adults, they were either: (1) processed with Golgi-Cox in order to analyze cortical dendritic arborization; (2) given injections of True Blue into the parietal or visual cortex, or (3) given injections of [ 3H]leucine into the substantia nigra. An additional group of normal rats were given injections of fluorescent dyes into the cortex on day 4 or 10 of life. The main findings were that (1) adult hemispheres with day 10 lesions had greater dendritic arbor than normal hemispheres, (2) adult hemispheres with day 1 lesions had reduced dentritic branching relative to normal hemispheres, (3) adult rats with day 10 lesions had no obvious abnormalities in cortical connections, (4) adult rats with day 1 lesions had abnormal thalamo-cortical, amygdalo-cortical, and nigro-cortical connections, and (5) many of these abnormal connections were present in the brains of 4-day-old normal rats. Since the ‘abnormal’ connections in the very early frontal operates were present in day 4 animals, it appears that they result from the failure of exuberant connections to retract after the lesions. The increased dendritic growth in day 10 operates does not appear related to qualitative changes in cortical afferents or efferents and may related to increased intrinsic cortical connectivity. Since rats with day 10 lesions have previously been shown to exhibit significant recovery of function, it is possible that the increased dendritic arborization is supporting the functional restitution.

Cholinergic basal forebrain transplants restore diminished metabolic activity in the somatosensory cortex of rats with acetylcholine depletion [published erratum appears in J Neurosci 1994 Mar;14(3): following table of contents

It has been known for several years that stimulus-evoked metabolic activity is reduced in the somatosensory cortex of animals with basal forebrain lesions that deplete the neocortex of acetylcholine (ACh). During 2-deoxyglucose (2-DG) experiments, animals with unilateral basal forebrain lesions demonstrate a decreased response to somatic stimulation, while background metabolic activity in the surrounding cortical regions remains normal. In an attempt to ameliorate these deficits, we examined the ability of embryonic cholinergic basal forebrain transplants inserted into neocortex to innervate surrounding cortical regions and restore functional 2-DG activity in adult host rats previously depleted of ACh by basal forebrain lesions. To accomplish this goal, a series of experiments were conducted in which we (1) depleted the cerebral cortex of ACh by injecting an excitotoxin into the rat basal forebrain, (2) transplanted embryonic basal forebrain or embryonic neocortical (control) tissue into the ACh-depleted cortex and, (3) 6-12 months later, used the 2-DG metabolic mapping technique to examine effects of the transplants on metabolic activity evoked by whisker stimulation in rat somatosensory (barrel) cortex. Histochemical analysis revealed that acetylcholinesterase (AChE) staining within 2 mm of the basal forebrain transplants was similar in density to the contralateral normal hemisphere. AChE staining farther than 2 mm from the basal forebrain transplants and throughout hemispheres containing neocortical (control) transplants was greatly reduced, with few AChE-positive fibers present, a finding typical of cerebral cortex in basal forebrain-lesioned animals. Stimulus-evoked 2-DG uptake in barrels adjacent to the basal forebrain transplants, and therefore within AChE-rich territory, was similar to that in corresponding barrels identically activated in the contralateral hemisphere. 2-DG activity was reduced, however, in stimulated barrels outside the region of dense AChE-positive staining, as well as in all activated barrels in hemispheres containing control transplants of embryonic neocortex. These results indicate that transplantation of cell suspensions containing embryonic cholinergic basal forebrain, but not neocortex, can ameliorate basal forebrain lesion-induced deficits in functional activity, and that the restoration of activity is influenced by proximity to the transplant.