Cortical Microhemorrhages Research Articles

Cortical Microhemorrhage Presentation of Small Vessel Primary Angiitis of the Central Nervous System.

Primary angiitis of the central nervous system (PACNS) is a rare vasculitis restricted to the brain, spinal cord, and leptomeninges. This study aimed to describe the imaging characteristics of patients with small vessel PACNS (SV-PACNS) using 7 T magnetic resonance imaging (MRI). This ongoing prospective observational cohort study included patients who met the Calabrese and Mallek criteria and underwent 7 T MRI scan. The MRI protocol includes T1-weighted magnetization-prepared rapid gradient echo imaging, T2 star weighted imaging, and susceptibility-weighted imaging. Two experienced readers independently reviewed the neuroimages. Clinical data were extracted from the electronic patient records. The findings were then applied to a cohort of patients with large vessel central nervous system (CNS) vasculitis. We included 21 patients with SV-PACNS from December 2021 to November 2023. Of these, 12 (57.14%) had cerebral cortical microhemorrhages with atrophy. The pattern with microhemorrhages was described in detail based on the gradient echo sequence, leading to the identification of what we have termed the "coral-like sign." The onset age of patients with coral-like sign (33.83 ± 9.93 years) appeared younger than that of patients without coral-like sign (42.11 ± 14.18 years) (P = 0.131). Furthermore, the cerebral lesions in patients with cortical microhemorrhagic SV-PACNS showed greater propensity toward bilateral lesions (P = 0.03). The coral-like sign was not observed in patients with large vessel CNS vasculitis. The key characteristics of the coral-like sign represent cerebral cortical diffuse microhemorrhages with atrophy, which may be an important MRI pattern of SV-PACNS. ANN NEUROL 2024;96:194-203.

Cerebral Proteomic Changes in the rTg-D Rat Model of Cerebral Amyloid Angiopathy Type-2 With Cortical Microhemorrhages and Cognitive Impairments.

Cerebral amyloid angiopathy (CAA) is a common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a novel transgenic rat model (rTg-D) that produces human familial CAA Dutch E22Q mutant amyloid β-protein (Aβ) in brain and develops arteriolar CAA type-2. Here, we show that deposition of fibrillar Aβ promotes arteriolar smooth muscle cell loss and cerebral microhemorrhages that can be detected by magnetic resonance imaging and confirmed by histopathology. Aged rTg-D rats also present with cognitive deficits. Cerebral proteomic analyses revealed 241 proteins that were significantly elevated with an increase of >50% in rTg-D rats presenting with CAA compared to wild-type rats. Fewer proteins were significantly decreased in rTg-D rats. Of note, high temperature requirement peptidase A (HTRA1), a proteinase linked to transforming growth factor beta 1 (TGF-β1) signaling, was elevated and found to accumulate in cerebral vessels harboring amyloid deposits. Pathway analysis indicated elevation of the TGF-β1 pathway and increased TGF-β1 levels were detected in rTg-D rats. In conclusion, the present findings provide new molecular insights into the pathogenesis of CAA and suggest a role for interactions between HTRA1 and TGF-β1 in the disease process.

7T MRI in transient ischemic attacks: Have we only seen the tip of the iceberg?

Transient ischemic attack (TIA) has gained significant attention recently due to the increased incidence of subsequent stroke. However, there are many nonvascular clinical mimics of TIA, creating a need for improved biomarkers to identify a vascular origin. Following the recent approval of ultra-high field (UHF) 7T MRI in clinical practice, several clinical studies have highlighted its added utility in neuroimaging compared to lower-field 1.5T and 3T MRI, particularly in epilepsy and multiple sclerosis. Our case series of three patients with TIA illustrates that 7T MRI can depict small areas of intracortical microhemorrhages and microinfarctions, which could not be resolved with 3T or 1.5T MRI. There are currently no reports of intracortical localization of microhemorrhages in patients with TIA. This discovery may enhance our understanding and characterization of cerebrovascular abnormalities in TIAs. In addition, UHF imaging could potentially be utilized to distinguish transient neurological episodes secondary to cerebrovascular events from other differential considerations. Our cases highlight the underestimation of imaging abnormalities in cases of TIA and support the potential expanded application of clinical 7T to assess patients with TIA. Future studies are necessary at 7T redundant to determine the true incidence of such lesions in TIA and to examine the correlation between cortical microhemorrhages and subsequent ischemic stroke, hemorrhagic events, and neurocognitive impairment.

Susceptibility-Weighted Imaging in Neurodegenerative Disorders: A Review.

As human life expectancy increases, there is an increased prevalence of neurodegenerative disorders and dementia. There are many ongoing research trials for early diagnosis and management of dementia, and neuroimaging is a critical part of such studies. However, conventional neuroimaging often fails to provide enough diagnostic findings in patients with neurodegenerative disorders. In this context, different MRI sequences are currently under investigation to facilitate the accurate diagnosis of such disorders. Susceptibility-weighted imaging (SWI) is an innovative MRI technique that utilizes "magnitude" and "phase" images to produce an image contrast that is sensitive for the detection of susceptibility differences of the tissues. As many neurodegenerative disorders are associated with accelerated iron deposition and/or microhemorrhages in different parts of the brain, SWI can be applied to detect these diagnostic clues. For instance, in cerebral amyloid angiopathy, SWI can demonstrate cortical microhemorrhages, which are predominantly in the frontal and parietal regions. Or in Parkinson disease, abnormal swallow-tail sign on high-resolution SWI is highly diagnostic. Also, SWI is a useful sequence to detect the low signal intensity of precentral cortices in patients with amyotrophic lateral sclerosis. Being familiar with SWI findings in neurodegenerative disorders is critical for an accurate diagnosis. In this paper, the authors review the technical parameters of SWI, physiologic, and pathologic iron deposition in the brain, and the role of SWI in the evaluation of neurodegenerative disorders in daily practice.

Brain MRI Findings in Patients in the Intensive Care Unit with COVID-19 Infection.

Online supplemental material is available for this article.

Neuropathological findings in comatose patients with venoarterial extracorporeal membrane oxygenation.

We sought to describe the relation between neuropathology and clinical information including neurological examination and electroencephalogram findings in extracorporeal membrane oxygenation. We reviewed the patients who had undergone brain autopsy from November 2017 through December 2018. Four patients with neuromonitoring had post mortem examination with brain autopsy. The median age was 56, and all had venoarterial extracorporeal membrane oxygenation cannulation. There was no known acute neurologic injury prior to extracorporeal membrane oxygenation. While on extracorporeal membrane oxygenation, all were persistently comatose off sedation. Continuous encephalogram was done on all four, all of which showed delta frequency with absent reactivity. In Case 1, the pathological evaluation demonstrated small infarcts in cerebral cortices. In Case 2, it showed cortical microhemorrhages and chronic microinfarcts in basal ganglia. In Cases 3 and 4, the neuropathological assessment demonstrated diffuse hypoxic-ischemic brain injury. The clinical presentation was consistent with the widespread neuropathologic injury in two cases (Cases 3 and 4) but not in the other two (Cases 1 and 2). While "poor neurological status" was provided in the end-of-life discussion in all four, only two had significant brain injuries. There is limited understanding about brain injury in extracorporeal membrane oxygenation. Extrapolations related to prognostication from experience in other brain injury needs to be approached cautiously.

Aspirin treatment does not increase microhemorrhage size in young or aged mice.

Microhemorrhages are common in the aging brain and are thought to contribute to cognitive decline and the development of neurodegenerative diseases, such as Alzheimer’s disease. Chronic aspirin therapy is widespread in older individuals and decreases the risk of coronary artery occlusions and stroke. There remains a concern that such aspirin usage may prolong bleeding after a vessel rupture in the brain, leading to larger bleeds that cause more damage to the surrounding tissue. Here, we aimed to understand the influence of aspirin usage on the size of cortical microhemorrhages and explored the impact of age. We used femtosecond laser ablation to rupture arterioles in the cortex of both young (2–5 months old) and aged (18–29 months old) mice dosed on aspirin in their drinking water and measured the extent of penetration of both red blood cells and blood plasma into the surrounding tissue. We found no difference in microhemorrhage size for both young and aged mice dosed on aspirin, as compared to controls (hematoma diameter = 104 +/- 39 (97 +/- 38) μm in controls and 109 +/- 25 (101 +/- 28) μm in aspirin-treated young (aged) mice; mean +/- SD). In contrast, young mice treated with intravenous heparin had an increased hematoma diameter of 136 +/- 44 μm. These data suggest that aspirin does not increase the size of microhemorrhages, supporting the safety of aspirin usage.

Diverse Inflammatory Response After Cerebral Microbleeds Includes Coordinated Microglial Migration and Proliferation.

Cerebral microbleeds are linked to cognitive decline, but it remains unclear how they impair neuronal function. Infarction is not typically observed near microbleeds, suggesting more subtle mechanisms, such as inflammation, may play a role. Because of their small size and largely asymptomatic nature, real-time detection and study of spontaneous cerebral microbleeds in humans and animal models are difficult. We used in vivo 2-photon microscopy through a chronic cranial window in adult mice to follow the inflammatory response after a cortical microhemorrhage of ≈100 µm diameter, induced by rupturing a targeted cortical arteriole with a laser. The inflammatory response included the invasion of blood-borne leukocytes, the migration and proliferation of brain-resident microglia, and the activation of astrocytes. Nearly all inflammatory cells responding to the microhemorrhage were brain-resident microglia, but a small number of CX3CR1+ and CCR2+ macrophages, ultimately originating from the invasion of blood-borne monocytes, were also found near the lesion. We found a coordinated pattern of microglia migration and proliferation, where microglia within 200 µm of the microhemorrhage migrated toward the lesion over hours to days. In contrast, microglia proliferation was not observed until ≈40 hours after the lesion and occurred primarily in a shell-shaped region where the migration of microglia decreased their local density. These data suggest that local microglia density changes may trigger proliferation. Astrocytes activated in a similar region as microglia but delayed by a few days. By 2 weeks, this inflammatory response had largely resolved. Although microhemorrhages are small in size, the brain responds to a single bleed with an inflammatory response that involves brain-resident and blood-derived cells, persists for weeks, and may impact the adjacent brain microenvironment.

Rodent Models of Cerebral Microinfarct and Microhemorrhage.

Microinfarcts are prevalent but tiny ischemic lesions that may contribute to vascular cognitive impairment and dementia (Figure 1A and 1B).1 They are defined as areas of tissue infarction, often with gliosis or cavitation, visible only by examination of the autopsied brain at a microscopic level.2,3 Numerous autopsy studies have now shown that a greater microinfarct burden is correlated with increased likelihood of cognitive impairment.2,3 Cerebral microinfarcts are observed postmortem in the brains of ≈43% of patients with Alzheimer’s disease, 62% of patients with vascular dementia, and 24% of nondemented elderly subjects.4 However, reported microinfarct numbers are a significant underestimation of total burden, as only a small portion of the brain is examined at routine autopsy.1 Indeed, they can number in the hundreds to thousands within a single brain. Microinfarcts can arise from a variety of etiologies, including cerebral small vessel disease, large vessel disease, cerebral hypoperfusion, and cardiac disease, but their role in the pathogenesis of vascular cognitive impairment and dementia remains poorly understood.3,5–7 Figure 1. Human microinfarcts and microhemorrhages in cerebral amyloid angiopathy (CAA) cases. A , A cortical microinfarct on a hematoxylin & eosin–stained section. B , Microinfarct (black arrow) on a T2-weighted ex vivo magnetic resonance imaging (MRI) scan. C , A cortical microhemorrhage on a hematoxylin & eosin–stained section. D , Multiple lobar microbleeds (white arrows) on a gradient-repeat echo ex vivo MRI scan. Microhemorrhages are microscopic bleeds caused by rupture of cerebral microvessels, generating lesions on a similar scale as microinfarcts (Figure 1C and 1D).5 Pathologically, old microhemorrhages are defined as focal depositions of iron-positive hemosiderin-containing macrophages. Unlike microinfarcts, microhemorrhages easily escape detection on neuropathological examination, suggesting that they are not as widespread as microinfarcts. However, they can be detected …

Clinical pathologic case report: A 70-year-old man with inflammatory cerebral amyloid angiopathy causing headache, cognitive impairment, and aphasia

A 70-year-old man presented with two months of worsening cognitive impairment, hallucinations, and difficulty speaking, with superimposed headaches. Cerebrospinal fluid analysis was notable for lymphocytic pleocytosis and elevated protein. Imaging studies revealed multiple acute and subacute infarcts with cortical microhemorrhages. The patient underwent a stereotactic brain biopsy. In this article, we discuss the patient’s differential diagnosis, pathologic findings, ultimate diagnosis, and clinical outcome.

Microstructural and microglial changes after repetitive mild traumatic brain injury in mice.

Traumatic brain injury (TBI) is a major public health issue, with recently increased awareness of the potential long-term sequelae of repetitive injury. Although TBI is common, objective diagnostic tools with sound neurobiological predictors of outcome are lacking. Indeed, such tools could help to identify those at risk for more severe outcomes after repetitive injury and improve understanding of biological underpinnings to provide important mechanistic insights. We tested the hypothesis that acute and subacute pathological injury, including the microgliosis that results from repeated mild closed head injury (rmCHI), is reflected in susceptibility-weighted magnetic resonance imaging and diffusion-tensor imaging microstructural abnormalities. Using a combination of high-resolution magnetic resonance imaging, stereology, and quantitative PCR, we studied the pathophysiology of male mice that sustained seven consecutive mild traumatic brain injuries over 9 days in acute (24 hr) and subacute (1 week) time periods. rmCHI induced focal cortical microhemorrhages and impaired axial diffusivity at 1 week postinjury. These microstructural abnormalities were associated with a significant increase in microglia. Notably, microgliosis was accompanied by a change in inflammatory microenvironment defined by robust spatiotemporal alterations in tumor necrosis factor-α receptor mRNA. Together these data contribute novel insight into the fundamental biological processes associated with repeated mild brain injury concomitant with subacute imaging abnormalities in a clinically relevant animal model of repeated mild TBI. These findings suggest new diagnostic techniques that can be used as biomarkers to guide the use of future protective or reparative interventions. © 2016 Wiley Periodicals, Inc.

Neuroprotective effect of hyperbaric oxygen therapy in a juvenile rat model of repetitive mild traumatic brain injury.

Repetitive mild traumatic brain injury (rmTBI) is an important medical concern for adolescent athletes that can lead to long-term disabilities. Multiple mild injuries may exacerbate tissue damage resulting in cumulative brain injury and poor functional recovery. In the present study, we investigated the increased brain vulnerability to rmTBI and the effect of hyperbaric oxygen treatment using a juvenile rat model of rmTBI. Two episodes of mild cortical controlled impact (3 days apart) were induced in juvenile rats. Hyperbaric oxygen (HBO) was applied 1 hour/day × 3 days at 2 atmosphere absolute consecutively, starting at 1 day after initial mild traumatic brain injury (mTBI). Neuropathology was assessed by multi-modal magnetic resonance imaging (MRI) and tissue immunohistochemistry. After repetitive mTBI, there were increases in T2-weighted imaging-defined cortical lesions and susceptibility weighted imaging-defined cortical microhemorrhages, correlated with brain tissue gliosis at the site of impact. HBO treatment significantly decreased the MRI-identified abnormalities and tissue histopathology. Our findings suggest that HBO treatment improves the cumulative tissue damage in juvenile brain following rmTBI. Such therapy regimens could be considered in adolescent athletes at the risk of repeated concussions exposures.

Long-term follow-up study on the safety of deep brain stimulation for treating Parkinson's disease

Objective To evaluate the safety of deep brain stimulation (DBS) for treating Parkinson's disease (PD) under long-term follow-up and modify the surgical procedure. Methods A total of 362 PD patients underwent DBS, and almost 613 electrodes were implanted into these patients. Both surgical and hardware-related complications of DBS were retrospectively analyzed. Results Perioperative complications included postoperative confusion or delirium in 21 cases (5.80%), intracranial hemorrhage in 4 cases (1.10%; 2 asymptomatic cortical microhemorrhage and 2 basal ganglia trajectory microhemorrhage), generalized tonic-clonic seizures (GTCS) in 2 cases (0.55% ), urinary tract infection in 4 cases (1.10% ), pulmonary infection in 7 cases (1.93%), implantable pulse generator (IPG) hematoma in 11 cases (3.04%), IPG seroma in 3 cases (0.83%). All these patients were cured. They were followed-up for 12-146 months (median 34 months). Hardware-related complications included infection of incisional wound and/or skin erosion (9 cases, 2.49% ), extension wire fracture caused by IPG displacement (one case, 0.28% ), IPG shifting to abdomen due to fixation wire fracture (one case, 0.28%), slightly migrated electrode due to fall (one case, 0.28%), and discomfort about occipital incision (one case, 0.28%). Conclusions The overall risk of both surgical and hardware-related adverse events of DBS for treating PD is acceptably low. DOI: 10.3969/j.issn.1672-6731.2015.10.005

Cerebral amyloid angiopathy: emerging concepts.

Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid β-protein (Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Aβ deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2* imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Aβ40 for CAA and anti-Aβ antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Aβ immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis, treatment, risk factors, and future perspectives.

Brain Hemorrhages in Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is cerebrovascular amyloid deposition. It is classified into several types according to the cerebrovascular amyloid proteins involved. Sporadic amyloid β-protein (Aβ)-type CAA is commonly found in elderly individuals and patients with Alzheimer disease. CAA-related disorders include hemorrhagic and ischemic stroke and dementia. CAA-related hemorrhages include intracerebral lobar macrohemorrhages, cortical microhemorrhages, and focal subarachnoidal hemorrhages/superficial siderosis. CAA-associated vasculopathies, such as microaneurysmal formation with fibrinoid necrosis, underlie such cerebrovascular events. Sensitive magnetic resonance imaging procedures, such as gradient-echo T2* imaging and susceptibility-weighted images, are useful to detect microhemorrhagic lesions. Amyloid images with amyloid-binding positron emission tomography ligands can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. Hemorrhage-inducing factors for sporadic Aβ-type CAA include apolipoprotein E genotype, thrombolytic, anticoagulation, and antiplatelet therapies, hypertension, minor head trauma, and antiamyloid therapies. We need future strategies for protection of vessel walls against amyloid-related vascular damage, such as toxicity of Aβ oligomers, Aβ-induced oxidative stress, and inflammation, as well as development of antiamyloid therapies for CAA.

A novel APP mutation (D678H) in a Taiwanese patient exhibiting dementia and cerebral microvasculopathy

We report a novel missense mutation, D678H, in the APP gene in a Taiwanese patient who had progressive cognitive decline beginning in middle age. Brain MRI showed leukoencephalopathy, cortical microhemorrhages and focal superficial cortical hemosiderosis, which are consistent with cerebral amyloid angiopathy. A phenotype of combined dementia and cerebral microvasculopathy suggested concurrent increases in brain parenchymal and cerebrovascular beta-amyloid peptide (Aβ) deposition in this patient. The promotion of Aβ aggregation has been postulated to underlie the pathogenic mechanism of the mutation.

Cortical Microhemorrhages Cause Local Inflammation but Do Not Trigger Widespread Dendrite Degeneration

Microhemorrhages are common in the aging brain, and their incidence is correlated with increased risk of neurodegenerative disease. Past work has shown that occlusion of individual cortical microvessels as well as large-scale hemorrhages can lead to degeneration of neurons and increased inflammation. Using two-photon excited fluorescence microscopy in anesthetized mice, we characterized the acute and chronic dynamics of vessel bleeding, tissue compression, blood flow change, neural degeneration, and inflammation following a microhemorrhage caused by rupturing a single penetrating arteriole with tightly-focused femtosecond laser pulses. We quantified the extravasation of red blood cells (RBCs) and blood plasma into the brain and determined that the bleeding was limited by clotting. The vascular bleeding formed a RBC-filled core that compressed the surrounding parenchymal tissue, but this compression was not sufficient to crush nearby brain capillaries, although blood flow speeds in these vessels was reduced by 20%. Imaging of cortical dendrites revealed no degeneration of the large-scale structure of the dendritic arbor up to 14 days after the microhemorrhage. Dendrites close to the RBC core were displaced by extravasating RBCs but began to relax back one day after the lesion. Finally, we observed a rapid inflammatory response characterized by morphology changes in microglia/macrophages up to 200 µm from the microhemorrhage as well as extension of cellular processes into the RBC core. This inflammation persisted over seven days. Taken together, our data suggest that a cortical microhemorrhage does not directly cause significant neural pathology but does trigger a sustained, local inflammatory response.

Cerebral amyloid angiopathy and microhemorrhages after amyloid beta vaccination: case report and brief review

After the interruption of the international multicenter Phase 2 clinical trial with active immunotherapy based on synthetic Abeta42 (AN1792), few reports about the neuropathological findings in those patients and those from the Phase 1 clinical trial were published. These reports described some pathological similarities among the patients such as a reduction in the burden of amyloid plaques, the reactions of microglia/macrophages and the persistence of neurofibrillary tangles and neuropil threads. In addition, a lymphocytic inflammatory infiltrate as well as white matter lesions were present in some cases with meningoencephalitis. In both animal models of vaccination, as well as some vaccinated patient samples, there appears to be a correlation between vaccination and hemorrhages. Subsequently, two series reports concerning 8 patients from the Phase 1 initial trial showed that immunization with Abeta42 seemed to result in clearance of amyloid plaques, but did not prevent progressive neurodegeneration and that it increased vessel wall amyloid angiopathy as well as cortical microhemorrhages. Recent clinical data gave further encouraging results regarding vaccination in humans demonstrating that long term follow-up of patients from the second clinical trial revealed reduced functional decline, at least, in antibody responders. Here we describe a patient diagnosed with Alzheimer's disease who also participated in the Phase 2 clinical trial. A neuropathological examination confirmed Alzheimer's disease without meningoencephalitis and revealed a severe amyloid angiopathy with frequent microhemorrhages, the decrease of amyloid load being difficult to ascertain. Our results are in agreement with previous studies and confirm the presence of severe amyloid angiopathy after vaccination. The latter may be a transient phenomenon depending on the degree of immune response and the pathological stage of the disease when the patient underwent treatment. In addition, our vaccinated case also demonstrated microhemorrhages and microinfarcts which were already noticed to occur with a higher density in immunized Alzheimer's disease patients.

Effect of local brain retraction on local cerebral blood flow and neural function. Experimental study

Changes in N1 amplitude of somatosensory evoked potential (SEP) with median nerve stimulation, cortical blood flow (CoBF) by a hydrogen clearance method, and histology were studied during brain retraction with graded local compression pressure (LCP) in 56 dogs. Local brain compression was applied with a brain spatula on the primary somatosensory cortex after right frontotemporal craniectomy and opening of the dura. In the first experiment, cerebral perfusion pressure (CPP) was reduced by three different methods, namely, exsanguination, infusion of saline solution into the cisterne magna, and continuous local brain compression. CPP was reduced by a 10 mmHg step every 30 minutes. Continuous local brain compression decreased both N1 amplitude and CoBF more markedly than did the other two methods. N1 amplitude decreased as soon as the local compression was started, and was reduced to 50% at 50 mmHg of LCP (CPP, 90-100 mmHg), and became null when LCP was elevated over 90 mmHg (CPP, below 60 mmHg). CoBF was significantly reduced at 110 mmHg of CPP. This suggests that immediate and severe neural dysfunction in local brain compression was due not only to destruction of the neural architecture by brain distortion but also to disturbance of cerebral circulation. As the second experimental step, intermittent local compressions with initial pressures of 20, 40, 60, and 80 mmHg was performed. Local compressions were applied four times for 30 minutes duration with five minute intermissions. At the initial levels of 40 mmHg of LCP, and higher the more the compressions were repeated or the higher the LCP was raised, the more both N1 amplitude and CoBF decreased. At 60 and 80 mmHg of LCP, N1 amplitude decreased significantly to 35% and 11% during compression and remained reduced to 70% and 35% at two hours after decompression, respectively. When the N1 amplitude was reduced more than 50% during compression, it remained suppressed to 55% 2 hours after decompression. In these dogs, histological study of the compressed area showed cortical microhemorrhage and edema. This study suggests that LCP over 40 mmHg and/or reduction of N1 amplitude by greater than 50% during brain retraction produce postoperative neuronal dysfunction and histological changes.