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Objective: To study associations of clinical characteristics and treatment choice with functional outcome, mortality, and time to death in a national sample of aneurysmal subarachnoidal hemorrhage patients., Methods: Data were extracted from a prospective nationwide multicenter study performed in September 2014 to March 2018. Glasgow Outcome Scale Extended (GOSE) grade, 1-year mortality, and survival probability were assessed at one year after ictus. Logistic univariate, multivariate, and Cox regression analyses were used to study the variables' associations with the outcomes., Results: Unfavorable dichotomized GOSE (dGOSE; grades 1-4) was observed in 35.4% of patients. Microsurgery was preferred for middle cerebral artery aneurysms and Fisher grade 4. Treatment modality was not associated with any outcome measure. Dichotomized World Federation of Neurosurgical Societies (dWFNS), age, and delayed ischemic neurological deficit (DIND) showed significant correlations with dGOSE and 1-year mortality in multivariate regression analyses. Pupil dilatation was associated with a 1-year mortality outcome. Cox regression analysis showed lower survival probability for pupil dilatation (hazard ratio [HR]: 3.546), poor dWFNS (HR: 3.688), higher age (HR: 1.051), and DIND occurrence (HR: 2.214)., Conclusions: The patient selection in Sweden after aneurysmal subarachnoidal hemorrhage showed similar values for dGOSE, 1-year mortality, and survival probability between patients treated with microsurgery or endovascular technique. Poor dWFNS, higher age, and DIND were significantly associated with unfavorable dGOSE, mortality, and survival probability. Pupil dilatation was significantly associated with mortality and survival probability., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: A range of adverse events (AEs) may occur in patients with subarachnoid hemorrhage (SAH). Endovascular treatment is commonly used to prevent aneurysm re-rupture., Research Question: The aim of this study was to identify AEs related to endovascular treatment, analyze risk factors for AEs and how AEs affect patient outcome., Material and Methods: Patients with aneurysmal SAH admitted to all neurosurgical centers in Sweden during a 3.5-year period (2014-2018) were prospectively registered. AEs related to endovascular aneurysm treatment were thromboembolic events, aneurysm re-rupture, vessel dissection and puncture site hematoma. Potential risk factors for the AEs were analyzed using multivariate logistic regression. Functional outcome was assessed at one year using the extended Glasgow outcome scale., Results: In total, 1037 patients were treated for ruptured aneurysms. Of which, 715 patients were treated with endovascular occlusion. There were 115 AEs reported in 113 patients (16%). Thromboembolic events were noted in 78 patients (11%). Aneurysm re-rupture occurred in 28 (4%), vessel dissection in 4 (0.6%) and puncture site hematoma in 5 (0.7%). Blister type aneurysm, aneurysm smaller than 5 mm and endovascular techniques other than coiling were risk factors for treatment-related AEs. At follow-up, 230 (32%) of the patients had unfavorable outcome. Patients suffering intraprocedural aneurysm re-rupture were more likely to have unfavorable outcome (OR 6.9, 95% CI 2.3-20.9)., Discussion and Conclusion: Adverse events related to endovascular occlusion of a ruptured aneurysm were seen in 16% of patients. Aneurysm re-rupture during endovascular treatment was associated with increased risk of unfavorable functional outcome., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Adverse events (AEs) or complications may arise secondary to the treatment of aneurysmal subarachnoid haemorrhage (SAH). The aim of this study was to identify AEs associated with microsurgical occlusion of ruptured aneurysms, as well as to analyse their risk factors and impact on functional outcome., Methods: Patients with aneurysmal SAH admitted to the neurosurgical centres in Sweden were prospectively registered during a 3.5-year period (2014-2018). AEs were categorised as intraoperative or postoperative. A range of variables from patient history and SAH characteristics were explored as potential risk factors for an AE. Functional outcome was assessed approximately 1 year after the bleeding using the extended Glasgow Outcome Scale., Results: In total, 1037 patients were treated for ruptured aneurysms, of which, 322 patients were treated with microsurgery. There were 105 surgical AEs in 97 patients (30%); 94 were intraoperative AEs in 79 patients (25%). Aneurysm rerupture occurred in 43 patients (13%), temporary occlusion of the parent artery >5 min in 26 patients (8%) and adjacent vessel injury in 25 patients (8%). High Fisher grade and brain oedema on CT were related to increased risk of AEs. At follow-up, 38% of patients had unfavourable outcome. Patients suffering AEs were more likely to have unfavourable outcome (OR 2.3, 95% CI 1.10 to 4.69)., Conclusion: Intraoperative AEs occurred in 25% of patients treated with microsurgery for ruptured intracerebral aneurysm in this nationwide survey. Although most operated patients had favourable outcome, AEs were associated with increased risk of unfavourable outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: There is an an increasing awareness of the importance of health and lifestyle for stroke diseases like spontaneous subarachnoid hemorrhage (SAH). However, the importance of pre-existing medical conditions for clinical course and mortality after SAH has not been studied. The aim of the present study was to identify pre-existing conditions contributing to mortality after SAH., Methods: Data were extracted from a Swedish national prospective study on patients with SAH. Variables were defined for age, sex, body mass index (BMI), clinical condition at admission, and for 10 pre-existing medical conditions. Models predicting mortality in three time intervals with all possible subsets of these variables were generated, compared and selected using Akaike's information criterion., Results: 1155 patients with ruptured aneurysms were included. The mortality within 1 week was 7.6%, 1 month 14.3%, and 1 year 18.7%. The most common pre-existing medical conditions were smoking (57.6%) and hypertension (38.7%). The model's best predicting mortality within 1 week and from 1 week to 1 month included only the level of consciousness at admission and age, and these two variables were present in all the models among the top 200 in Akaike score for each time period. The most predictive model for mortality between 1 month and 1 year added previous stroke, diabetes, psychiatric disease, and BMI as predictors., Conclusion: Mortality within the first month was best predicted simply by initial level of consciousness and age, while mortality within from 1 month to 1 year was significantly influenced by pre-existing medical conditions., (© 2023. The Author(s).)

Background: Surgery for spontaneous primary intracerebral hemorrhage (ICH) remains controversial. Previous surgical trials have primarily focused on short-term mortality while studies on long-term functional outcome are rare. We therefore conducted this retrospective study of long-term outcome on all ICH patients who underwent craniotomy at a single neurosurgical center during a 10-year period., Methods: We included all patients >15 years of age who underwent evacuation of spontaneous ICH at Skåne University Hospital between 2003 and 2012. Case fatality at 30 days, 1 year, and long-term follow-up (up to 10 years) were analyzed in relation to potential predictors of outcome. Long-term functional outcome was assessed in 2013 by telephone interview using the modified Rankin Scale (mRS)., Results: Of 229 operated patients, overall case fatality was 20% at 30 days and 31% at 1 year. For patients with supratentorial ICH, the case fatality was 16% at 30 days and 27% at 1 year, and 29% at 30 days and 41% at 1 year for patients with cerebellar ICH. The most consistent independent predictors of mortality were preictal heart disease and level of consciousness on admission. Of 185 patients with long-term functional outcome available (median follow-up 6.14 years), 44 of them (24%) had a good outcome (mRS score 0-3) and 141 (76%) were severely disabled or dead (mRS score 4-6)., Conclusions: The case fatality in our study was comparatively low, but most survivors lived dependently several years after surgery. Heart disease and level of consciousness were the most consistent predictors of mortality., (Copyright © 2019 Elsevier Inc. All rights reserved.)

OBJECTIVE The goal of this study was to examine long-term quality of life (QOL) and reintegration in patients with good neurological recovery after aneurysmal subarachnoid hemorrhage (aSAH) and SAH of unknown cause (SAH NUD). METHODS A long-term follow-up was performed in an original cohort of 113 individuals who had suffered SAH (93 with aSAH and 20 with SAH NUD) between 1977 and 1984. Self-reporting assessments, performed > 20 years after the bleeding episode, included the Quality of Life Scale (QOLS), Psychological General Well-Being (PGWB) index, and Reintegration to Normal Living (RNL) index, along with information on sleep disturbances and work status. RESULTS Seventy-one survivors were identified. Questionnaires were returned by 67 individuals who had suffered SAH 20-28 years previously. The QOL was rated in the normal range for both the QOLS score (aSAH 90.3 vs SAH NUD 88.6) and the PGWB index (aSAH 105.9 vs SAH NUD 102.8). Ninety percent of patients had returned to their previous employment. Complete RNL was reported by 40% of patients with aSAH and by 46% of patients with SAH NUD; mild to moderate readjustment difficulties by 55% and 38%, respectively; and severe difficulties by 5% of patients with aSAH and 15% of patients with SAH NUD. Self-rated aspects of cognition, mood, and energy resources in addition resulted in a substantial drop in overall reintegration. Sleep disturbances were reported by 26%. CONCLUSIONS More than half of patients with SAH who had early good neurological recovery experienced reintegration difficulties after > 20 years. However, the general QOL was not adversely affected by this impairment. Inability to return to work after SAH was associated with lower QOLS scores. Sleep disturbances were associated with lower PGWB scores.

Objective: Pituitary dysfunction (PD) after aneurysmal subarachnoid hemorrhage (SAH) has been demonstrated in several studies. Given the similarities between psychological symptoms and reduced quality of life (QoL) in patients with PD and fatigue commonly seen in patients after SAH, we investigated the relationship between QoL and PD after SAH., Methods: There were 51 patients with aneurysmal SAH prospectively recruited and evaluated for health-related QoL using the Psychological General Well-Being Index. Evaluations were conducted 3-6 months (n = 45), 6-12 months (n = 44), and 12-24 months (n = 44) after SAH, with concomitant assessment of endocrine function. The study protocol also included a magnetic resonance imaging examination 3 months after SAH., Results: Mean general well-being scores showed a positive trend from 97.3 at 3-6 months to 104.3 at 12-24 months for all patients. Multiple regression analysis identified age, sex, Hunt and Hess grade, and PD as independent predictors for general well-being. Patients with PD had significantly lower scores compared with patients with normal pituitary function at 3-6 months (85.4 vs. 101.7) and 6-12 months (90.4 vs. 105.3). This result was due to central hypoadrenalism (score 81.6 at 3-6 months and score 82.2 at 6-12 months) but not other types of PD. The extent of magnetic resonance imaging lesions had a significant negative correlation to Glasgow Outcome Scale score at all follow-up evaluations. All patients with hypothalamic magnetic resonance imaging lesions had evidence of PD at some point during the follow-up period., Conclusions: The results support PD, and central hypoadrenalism in particular, as a contributing factor for impaired health-related QoL in patients after SAH., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Computed tomography angiography (CTA) is today the primary method for the detection of intracranial aneurysms. The technique has evolved considerably during the last decade, and it is important to establish criteria for high image quality, especially with regard to improving the diagnosis of small aneurysms., Purpose: To evaluate diagnostic accuracy and image quality by arterial attenuation of CTA in patients with non-traumatic subarachnoid hemorrhage (SAH)., Material and Methods: Between 2005 and 2011, CTA and digital subtraction angiography (DSA) were performed in 326 patients with non-traumatic SAH. Sensitivity and specificity for aneurysm detection were evaluated per patient, per aneurysm, and per ruptured aneurysm. The image quality of CTA was evaluated by arterial attenuation measurements (mean Hounsfield units [HU]) in the internal carotid artery (ICA)., Results: In all, 285 aneurysms in 235 patients were detected by DSA, 19 aneurysms were missed on CTA, and 223 aneurysms were classified as ruptured. In 91 patients, no aneurysm was found. Correct diagnosis with CTA was made in 28 patients with perimesencephalic hemorrhage. Sensitivity and specificity (95% confidence interval) calculated per patient were 91.6% (87.3-94.9) and 87.9% (79.8-93.6), respectively, per aneurysm 93.3% (89.7-95.9) and 88% (79.9-93.6), and per ruptured aneurysm 94.9% (91.3-97.3) and 96.7% (90.7-99.3). Arterial attenuation (in HU) in CTA revealing true positive ruptured aneurysms and true negative aneurysms (mean 535 ± 110 HU) differed significantly (P = 0.02) from false negative ruptured aneurysms (mean 424 ± 30 HU)., Conclusion: CTA has high sensitivity and specificity for the detection of ruptured aneurysms. The sensitivity is related to arterial attenuation in the ICA., (© The Foundation Acta Radiologica 2014.)

Objective: Impaired systemic hormonal activity caused by hypothalamic and pituitary injury may contribute to neuropsychologic disturbances and poor quality of life after aneurysmal subarachnoid hemorrhage (SAH). This prospective study was designed to longitudinally evaluate long-term clinical outcome and pituitary function after SAH using dynamic tests for adrencorticotropic and somatotropic secretory capacity., Methods: Endocrine function was assessed by basal hormonal concentrations at 6-12 months and 12-24 months after SAH. At the 12-24 months follow-up, dynamic provocative evaluation of adrenocorticotropic hormone (ACTH) and growth hormone (GH) was performed using the insulin tolerance test (ITT). In patients where ITT was contraindicated, an ACTH stimulation test was used to assess ACTH capacity, and a growth hormone releasing hormone (GHRH)-arginine stimulation test was used to assess GH capacity., Results: Of 60 patients with SAH screened, 51 were included in the study, and 44 remained to be tested at the two follow-up visits. As assessed by basal hormone concentrations alone, the prevalence of pituitary dysfunction was 34% at 6-12 months and 41% at 12-24 months. When using dynamic tests (12-24 months), impaired pituitary function was detected in 43%. The ITT detected more cases of central hypoadrenalism and GH deficiency compared with the ACTH- and GHRH-arginine-stimulation tests, respectively., Conclusions: Application of dynamic endocrine tests revealed a high frequency of long-term hypothalamic-pituitary dysfunction after aneurysmal SAH. The role of pituitary dysfunction in the recovery after SAH merits further evaluation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Poor outcome and neuropsychological sequelae after aneurysmal subarachnoid hemorrhage (SAH) is a persistent problem. Pituitary dysfunction has been proposed as a contributing factor. Clinical studies have given variable and conflicting results on its importance and incidence after SAH. The aim of this study was to prospectively examine SAH patients with assessment of endocrine function in the acute stage and at early follow-up and to compare clinical SAH features to endocrine abnormalities indicating pituitary dysfunction., Methods: Endocrine function was assessed by basal hormonal concentrations at 5 to 10 days and 3 to 6 months after SAH. Growth hormone deficiency also was evaluated by the growth hormone releasing hormone-arginine stimulation test at follow-up. Clinical outcome was assessed and scored according to the Glasgow Outcome Scale., Results: Fifty-one SAH patients were included and assessed in the acute stage after the bleed. Six were lost to follow-up. The overall prevalence of pituitary dysfunction was 37% and 27% in the acute stage and at follow-up, respectively. Patients with evidence of pituitary dysfunction had significantly worse outcome according to Glasgow Outcome Scale at both occasions. The ruptured aneurysm was more commonly located in the circle of Willis among patients with pituitary dysfunction in the acute stage., Conclusions: The present results support earlier findings that hormonal abnormalities are not infrequent after SAH. Furthermore, our data suggest that pituitary dysfunction is associated with worse clinical outcome and is more common among patients with bleeding sites close to the hypothalamus., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Many studies have focused on short term mortality after primary intracerebral haemorrhage (ICH) whereas long term prognosis and causes of death have been less studied. We therefore examined these issues in a population based cohort of 1 year ICH survivors., Methods: ICH patients in a defined Swedish population (1.14 million inhabitants) were prospectively registered during 1996. Patients surviving 1 year after ICH onset were followed-up regarding survival status and cause of death until December 2009 using data from the National Census Office and the National Cause of Death Register. Patient prognosis was also compared with the general population using official Swedish mortality data. Clinical and radiological prognostic factors were evaluated., Results: Of 323 patients with ICH, 172 (53%) survived after 1 year, 127 (39%) after 5 years and 57 (18%) after 13 years. Mortality of the 172, 1 year survivors (mean age 67.7 years at ICH) persistently exceeded expected mortality; 13 years post ictus survival was only 34% compared with 61% in the general population. Of 115 deaths among the 172, 1 year survivors, 36% were from cerebrovascular disease and 19% from ischaemic heart disease. Independent risk factors for death among 1 year survivors were age (HR 1.08 per year; 95% CI 1.06 to 1.10; p<0.001), diabetes mellitus at baseline (HR 2.10; 95% CI 1.18 to 3.74; p=0.012) and anticoagulant therapy (HR 1.99; 95% CI 1.12 to 3.53; p=0.018) at ICH onset., Conclusions: One year survivors after ICH had a substantial and persisting excess mortality compared with the general population. Major causes of death were stroke and ischaemic heart disease.

Background and Purpose: Male-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which is associated with lower blood flow. The present study investigates if cerebral arteries from men and women differ in cerebrovascular receptor upregulation., Experimental Approach: Freshly obtained human cerebral arteries were placed in organ culture, an established model for studying receptor upregulation. 5-hydroxtryptamine type 1B (5-HT1B), angiotensin II type 1 (AT1) and endothelin-1 type A and B (ETA and ETB) receptors were evaluated using wire myograph for contractile responses, real-time PCR for mRNA and immunohistochemistry for receptor expression., Key Results: Vascular sensitivity to angiotensin II and endothelin-1 was markedly lower in cultured cerebral arteries from women as compared to men. ETB receptor-mediated contraction occurred in male but not female arteries. Interestingly, there were similar upregulation in mRNA and expression of 5-HT1B, AT1, and ETB receptors and in local expression of Ang II after organ culture., Conclusions and Implications: In spite of receptor upregulation after organ culture in both sexes, cerebral arteries from women were significantly less responsive to vasoconstrictors angiotensin II and endothelin-1 as compared to arteries from men. This suggests receptor coupling and/or signal transduction mechanisms involved in cerebrovascular contractility may be suppressed in females. This is the first study to demonstrate sex differences in the vascular function of human brain arteries.

Background and Purpose: BBA is a rare type of intracranial aneurysm that is difficult to treat both surgically and endovascularly and is often associated with a high degree of morbidity/mortality. The aim of this study was to present clinical and angiographic results, as well as antiplatelet/anticoagulation regimens, of endovascular BBA treatment by using predominantly stent-assisted coil embolization., Materials and Methods: Thirteen patients (men/women, 6/7; mean age, 49.3 years) with ruptured BBAs were included from 2 different institutions. Angiographic findings, treatment strategies, anticoagulation/antiplatelet protocols, and clinical (mRS) and angiographic outcome were retrospectively analyzed., Results: Eleven BBAs were located in the supraclinoid ICA, and 2 on the basilar artery trunk. Nine of 13 were ≤3 mm in the largest diameter, and 8/13 showed early growth before treatment. Primary stent-assisted coiling was performed in 11/13 patients, double stents and PAO in 1 patient, each. Early complementary treatment was required in 3 patients, including PAO in 2. In stent-placement procedures, altered periprocedural antiplatelet (11/12) and postprocedural heparin (6/12) protocols were used without evidence of thromboembolic events. Two patients had early rehemorrhage, including 1 major fatal SAH. Twelve of 13 BBAs showed complete or progressive occlusion at late angiographic follow-up. Clinical midterm outcome was good (mRS scores, 0-2) in 12/13 patients., Conclusions: Stent-assisted coiling of ruptured BBAs is technically challenging but can be done with good midterm results. Reduced periprocedural and postprocedural antiplatelet/anticoagulation protocols may be used with a low reasonable risk of thromboembolic complications. However, regrowth/rerupture remains a problem underlining the importance of early angiographic follow-up and re-treatment, including PAO if necessary.

Object: The calcium antagonist nimodipine has been shown to reduce the incidence of ischemic complications following aneurysmal subarachnoid hemorrhage (SAH). Although most randomized studies have been focused on the effect of the peroral administration of nimodipine, intravenous infusion is an alternative and the preferred mode of treatment in many centers. It is unknown whether the route of administration is of any importance for the clinical efficacy of the drug., Methods: One hundred six patients with acute aneurysmal SAH were randomized to receive either peroral or intravenous nimodipine treatment. The patients were monitored for at least 10 days after bleeding in terms of delayed ischemic neurological deficits (DINDs) and with daily measurements of blood flow velocities in the middle cerebral arteries by using transcranial Doppler ultrasonography. Three months after SAH, clinical outcome and new cerebral infarctions according to MR imaging studies were recorded., Results: Baseline characteristics (age, sex distribution, clinical status on admission, radiological findings, and aneurysm treatment) did not differ between the treatment groups. There was no significant difference in the incidence of DINDs (28 vs 30% in the peroral and intravenous groups, respectively) or middle cerebral artery blood flow velocities (> 120 cm/second, 50 vs 45%, respectively). Clinical outcome according to the Glasgow Outcome Scale was the same in both groups, and there was no difference in the number of patients with new infarctions on MR imaging., Conclusions: The results suggest that there is no clinically relevant difference in efficacy between peroral and intravenous administration of nimodipine in preventing DINDs or cerebral vasospasm following SAH.

Introduction: The purpose of this prospective study was to compare 3T and 1.5T magnetic resonance angiography (MRA) with digital subtraction angiography (DSA) for the follow-up of endovascular treated intracranial aneurysms to assess the grade of occlusion., Materials and Methods: Thirty-seven patients with 41 aneurysms who had undergone endovascular treatment with detachable coils were included. MRA was performed on the same day using an eight-channel sensitivity encoding head-coil with 3D axial inflow technique. At 3T, a contrast-enhanced transverse 3D fast gradient echo acquisition was also performed. Most patients underwent DSA the following day. MRA scans and DSA were classified first independently by two neuroradiologists and an interventional neuroradiologist. Secondly, a consensus was done. Source images, maximum intensity projection, multiplanar reconstruction and volume rendering reconstructions were used for MRA evaluations. A modification of the Raymond classification, previously used for DSA evaluation of recanalization, was used., Results: Statistical comparison of the consensus showed that 3T MRA with 3D axial inflow technique had better agreement with DSA (kappa = 0.43) than 1.5T MRA(kappa = 0.21) and contrast-enhanced MRA (CE-MRA) at 3T (kappa = 0.17). The susceptibility artefacts from the coil mesh were significally smaller at 3T (p = 0.002-0.007) than at 1.5T., Conclusion: 3T MRA, using a sensitivity encoding head-coil, showed better agreement with DSA than 1.5T and CE-MRA at 3T for evaluation of aneurysms treated with endovascular coiling.

Objective: Opinions vary regarding the indications for surgical evacuation of spontaneous intracerebral hemorrhages (ICH) and whether or not penumbra zones surround them., Methods: We performed intracerebral microdialysis (mean duration, 3.5 d) after surgical evacuation of ICH in 22 patients. Probes were placed in the parenchyma within 1 to 2 cm of the evacuated hematoma; a postoperative computed tomographic scanning verified their positions. The catheters were perfused with an artificial cerebrospinal fluid solution at 0.3 microl/min. Biochemical variables (glucose, pyruvate, lactate, glutamate, and glycerol) were analyzed and displayed at the bedside. The levels obtained were compared with previous data from normal human brains and the pericontusional penumbra zones of patients with severe traumatic brain lesions., Results: During 1 to 12 hours after surgery, interstitial levels of glucose (median level, 1.3 mmol/L; interquartile range, 0.6-2.2 mmol/L) were within normal variations, whereas the levels of lactate (median level, 6.4 mmol/L; interquartile range, 3.9-9.0 mmol/L), glutamate (median level, 14 micromol/L; interquartile range, 5-370 micromol/L), and glycerol (median level, 190 micromol/L; interquartile range, 74-380 micromol/L), as well as the lactate/pyruvate ratio (median ratio, 35; interquartile range, 23-50) were increased. A gradual normalization of the lactate/pyruvate ratio and glycerol level was observed within 48 hours., Conclusion: The area close to an evacuated ICH exhibits a biochemical pattern similar to that of the biochemical penumbra zone surrounding focal traumatic brain contusions. The presence of a penumbra zone around large ICH may be of importance for making surgical decisions.

Background Context: Methylprednisolone has evolved during the 1990s, through the results obtained from the National Acute Spinal Cord Injury Studies NASCIS II and III, as a standard treatment in acute spinal injury., Purpose: To evaluate the scientific basic for the use of methylprednisolone in acute spinal cord injury., Study Design: Systematic review of the accumulated literature., Methods: Critical evaluation of the data obtained in the NASCIS II and III studies plus other accumulated literature., Results: Analyses have been made on subgroups of the study populations, and the results were based on statistical artefacts. Furthermore, improved functional recovery shown by these studies was not clinically significant., Conclusion: There is insufficient evidence to support the use of methylprednisolone as a standard treatment in acute spinal cord injury.

Objective: We report on the consequences of introducing coil embolization for the total management of and outcome in patients with subarachnoid hemorrhage (SAH)., Methods: In southern Sweden, a prospective analysis of all patients with SAH of verified aneurysmal origin was conducted during the 3 years when coiling was gradually being introduced. The incidence of acute or chronic hydrocephalus, vasospasm, delayed ischemic deterioration, and outcome at 3 to 6 months after bleeding was analyzed., Results: Coiling of aneurysms was used progressively more compared with clipping during the study period. The number of patients subjected to coiling was 26 (36%) of 73 patients during calendar year 1997, 43 (53%) of 81 patients in 1999, and 55 (74%) of 74 patients in 2001 (P < 0.0001). Gradually, more elderly patients were admitted during the study period. Virtually all aneurysms located in the posterior circulation were treated by coil embolization, even at the start of the study, whereas aneurysms at all other locations were progressively more likely to be treated similarly. The incidence of hydrocephalus in the acute (average for all 3 yr, 39%) or chronic (16%) phase, vasospasm as measured by Doppler sonography (33%), and delayed ischemic deterioration (29%), as well as outcome at 3 to 6 months (61% good recovery, 13% deceased), did not change significantly during the study. The main cause of unfavorable outcome was the severity of the SAH., Conclusion: The increasing use of coil embolization for ruptured aneurysms in the anterior circulation did not have any significant impact on the overall incidence of SAH-related complications or outcome. The main determinant for outcome after SAH is still the severity of the SAH.

Methylprednisolone (MP) has, through the results from the clinical multi-center studies National Acute Spinal Cord Injury Study II and III, during the 1990's become standard treatment in acute spinal cord injury (ASCI). Critical reappraisals of the data have later shown that analyses have been made on subgroups of the study-populations and argue that the results are based on statistical artefacts. This, combined with the failure to show improved functional recovery, puts into question earlier conclusions drawn on the efficacy of MP on ASCI. This review of the recent literature on the subject concludes that there is no scientific evidence to support MP as standard treatment in ASCI.

Object: Predictors of early (30-day) and long-term (1-year) mortality rates after primary intracerebral hemorrhage (ICH) were studied in a large population in southern Sweden., Methods: All cases of primary ICH, verified using computerized tomography (CT) scanning or autopsy study, were prospectively registered at the 12 hospitals covering a defined population of 1.14 million during the calendar year 1996. Mortality was analyzed in relation to CT findings (hematoma location and volume and ventricular extension) and clinical parameters (patient age and sex, level of consciousness on admission, and history of preictal risk factors) by using univariate and multivariate statistical methods. Three hundred forty-one cases of primary ICH were detected. The overall mortality rate was 36% at the 30-day and 47% at the 1-year follow up. Multivariate analysis revealed that initial level of consciousness, hematoma volume, and a history of heart disease were independent predictors of death at 30 days postictus. One year after bleeding, independent predictors of mortality were the initial level of consciousness, patient age, and hematoma location., Conclusions: Primary ICH remains a stroke subtype associated with a high mortality rate and for which the level of consciousness on admission is the strongest predictor of fatal outcome both at 30 days and during the 1st year after bleeding. A preictal history of heart disease increased the 30-day mortality rate.

Objectives: Spontaneous intracranial haemorrhage-that is, mainly subarachnoid haemorrhage (SAH) and primary intracerebral haemorrhage (PICH)-constitutes an important part of all strokes. As previous epidemiological studies have demonstrated highly variable incidence rates, we conducted a large prospective investigation of all haemorrhagic strokes during a 1 year period., Methods: Twelve hospitals serving a defined population of 1.14 million in southern Sweden registered all cases with spontaneous intracranial haemorrhage, including those found dead outside hospitals, during 1996. All patients were examined with CT of the brain or underwent necropsy. Incidence rates adjusted to the Swedish population for age and sex, as well as location of haematoma and prevalence of risk factors were calculated., Results: A total of 106 patients with SAH and 341 patients with PICH were identified. The annual incidence/100 000 was 10.0 (6.4 for men and 13.5 for women) for SAH and 28.4 (32.2 for men and 24.7 for women) for PICH when adjusted to the Swedish population. Subarachnoid haemorrhage affected twice as many women as men. The incidence of both types of haemorrhage increased with advancing age, but in particular, this was the case for supratentorial PICH. Lobar haematomas were the most common (51.6%) type of PICH. Among patients with PICH, 37% had hypertension, 41% other vascular disease, and 12% were on oral anticoagulation. Among patients with SAH, 28% had hypertension and 18% vascular disease before the haemorrhage but no one was on treatment with oral anticoagulation., Conclusions: The incidence of PICH was high, especially for the older age groups. PICH was, on average, three times as common as SAH. The study underscores the importance of PICH and SAH as significant stroke subgroups.

Objective: Intracerebral microdialysis has been demonstrated to be a useful method for detection of brain ischemia in experimental models and in patients. We have applied new mobile microdialysate analysis equipment that allows a bedside comparison of changes in neurochemistry with the neurological status of the patient. Ten patients with severe aneurysmal subarachnoid hemorrhage (that is, with a high risk of vasospasm and a high risk of subsequent ischemic deficits) were selected., Methods: Microdialysis catheters were inserted into the temporal and subfrontal cortex at the end of aneurysm surgery. Samples, collected hourly for 4 to 11 days, were analyzed immediately at the bedside for glucose, lactate, and glycerol and later for pyruvate and glutamate. The patients' neurological status was monitored constantly, and daily recordings of blood flow velocities were performed using transcranial Doppler sonography., Results: Concentrations of the measured substances varied widely. Individual analyses revealed that patients with uneventful clinical courses generally demonstrated low and stable levels of the different metabolites, and those with signs of cerebral ischemia demonstrated various patterns of neurochemical changes. Lactate and glutamate seemed to be sensitive markers of impending ischemia, and increased glycerol levels were associated with severe ischemic deficits. Obtaining the microdialysis data directly at the bedside seemed to be of great advantage when relating the values to other clinical findings., Conclusion: Bedside intracerebral microdialysis monitoring of patients with subarachnoid hemorrhage and signs of delayed ischemia revealed dramatic changes in extracellular concentrations of glucose, lactate, and glycerol that could be directly correlated to the clinical status of the patients. These findings emphasize the potential of microdialysis in neurosurgical intensive care patients.

Reconstruction of the septohippocampal pathways by axons extending from embryonic cholinergic neuroblasts grafted into the neuron-depleted septum has been explored in the neonatal rat by using a novel lesioning and grafting protocol. Neonatal ablation of the basal forebrain cholinergic projection neurons, accompanied by extensive bilateral cholinergic denervation of the hippocampus and neocortex, was produced at postnatal day (PD) 4 by 192 immunoglobulin (IgG)-saporin intraventricularly. Four days later, cholinergic neuroblasts (from embryonic day 14 rats) were implanted bilaterally into the neuron-depleted septum by using a microtransplantation approach. The results show that homotopically implanted septal neurons survive and integrate well into the developing septal area, extending axons caudally along the myelinated fimbria-fornix and supracallosal pathways that are able to reach the appropriate targets in the denervated hippocampus and cingulate cortex as early as 4 weeks postgrafting. Moreover, the laminar innervation patterns established by the graft-derived axons closely resembled the normal ones and remained essentially unchanged up to at least 6 months, which was the longest postoperative time studied. The reinnervating fibers restored tissue choline acetyltransferase activity (up to 50% of normal) in the dorsal hippocampus and the parietooccipital cortex. Retrograde labeling with Fluoro-Gold from the host hippocampus combined with immunocytochemistry confirmed that most of the projecting neurons, indeed, were cholinergic. The results suggest that the graft-host interactions that are necessary for target-directed axon growth are present in the septohippocampal system during early postnatal maturation. Thus, the present approach may contribute to overcome the functional limitations inherent in the use of ectopically placed intrahippocampal transplants.

Selective removal of the basal forebrain cholinergic neurons by the immunotoxin 192 immunoglobulin G-saporin has offered a new powerful tool for the study of the relationships between cholinergic dysfunction and cognitive impairments. In the present study the morphological and functional consequences of selective lesions of the basal forebrain cholinergic system during early postnatal development have been investigated following bilateral intraventricular injections of 192 immunoglobulin G-saporin to immature (four-day-old) rats. Administration of increasing doses (0.2-0.8 microgram) of the immunotoxin produced dose-dependent loss of cholinergic neurons in the septal/diagonal band area (up to 72-86%) and in the nucleus basalis magnocellularis (up to 91-93%), paralleled by marked reductions in choline acetyltransferase activity in the hippocampus and several cortical regions (73-84%). The parvalbumin-positive neurons in the septal/diagonal band area and the calbindin-positive Purkinje cells in the cerebellum were unaffected at all dose levels. Brain dopamine or noradrenaline levels were unaffected or increased by the immunotoxin treatment. At the optimal dose, 0.4 microgram, the toxin conjugate produced maximal cholinergic depletion without significant mortality. Higher doses (0.8, 1.2 and 1.6 micrograms) of toxin, on the other hand, proved to be lethal for most or all of the injected animals. When tested at three and eight months after the optimal dose, in spite of persisting cholinergic depletion, the noenatally lesioned animals showed no impairment in the water maze task or in locomotor activity and exploration as compared to normal controls, probably reflecting partial sparing of the cholinergic neurons by the neonatal immunotoxic lesion (above all in the vertical and horizontal limbs of the diagonal band area), and/or a greater degree of plasticity in the developing as compared to the mature cholinergic system. The place navigational performance of the neonatally lesioned animals in the water maze task was abolished by central muscarinic cholinergic receptor blockade (by atropine) or by a second immunotoxic lesion, which eliminated virtually all residual cholinergic neurons in the septal/diagonal band area and the nucleus basalis. Administration of 192 immunoglobulin G-saporin to similarly trained, but previously normal adult rats, produced similar cholinergic depletions but much less severe place navigation deficits, suggesting that preoperative training on the task may reduce the functional consequences of a subsequent cholinergic lesion. The results thus support the view that the basal forebrain cholinergic system may be implicated in the acquisition rather than retention of spatial memory in the water maze task.

Selective depletion of nerve growth factor receptor-bearing neurons in the basal forebrain cholinergic system nuclei by the immunotoxin 192 IgG-saporin offers a new and highly useful tool for the study of the role of the forebrain cholinergic system in cognitive functions. In the present study, we have tested the effects of 192 IpG-saporin in an operant delayed matching-to-position task which has previously been used to discriminate between delay-dependent learning impairments and delay-independent disturbances of non-mnemonic processes. Rats were first trained to criterion performance and then received intraventricular injections of 5 microg of 192 IgG-saporin 4 weeks prior to a second testing session. Rats with 192 IgG-saporin lesions displayed a significant delay-dependent decline in performance compared to normal controls, indicating a deficit in short-term memory. Administration of the muscarinic blocker scopolamine (0.5 mg/kg, i.p.) produced more pronounced impairment in the performance of the normal control rats across all delays, and induced further impairment also in animals with 192 IgG-saporin lesions. These effects were not observed following control injections of methyl scopolamine, suggesting that the impairment induced by scopolamine was due to the blockade of central muscarinic receptors. No improvement in performance was observed in either group following systemic treatment with the muscarinic cholinergic agonist arecoline (1.00 mg/kg). Biochemical and morphological analyses confirmed the selective and severe (>90-95%) depletion of cholinergic neurons throughout the septal-diagonal band area and the nucleus basalis region by the intraventricular 192 IgG-saporin treatment. Although the immunotoxin was observed to produce additional damage to the cerebellar Purkinje cells, no gross motor abnormalities were observed that could contribute to the effects on accuracy in the task used here. In conclusion, the results show that selective combined lesions of the basal forebrain cholinergic neurons in the septal-diagonal band area and nucleus basalis produce long-lasting impairments in short-term memory, thus providing further support for a role of this system in cognitive functions.

Cerebral ischemia associated with subarachnoid hemorrhage may have severe consequences for neuronal functioning. The excitatory amino acid neurotransmitters glutamate and aspartate have been shown to be of particular importance for ischemia and ischemic neuronal damage. For seven patients who underwent early surgery for ruptured intracranial aneurysms, intracerebral microdialysis of glutamate and aspartate was performed to monitor local metabolic changes in the medial temporal (all seven patients) and subfrontal cortex (Patients 4 through 7). Samples were collected every 30 or 60 minutes, using an autosampler. The results show that extracellular glutamate and aspartate concentrations can rise to very high levels after surgery for subarachnoid hemorrhage and aneurysm. These increased levels of excitatory amino acids correlated well with the clinical course and neurological symptoms of the patients. Simultaneous sampling from two vascular territories (middle cerebral artery and anterior cerebral artery) also showed that a rise in extracellular glutamate and aspartate in one territory is not necessarily parallel with a rise in the other. The application of the microdialysis technique with an on-line assay system might be of value in the future for continuous monitoring of ischemic events to optimize treatment with, for example, blockers of glutamatergic neurotransmission.

Cerebral ischemia associated with subarachnoid haemorrhage (SAH) may have severe consequences for neuronal function leading to reversible or permanent neurological deficits. The excitatory amino acid neurotransmitters, such as glutamate, have been shown to be of particular importance for ischemic neuronal damage. In seven patients who underwent early surgery for a ruptured intracranial aneurysm, microdialysis of glutamate was performed in order to monitor local metabolic changes in the medial temporal tall patients) and subfrontal cortex (four patients). The preliminary results indicate that: (i) extracellular glutamate concentrations may rise to very high levels after SAH and aneurysm surgery, (ii) the increased levels of excitatory amino acids correlate with the clinical course, and (iii) a rise in extracellular glutamate in one region is not necessarily paralleled with a rise in the other, as seen by the simultaneous sampling from two different vascular territories.

The elucidation of the functional role of the basal forebrain cholinergic system will require access to a highly specific and efficient cholinergic neurotoxin. Recently, selective depletion of the nerve growth factor (NGF) receptor-bearing cholinergic neurons in the rat basal forebrain and a dramatic loss of cholinergic innervation in the related cortical regions have been obtained following intraventricular injection of a newly introduced immunotoxin, 192 IgG-saporin. Here we extend these initial findings and report that administration of increasing doses (1.25, 2.5, 5.0 or 10 micrograms) of the 192 IgG-saporin conjugate into the lateral ventricles of adult rats induced dose-dependent impairments in the water maze task and passive avoidance retention, but only weak and inconsistent effects on locomotor activity. These behavioural changes were paralleled by a reduction in choline acetyltransferase activity in hippocampus and several cortical areas (up to 97%) and selective depletions of NGF receptor-positive cholinergic neurons in the septal-diagonal band area and nucleus basalis magnocellularis (up to 99%). By contrast, the non-cholinergic parvalbumin-containing neurons in the septum were completely spared, and other cholinergic projection systems (such as in the striatum, thalamus, brainstem and spinal cord) were unaffected even at the highest dose. The observed changes in the water maze and passive avoidance tasks, as well as the cholinergic cell loss, were maintained up to at least 8 months following the intraventricular injection of a single dose (5 micrograms) of the immunotoxin. The results confirm the usefulness of the 192 IgG-saporin toxin for selective and profound lesions of the basal forebrain cholinergic neurons and provide further support for a role of the basal forebrain cholinergic system in cognitive functions.

Solid pieces of fetal locus coeruleus (LC) or superior cervical ganglion (SCG) were placed into a fimbria-fornix lesion cavity in 6-hydroxydopamine-treated, noradrenaline (NA)-denervated rats. Six to 8 months later, all animals were subjected to electrical kindling stimulations in the hippocampus until they had reached the fully kindled state. Nongrafted lesioned animals showed markedly increased kindling rate which was partly attenuated by LC but not SCG grafts. In both LC- and SCG-grafted animals, dopamine beta-hydroxylase immunocytochemistry demonstrated a high density of graft-derived noradrenergic fibers in the dorsal hippocampus, whereas reinnervation of the ventral hippocampus was much more sparse. Subregional distribution of these fibers within the hippocampus was different in the two grafted groups. Both grafts partly restored basal extracellular NA levels in the hippocampus and reacted to generalized seizures by a significant (two- to threefold) increase of NA release, as measured by intracerebral microdialysis. Our data indicate (i) that seizure activity can regulate transmitter release from noradrenergic neurons in both LC and SCG grafts, (ii) that only fetal LC grafts retard seizure development in kindling, and (iii) that the inability of SCG implants to influence kindling epileptogenesis could be due to a lack of synaptic contacts between the graft-derived ganglionic fibers and host hippocampal neurons.

The effect of amphetamine on striatal acetylcholine (ACh) release was studied by an in vivo intrastriatal microdialysis technique. Although we expected systemic amphetamine to inhibit baseline striatal ACh release, the opposite was found. In addition, we found that the amphetamine-induced striatal ACh release did not depend on nigrostriatal DA since 6-hydroxydopamine (6-OHDA) lesions had no effect on amphetamine-induced ACh release. Local intrastriatal injection of amphetamine via the microdialysis probe had no effect on striatal ACh release even when the probe was located more laterally in striatum to take advantage of the medial to lateral gradient of striatal ACh and D2 receptors. The hypothesis that amphetamine increased extracellular striatal ACh by increasing the release of biogenic amines besides dopamine was tested by pharmacological manipulations designed to specifically increase local striatal norepinephrine or serotonin levels. The serotonergic and noradrenergic manipulations had no effect on striatal ACh levels. These results indicate that amphetamine-induced release of ACh in striatum is mediated via distal brain regions that are functionally connected with the striatum.

The regulation of acetylcholine (ACh) release from cholinergic neurons transplanted to the hippocampus or neocortex was studied by microdialysis in awake rats. Fetal basal forebrain tissue was implanted as a cell suspension or solid graft into the fimbria-fornix-lesioned hippocampus, or as a cell suspension into the frontal cortex after excitotoxic lesion of the nucleus basalis. Several months after transplantation, microdialysis probes were implanted in areas of the hippocampus or frontal cortex reinnervated by the grafts. The grafts restored lesion-induced deficits in steady-state ACh release up to normal or above normal levels in both hippocampus and frontal cortex. The responses to KCl and tetrodotoxin suggested that the ACh release exhibited normal firing-dependent properties. By applying various behaviorally arousing stimuli that normally activate the basal forebrain projection systems, we wished to investigate the functional integration of the grafts in the host brain. In the hippocampus, sensory stimulation, immobilization stress and motor activity all resulted in increased release of graft-derived ACh amounting to 25-65% of the normal response. Variations in ACh levels during the day-night cycle was, however, not observed in the grafted rats. In the frontal cortex, immobilization enhanced the graft-derived ACh release (60% of normal response), whereas the response to sensory stimulation did not reach significance. Since the activity of the normal basal forebrain projection systems is under influence of monoaminergic brainstem afferents, we investigated the effects of systemic administration of amphetamine or apomorphine on ACh release in the hippocampus. Both drugs produced increases in graft-derived ACh release although the response was variable and less pronounced than normal. In conclusion, the graft-derived ACh release was affected by behavioral manipulations and catecholaminergic drugs that normally modify cholinergic septo-hippocampal and basalo-cortical activity. This strongly suggests a high degree of functional integration of the graft in the host brain allowing for a regulated release of transmitter that can be adjusted during ongoing behavior.

The effects of central cholinergic blockade on spatial memory were tested in aged and basal forebrain-lesioned rats using the Morris Water Maze. In Experiment 1, aged rats (18-21 months old) were characterized as behaviorally impaired or nonimpaired based on water maze performance prior to an atropine sulfate challenge. In the atropine test (50 mg/kg, IP), both the impaired and the nonimpaired rats showed a severe disruption of their search behavior compared to young subjects. This effect was due to blockade of central receptors since peripheral cholinergic blockade using atropine methylbromide did not produce any impairments. Experiment 2 investigated effects of atropine on rats with septal lesions (SL), nucleus basalis lesions (NBL), and rats with both lesions combined (SL + NBL). Before drug treatment, the groups with septal lesions (SL and SL + NBL groups) displayed a moderate impairment in locating the platform site. However, similar to the aged rats, the septal-lesioned rats exhibited severe impairments in the water maze during atropine treatment. This effect was not seen in the normal controls or in the NBL rats. Aged rats, either impaired or nonimpaired in a spatial memory task, showed a pronounced sensitivity to pharmacological blockade of central cholinergic neurotransmission which resulted in severe deficits in spatial navigation in the water maze. Since the same behavioral deficit was produced by cholinergic blockade in young rats with septal lesions, we concluded that the impaired water maze performance seen in the aged rats during cholinergic blockade resulted from impaired function in the septohippocampal system.

Previous microdialysis experiments have shown that acetylcholine (ACh) release from septal grafts in the hippocampus of awake rats is influenced by the behaviour of the animals, which strongly suggests that the host brain can exert a regulatory control over the activity of the grafted neurons. Since the activity of the normal septo-hippocampal cholinergic system is likely to be regulated, in part, by brainstem catecholaminergic afferents, we wished to study the effect of catecholaminergic drugs on ACh release in the hippocampus reinnervated by septal grafts. Rats were subjected to a unilateral aspirative fimbria-fornix (FF) transection and grafted with tissue from the fetal septal-diagonal band area, either as a cell suspension injection into the depth of the hippocampus or as a solid implant in the FF lesion cavity. Microdialysis of ACh release was carried out 17-20 months after transplantation in awake, freely-moving animals. The reduction in steady-state ACh overflow induced by the FF lesion (-81%) was restored to normal or above normal levels in rats with either solid or suspension grafts. In normal rats, systemic administration of apomorphine (2.0 mg/kg, s.c.) or amphetamine (2.5 mg/kg, i.p.) caused a 3.7 (+189%) or 7.8 (+301%) pmol/15 min increase in ACh overflow compared to the previous baseline level, respectively. The drug-induced increases in ACh levels in the FF-lesioned controls was substantially lower than normal (86-89% reduction). Both apomorphine and amphetamine resulted in an approximately two-fold increase in hippocampal ACh release in rats with suspension grafts. These responses were significantly increased over those seen in rats with FF lesions only, but they tended to be lower and more variable than normal. Rats with solid septal grafts responded significantly stronger than FF lesion controls to amphetamine with two-fold increased ACh overflow, whereas the response to apomorphine was less clear-cut. Pretreatment with the catecholamine synthesis blocker alpha-methyl-p-tyrosine (AMPT; 200 mg/kg x 3) did not affect steady-state or apomorphine-stimulated release of ACh in any of the groups, whereas the effect of amphetamine was abolished in both normal and grafted rats. The results suggest that ACh release derived from septal grafts in the hippocampus, similar to the normal septo-hippocampal system, can be affected by manipulations of the host catecholaminergic systems. This mechanism may, at least in part, underlie the ability of the host brain to influence and control the activity of grafted cholinergic neurons.

Acetylcholine release in the frontal cortex of awake rats after acute or chronic lesions of the nucleus basalis magnocellularis and grafting of cholinergic-rich basal forebrain tissue was studied by in vivo microdialysis. Three to four weeks and five months after a unilateral quisqualic acid lesion of the nucleus basalis, and five months after lesion and cortical implantation of a basal forebrain cell suspension, acetylcholine release was characterized during a range of pharmacological and behavioural manipulations. Neostigmine (5 microM) was added to the perfusion fluid in order to inhibit the degradation of acetylcholine. The extracellular levels of acetylcholine in normal animals increased three- to four-fold when KCl (100 mM) was added to the perfusion medium and was reduced by 80% after addition of tetrodotoxin (1 microM). The nucleus basalis lesion resulted in a 60% reduction in baseline acetylcholine levels compared to normal and the response to KCl-evoked depolarization was significantly reduced. There were no differences between the acute and chronic lesion groups during any of the manipulations performed. Rats with grafts showed baseline levels of acetylcholine about 70% higher than normal, and responded to both KCl (two-fold increased acetylcholine release) and tetrodotoxin (85% reduced levels). All groups showed lower acetylcholine levels during halothane anaesthesia (on average 70-85% reduction). Sensory stimulation by handling resulted in a two-fold increase in acetylcholine release in normal animals, whereas the absolute responses in the lesioned controls were significantly weaker. Rats with grafts increased their acetylcholine release after handling to an extent not different to normal or lesioned controls. Immobilization stress induced an almost two-fold increase in cortical acetylcholine levels in normal rats, whereas the effect in the lesion-only groups was very weak. The grafts responded to the immobilization with an enhanced acetylcholine overflow that was significantly higher than in lesioned controls. The results showed that the reduction in frontocortical acetylcholine release induced by excitotoxic lesions of the nucleus basalis did not recover spontaneously over several months. Intracortical cholinergic-rich grafts obtained from the fetal basal forebrain provided a source of acetylcholine release with firing-dependent properties which could be modulated by behaviourally stressful stimuli. The ability of the grafts to respond to behavioural manipulation strongly suggests that the host brain can functionally influence graft neuronal activity during ongoing behaviour. Host control of graft activity may play a role in the recovery of the lesion-induced deficits seen with these types of grafts.

Solid grafts of autologous superior cervical ganglia (SCG) or fetal locus coeruleus (LC) were implanted unilaterally into a fimbria-fornix lesion cavity adjacent to the hippocampal formation after a 6-hydroxydopamine lesion of the intrinsic noradrenergic system. Twelve to 15 months after transplantation, one microdialysis probe was implanted in the dorsal hippocampus ipsilateral to the graft, and extracellular levels of noradrenaline (NA) were monitored during the application of pharmacological or behavioral stimuli. Age-matched intact and lesion-only animals served as controls. Morphological examination of the grafts was performed on sections processed for dopamine-beta-hydroxylase (DBH) immunohistochemistry. In the lesion-only controls, the hippocampus was totally devoid of DBH-immunoreactive fibers and hippocampal levels of NA were generally undetectable. Although both SCG and LC grafts gave rise to an extensive DBH-immunoreactive fiber ingrowth in the ipsilateral hippocampus, baseline NA release was strikingly different in the two graft groups, being markedly lower than normal in the SCG-grafted rats (3.5 +/- 0.1 fmol/30 microliters) and significantly higher than normal in the LC-grafted rats (44.5 +/- 12.3 fmol/30 microliters). The response to potassium-induced depolarization (100 mM KCl in the perfusion fluid), neuronal uptake blockade (5 microM desipramine), and sodium-channel blockade (1 microM TTX) was similar to normal in both graft groups. Exposure of the animals to mild (handling) or severe (immobilization) stressful stimuli significantly enhanced NA release in the intact controls, whereas no clear-cut effect could be detected in either graft group. Electrical stimulation of the medial septum, applied in an attempt to activate possible afferents to the grafts from the host septum, did not enhance NA release in any of the groups. The results show that grafts of both central and peripheral noradrenergic neurons can provide a source of steady-state NA release in the denervated hippocampus, but that the spontaneous activity of the grafted ganglionic neurons is very low compared to that of the LC neurons, probably due to the absence of a functional preganglionic input to the grafted SCG neurons. Although extracellular NA recovered from both the SCG- and the LC-grafted hippocampi is likely to derive from impulse-dependent neuronal release, it was largely unaffected by physiological stimuli applied to the host.

Lesions of the fimbria-fornix pathways are known to induce a partial cholinergic and noradrenergic denervation of the hippocampal formation, which is followed by a slow and protracted collateral sprouting by the spared afferents. Using the intracerebral microdialysis technique, compensatory changes in extracellular levels of acetylcholine (ACh) and noradrenaline (NA) have been monitored over time in the partially denervated hippocampus of awake unrestrained rats subjected to an unilateral fimbria-fornix (FF) transection. One week after the lesion, baseline ACh output was reduced by 90% and 80% in the dorsal and ventral hippocampus, respectively, and it remained depressed still by 6 months after lesion. KCl-evoked and atropine-stimulated ACh efflux were equally reduced by 1 week after lesion, remained depressed at 3 months, but showed a significant recovery by 6 months post-lesion. Tissue choline acetyltransferase (ChAT) activity levels, initially reduced by 92% and 86%, in the dorsal and ventral hippocampus, respectively, recovered significantly by 3 months and remained unchanged at 6 months. Baseline NA output was significantly reduced (-80%) in the dorsal hippocampus by 1 week after the lesion and showed a partial recovery over time (to 50% of normal), whereas the ventral part was not significantly affected by the FF lesion. The significant FF lesion-induced reduction in KCl- or desipramine (DMI)-stimulated NA release observed in the dorsal hippocampus at 1 week after the lesion remained unchanged during the subsequent months. By contrast, in the ventral hippocampus, the initial 65-70% reduction in KCl- and DMI-stimulated NA release significantly recovered to normal levels within 3 months post-lesion. The NA tissue levels were significantly reduced by 4 weeks after lesion, in the dorsal hippocampus and did not show any significant recovery over time. In the ventral hippocampus, these levels were significantly reduced only at 4 weeks. Transmitter turnover, expressed as the ratio between dialysate levels and tissue ChAT or NA content, showed a 3-fold increase in the dorsal hippocampus at 4 weeks after lesion, but not at later time points. This indicates that the spared noradrenergic and cholinergic afferents respond to the partial denervation by a transient increase in transmitter turnover, evident as early as 4 weeks post-lesion in the region of maximal denervation. This was followed by a long-term increase in evoked transmitter release which may result from a slowly progressing compensatory sprouting of the spared afferents.

Levels of messenger RNA for nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and the tyrosine kinase receptors trkA, trkB and trkC have been studied using in situ hybridization in the rat brain 2 h and four weeks after kindling-induced seizures. Epileptiform activity evoked by hippocampal stimulation and exceeding 70 s lead to a concomitant and transient increase of brain- derived neurotrophic factor, nerve growth factor, trkB and trkC messenger RNA expression in dentate granule cells after both focal and generalized seizures. Brain-derived neurotrophic factor messenger RNA levels were also increased bilaterally in the CA1-CA3 regions, amygdala and the piriform, entorhinal, perirhinal, retrosplenial and temporal cortices after generalized seizures. The magnitude of the increases was similar throughout the development of kindling and in the fully kindled brain. No changes of trkA messenger RNA were observed. In amygdalar kindling, elevated brain-derived neurotrophic factor messenger RNA levels developed more rapidly in the amygdala-piriform cortex than after stimulation in the hippocampus but changes in the hippocampal formation were only seen in few animals. Intraventricular 6-hydroxydopamine or a bilateral fimbria-fornix lesion did not alter basal expression or seizure-evoked changes in messenger RNA levels for neurotrophins or trk receptors but increased the number of animals exhibiting elevated levels after the first stimulation, probably due to a prolongation of seizure activity. Both in sham-operated and fimbria-fornix-lesioned rats seizure activity caused a marked reduction of neurotrophin-3 messenger RNA levels in dentate granule cells. The results indicate that activation of the brain-derived neurotrophic factor gene, at least in dentate granule cells, is an "all-or-none" type of response and dependent on the duration but not the severity of seizures or the stage of kindling epileptogenesis. Changes in brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 and trkB and trkC were observed concomitantly in the dentate gyrus, which suggests that seizure activity sets in motion a cascade of genomic events possibly mediated via a common mechanism. Since altered messenger RNA levels outside hippocampus were detected only for brain-derived neurotrophic factor, neurotrophin and trk gene expression in these regions seems to be regulated differently.

A monoclonal antibody to the low-affinity NGF receptor, 192 IgG, coupled to a cytotoxin, saporin, was recently introduced as an efficient selective neurotoxin for the NGFr-bearing cholinergic neurones in the rat basal forebrain. In the present study we report that an intracerebroventricular injection of this 192 IgG-saporin conjugate induces a severe, long-lasting spatial learning impairment, as assessed in the Morris water-maze task. This behavioural impairment was associated with 65-90% depletion of choline acetyltransferase activity (ChAT) in the hippocampus and cortex. ChAT activity associated with other cholinergic neurone systems in the brain (striatum, mesencephalon, spinal cord), was left virtually unaffected. This new immunotoxin holds great promise as a tool for selective and efficient lesions of the forebrain cholinergic system in functional and behavioural studies.

The role of monoamines in the functional regulation of the septo-hippocampal cholinergic system was studied using in vivo microdialysis of acetylcholine (ACh) release in the hippocampus of awake unrestrained rats. Systemic administration of the dopamine receptor agonist apomorphine (2.0 mg/kg) resulted in a 170% increase in hippocampal ACh overflow. Similarly the catecholamine-releasing agent amphetamine (2.5 mg/kg) produced a 400% increase in ACh overflow. The effect induced by amphetamine, but not that of apomorphine, was blocked in animals pretreated with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). The effect of amphetamine on ACh release was reduced by 75% after a 6-hydroxydopamine (6-OHDA) lesion of the ventral tegmental area (VTA) but was not affected by 6-OHDA lesions of the noradrenergic dorsal and ventral bundles. However, baseline ACh overflow was increased by 130% by the dorsal and ventral bundle lesions. The serotonin-releasing agent p-chloroamphetamine (2.5 mg/kg) produced a 160% increase in hippocampal ACh release, and this effect was enhanced after a 5,7-dihydroxytryptamine (5,7-DHT) lesion of the serotonin projection system. The results show that surgical or pharmacological manipulations of the ascending brainstem monoaminergic systems, which innervate wide areas of the forebrain, including the septum and the hippocampal formation, have pronounced effects on septo-hippocampal cholinergic activity. Thus, the present data provide support for the view that information regarding behavioral state and arousal is conveyed to the septo-hippocampal system via ascending monoaminergic systems.

Grafted neurons obtained from the fetal basal forebrain can provide a functional cholinergic reinnervation of the hippocampal formation in rats with a lesion of the intrinsic septal cholinergic afferents. In the present experiments graft-derived acetylcholine release in the hippocampus was studied by microdialysis in awake rats during different types of behaviours which are known to activate the innate septohippocampal cholinergic system and during different activity periods of the day-night cycle. Two types of basal forebrain grafts were studied: cell suspensions implanted into the hippocampus in rats with an aspirative lesion of the fimbria-fornix, and grafts of solid tissue implanted as a tissue bridge into the fimbria-fornix lesion cavity. Increased acetylcholine overflow was seen in both groups with grafts during sensory stimulation (by handling). The strongest response (50% increase in acetylcholine release) was seen in rats with solid basal forebrain grafts (equivalent to two-thirds of that seen in intact rats). Immobilization stress and motor activity (swimming) also resulted in increased, but more variable, acetylcholine release (+ 30%; about one-third of the normal response). None of these effects was seen in the control rats with fimbria-fornix lesion only. The two-fold difference in hippocampal acetylcholine release in normal animals between day and night was absent in both types of grafted rats. An acute knife-cut, transecting the connections between the solid basal forebrain graft and the host hippocampus, caused an immediate 75% reduction in acetylcholine release (similar to the effect of an acute fimbria-fornix transection in the normal rats) and the response to swimming was no longer evident. The results show that grafted cholinergic neurons can be functionally integrated into the host brain, allowing the grafted neurons to be activated in the correct behavioural contexts, although the changes in acetylcholine overflow were overall smaller and more variable than normal. The ability of the host to influence cholinergic graft activity, most probably mediated via activation of afferent host-graft connections, may contribute to the efficacy of basal forebrain grafts in the amelioration of behavioural impairments in animals with lesions of the forebrain cholinergic system.

Acetylcholine (ACh) release was studied in awake, freely moving animals using in vivo microdialysis in the hippocampus of young (3-month-old) and aged (24-month-old) female Sprague-Dawley rats. Two groups of aged rats were selected on basis of their spatial learning performance in the Morris water maze: non-impaired aged rats which performed as well as the young control animals, and impaired aged rats which learnt the task very poorly. Baseline ACh overflow (in the presence of 5 microM neostigmine) was 1.9 +/- 0.3 +/- pmol/15 min in the young animals and 1.6 +/- 0.4 pmol/15 min in both the impaired and the non-impaired aged rats; these levels did not differ from each other. Depolarization by KCl (100 mM) or muscarinic receptor blockade by atropine (3 microM) added to the perfusion fluid produced dramatic, 4-6-fold, increases in ACh overflow that was similar in magnitude in both the young and the aged impaired and non-impaired rats. Behavioral activation by either handling or electrical stimulation of the lateral habenula produced 2-3-fold increases in extracellular ACh-levels in the hippocampus similarly in all three groups. The results indicate that hippocampal ACh release is maintained in aged rats that exhibit severe spatial learning and memory impairments and that the septo-hippocampal cholinergic system retains its capacity to increase its ACh release in response to both K(+)-induced depolarization and behavioral activation in the aged rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Grafts of Embryonic Day 14-15 basal forebrain tissue (medial septal/diagonal band nuclei) were transplanted into an aspirative fimbria-fornix cavity or the hippocampus of young adult rats. After extended periods of survival (1 and 2 years) the grafts were examined with immunocytochemical probes to identify specific types of neurons and assess the (spatial) distribution of the phosphorylated heavy neurofilament protein. Subpopulations of the long-term transplanted neurons expressed immunoreactivity to choline acetyl-transferase (CAT) and the low-affinity nerve growth factor receptor (192-IgG). Axons from the grafted neurons, visualized with the monoclonal antibody RT97 to the Mr 200,000 phosphorylated neurofilament unit, were observed to extend over the surfaces of the brain and connect with the host hippocampus. In subgroups of neurons without apparent axonal connections to the hippocampus, a change from axonal to cell body RT97 immunoreactivity was evident. A population of these neurons with abnormal neurofilament immunostaining in the soma was simultaneously identified as cholinergic with the CAT antibody. These studies indicate that abnormal changes can develop in the cytoskeleton of neurons in long-term intracerebral septal transplants. Although the reasons for this type of neurofilament modification in the grafted neurons are unknown, inappropriate terminal connections may be an important factor in the expression of this cytoskeletal change.