Reduced Hypoxic Tissue and Cognitive Improvement after Revascularization Surgery for Chronic Cerebral Ischemia.

BACKGROUND: Hypoxic but viable neural tissue is seen on 1-(2-18F-fluoro-1-[hydroxymethyl]ethoxy) methyl-2-nitroimidazole (18F-FRP170) positron emission tomography (PET) in patients with chronic cerebral ischemia with a combination of misery perfusion and moderately reduced oxygen metabolism. Cognitive function sometimes improves after revascularization surgery in patients with chronic cerebral ischemia. OBJECTIVES: We used brain perfusion single-photon emission computed tomography (SPECT) and 18F-FRP170 PET to determine whether hypoxic tissue was reduced following the restoration of cerebral perfusion after carotid endarterectomy (CEA) in patients with severe stenosis of the cervical internal carotid artery (ICA) and whether the reduction in hypoxic tissue was associated with cognitive improvement. METHOD: Eighteen patients with abnormally reduced cerebral blood flow (CBF) in the affected cerebral hemispheres on preoperative brain perfusion SPECT -underwent CEA. They underwent 18F-FRP170 PET and neuropsychological tests preoperatively and 6 months postoperatively. Brain perfusion SPECT was also performed 6 months postoperatively. Regions of interest were placed in the bilateral middle cerebral artery territories on SPECT and PET images, and the ratio of values in the affected versus contralateral hemispheres was calculated. RESULTS: The CBF ratio (p = 0.0006) and 18F-FRP170 ratio (p = 0.0084) were significantly increased and reduced, respectively, after surgery compared to the corresponding ratios before surgery. The difference in the 18F-FRP170 ratio (postoperative - preoperative value) was negatively correlated with the difference in the CBF ratio (ρ = -0.695; p = 0.0009). The difference in the 18F-FRP170 ratio was significantly lower in patients with postoperative improved cognition compared to that in those without (p = 0.0007). The area under the receiver operating characteristics curve for the difference in the 18F-FRP170 ratio for detecting postoperative improved cognition was significantly greater than that for the difference in the CBF ratio (difference between areas, 0.278; p = 0.0248). CONCLUSIONS: Hypoxic tissue is reduced following the restoration of cerebral perfusion with revascularization surgery in patients with severe atherosclerotic stenosis of the cervical ICA. The reduction in hypoxic tissue is associated with cognitive improvement in such patients.

Succinate Dehydrogenase B Subunit-Negative Jugular Foramen Paraganglioma Manifesting Malignant Progression with Pseudohypoxia-Related Atypical Uptake of [18F]-Fluoro-2-Deoxy-d-Glucose: A Case Report.

BACKGROUND: Paragangliomas are generally benign, slow-growing tumors. However, approximately 10%-20% are malignant, characterized by distant metastasis. Recently, a germ line mutation in succinate dehydrogenase B subunit (SDHB) has been shown to be associated with malignant behavior in paraganglioma. Here we present a case of SDHB-negative malignant paraganglioma of the jugular foramen with a pseudohypoxic microenvironment and unique imaging features on [18F]-fluoro-2-deoxy-d-glucose positron emission tomography ([18F]-FDG PET), and discuss the significance of SDHB immunohistochemistry and the potential of [18F]-FDG PET for clinical management. CASE DESCRIPTION: A 55-year-old woman was diagnosed with jugular foramen paraganglioma. Initial surgical resection was performed; however, follow-up [18F]-FDG PET indicated multiple uptake regions throughout the body. Biopsies for multiple recurrent lesions revealed consistent pathological features, suggesting distant metastasis. Immunohistochemical analysis revealed a lack of SDHB immunostaining in all specimens. Pseudohypoxic markers, including hypoxia-inducible factor-1α and downstream glycolysis enzymes, were strongly expressed. [18F]-FDG PET demonstrated increased uptake in the lesions, and the patient died 3 years after initial metastasis. CONCLUSION: In patients with head and neck paraganglioma without SDHB expression, close follow-up should be considered because of the risk for metastasis. In such cases, [18F]-FDG PET might be useful for detecting metastasis due to atypical accumulation from pseudohypoxia-induced glycolysis.

Percutaneous Dilatational Tracheostomy via Griggs Technique.

BACKGROUND: Tracheostomy is considered the airway management of choice for patients who need prolonged mechanical ventilation support. Percutaneous Dilatational Tracheotomy (PDT) is a technique that can be performed easily and rapidly at bedside and is particularly useful in the intensive care setting. The Griggs percutaneous tracheotomy is unique in its utilization of a guide wire dilator forceps. OBJECTIVE: We aimed to describe the early perioperative and late postoperative complications of PDT using the Griggs technique in patients in the intensive care unit (ICU). PATIENTS AND METHODS: This cross-sectional study was conducted on all patients who underwent tracheostomy in the ICU of the Imam Reza Hospital of Kermanshah, Iran, from June 2011 to June 2015. PDT was performed in 184 patients with the Griggs technique. Demographic variables, as well as perioperative and late postoperative complications were recorded. RESULTS: The mean age of patients was 57.3 ± 15.37 years. The most common primary causes of tracheostomy were hypoxic brain damage disorders (43.2%) and pneumonia (14.8%). Perioperative and early complications occurred in 16.7 % of procedures, of which 9.3% were bleedings (minor, significant and major). Furthermore, the incidence of late complications was 8.6%, including: stomal infection, difficult replace tracheostomy tube, tracheoesophageal fistula, tracheal stenosis, and tracheomalacia. CONCLUSION: PDT via Griggs technique is a safe, quick, and effective method. The low incidence of complications indicates that bedside percutaneous tracheostomy can be performed safely as a routine procedure for daily care implemented in the ICU.

First experiences with a combined usage of veno-arterial and veno-venous ECMO in therapy-refractory cardiogenic shock patients with cerebral hypoxemia.

The use of extracorporeal membrane oxygenation (ECMO) is becoming a popular tool in the treatment of cardiogenic shock. We present two case reports where classical veno-arterial peripherally cannulated ECMO therapy proved insufficient with profuse cerebral hypoxemia. After augmenting the setting into veno-veno-arterial ECMO, we achieved a remarkable improvement of all oxygenation parameters. The simultaneous use of veno-venous and veno-arterial ECMO might display as a novel strategy to counteract the coronary and cerebral hypoxemia in veno-arterial ECMO therapy in patients with therapy-refractory cardiogenic shock or in combined cardiopulmonary failure. In this manuscript, the veno-veno-arterial ECMO setup is described in full detail and different venous cannulas are discussed.

Human umbilical cord blood cells restore brain damage induced changes in rat somatosensory cortex.

Intraperitoneal transplantation of human umbilical cord blood (hUCB) cells has been shown to reduce sensorimotor deficits after hypoxic ischemic brain injury in neonatal rats. However, the neuronal correlate of the functional recovery and how such a treatment enforces plastic remodelling at the level of neural processing remains elusive. Here we show by in-vivo recordings that hUCB cells have the capability of ameliorating the injury-related impairment of neural processing in primary somatosensory cortex. Intact cortical processing depends on a delicate balance of inhibitory and excitatory transmission, which is disturbed after injury. We found that the dimensions of cortical maps and receptive fields, which are significantly altered after injury, were largely restored. Additionally, the lesion induced hyperexcitability was no longer observed in hUCB treated animals as indicated by a paired-pulse behaviour resembling that observed in control animals. The beneficial effects on cortical processing were reflected in an almost complete recovery of sensorimotor behaviour. Our results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes. We propose that the intermediate level of cortical processing will become relevant as a new stage to investigate efficacy and mechanisms of cell therapy in the treatment of brain injury.

Applying cerebral hypothermia and brain oxygen monitoring in treating severe traumatic brain injury.

BACKGROUND: Severe traumatic brain injury (TBI) was to be one of the major health problems encountered in modern medicine and had an incalculable socioeconomic impact. The initial cerebral damage after acute brain injury is often exacerbated by postischemic hyperthermia and worsens the outcome. Hypothermia is one of the current therapies designed to combat this deleterious effect. The brain tissue oxygen (P(ti)o(2))-guided cerebral perfusion pressure (CPP) management was successfully reduced because of cerebral hypoxic episodes following TBI. MATERIALS AND METHODS: Forty-five patients with severe TBI whose Glasgow Coma Scale (GCS) score ranged between 4 and 8 during September 2006 and August 2007 were enrolled in China Medical University Hospital, Taichung, Taiwan. One patient with a GCS score of 3 was excluded for poor outcome. These patients were randomized into three groups. Group A (16 patients) was intracranial pressure/cerebral perfusion pressure (ICP/CPP)-guided management only, Group B (15 patients) was ICP/CPP guided with mild hypothermia, and Group C (14 patients) was combined mild hypothermia and P(ti)o(2) guided with CPP management on patients with severe TBI. All patients were treated with ICP/CPP management (ICP <20 mm Hg, CPP >60 mm Hg). However, the group with P(ti)o(2) monitoring was required to raise the P(ti)o(2) above 20 mm Hg. Length of intensive care unit stay, ICP, P(ti)o(2), Glasgow Outcome Scale (GOS) score, mortality, and complications were analyzed. RESULTS: The ICP values progressively increased in the first 3 days but showed smaller changes in hypothermia groups (Groups B and C) and were significantly lower than those of the normothermia group (Group A) at the same time point. We also found out that the averaged ICP were significantly related to days and the daily variations [measured as (daily observation - daily group mean)(2)] of ICP were shown to the significantly different among three treatment groups after the third posttraumatic day. The values of P(ti)o(2) in Group C tended to rise when the ICP decreased were also observed. A favorable outcome is divided by the result of GOS scores. The percentage of favorable neurologic outcome was 50% in the normothermia group, 60% in the hypothermia-only group, and 71.4% in the P(ti)o(2) group, with statistical significance. The percentage of mortality was 12.5% in the normothermia group, 6.7% in the hypothermia-only group, and 8.5% in the P(ti)o(2) group, without statistical significance in three groups. Complications included pulmonary infections, peptic ulcer, and leukocytopenia (43.8% in the normothermia group, 55.6% in the hypothermia-only group, and 50% in the P(ti)o(2) group). CONCLUSIONS: Therapeutic mild hypothermia combined with P(ti)o(2)-guided CPP/ICP management allows reducing elevated ICP before 24 hours after injury, and daily variations of ICP were shown to be significantly different among the three treatment groups after the third posttraumatic day. It means that the hypothermia groups may reduce the ICP earlier and inhibit the elicitation of acute inflammation after cerebral contusion. Our data also provided evidence that early treatment that lowers P(ti)o(2) may improve the outcome and seems the best medical treatment method in these three groups. We concluded that therapeutic mild hypothermia combined with P(ti)o(2)-guided CPP/ICP management provides beneficial effects when treating TBI, and a multicenter randomized trial needs to be undertaken.

Human cord blood transplantation in a neonatal rat model of hypoxic-ischemic brain damage: functional outcome related to neuroprotection in the striatum.

Human umbilical cord blood mononuclear cells (HUCB) have been shown to have a therapeutic role in different models of central nervous system (CNS) damage, including stroke. We evaluated the possible therapeutic potential of HUCB in P7 rats submitted to the Rice-Vannucci model of neonatal hypoxic-ischemic (HI) brain damage. Our results demonstrated that intraperitoneal transplantation of HUCB, 3 h after the HI insult, resulted in better performance in two developmental sensorimotor reflexes, in the first week after the injury. We also showed a neuroprotective effect in the striatum, and a decrease in the number of activated microglial cells in the cerebral cortex of treated animals. We suggest that HUCB transplantation might rescue striatal neurons from cell death after a neonatal HI injury resulting in better functional recovery.

The effect of haematoma, brain injury, and secondary insult on brain swelling in traumatic acute subdural haemorrhage.

OBJECTIVE: The high mortality of acute subdural haematoma (ASDH) is largely explained by its frequent association with primary brain damage consisting of contusion and brain swelling. However, the nature and causes of brain swelling after traumatic brain injury are multifactorial and poorly understood. The purpose of this study was to investigate the pathophysiology of brain swelling associated with ASDH in traumatic brain injury. METHODS: We examined whether the thickness of the haematoma, parenchymal injury, or presence of a secondary insult had an effect on traumatic brain swelling. The variables that might affect the pathophysiology of ASDH were examined, including: (1) age and mechanism of injury, (2) neurological findings, (3) secondary insult and extracranial injuries, (4) pre-operative computed tomography (CT) scan results, and (5) outcome. RESULTS: A total of 212 patients were included in this study. On CT scan, 159 patients (75.0%) did not have brain swelling, 29 (13.7%) had hemispheric brain swelling, and 24 (11.3%) had diffuse brain swelling. Brain swelling associated with ASDH is caused by secondary insult in addition to parenchymal injury. In the present study, the outcome of ASDH associated with brain swelling was poor, even when treated with early surgical evacuation; the mortality rate of such patients was over 75%. CONCLUSIONS: Given our findings, it is possible that the poor outcome of ASDH patients depends not only on the characteristics of the haematoma itself, but also on the presence of additional cerebral parenchymal injury and secondary insult.

Long-term outcome of speech and language in children after corrective surgery for cyanotic or acyanotic cardiac defects in infancy.

The purpose of this prospective study was to assess whether outcome of speech and language in children 5-10 years after corrective surgery for tetralogy of Fallot (TOF) or ventricular septal defect (VSD) in infancy was influenced by the preoperative condition of hypoxemia or cardiac insufficiency and whether it was associated with perioperative risk factors and neurodevelopmental outcome. A total of 35 unselected children, 19 with TOF and hypoxemia and 16 with VSD and cardiac insufficiency, operated with combined deep hypothermic circulatory arrest and low-flow cardiopulmonary bypass at mean age 0.7+/-0.3 (mean+/-standard deviation) years, underwent, at mean age 7.4+/-1.6 years, standardized evaluation of speech and language functions. Results were compared between subgroups and related to perioperative factors, sociodemographic and neurodevelopmental status. Age at testing, socioeconomic status and history of speech and language development were not different between the subgroups. In contrast, total scores on oral and speech motor control functions (TFS) as well as on oral and speech apraxia (Mayo Test) were significantly reduced (p<0.02 to <0.05), and scores on anatomical oral structures tended to be lower (p<0.09) in the TOF group as compared to the VSD group. No differences were found for auditory word recognition and phonological awareness as assessed by the Auditory Closure subtest of the Illinois Test of Psycholinguistic Abilities and the test of auditory analysis skills, respectively. In all children, higher age at testing and better socioeconomic status were associated with better results in all domains of assessment (p<0.001 to <0.04). Consistent impairments of all oral and speech motor control functions (TFS and Mayo Test) were present in 29% of all children with a mean age of 6.5 years in contrast to 43% with normal performance and a mean age of 8.3 years. On the receptive speech tasks, only 6% scored below the normal range of their age group. TFS subscores were significantly correlated with age, bypass duration and motor function, but not correlated with socioeconomic status, duration of cardiac arrest, intelligence and academic achievement. Children with preoperative hypoxemia due to cyanotic cardiac defects in infancy are at higher risk for dysfunction in speech and language than those with cardiac insufficiency due to acyanotic heart defects. Age at testing, socioeconomic status, and duration of cardiopulmonary bypass influenced test results. Long-term outcome in speech and language functions can be considered as a sensitive indicator of overall child development after cardiac surgery.

Stem cell therapies for perinatal brain injuries.

This chapter reviews four groups of paediatric brain injury. The pathophysiology of these injuries is discussed to establish which cells are damaged and therefore which cells represent targets for cell replacement. Next, we review potential sources of cellular replacements, including embryonic stem cells, fetal and neonatal neural stem cells and a variety of mesenchymal stem cells. The advantages and disadvantages of each source are discussed. We review published studies to illustrate where stem cell therapies have been evaluated for therapeutic gain and discuss the hurdles that will need to be overcome to achieve therapeutic benefit. Overall, we conclude that children with paediatric brain injuries or inherited genetic disorders that affect the brain are worthy candidates for stem cell therapeutics.

Successful outcome in severe traumatic brain injury: a case study.

This case study describes the management of a 54-year-old male who presented to the Hospital of the University of Pennsylvania (HUP) with a traumatic brain injury (TBI) after being assaulted. He underwent an emergent bifrontal decompressive hemicraniectomy for multiple, severe frontal contusions. His postoperative course included monitoring of intracranial pressure, cerebral perfusion pressure, partial pressure of brain oxygen, brain temperature, and medical management based on HUP's established TBI algorithm. This case study explores the potential benefit of combining multimodality monitoring and TBI guidelines in the management of severe TBI.

Percutaneous tracheotomy in children.

We present three cases of the Fantoni percutaneous translaryngeal tracheostomy (TLT) performed under direct rigid bronchoscopy. The surgeries were performed in the near-drowned 5-year-old boy, and 15-year-old lupus erythematosus girl with a permanent brain damage resulted from a cardiac arrest, 11-year-old cardiac girl with postintubation laryngeal stenosis. In the first two cases, the procedure went uneventful; in one case the tube was accidentally pulled out during the rotation phase and surgical tracheostomy was performed. We describe the TLT procedure in details, calling special attention at the fact that the TLT is especially suitable for children below 10 years of age and is associated with very few complications.

Transplantation of cultured neural cells from human fetuses into the brain of rats exposed to acute hypoxia.

Neural stem cells of human brain were cultured for a long time and successfully transplanted into the brain of rats exposed to acute hypoxia. Stem and committed cells, neuroblasts, and astrocytes were revealed in transplants by immunohistochemical assay. The transplants and brain tissue were not separated with a glial barrier. Human neuroblasts widely migrated into regions of neuronal degeneration in the host brain.

New methods for monitoring cerebral oxygenation and hemodynamics in patients with subarachnoid hemorrhage.

Radiographic cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) do not reflect cerebral hemodynamics and oxygenation and may occur in the absence of clinical deficit and vice-versa. This report is to describe preliminary findings in further development of a non invasive method to estimate regional cerebral oxygenation and perfusion. Measurements were performed with a technique combining near infrared spectroscopy (NIRS) and indocyaningreen (ICG) dye dilution. Successful data analysis has been performed based on the decomposition in pulsatile and non-pulsatile components of NIRS absorption data collected before and during the passage of ICG through the vascular bed under the NIRS-detector. First measurements in patients with CVS suggest that the technique could become a powerful tool in the detection and treatment of CVS. This non invasive technique can be done at the bedside, it seems to be safe, easy to perform and less time-consuming compared to conventional techniques. The influence of extracerebral bone and surface tissue on cerebral NIRS signal has not been clarified yet. Therefore a new subdural NIRS probe has been developed, which gives the opportunity to measure directly the concentration of the chromophores in the brain without the influence of extracerebral contamination. In future comparative measurements with conventional NIRS probes on the scalp will allow to quantify and eliminate extracerebral contamination from the NIRS signal.

Diffuse brain injury complicated by acute subdural hematoma and secondary insults in the rodents: the effect of surgical evacuation.

Head Trauma associated with acute sudural hematoma (SDH) and complicated by secondary insult is a grave clinical combination with complex pathophysiology. The aim of this study was to develop a clinically relevant injury model, which can be used to study the interaction between injury mechanisms. We present a novel model of SDH combined with diffuse brain injury (DBI) and a hypoxic secondary insult, and investigate the effects of surgical evacuation. Adult Sprague-Dawley rats were given a 300 microliters SDH and 20 minute-hypoxia following Impact Acceleration DBI. Hematoma was evacuated at one hour post-injury. Physiological parameters were measured for 5 hours, together with assessment of brain water content. Secondary insult after traumatic SDH was associated with significant brain swelling and stimulated refractory rise in ICP. In traumatic SDH complicated by secondary insult, brain swelling is exacerbated by surgical evacuation.

Metabolic changes in the brain during transient ischemia measured with microdialysis.

Forty-four patients with severe head injury were monitored for episodes of cerebral ischemia using jugular venous oxygen saturation (sjvO2), brain tissue pO2 (ti-pO2), and a microdialysis probe. The concentration of lactate and glucose were measured in the microdialysate. A total of 10 episodes of global ischemia were observed. The characteristic pattern of a simultaneous decrease in sjvO2 and brain ti-pO2 with an increase in the concentration of lactate occurred in all 10 patients. In addition, 3 episodes of regional ischemia were observed. Although brain ti-pO2 decreased to very low values and the concentration of lactate increased in the microdialysate, sjvO2 remained unchanged. Brain ti-pO2 adds another dimension to our cerebral monitoring by allowing the detection of regional cerebral ischemia.

Transplantation of fetal neocortex ameliorates sensorimotor and locomotor deficits following neonatal ischemic-hypoxic brain injury in rats.

Ischemic brain injury in neonates can result in the degeneration of cortical and subcortical areas of brain and is associated with neurologic deficits. One approach to restoring function in conditions of ischemic brain injury is the use of neural transplants to repair damaged connections. This approach has been shown to reestablish neural circuitry and to ameliorate associated motor deficits in models of neonatal sensorimotor cortex damage. In this study, we utilized the Rice et al. rodent model of neonatal ischemic-hypoxic (IH) brain injury to assess whether transplantation of fetal neocortical tissue can promote functional recovery in tests of sensorimotor and locomotor ability throughout development and as adults. We show that animals that received neocortical grafts 3 days following the IH injury performed significantly better as adults on two measures of motor ability, the Rota-Rod treadmill and apomorphine-induced rotations, than did control animals that received sham transplants after the IH injury. Transplants were identifiable in 72% of the animals 10-12 weeks after implantation. Histochemical studies revealed that while the transplanted tissue did not establish normal cortical cytoarchitecture, cells and fibers within the grafts stained for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), choline acetyl transferase (ChAT), cholecystokinin (CCK), and glial fibrillary acidic protein (GFAP). These results suggest that transplantation of fetal neocortical tissue following IH injury in the neonatal period is associated with amelioration of motor deficits and that the grafted tissue demonstrated a neurochemical phenotype that resembled normal neocortex. This approach warrants continued investigation in light of potential therapeutic uses.

Multiparametric continuous monitoring of brain metabolism and substrate delivery in neurosurgical patients.

Brain function and tissue integrity are highly dependent on continuous oxygen supply and clearance of CO2. Aerobic metabolism is the major energy source to normal brain, however, during hypoxia and ischemia, lactate accumulation may sometimes be seen, indicating anaerobic glycolysis after severe head injury. Current monitoring techniques often fail to detect such events which can affect substrate delivery to the injured brain. We have recently adapted a method for continuous monitoring of brain tissue pO2, pCO2, pH and temperature, using a single sensor. The multiparameter sensor is inserted into brain tissue, via a new three lumen bolt, together with a standard ventriculostomy catheter and a microdialysis probe. The system has been left in place as long as needed, but never more than 7 days. All readings were compared to clinical parameters, and outcome. Stable measurements could be obtained in the first group of 20 patients, after calibration and rigid fixation, using the new bolt. Severely head injured patients had brain oxygen levels of less than 25-30 mmHg for the first hours after injury. Thereafter two patterns could be seen. Patients with favorable outcome had a slow increase in brain oxygen, and brain CO2 decreased to normal values, as long as the cerebral perfusion pressure (CPP) was kept above 70 mmHg. However, in those patients with secondary ischemic events, and bad outcome, a further decline in brain oxygen to anaerobic levels (< 20 mmHg) was seen. For these patients, both decreased and increased brain CO2 levels could be seen. Brain CO2 levels of 90-150 mmHg were consistently seen after brain death. Brain pH was inversely related to brain CO2 for all patients. Brain glucose and lactate in patients with poor outcome were 639 microM l-1 +/- 330, and 1642 microM l-1 +/- 788, whereas patients with good outcome had brain glucose levels of 808 microM l-1 +/- 321 and lactate levels of 1001 microM l-1 +/- 417. Extended neuromonitoring using a combined sensor for brain oxygen, CO2, pH and temperature measurements, as well as a microdialysis probe for glucose and lactate analysis may optimize the management of comatose neurosurgical patients in the future, by allowing a fuller understanding of dynamic factors affecting brain metabolism.

[Clinico-anatomical analysis of the causes of death in ruptures of intracranial arterial aneurysms]. / Kliniko-anatomicheskii analiz prichin smerti pri razryvakh intrakranial'nykh arterial'nykh anevrizm.

Causes of lethal outcome in patients after subarachnoid hemorrhage due to cerebral aneurysm rupture were analysed. The major death cause in the operated patients was cerebral edema and dislocation, while in non-operated ones it was the penetration of blood into the ventricles of the brain. Cerebral edema and dislocation syndrome were mainly caused after surgery by ischemic changes in cerebral tissue. A relationship between the aneurysm localization and the extent of subarachnoid hemorrhage was revealed as well as between the hematoma localization and incidence of hemorrhage into the ventricles of the brain.