Subspace partitioning in the human prefrontal cortex resolves cognitive interference.

The human prefrontal cortex (PFC) constitutes the structural basis underlying flexible cognitive control, where mixed-selective neural populations encode multiple task features to guide subsequent behavior. The mechanisms by which the brain simultaneously encodes multiple task-relevant variables while minimizing interference from task-irrelevant features remain unknown. Leveraging intracranial recordings from the human PFC, we first demonstrate that competition between coexisting representations of past and present task variables incurs a behavioral switch cost. Our results reveal that this interference between past and present states in the PFC is resolved through coding partitioning into distinct low-dimensional neural states; thereby strongly attenuating behavioral switch costs. In sum, these findings uncover a fundamental coding mechanism that constitutes a central building block of flexible cognitive control.

Intracranial Recordings Demonstrate Both Cortical and Medial Temporal Lobe Engagement in Visual Search in Humans.

Visual search is a fundamental human behavior, providing a gateway to understanding other sensory domains as well as the role of search in higher-order cognition. Search has been proposed to include two component processes: inefficient search (Search) and efficient search (Pop-out). According to extant research, these two processes map onto two separable neural systems located in the frontal and parietal association cortices. In this study, we use intracranial recordings from 23 participants to delineate the neural correlates of Search and Pop-out with an unprecedented combination of spatiotemporal resolution and coverage across cortical and subcortical structures. First, we demonstrate a role for the medial temporal lobe in visual search, on par with engagement in frontal and parietal association cortex. Second, we show a gradient of increasing engagement over anatomical space from dorsal to ventral lateral frontal cortex. Third, we confirm previous intracranial work demonstrating nearly complete overlap in neural engagement across cortical regions in Search and Pop-out. We further demonstrate Pop-out selectivity, manifesting as activity increase in Pop-out as compared to Search, in a distributed set of sites including frontal cortex. This result is at odds with the view that Pop-out is implemented in low-level visual cortex or parietal cortex alone. Finally, we affirm a central role for the right lateral frontal cortex in Search.

Dynamic frontotemporal systems process space and time in working memory.

How do we rapidly process incoming streams of information in working memory, a cognitive mechanism central to human behavior? Dominant views of working memory focus on the prefrontal cortex (PFC), but human hippocampal recordings provide a neurophysiological signature distinct from the PFC. Are these regions independent, or do they interact in the service of working memory? We addressed this core issue in behavior by recording directly from frontotemporal sites in humans performing a visuospatial working memory task that operationalizes the types of identity and spatiotemporal information we encounter every day. Theta band oscillations drove bidirectional interactions between the PFC and medial temporal lobe (MTL; including the hippocampus). MTL theta oscillations directed the PFC preferentially during the processing of spatiotemporal information, while PFC theta oscillations directed the MTL for all types of information being processed in working memory. These findings reveal an MTL theta mechanism for processing space and time and a domain-general PFC theta mechanism, providing evidence that rapid, dynamic MTL-PFC interactions underlie working memory for everyday experiences.

Seizure outcomes of temporal lobe epilepsy surgery in patients with normal MRI and without specific histopathology.

BACKGROUND: Seizure outcome following surgery in pharmacoresistant temporal lobe epilepsy patients with normal magnetic resonance imaging and normal or non-specific histopathology is not sufficiently presented in the literature. METHODS: In a retrospective design, we reviewed data of 263 patients who had undergone temporal lobe epilepsy surgery and identified 26 (9.9%) who met the inclusion criteria. Seizure outcomes were determined at 2-year follow-up. Potential predictors of Engel class I (satisfactory outcome) were identified by logistic regression analyses. RESULTS: Engel class I outcome was achieved in 61.5% of patients, 50% being completely seizure free (Engel class IA outcome). The strongest predictors of satisfactory outcome were typical ictal seizure semiology (p = 0.048) and localised ictal discharges on scalp EEG (p = 0.036). CONCLUSION: Surgery might be an effective treatment choice for the majority of these patients, although outcomes are less favourable than in patients with magnetic resonance imaging-defined lesional temporal lobe epilepsy. Typical ictal seizure semiology and localised ictal discharges on scalp EEG were predictors of Engel class I outcome.

Seizure outcomes in relation to the extent of resection of the perifocal fluorodeoxyglucose and flumazenil PET abnormalities in anteromedial temporal lobectomy.

BACKGROUND: The area of predominant perifocal [(18)F]fluorodeoxyglucose ((18)F-FDG) hypometabolism and reduced [(11)C]flumazenil ((11)C-FMZ) -binding on PET scans is currently considered to contain the epileptogenic zone and corresponds anatomically to the area localizing epileptogenicity in patients with temporal lobe epilepsy (TLE). The question is whether the volume of the perifocal pre-operative PET abnormalities, the extent of their resection, and the volume of the non-resected abnormalities affects the post-operative seizure outcome. METHODS: The sample group consisted of 32 patients with mesial temporal sclerosis who underwent anteromedial temporal lobe resection for refractory TLE. All patients had pathologic perifocal findings on both of the PET modalities as well as on the whole-brain MRI. The volumetric data of the PET and MRI abnormalities within the resected temporal lobe were estimated by automated quantitative voxel-based analysis. The obtained volumetric data were investigated in relation to the outcome subgroups of patients (Engel classification) determined at the 2-year post-operative follow-up. RESULTS: The mean volume of the pre-operative perifocal (18)F-FDG- and (11)C-FMZ PET abnormalities in the volumes of interest (VOI) of the epileptogenic temporal lobe, the mean resected volume of these PET abnormalities, the mean volume of the non-resected PET abnormalities, and the mean MRI-derived resected volume were not significantly related to the outcome subgroups and had a low prediction for individual freedom from seizures. CONCLUSIONS: The extent of pre-surgical perifocal PET abnormalities, the extent of their resection, and the extent of non-resected abnormalities were not useful predictors of individual freedom from seizures in patients with TLE.

Anatomical registration of intracranial electrodes. Robust model-based localization and deformable smooth brain-shift compensation methods.

BACKGROUND: Intracranial electrodes are typically localized from post-implantation CT artifacts. Automatic algorithms localizing low signal-to-noise ratio artifacts and high-density electrode arrays are missing. Additionally, implantation of grids/strips introduces brain deformations, resulting in registration errors when fusing post-implantation CT and pre-implantation MR images. Brain-shift compensation methods project electrode coordinates to cortex, but either fail to produce smooth solutions or do not account for brain deformations. NEW METHODS: We first introduce GridFit, a model-based fitting approach that simultaneously localizes all electrodes' CT artifacts in grids, strips, or depth arrays. Second, we present CEPA, a brain-shift compensation algorithm combining orthogonal-based projections, spring-mesh models, and spatial regularization constraints. RESULTS: We tested GridFit on ∼6000 simulated scenarios. The localization of CT artifacts showed robust performance under difficult scenarios, such as noise, overlaps, and high-density implants (<1 mm errors). Validation with data from 20 challenging patients showed 99% accurate localization of the electrodes (3160/3192). We tested CEPA brain-shift compensation with data from 15 patients. Projections accounted for simple mechanical deformation principles with < 0.4 mm errors. The inter-electrode distances smoothly changed across neighbor electrodes, while changes in inter-electrode distances linearly increased with projection distance. COMPARISON WITH EXISTING METHODS: GridFit succeeded in difficult scenarios that challenged available methods and outperformed visual localization by preserving the inter-electrode distance. CEPA registration errors were smaller than those obtained for well-established alternatives. Additionally, modeling resting-state high-frequency activity in five patients further supported CEPA. CONCLUSION: GridFit and CEPA are versatile tools for registering intracranial electrode coordinates, providing highly accurate results even in the most challenging implantation scenarios. The methods are implemented in the iElectrodes open-source toolbox.

Ramping dynamics and theta oscillations reflect dissociable signatures during rule-guided human behavior.

Contextual cues and prior evidence guide human goal-directed behavior. The neurophysiological mechanisms that implement contextual priors to guide subsequent actions in the human brain remain unclear. Using intracranial electroencephalography (iEEG), we demonstrate that increasing uncertainty introduces a shift from a purely oscillatory to a mixed processing regime with an additional ramping component. Oscillatory and ramping dynamics reflect dissociable signatures, which likely differentially contribute to the encoding and transfer of different cognitive variables in a cue-guided motor task. The results support the idea that prefrontal activity encodes rules and ensuing actions in distinct coding subspaces, while theta oscillations synchronize the prefrontal-motor network, possibly to guide action execution. Collectively, our results reveal how two key features of large-scale neural population activity, namely continuous ramping dynamics and oscillatory synchrony, jointly support rule-guided human behavior.

Functional hemispheric disconnection procedures for chronic epilepsy: history, indications, techniques, complications and current practice in Europe. A consensus statement on behalf of the EANS functional neurosurgery section.

Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure. Research question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy. Material and methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines. Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported. Discussion and conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe.

Volume and densities of chronic subdural haematoma obtained from CT imaging as predictors of postoperative recurrence: a prospective study of 107 operated patients.

BACKGROUND: Chronic subdural haematoma (CSDH) is a common entity in neurosurgery with a considerable postoperative recurrence rate. Computerised tomography (CT) scanning remains the most important diagnostic test for this disorder. The aim of this study was to characterise the relationship between the recurrence of CSDH after treatment with burr-hole irrigation and closed-system drainage technique and CT scan features of these lesions to assess whether CT findings can be used to predict recurrence. METHODS: We investigated preoperative and postoperative CT scan features and recurrence rate of 107 consecutive adult surgical cases of CSDH and assessed any relationship with univariate and multivariate regression analyses. RESULTS: Seventeen patients (15.9 %) experienced recurrence of CSDH. The preoperative haematoma volume, the isodense, hyperdense, laminar and separated CT densities and the residual total haematoma cavity volume on the 1st postoperative day after removal of the drainage were identified as radiological predictors of recurrence. If the preoperative haematoma volume was under 115 ml and the residual total haematoma cavity volume postoperatively was under 80 ml, the probability of no recurrence was very high (94.4 % and 97.4 % respectively). CONCLUSIONS: These findings from CT imaging may help to identify patients at risk for postoperative recurrence.

Decision and response monitoring during working memory are sequentially represented in the human insula.

Emerging research supports a role of the insula in human cognition. Here, we used intracranial EEG to investigate the spatiotemporal dynamics in the insula during a verbal working memory (vWM) task. We found robust effects for theta, beta, and high frequency activity (HFA) during probe presentation requiring a decision. Theta band activity showed differential involvement across left and right insulae while sequential HFA modulations were observed along the anteroposterior axis. HFA in anterior insula tracked decision making and subsequent HFA was observed in posterior insula after the behavioral response. Our results provide electrophysiological evidence of engagement of different insula subregions in both decision-making and response monitoring during vWM and expand our knowledge of the role of the insula in complex human behavior.

Anatomical registration of intracranial electrodes. Robust model-based localization and deformable smooth brain-shift compensation methods.

Precise electrode localization is important for maximizing the utility of intracranial EEG data. Electrodes are typically localized from post-implantation CT artifacts, but algorithms can fail due to low signal-to-noise ratio, unrelated artifacts, or high-density electrode arrays. Minimizing these errors usually requires time-consuming visual localization and can still result in inaccurate localizations. In addition, surgical implantation of grids and strips typically introduces non-linear brain deformations, which result in anatomical registration errors when post-implantation CT images are fused with the pre-implantation MRI images. Several projection methods are currently available, but they either fail to produce smooth solutions or do not account for brain deformations. To address these shortcomings, we propose two novel algorithms for the anatomical registration of intracranial electrodes that are almost fully automatic and provide highly accurate results. We first present GridFit, an algorithm that simultaneously localizes all contacts in grids, strips, or depth arrays by fitting flexible models to the electrodes' CT artifacts. We observed localization errors of less than one millimeter (below 8% relative to the inter-electrode distance) and robust performance under the presence of noise, unrelated artifacts, and high-density implants when we ran ~6000 simulated scenarios. Furthermore, we validated the method with real data from 20 intracranial patients. As a second registration step, we introduce CEPA, a brain-shift compensation algorithm that combines orthogonal-based projections, spring-mesh models, and spatial regularization constraints. When tested with real data from 15 patients, anatomical registration errors were smaller than those obtained for well-established alternatives. Additionally, CEPA accounted simultaneously for simple mechanical deformation principles, which is not possible with other available methods. Inter-electrode distances of projected coordinates smoothly changed across neighbor electrodes, while changes in inter-electrode distances linearly increased with projection distance. Moreover, in an additional validation procedure, we found that modeling resting-state high-frequency activity (75-145 Hz ) in five patients further supported our new algorithm. Together, GridFit and CEPA constitute a versatile set of tools for the registration of subdural grid, strip, and depth electrode coordinates that provide highly accurate results even in the most challenging implantation scenarios. The methods presented here are implemented in the iElectrodes open-source toolbox, making their use simple, accessible, and straightforward to integrate with other popular toolboxes used for analyzing electrophysiological data.

Local and systemic pro-inflammatory and anti-inflammatory cytokine patterns in patients with chronic subdural hematoma: a prospective study.

OBJECTIVE AND DESIGN: Innate immune pro- and anti-inflammatory responses in patients with chronic subdural hematoma (CSDH) were investigated by measuring and comparing the systemic and subdural fluid levels of cytokines. MATERIALS AND METHOD: Cytokine values were analyzed in samples obtained during surgery of 56 adult patients who were operated on for unilateral CSDHs using a Multiplex antibody bead kit. RESULTS: There were significantly higher levels of the pro-inflammatory IL-2R (p = 0.004), IL-5 (p < 0.001), IL-6 (p < 0.001), and IL-7 (p < 0.001), and anti-inflammatory mediators IL-10 (p < 0.001) and IL-13 (p = 0.002) in CSDH fluid compared with systemic levels. The pro-inflammatory TNF-alpha (p < 0.001), IL-1beta (p < 0.001), IL-2 (p = 0.007) and IL-4 (p < 0.001) were significantly lower in hematoma fluid compared with systemic levels. The ratios between pro- versus anti-inflammatory cytokines were statistically significant higher in CSDH (7.8) compared with systemic levels (1.3). CONCLUSIONS: The innate immune responses occur both locally at the site of CSDH, as well as systematically in patients with CSDH. The local hyper-inflammatory and low anti-inflammatory responses exist simultaneously. The findings suggest poorly coordinated innate immune responses at the site of CSDH that may lead to propagating of local inflammatory process and basically contribute to formation and progression of CSDH.

Chemokines as markers of local inflammation and angiogenesis in patients with chronic subdural hematoma: a prospective study.

OBJECTIVE: The goal of this study was to investigate the chemokines CCL2, CXCL8, CXCL9 and CXCL10 as markers of the inflammatory responses in chronic subdural hematoma (CSDH). METHODS: Samples of peripheral venous blood and CSDH fluid (obtained during surgery) in 76 adult patients were prospectively analyzed. Chemokine values were assessed by a Multiplex antibody bead kit. RESULTS: We found significantly higher levels of chemokines CCL2, CXCL8, CXCL9 and CXCL10 in hematoma fluid compared with serum. CONCLUSIONS: Chemokines are elevated in the hematoma cavity of patients with CSDH. It is likely that these signaling modulators play an important role in promoting local inflammation. Furthermore, biological activity of CCL2 and CXCL8 may promote neovascularization within the outer CSDH membrane, and a compensatory angiostatic activity of CXCL9 and CXCL10 may contribute to repairing this disorder. This phenomenon was restricted to the hematoma site, and the systemic chemokine levels might not reflect local immune responses.

Modeling intracranial electrodes. A simulation platform for the evaluation of localization algorithms.

Introduction: Intracranial electrodes are implanted in patients with drug-resistant epilepsy as part of their pre-surgical evaluation. This allows the investigation of normal and pathological brain functions with excellent spatial and temporal resolution. The spatial resolution relies on methods that precisely localize the implanted electrodes in the cerebral cortex, which is critical for drawing valid inferences about the anatomical localization of brain function. Multiple methods have been developed to localize the electrodes, mainly relying on pre-implantation MRI and post-implantation computer tomography (CT) images. However, they are hard to validate because there is no ground truth data to test them and there is no standard approach to systematically quantify their performance. In other words, their validation lacks standardization. Our work aimed to model intracranial electrode arrays and simulate realistic implantation scenarios, thereby providing localization algorithms with new ways to evaluate and optimize their performance. Results: We implemented novel methods to model the coordinates of implanted grids, strips, and depth electrodes, as well as the CT artifacts produced by these. We successfully modeled realistic implantation scenarios, including different sizes, inter-electrode distances, and brain areas. In total, ∼3,300 grids and strips were fitted over the brain surface, and ∼850 depth electrode arrays penetrating the cortical tissue were modeled. Realistic CT artifacts were simulated at the electrode locations under 12 different noise levels. Altogether, ∼50,000 thresholded CT artifact arrays were simulated in these scenarios, and validated with real data from 17 patients regarding the coordinates' spatial deformation, and the CT artifacts' shape, intensity distribution, and noise level. Finally, we provide an example of how the simulation platform is used to characterize the performance of two cluster-based localization methods. Conclusion: We successfully developed the first platform to model implanted intracranial grids, strips, and depth electrodes and realistically simulate thresholded CT artifacts and their noise. These methods provide a basis for developing more complex models, while simulations allow systematic evaluation of the performance of electrode localization techniques. The methods described in this article, and the results obtained from the simulations, are freely available via open repositories. A graphical user interface implementation is also accessible via the open-source iElectrodes toolbox.

Orbitofrontal cortex governs working memory for temporal order.

How do we think about time? Converging lesion and neuroimaging evidence indicates that orbitofrontal cortex (OFC) supports the encoding and retrieval of temporal context in long-term memory1, which may contribute to confabulation in individuals with OFC damage2. Here, we reveal that OFC damage diminishes working memory for temporal order, that is, the ability to disentangle the relative recency of events as they unfold. OFC lesions reduced working memory for temporal order but not spatial position, and individual deficits were commensurate with lesion size. Comparable effects were absent in patients with lesions restricted to lateral prefrontal cortex (PFC). Based on these findings, we propose that OFC supports understanding of the order of events. Well-documented behavioral changes in individuals with OFC damage2 may relate to impaired temporal-order understanding.

Auditory deviance detection in the human insula: An intracranial EEG study.

The human insula is known to be involved in auditory processing, but knowledge about its precise functional role and the underlying electrophysiology is limited. To assess its role in automatic auditory deviance detection we analyzed the EEG high frequency activity (HFA; 75-145 Hz) and ERPs from 90 intracranial insular channels across 16 patients undergoing pre-surgical intracranial monitoring for epilepsy treatment. Subjects passively listened to a stream of standard and deviant tones differing in four physical dimensions: intensity, frequency, location or time. HFA responses to auditory stimuli were found in the short and long gyri, and the anterior, superior, and inferior segments of the circular sulcus of the insular cortex. Only a subset of channels in the inferior segment of the circular sulcus of the insula showed HFA deviance detection responses, i.e., a greater and longer latency response to specific deviants relative to standards. Auditory deviancy processing was also later in the insula when compared with the superior temporal cortex. ERP results were more widespread and supported the HFA insular findings. These results provide evidence that the human insula is engaged during auditory deviance detection.

The proteome of pus from human brain abscesses: host-derived neurotoxic proteins and the cell-type diversity of CNS pus.

OBJECTIVE What determines the extent of tissue destruction during brain abscess formation is not known. Pyogenic brain infections cause destruction of brain tissue that greatly exceeds the area occupied by microbes, as seen in experimental studies, pointing to cytotoxic factors other than microbes in pus. This study examined whether brain abscess pus contains cytotoxic proteins that might explain the extent of tissue destruction. METHODS Pus proteins from 20 human brain abscesses and, for comparison, 7 subdural empyemas were analyzed by proteomics mass spectrometry. Tissue destruction was determined from brain abscess volumes as measured by MRI. RESULTS Brain abscess volume correlated with extracellular pus levels of antibacterial proteins from neutrophils and macrophages: myeloperoxidase (r = 0.64), azurocidin (r = 0.61), lactotransferrin (r = 0.57), and cathelicidin (r = 0.52) (p values 0.002-0.018), suggesting an association between leukocytic activity and tissue damage. In contrast, perfringolysin O, a cytotoxic protein from Streptococcus intermedius that was detected in 16 patients, did not correlate with abscess volume (r = 0.12, p = 0.66). The median number of proteins identified in each pus sample was 870 (range 643-1094). Antibiotic or steroid treatment prior to pus evacuation did not reduce the number or levels of pus proteins. Some of the identified proteins have well-known neurotoxic effects, e.g., eosinophil cationic protein and nonsecretory ribonuclease (also known as eosinophil-derived neurotoxin). The cellular response to brain infection was highly complex, as reflected by the presence of proteins that were specific for neutrophils, eosinophils, macrophages, platelets, fibroblasts, or mast cells in addition to plasma and erythrocytic proteins. Other proteins (neurofilaments, myelin basic protein, and glial fibrillary acidic protein) were specific for brain cells and reflected damage to neurons, oligodendrocytes, and astrocytes, respectively. Pus from subdural empyemas had significantly higher levels of plasma proteins and lower levels of leukocytic proteins than pus from intracerebral abscesses, suggesting greater turnover of the extracellular fluid of empyemas and washout of pus constituents. CONCLUSIONS Brain abscess pus contains leukocytic proteins that are neurotoxic and likely participate actively in the excessive tissue destruction inherent in brain abscess formation. These findings underscore the importance of rapid evacuation of brain abscess pus.

Toxic levels of ammonia in human brain abscess.

OBJECTIVE: Brain abscesses could lead to cerebral symptoms through tissue destruction, edema, changes in brain architecture, and increased intracranial pressure. However, the possibility that the pus itself could contribute to symptoms has received little attention. Brain abscesses are areas of tissue destruction, proteolysis, and formation of free amino acids, which are energy substrates for bacteria and possible sources of ammonia. Ammonia is neurotoxic, may cause brain edema, and could contribute to the symptoms of brain abscesses. METHODS: The authors analyzed the extracellular phase of pus from 14 patients with brain abscesses with respect to ammonia and amino acids. For comparison, CSF from 10 patients undergoing external ventricular drainage was included. The ammonia-forming ability of Streptococcus intermedius and Staphylococcus aureus, two common microbial isolates in brain abscesses, was studied in vitro. RESULTS: In brain abscesses ammonia was 15.5 mmol/L (median value; range 1.7-69.2 mmol/L). In CSF ammonia was 29 µmol/L (range 17-55 µmol/L; difference from value in pus: p < 0.001). The total concentration of amino acids in brain abscesses was 1.12-16 times higher than the ammonia concentration (p = 0.011). The median glucose value in pus was 0 mmol/L (range 0-2.1 mmol/L), lactate was 21 mmol/L (range 3.3-26.5 mmol/L), and pH was 6.8 (range 6.2-7.3). In vitro, S. intermedius and S. aureus formed ammonia at 6-7 mmol/L in 24 hours when incubated with 20 proteinogenic amino acids plus g-aminobutyric acid (GABA), taurine, and glutathione at 1 mmol/L. CONCLUSIONS: Intracerebral abscesses contain toxic levels of ammonia. At the concentrations found in pus, ammonia could contribute to the brain edema and the symptoms of brain abscesses.

High extracellular levels of potassium and trace metals in human brain abscess.

Brain abscesses frequently cause symptoms such as seizures, delirium, paresis and sensory deficits that could reflect brain edema, increased intracranial pressure, or tissue destruction. However, it is also possible that pus constituents could disturb neuronal function in the surrounding brain tissue. In pus from 16 human brain abscesses, extracellular potassium ([K(+)]o) was 10.6 ± 4.8 mmol/L (mean ± SD; maximum value 22.0 mmol/L). In cerebrospinal fluid (CSF), [K(+)]o was 2.7 ± 0.6 mmol/L (N = 14; difference from pus p < 0.001), which is similar to previous control values for [K(+)]o in CSF and brain parenchyma. Zinc and iron were >40-fold higher in pus than in CSF; calcium, copper, manganese, and chromium were also higher, whereas sodium and magnesium were similar. Pus from 10 extracerebral abscesses (empyemas) also had higher [K(+)]o, zinc, iron, calcium, copper, manganese, and chromium than did CSF. Brain abscess [K(+)]o was significantly higher than serum potassium (3.8 ± 0.5 mmol/L; p = 0.0001), indicating that the elevated abscess [K(+)]o originated from damaged cells (e.g. brain cells and leukocytes), not from serum. High [K(+)]o could depolarize neurons, high levels of zinc could inhibit glutamate and GABA receptors, and high levels of iron and copper could cause oxidative damage, all of which could contribute to neuronal dysfunction in brain abscess patients.

High extracellular concentration of excitatory amino acids glutamate and aspartate in human brain abscess.

Brain abscesses often cause symptoms of brain dysfunction, including seizures, suggesting interference with normal neurotransmission. We determined the concentration of extracellular neuroactive amino acids in brain abscesses from 16 human patients. Glutamate was present at 3.6 mmol/L (median value, range 0.5-10.8), aspartate at 1.0 mmol/L (range 0.09-6.8). For comparison, in cerebroventricular fluid glutamate was ∼0.6 µmol/L, and aspartate was not different from zero. The total concentration of amino acids was higher in eight patients with seizures: 66 mmol/L (median value, range 19-109) vs. 21 mmol/L (range 4-52) in eight patients without seizures (p=0.026). The concentration of aspartate and essential amino acids tryptophan, phenylalanine, tyrosine, leucine, and isoleucine was higher in pus from patients with seizures (p⩽0.040), whereas that of glutamate was not (p=0.095). The median concentration of the non-proteinogenic, inhibitory amino acid taurine was similar in the two groups, 0.7-0.8 mmol/L (range 0.1-6.1). GABA could not be detected in pus. The patient groups did not differ with respect to abscess volume, the cerebral lobe affected, age, or time from symptom onset to surgery. Seven patients with extracerebral, intracranial abscesses had significantly lower pus concentration of glutamate (352 µmol/L, range 83-1368) and aspartate (71 µmol/L, range 22-330) than intracerebral abscesses (p<0.001). We conclude that excitatory amino acids glutamate and aspartate may reach very high concentrations in brain abscesses, probably contributing to symptoms through activation of glutamate receptors in the surrounding brain tissue.