T he pursuit of defining how the human brain processes language is one of the greatest challenges in neuroscience. Pierre Broca and Karl Wernicke made fundamental contributions at a time when the practice of localization by phrenology was pervasive. Their careful studies were some of the first to define functional localization in the brain by studying patients with defined brain injuries and lesions. Over time, their names have become synonymous with two key brain areas for language function: the inferior frontal gyrus and superior posterior temporal area, respectively. The brain regions that bear their names are now universal in every medical student's education. However, the dichotomy of language production based in the frontal lobe and language comprehension based in the temporal lobe is a commonly oversimplified interpretation of their work. For example, injuries to Wernicke's area result in abnormal speech production in addition to deficits in comprehension. Frontal lesions can also result in higherorder comprehension deficits. Thus, the language network is more complicated and integrated than commonly appreciated. In the last 15 years, an exponential increase in the number of studies on the neurobiology of language has improved our understanding of potential mechanisms, but many fundamental questions remain unresolved.Our goal in this overview is to provide an update to neurosurgeons by comparing classic with more recent models of language organization. It is not meant to be an exhaustive review of language research, which is beyond our intended scope, but rather to introduce contemporary theories and briefly review selected neurosurgical experience with stimulation-based language mapping. This will abbreviatioNs DTI = diffusion tensor imaging; fMRI = functional MRI; IFOF = inferior fronto-occipital fasciculus; MTG = middle temporal gyrus; PVWM = periventricular white matter; SLF = superior longitudinal fasciculus; SMA = supplementary motor area; STG = superior temporal gyrus; STS = superior temporal sulcus. Classic models of language organization posited that separate motor and sensory language foci existed in the inferior frontal gyrus (Broca's area) and superior temporal gyrus (Wernicke's area), respectively, and that connections between these sites (arcuate fasciculus) allowed for auditory-motor interaction. These theories have predominated for more than a century, but advances in neuroimaging and stimulation mapping have provided a more detailed description of the functional neuroanatomy of language. New insights have shaped modern network-based models of speech processing composed of parallel and interconnected streams involving both cortical and subcortical areas. Recent models emphasize processing in "dorsal" and "ventral" pathways, mediating phonological and semantic processing, respectively. Phonological processing occurs along a dorsal pathway, from the posterosuperior temporal to the inferior frontal cortices. On the other hand, semantic information is carried in a ventral pathway that runs fro...

Cerebrovascular diseases are a leading cause of death and neurologic disability. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of cerebrovascular cells in humans. We profiled transcriptomes of 181,388 cells to define a cell atlas of the adult human cerebrovasculature, including endothelial cell molecular signatures with arteriovenous segmentation and expanded perivascular cell diversity. By leveraging this reference, we investigated cellular and molecular perturbations in brain arteriovenous malformations, a leading cause of stroke in young people, and identified pathologic endothelial transformations with abnormal vascular patterning and the ontology of vascularly derived inflammation. Here, we illustrate the interplay between vascular and immune cells that contributes to brain hemorrhage and catalog opportunities for targeting angiogenic and inflammatory programs in vascular malformations.

Background-Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of ␤-amyloid impair cell function and lead to cell death. Methods and Results-We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca 2ϩ homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. Conclusions-On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca 2ϩ handling and a direct effect of PSEN1 sequence variants on excitationcontraction coupling protein function. (Circulation. 2010;121:1216-1226.) Key Words: calcium Ⅲ cardiomyopathy Ⅲ genetics Ⅲ heart failure Ⅲ myocytes I n 1906, Alois Alzheimer discovered, in the brain of a patient suffering from early-age onset of dementia, aggregates of a proteinaceous material, later identified to be composed of amyloid fibers. 1 Alzheimer disease (AD) is associated with several genetic defects and the abnormal accumulation of the amyloid-␤ protein (A␤) and in the form of extracellular (senile plaques) and intracellular (neurofibrillar tangles) aggregates, respectively. 2 In the heart, amyloid degeneration leading to dilated cardiomyopathy (DCM) has been limited to 3 conditions: (1) light-chain amyloidosis secondary to multiple myeloma; (2) transthyretin cardiomyopathy 3 ; and (3) desmin cardiomyopathy. 4,5 In a smaller number of cases of nonischemic origin, the pathogenesis of heart failure (HF) is infective, toxic, or genetically determined. When 1 of these causative events cannot be recognized, the myocardial disease is classified as idiopathic DCM (iDCM). Clinical Perspective on p 1226Genetically, DCM has been found in only 35% of HF cases, indicating that the cause of this disease remains largely unknown. 6 Mutations in genes encoding sarcomeric, cytoskeletal, and nuclear proteins as well as proteins involved in the regulation of Ca 2ϩ homeostasis have been described. 7,8 Allelic and locus heterogeneities occur in DCM, 9 and these alterations, together with environmental factors, can disclose an otherwise silent genetic background as occurs in neurodegenerative diseases. Recently, 2 mutations in the familial early-onset AD-associated presenilin genes (PSEN1 D333G and PSEN2 S130L), 2 have been found in 0.9% of tested DCM families (3/325). 10 The presenilins (PS1 and PS2) are highly conserved polytopic membrane proteins that are required for ␥-secretase activity, an enzyme responsible for proteolytic processing of the amyloid precursor protein to genera...

Objective The efficacy of epilepsy surgery depends critically upon successful localization of the epileptogenic zone. Magnetoencephalography (MEG) enables non-invasive detection of interictal spike activity in epilepsy, which can then be localized in three dimensions using magnetic source imaging (MSI) techniques. However, the clinical value of MEG in the pre-surgical epilepsy evaluation is not fully understood, as studies to date are limited by either a lack of long-term seizure outcomes or small sample size. Methods We performed a retrospective cohort study of focal epilepsy patients who received MEG for interictal spike mapping followed by surgical resection at our institution. Results We studied 132 surgical patients, with mean post-operative follow-up of 3.6 years (minimum 1 year). Dipole source modelling was successful in 103 (78%) patients, while no interictal spikes were seen in others. Among patients with successful dipole modelling, MEG findings were concordant with and specific to: i) the region of resection in 66% of patients, ii) invasive electrocorticography (ECoG) findings in 67% of individuals, and iii) the MRI abnormality in 74% of cases. MEG showed discordant lateralization in ~5% of cases. After surgery, 70% of all patients achieved seizure-freedom (Engel class I outcome). Whereas 85% of patients with concordant and specific MEG findings became seizure-free, this outcome was achieved by only 37% of individuals with MEG findings that were non-specific or discordant with the region of resection (χ2 = 26.4, p < 0.001). MEG reliability was comparable in patients with or without localized scalp EEG, and overall, localizing MEG findings predicted seizure freedom with an odds ratio of 5.11 (2.23–11.8, 95% CI). Significance MEG is a valuable tool for non-invasive interictal spike mapping in epilepsy surgery, including patients with non-localized findings on long-term EEG monitoring, and localization of the epileptogenic zone using MEG is associated with improved seizure outcomes.

OBJECTIVE Common surgical treatments for trigeminal neuralgia (TN) include microvascular decompression (MVD), stereotactic radiosurgery (SRS), and radiofrequency ablation (RFA). Although the efficacy of each procedure has been described, few studies have directly compared these treatment modalities on pain control for TN. Using a large prospective longitudinal database, the authors aimed to 1) directly compare long-term pain control rates for first-time surgical treatments for idiopathic TN, and 2) identify predictors of pain control. METHODS The authors reviewed a prospectively collected database for all patients who underwent treatment for TN between 1997 and 2014 at the University of California, San Francisco. Standardized collection of data on preoperative clinical characteristics, surgical procedure, and postoperative outcomes was performed. Data analyses were limited to those patients who received a first-time procedure for treatment of idiopathic TN with > 1 year of follow-up. RESULTS Of 764 surgical procedures performed at the University of California, San Francisco, for TN (364 SRS, 316 MVD, and 84 RFA), 340 patients underwent first-time treatment for idiopathic TN (164 MVD, 168 SRS, and 8 RFA) and had > 1 year of follow-up. The analysis was restricted to patients who underwent MVD or SRS. Patients who received MVD were younger than those who underwent SRS (median age 63 vs 72 years, respectively; p < 0.001). The mean follow-up was 59 ± 35 months for MVD and 59 ± 45 months for SRS. Approximately 38% of patients who underwent MVD or SRS had > 5 years of follow-up (60 of 164 and 64 of 168 patients, respectively). Immediate or short-term (< 3 months) postoperative pain-free rates (Barrow Neurological Institute Pain Intensity score of I) were 96% for MVD and 75% for SRS. Percentages of patients with Barrow Neurological Institute Pain Intensity score of I at 1, 5, and 10 years after MVD were 83%, 61%, and 44%, and the corresponding percentages after SRS were 71%, 47%, and 27%, respectively. The median time to pain recurrence was 94 months (25th-75th quartiles: 57-131 months) for MVD and 53 months (25th-75th quartiles: 37-69 months) for SRS (p = 0.006). A subset of patients who had MVD also underwent partial sensory rhizotomy, usually in the setting of insignificant vascular compression. Compared with MVD alone, those who underwent MVD plus partial sensory rhizotomy had shorter pain-free intervals (median 45 months vs no median reached; p = 0.022). Multivariable regression demonstrated that shorter preoperative symptom duration (HR 1.005, 95% CI 1.001-1.008; p = 0.006) was associated with favorable outcome for MVD and that post-SRS sensory changes (HR 0.392, 95% CI 0.213-0.723; p = 0.003) were associated with favorable outcome for SRS. CONCLUSIONS In this longitudinal study, patients who received MVD had longer pain-free intervals compared with those who underwent SRS. For patients who received SRS, postoperative sensory change was predictive of favorable outcome. However, surgical decision making depends upon...

OBJECTIVE Functional mapping using direct cortical stimulation is the gold standard for the prevention of postoperative morbidity during resective surgery in dominant-hemisphere perisylvian regions. Its role is necessitated by the significant interindividual variability that has been observed for essential language sites. The aim in this study was to determine the statistical probability distribution of eliciting aphasic errors for any given stereotactically based cortical position in a patient cohort and to quantify the variability at each cortical site. METHODS Patients undergoing awake craniotomy for dominant-hemisphere primary brain tumor resection between 1999 and 2014 at the authors' institution were included in this study, which included counting and picture-naming tasks during dense speech mapping via cortical stimulation. Positive and negative stimulation sites were collected using an intraoperative frameless stereotactic neuronavigation system and were converted to Montreal Neurological Institute coordinates. Data were iteratively resampled to create mean and standard deviation probability maps for speech arrest and anomia. Patients were divided into groups with a "classic" or an "atypical" location of speech function, based on the resultant probability maps. Patient and clinical factors were then assessed for their association with an atypical location of speech sites by univariate and multivariate analysis. RESULTS Across 102 patients undergoing speech mapping, the overall probabilities of speech arrest and anomia were 0.51 and 0.33, respectively. Speech arrest was most likely to occur with stimulation of the posterior inferior frontal gyrus (maximum probability from individual bin = 0.025), and variance was highest in the dorsal premotor cortex and the posterior superior temporal gyrus. In contrast, stimulation within the posterior perisylvian cortex resulted in the maximum mean probability of anomia (maximum probability = 0.012), with large variance in the regions surrounding the posterior superior temporal gyrus, including the posterior middle temporal, angular, and supramarginal gyri. Patients with atypical speech localization were far more likely to have tumors in canonical Broca's or Wernicke's areas (OR 7.21, 95% CI 1.67-31.09, p < 0.01) or to have multilobar tumors (OR 12.58, 95% CI 2.22-71.42, p < 0.01), than were patients with classic speech localization. CONCLUSIONS This study provides statistical probability distribution maps for aphasic errors during cortical stimulation mapping in a patient cohort. Thus, the authors provide an expected probability of inducing speech arrest and anomia from specific 10-mm cortical bins in an individual patient. In addition, they highlight key regions of interindividual mapping variability that should be considered preoperatively. They believe these results will aid surgeons in their preoperative planning of eloquent cortex resection.

BACKGROUND Seizure outcomes after focal neocortical epilepsy (FNE) surgery are less favorable than after temporal lobectomy, and the reasons for surgical failure are incompletely understood. Few groups have performed an in-depth examination of seizure recurrences to identify possible reasons for failure. OBJECTIVE To elucidate factors contributing to FNE surgery failures. METHODS We reviewed resections for drug-resistant FNE performed at our institution between 1998 and 2011. We performed a quantitative analysis of seizure outcome predictors and a detailed qualitative review of failed surgical cases. RESULTS Of 138 resections in 125 FNE patients, 91 (66%) resulted in freedom from disabling seizures (Engel I outcome). Mean ± SEM patient age was 20.0 ± 1.2 years; mean follow-up was 3.8 years (range, 1-17 years); and 57% of patients were male. Less favorable (Engel II-IV) seizure outcome was predicted by higher preoperative seizure frequency (odds ratio = 0.85; 95% confidence interval, 0.78-0.93), a history of generalized tonic-clonic seizures (odds ratio = 0.42; 95% confidence interval, 0.18-0.97), and normal magnetic resonance imaging (odds ratio = 0.30; 95% confidence interval, 0.09-1.02). Among 36 surgical failures examined, 26 (72%) were related to extent of resection, with residual epileptic focus at the resection margins, whereas 10 (28%) involved location of resection, with an additional epileptogenic zone distant from the resection. Of 16 patients who received reoperation after seizure recurrence, 10 (63%) achieved seizure freedom. CONCLUSION Insufficient extent of resection is the most common reason for recurrent seizures after FNE surgery, although some patients harbor a remote epileptic focus. Many patients with incomplete seizure control are candidates for reoperation.

Mutations in the presenilin genes cause the majority of early-onset familial Alzheimer’s disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis.