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...