Anton, Balint, Charles Bonnet, and the Others: The ABC of Cerebral Visual Syndromes (A Historical Guide and an Update).

Cerebral visual impairments have been of great interest to neurologists, ophthalmologists, and neuroscientists. Complicated or partial varieties related to cortical blindness are discussed in this review. They are a fascinating alphabet of eponymic clinical syndromes, bordering neurology, ophthalmology, and even psychiatry. Recent functional imaging and experimental studies have contributed further knowledge of cognitive visual organization in addition to the classical lesion evidence.

Normative brain mapping of interictal intracranial EEG to localize epileptogenic tissue.

The identification of abnormal electrographic activity is important in a wide range of neurological disorders, including epilepsy for localizing epileptogenic tissue. However, this identification may be challenging during non-seizure (interictal) periods, especially if abnormalities are subtle compared to the repertoire of possible healthy brain dynamics. Here, we investigate if such interictal abnormalities become more salient by quantitatively accounting for the range of healthy brain dynamics in a location-specific manner. To this end, we constructed a normative map of brain dynamics, in terms of relative band power, from interictal intracranial recordings from 234 participants (21 598 electrode contacts). We then compared interictal recordings from 62 patients with epilepsy to the normative map to identify abnormal regions. We proposed that if the most abnormal regions were spared by surgery, then patients would be more likely to experience continued seizures postoperatively. We first confirmed that the spatial variations of band power in the normative map across brain regions were consistent with healthy variations reported in the literature. Second, when accounting for the normative variations, regions that were spared by surgery were more abnormal than those resected only in patients with persistent postoperative seizures (t = -3.6, P = 0.0003), confirming our hypothesis. Third, we found that this effect discriminated patient outcomes (area under curve 0.75 P = 0.0003). Normative mapping is a well-established practice in neuroscientific research. Our study suggests that this approach is feasible to detect interictal abnormalities in intracranial EEG, and of potential clinical value to identify pathological tissue in epilepsy. Finally, we make our normative intracranial map publicly available to facilitate future investigations in epilepsy and beyond.

Interictal intracranial electroencephalography for predicting surgical success: The importance of space and time.

OBJECTIVE: Predicting postoperative seizure freedom using functional correlation networks derived from interictal intracranial electroencephalography (EEG) has shown some success. However, there are important challenges to consider: (1) electrodes physically closer to each other naturally tend to be more correlated, causing a spatial bias; (2) implantation location and number of electrodes differ between patients, making cross-subject comparisons difficult; and (3) functional correlation networks can vary over time but are currently assumed to be static. METHODS: In this study, we address these three challenges using intracranial EEG data from 55 patients with intractable focal epilepsy. Patients additionally underwent preoperative magnetic resonance imaging (MRI), intraoperative computed tomography, and postoperative MRI, allowing accurate localization of electrodes and delineation of the removed tissue. RESULTS: We show that normalizing for spatial proximity between nearby electrodes improves prediction of postsurgery seizure outcomes. Moreover, patients with more extensive electrode coverage were more likely to have their outcome predicted correctly (area under the receiver operating characteristic curve > 0.9, P « 0.05) but not necessarily more likely to have a better outcome. Finally, our predictions are robust regardless of the time segment analyzed. SIGNIFICANCE: Future studies should account for the spatial proximity of electrodes in functional network construction to improve prediction of postsurgical seizure outcomes. Greater coverage of both removed and spared tissue allows for predictions with higher accuracy.

The trial of David Ferrier, November 1881: Context, proceedings, and aftermath.

In November 1881, the eminent physiologist and physician David Ferrier was prosecuted under the Cruelty to Animals Act 1876. The prosecution was raised by the Victoria Street Society, formerly known as the Society for the Protection of Animals Liable to Vivisection, through its activist founder, Frances Power Cobbe. This article examines the legislative context prior to Ferrier's trial, the personalities involved in the prosecution, and its course and outcome. The resultant impact, both personal, on Cobbe and Ferrier, and professional, on experimental neurophysiology, is discussed, in particular the foundation of the Association for the Advancement of Medicine by Research (AAMR) and the provision of legal support for medical practitioners subject to litigation.

The advent of epilepsy directed neurosurgery: The early pioneers and who was first.

Efforts to treat epileptic seizures likely date back to primitive, manmade skull openings or trephinations at the site of previous scalp or skull injuries. The purpose may have been the release of "evil spirits," removal of "cerebral excitement," and "restoral of bodily and intellectual functions." With progressive discoveries in brain function over the past 100 to 300 years, the cerebral cortical locations enabling voluntary movements, sensation, and speech have been well delineated. The locations of these functions have become surgical targets for the amelioration of disease processes. Disease entities in particular cerebral-cortical areas may predispose to the onset of focal and or generalized seizures, which secondarily interfere with normal cortical functioning. Modern neuroimaging and electroencephalography usually delineate the location of seizures and often the type of structural pathology. If noneloquent brain regions are involved, open surgical biopsy or removal of only abnormal tissue may be undertaken successfully. A number of the early neurosurgical pioneers in the development of epilepsy surgery are credited and discussed in this article.

Probabilistic landscape of seizure semiology localizing values.

Semiology describes the evolution of symptoms and signs during epileptic seizures and contributes to the evaluation of individuals with focal drug-resistant epilepsy for curative resection. Semiology varies in complexity from elementary sensorimotor seizures arising from primary cortex to complex behaviours and automatisms emerging from distributed cerebral networks. Detailed semiology interpreted by expert epileptologists may point towards the likely site of seizure onset, but this process is subjective. No study has captured the variances in semiological localizing values in a data-driven manner to allow objective and probabilistic determinations of implicated networks and nodes. We curated an open data set from the epilepsy literature, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, linking semiology to hierarchical brain localizations. A total of 11 230 data points were collected from 4643 patients across 309 articles, labelled using ground truths (postoperative seizure-freedom, concordance of imaging and neurophysiology, and/or invasive EEG) and a designation method that distinguished between semiologies arising from a predefined cortical region and descriptions of neuroanatomical localizations responsible for generating a particular semiology. This allowed us to mitigate temporal lobe publication bias by filtering studies that preselected patients based on prior knowledge of their seizure foci. Using this data set, we describe the probabilistic landscape of semiological localizing values as forest plots at the resolution of seven major brain regions: temporal, frontal, cingulate, parietal, occipital, insula, and hypothalamus, and five temporal subregions. We evaluated the intrinsic value of any one semiology over all other ictal manifestations. For example, epigastric auras implicated the temporal lobe with 83% probability when not accounting for the publication bias that favoured temporal lobe epilepsies. Unbiased results for a prior distribution of cortical localizations revised the prevalence of temporal lobe epilepsies from 66% to 44%. Therefore, knowledge about the presence of epigastric auras updates localization to the temporal lobe with an odds ratio (OR) of 2.4 [CI95% (1.9, 2.9); and specifically, mesial temporal structures OR: 2.8 (2.3, 2.9)], attesting the value of epigastric auras. As a further example, although head version is thought to implicate the frontal lobes, it did not add localizing value compared with the prior distribution of cortical localizations [OR: 0.9 (0.7, 1.2)]. Objectification of the localizing values of the 12 most common semiologies provides a complementary view of brain dysfunction to that of lesion-deficit mappings, as instead of linking brain regions to phenotypic-deficits, semiological phenotypes are linked back to brain sources. This work enables coupling of seizure propagation with ictal manifestations, and clinical support algorithms for localizing seizure phenotypes.

A distributed network supports spatiotemporal cerebral dynamics of visual naming.

OBJECTIVE: Cerebral spatiotemporal dynamics of visual naming were investigated in epilepsy patients undergoing stereo-electroencephalography (SEEG) monitoring. METHODS: Brain networks were defined by Parcel-Activation-Resection-Symptom matching (PARS) approach by matching high-gamma (50-150 Hz) modulations (HGM) in neuroanatomic parcels during visual naming, with neuropsychological outcomes after resection/ablation of those parcels. Brain parcels with >50% electrode contacts simultaneously showing significant HGM were aligned, to delineate spatiotemporal course of naming-related HGM. RESULTS: In 41 epilepsy patients, neuroanatomic parcels showed sequential yet temporally overlapping HGM course during visual naming. From bilateral occipital lobes, HGM became increasingly left lateralized, coursing through limbic system. Bilateral superior temporal HGM was noted around response time, and right frontal HGM thereafter. Correlations between resected/ablated parcels, and post-surgical neuropsychological outcomes showed specific regional groupings. CONCLUSIONS: Convergence of data from spatiotemporal course of HGM during visual naming, and functional role of specific parcels inferred from neuropsychological deficits after resection/ablation of those parcels, support a model with six cognitive subcomponents of visual naming having overlapping temporal profiles. SIGNIFICANCE: Cerebral substrates supporting visual naming are bilaterally distributed with relative hemispheric contribution dependent on cognitive demands at a specific time. PARS approach can be extended to study other cognitive and functional brain networks.

The Evolution of Cerebral Language Localization: Historical Analysis and Current Trends.

Language localization has been an evolving concept over the past 150 years, with the emergence of several important yet conflicting ideologies. The classical theory, starting from the phrenologic work of Gall to the identification of specific regions of language function by Broca, Wernicke, and others, proposed that discrete subcomponents of language were organized into separate anatomic structural regions. The holism theory was postulated in an attempt to disclose that language function was instead attributed to a larger region of the cortex, in which cerebral regions may have the capability of assuming the function of damaged areas. However, this theory was largely abandoned in favor of discrete structural localizationist viewpoints. The subsequent cortical stimulatory work of Penfield led to the development of maps of localization, assigning an eloquent designation to specific regions. The expanding knowledge of cortical and subcortical anatomy allowed for the development of anatomically and functionally integrative language models. In particular, the dual stream model revisited the concept of regional interconnectivity and expanded the concept of eloquence. Advancements in cortical-subcortical stimulation, neurophysiologic monitoring, magnetic resonance diffusion tensor imaging/functional magnetic resonance imaging, awake neurosurgical technique, and knowledge gained by white matter tract anatomy and the Human Connectome Project, shed new light on the dynamic interconnectivity of the cerebrum. New studies are progressively opening doors to this paradigm, showing the dynamic and interdependent nature of language function. In this review, the evolution of language toward the evolving paradigm of dynamic language function and interconnectivity and its impact on shaping the neurosurgical paradigm are outlined.

Intraoperative Corticocortical Evoked Potentials for Language Monitoring in Epilepsy Surgery.

OBJECTIVE: To evaluate the applicability of corticocortical evoked potentials (CCEP) for intraoperative monitoring of the language network in epilepsy surgery under general anesthesia. To investigate the clinical relevance on language functions of intraoperative changes of CCEP recorded under these conditions. METHODS: CCEP monitoring was performed in 14 epileptic patients (6 females, 4 children) during resections in the left perisylvian region under general anesthesia. Electrode strips were placed on the anterior language area (AL) and posterior language area (PL), identified by structural and functional magnetic resonance imaging. Single-pulse electric stimulations were delivered to pairs of adjacent contacts in a bipolar fashion. During resection, we monitored the integrity of the dorsal language pathway by stimulating either AL by recording CCEP from PL or vice versa, depending on stability and reproducibility of CCEP. We evaluated the first negative (N1) component of CCEP before, during, and after resection. RESULTS: All procedures were successfully completed without adverse events. The best response was obtained from AL during stimulation of PL in 8 patients and from PL during stimulation of AL in 6 patients. None of 12 patients with a postresection N1 amplitude decrease of 0%-15% from baseline presented postoperative language impairment. Decreases of 28% and 24%, respectively, of the N1 amplitude were observed in 2 patients who developed transient postoperative speech disturbances. CONCLUSIONS: The application of CCEP monitoring is possible and safe in epilepsy surgery under general anesthesia. Putative AL and PL can be identified using noninvasive presurgical neuroimaging. Decrease of N1 amplitude >15% from baseline may predict postoperative language deficits.

Pre-Brodmann pioneers of cortical cytoarchitectonics I: Theodor Meynert, Vladimir Betz and William Bevan-Lewis.

This study and the sequel paper revisit landmark discoveries that paved the way to the definition of the renowned Brodmann areas in the human cerebral cortex, in an attempt to rectify certain undeserved historical neglects. A 'first period of discoveries,' from 1867 to 1882, is represented by the work of neuropsychiatrists Theodor Meynert (1833-1892) in Vienna, Vladimir Betz (1834-1894) in Kiev and William Bevan-Lewis (1847-1929) in Wakefield. Their classical findings are placed in a modern perspective.

Electrical stimulation sensorimotor mapping with stereo-EEG.

OBJECTIVE: We evaluated stereo-EEG electrical stimulation mapping (ESM) for localization of anatomic sensorimotor parcels in pediatric patients with drug-resistant epilepsy. We also analyzed sensorimotor and after-discharge thresholds, and the somatotopy of sensorimotor responses. METHODS: ESM was performed with 50 Hz, biphasic, 2-3 s trains, using 1-9 mA current. Pre- and post-implant neuroimaging was co-registered and intersected with Neurosynth reference, to classify each electrode contact as lying within/outside an anatomic sensorimotor parcel. Indices of diagnostic performance were computed. Sensorimotor and after-discharge thresholds were analyzed using multivariable linear mixed models. RESULTS: In 15 patients (6 females), aged 5.5-21.2 years, ESM showed high accuracy (0.80), high specificity (0.86), and diagnostic odds ratio (11.4, p < 0.0001) for localization of sensorimotor parcels. Mean sensorimotor threshold (3.4 mA) was below mean after-discharge threshold (4.2 mA, p = 0.0004). Sensorimotor and after-discharge thresholds showed a significant decrease with increasing intelligence quotient. Somatotopy of sensorimotor responses was mapped to standardized brain parcels. CONCLUSIONS: We provide evidence for diagnostic validity and safety of stereo-EEG sensorimotor ESM. SIGNIFICANCE: The somatotopy of sensorimotor responses elicited with electrical stimulation provide new insights into mechanisms of motor control and sensory perception.

Pre-Brodmann pioneers of cortical cytoarchitectonics II: Carl Hammarberg, Alfred Walter Campbell and Grafton Elliot Smith.

The present study and the preceding paper revisit landmark discoveries that paved the way to the definition of the renowned Brodmann areas in the human cerebral cortex, in an attempt to rectify certain undeserved historical neglects. A 'second period of discoveries', from 1893 to 1908, is marked by the work of Carl Hammarberg (1865-1893) in Uppsala, Alfred Walter Campbell (1868-1937) in Liverpool and Grafton Elliot Smith (1871-1937) in Cairo. Their classical findings are placed in a modern perspective.

High-gamma modulation language mapping with stereo-EEG: A novel analytic approach and diagnostic validation.

OBJECTIVE: A novel analytic approach for task-related high-gamma modulation (HGM) in stereo-electroencephalography (SEEG) was developed and evaluated for language mapping. METHODS: SEEG signals, acquired from drug-resistant epilepsy patients during a visual naming task, were analyzed to find clusters of 50-150 Hz power modulations in time-frequency domain. Classifier models to identify electrode contacts within the reference neuroanatomy and electrical stimulation mapping (ESM) speech/language sites were developed and validated. RESULTS: In 21 patients (9 females), aged 4.8-21.2 years, SEEG HGM model predicted electrode locations within Neurosynth language parcels with high diagnostic odds ratio (DOR 10.9, p < 0.0001), high specificity (0.85), and fair sensitivity (0.66). Another SEEG HGM model classified ESM speech/language sites with significant DOR (5.0, p < 0.0001), high specificity (0.74), but insufficient sensitivity. Time to largest power change reliably localized electrodes within Neurosynth language parcels, while, time to center-of-mass power change identified ESM sites. CONCLUSIONS: SEEG HGM mapping can accurately localize neuroanatomic and ESM language sites. SIGNIFICANCE: Predictive modelling incorporating time, frequency, and magnitude of power change is a useful methodology for task-related HGM, which offers insights into discrepancies between HGM language maps and neuroanatomy or ESM.

The telencephalon of the Göttingen minipig, cytoarchitecture and cortical surface anatomy.

During the last 20 years pigs have become increasingly popular in large animal translational neuroscience research as an economical and ethical feasible substitute to non-human primates. The anatomy of the pig telencephalon is, however, not well known. We present, accordingly, a detailed description of the surface anatomy and cytoarchitecture of the Göttingen minipig telencephalon based on macrophotos and consecutive high-power microphotographs of 15 µm thick paraffin embedded Nissl-stained coronal sections. In 1-year-old specimens the formalin perfused brain measures approximately 55 × 47 × 36 mm (length, width, height) and weighs around 69 g. The telencephalic part of the Göttingen minipig cerebrum covers a large surface area, which can be divided into a neocortical gyrencephalic part located dorsal to the rhinal fissure, and a ventral subrhinal part dominated by olfactory, amygdaloid, septal, and hippocampal structures. This part of the telencephalon is named the subrhinal lobe, and based on cytoarchitectural and sulcal anatomy, can be discerned from the remaining dorsally located neocortical perirhinal/insular, pericallosal, frontal, parietal, temporal, and occipital lobes. The inner subcortical structure of the minipig telencephalon is dominated by a prominent ventricular system and large basal ganglia, wherein the putamen and the caudate nucleus posterior and dorsally are separated into two entities by the internal capsule, whereas both structures ventrally fuse into a large accumbens nucleus. The presented anatomical data is accompanied by surface renderings and high-power macrophotographs illustrating the telencephalic sulcal pattern, and the localization of the identified lobes and cytoarchitectonic areas. Additionally, 24 representative Nissl-stained telencephalic coronal sections are presented as supplementary material in atlas form on http://www.cense.dk/minipig_atlas/index.html and referred to as S1-S24 throughout the manuscript.

NeuroDebian Virtual Machine Deployment Facilitates Trainee-Driven Bedside Neuroimaging Research.

Freely available software, derived from the past 2 decades of neuroimaging research, is significantly more flexible for research purposes than presently available clinical tools. Here, we describe and demonstrate the utility of rapidly deployable analysis software to facilitate trainee-driven translational neuroimaging research. A recipe and video tutorial were created to guide the creation of a NeuroDebian-based virtual computer that conforms to current neuroimaging research standards and can exist within a HIPAA-compliant system. This allows for retrieval of clinical imaging data, conversion to standard file formats, and rapid visualization and quantification of individual patients' cortical and subcortical anatomy. As an example, we apply this pipeline to a pediatric patient's data to illustrate the advantages of research-derived neuroimaging tools in asking quantitative questions "at the bedside." Our goal is to provide a path of entry for trainees to become familiar with common neuroimaging tools and foster an increased interest in translational research.

Early craniometric tools as a predecessor to neurosurgical stereotaxis.

In this paper the authors trace the history of early craniometry, referring to the technique of obtaining cranial measurements for the accurate correlation of external skull landmarks to specific brain regions. Largely drawing on methods from the newly emerging fields of physical anthropology and phrenology in the late 19th and early 20th centuries, basic mathematical concepts were combined with simplistic (yet at the time, innovative) mechanical tools, leading to the first known attempts at craniocerebral topography. It is important to acknowledge the pioneers of this pre-imaging epoch, who applied creativity and ingenuity to tackle the challenge of reproducibly and reliably accessing a specific target in the brain. In particular, with the emergence of Broca's theory of cortical localization, in vivo craniometric tools, and the introduction of 3D coordinate systems, several innovative devices were conceived that subsequently paved the way for modern-day stereotactic techniques. In this context, the authors present a comprehensive and systematic review of the most popular craniometric tools developed during this time period (prior to the stereotactic era) for the purposes of craniocerebral measurement and target localization.

7 tesla T2*-weighted MRI as a tool to improve detection of focal cortical dysplasia.

Focal cortical dysplasia is one of the most common underlying pathologies in patients who undergo surgery for refractory epilepsy. Absence of a MRI-visible lesion necessitates additional diagnostic tests and is a predictor of poor surgical outcome. We describe a series of six patients with refractory epilepsy due to histopathologically-confirmed focal cortical dysplasia, for whom pre-surgical 7 tesla T2*-weighted MRI was acquired. In four of six patients, T2* sequences showed areas of marked superficial hypointensity, co-localizing with the epileptogenic lesion. 7 tesla T2* hypointensities overlying focal cortical dysplasia may represent leptomeningeal venous vascular abnormalities associated with the underlying dysplastic cortex. Adding T2* sequences to the MRI protocol may aid in the detection of focal cortical dysplasias.

Postmortem imaging and neuropathologic correlations.

Postmortem imaging refers to scanning autopsy specimens using magnetic resonance imaging (MRI) or optical imaging. This chapter summarizes postmortem imaging and its usefulness in brain mapping. Standard in vivo MRI has limited resolution due to time constraints and does not deliver cortical boundaries (e.g., Brodmann areas). Postmortem imaging offers a means to obtain ultra-high-resolution images with appropriate contrast for delineating cortical regions. Postmortem imaging provides the ability to validate MRI properties against histologic stained sections. This approach has enabled probabilistic mapping that is based on ex vivo MRI contrast, validated to histology, and subsequently mapped on to an in vivo model. This chapter emphasizes structural imaging, which can be validated with histologic assessment. Postmortem imaging has been applied to neuropathologic studies as well. This chapter includes many ex vivo studies, but focuses on studies of the medial temporal lobe, often involved in neurologic disease. New research using optical imaging is also highlighted.

The musical centers of the brain: Vladimir E. Larionov (1857-1929) and the functional neuroanatomy of auditory perception.

In 1899 a landmark paper entitled "On the musical centers of the brain" was published in Pflügers Archiv, based on work carried out in the Anatomo-Physiological Laboratory of the Neuropsychiatric Clinic of Vladimir M. Bekhterev (1857-1927) in St. Petersburg, Imperial Russia. The author of that paper was Vladimir E. Larionov (1857-1929), a military doctor and devoted brain scientist, who pursued the problem of the localization of function in the canine and human auditory cortex. His data detailed the existence of tonotopy in the temporal lobe and further demonstrated centrifugal auditory pathways emanating from the auditory cortex and directed to the opposite hemisphere and lower brain centers. Larionov's discoveries have been largely considered as findings of the Bekhterev school. Perhaps this is why there are limited resources on Larionov, especially keeping in mind his military medical career and the fact that after 1917 he just seems to have practiced otorhinolaryngology in Odessa. Larionov died two years after Bekhterev's mysterious death of 1927. The present study highlights the pioneering contributions of Larionov to auditory neuroscience, trusting that the life and work of Vladimir Efimovich will finally, and deservedly, emerge from the shadow of his celebrated master, Vladimir Mikhailovich.

Franz Joseph Gall on greatness in the fine arts: A collaboration of multiple cortical faculties of mind.

Although Franz Joseph Gall (1758-1828) is well known for his organology, i.e., his theory of cortical localization of function largely derived from skull features, little has been written about his ideas pertaining to specific faculties other than speech, and even less attention has been drawn to how the individual faculties might work together in specific situations. Our focus shall be on how Franz Joseph Gall viewed the fine arts, with special emphasis on what one must possess to be outstanding in this field, which he associated with perceiving and understanding relationships, and several higher faculties of mind, including color, "constructiveness," locality, and recognizing people. How these faculties are utilized, he tells us, will vary with whether an artist does portraits, landscapes, historical scenes, still life compositions, etc., as well as with the selected medium (e.g., oil paints, sketching on paper, stones to be carved). To put Gall's thoughts about the fine arts in context, brief mention will be made of his scientific career, his guiding philosophy, the questions he most wanted to answer, what he construed as "evidence," how he eliminated the soul or "controller" from his system, and how he presented his work to the public. Some comparisons will be made to what he wrote about having a talent for music.