From brain cytoarchitectonics to clinical neurology: Polish Institute for Brain Research in Vilnius, 1931-1938.

The Polish Institute for Brain Research was established in Warsaw in 1928 to support scientific research on the brain and its functions. The director of the institute was Maksymilian Rose (1883-1937), a distinguished Polish neurologist and neuroanatomist, a disciple of Oskar Vogt and Korbinian Brodmann. In 1931, the Institute was moved from Warsaw to Vilnius. The Institute was well-known in Europe at the time because of the research in the fields of neuroscience, clinical neurology, and psychiatry, as well as the cytoarchitectonic analysis of social activists' brains-a fashionable, neophrenological way to link the mental functions of deceased geniuses with the cellular composition of their central nervous systems. In 1939, the work of the Institute was interrupted by World War II; some of the preparations and materials were moved from Vilnius to Warsaw, some were stored in Vilnius, and some were lost. In this article, we analyze the primary and secondary sources, some of which were obscure for over 80 years, and evaluate the most important scientific achievements of the Polish Institute for Brain Research, as well as its legacy in the early period of modern neuroscience and neurology in interwar Vilnius.

Pioneers of cortical cytoarchitectonics: the forgotten contribution of Herbert Major.

The study of cortical cytoarchitectonics and the histology of the human cerebral cortex was pursued by many investigators in the second half of the nineteenth century, such as Jacob Lockhart Clarke, Theodor Meynert, and Vladimir Betz. Another of these pioneers, whose name has largely been lost to posterity, is considered here: Herbert Coddington Major (1850-1921). Working at the West Riding Asylum in Wakefield, United Kingdom, Major's thesis of 1875 described and illustrated six-layered cortical structure in both non-human primates and man, as well as "giant nerve cells" which corresponded to those cells previously described, but not illustrated, by Betz. Further journal publications by Major in 1876 and 1877 confirmed his finding of six cortical strata. However, Major's work was almost entirely neglected by his contemporaries, including his colleague and sometime pupil at the West Riding Asylum, William Bevan-Lewis (1847-1929), who later (1878) reported the presence of both pentalaminar and hexalaminar cortices. Bevan-Lewis's work was also later credited with the first illustration of Betz cells.

A different framework to classify preoptic and hypothalamic nuclei in reptiles.

The preoptic area and the hypothalamus are inextricably linked. Together, they represent an area of the forebrain that is essential for survival of the species. Observations in mammals have suggested a classification of these structures into four rostrocaudal areas and three mediolateral zones. Two species of crocodiles were investigated to determine if this scheme or a modification of it could be applied to these reptiles. The resulting classification identified three rostrocaudal areas based on their respective relationship to the ventricular system: preoptic, anterior, and tuberal and four mediolateral zones: ependyma, periventricular, medial, and lateral. This scheme avoided the cumbersome and complicated nomenclature that has traditionally been used for morphologic studies of these areas in other reptiles, including crocodiles. The present classification is simple, straightforward, and readily applicable to other reptiles.

A new 3D myeloarchitectonic map of the human neocortex based on data from the Vogt-Vogt school.

During the period extending from 1900 to 1970, Oskar and Cécile Vogt and their numerous collaborators ('the Vogt-Vogt school') published a large number of studies on the myeloarchitecture of the human cerebral cortex. During the last decade, we have concerned ourselves with a detailed meta-analysis of these now almost totally forgotten studies, with the aim to bringing them into the modern era of science. This scrutiny yielded inter alia a myeloarchitectonic map of the human neocortex, showing a parcellation into 182 areas (Nieuwenhuys et al. in Brain Struct Funct 220:2551-2573, 2015; Erratum in Brain Struct Funct 220: 3753-3755, 2015). This map, termed 2D'15, which is based on data derived from all of the 20 publications constituting the myeloarchitectonic legacy of the Vogt-Vogt school, has the limitation that it is two-dimensional i.e. it shows only the parts of the cortex exposed at the free surface of the cerebral hemispheres and not the extensive stretches of cortex hidden in the cortical sulci. However, a limited set of data, derived from four of the 20 publications available, has enabled us to create a 3D map, showing the myeloarchitectonic parcellation of the entire human neocortex. This map, designated as 3D'23, contains 182 areas: 64 frontal, 30 parietal, 6 insular, 19 occipital and 63 temporal. We have also prepared a 2D version (2D'23), of this 3D'23 map to serve as a link between the latter and our original 2D'15 map. Detailed comparison of the parcellations visualized in our three maps (2D'15, 2D'23 and 3D'23) warrants the conclusion that our new 3D'23 map may be considered as representative for the entire myeloarchitectural legacy of the Vogt-Vogt School. Hence it is now possible to compare the rich amount of myeloarchitectonic data assembled by that school directly with the results of current 3D analyses of the architecture of the human cortex, such as the meticulous quantitative cyto- and receptor architectonic studies of Zilles, Amunts and their numerous associates (Amunts et al. in Science 369:988-992, 2020), and the multimodal parcellation of the human cortex based on magnetic resonance images from the Human Connectome Project, performed by Glasser et al. in Nature 536:171-178, 2016).

Myeloarchitectonic cortical parcellation data for contemporary neuroimaging - the Vogt-Vogt legacy in the 21st century.

Obtaining precise and detailed parcellations of the human brain has been a major focus of neuroscience research. Here, we present a multimodal dataset, MYATLAS, based on histology-derived myeloarchitectonic parcellations for use with contemporary neuroimaging analyses software. The core of MYATLAS is a novel 3D neocortical, surface-based atlas derived from legacy myeloarchitectonic histology studies. Additionally, we provide digitized quantitative laminar profiles of intracortical myelin content derived from postmortem photometric data, cross-correlated with in vivo myeloarchitectonic features obtained by quantitative MRI mapping. Moreover, congregated, digitized and quality-improved Vogt-Vogt legacy histology data is made available. Finally, to allow for cross-modality correlations, maps of quantitative myelin estimates and corresponding von Economo-Koskinas' cytoarchitectonic features are also included. We share all necessary surface and volume-based registration files as well as shell scripts to facilitate applications of MYATLAS to future in vivo MRI studies.

Structural Organization of the Motor Speech Area of an Outstanding Writer.

The current study is concerned with the macroscopic and cytoarchitectonic structure of the motor speech area 44 in the left and right hemispheres of the brain of an outstanding writer (age 62 years). In a series of 20-µm frontal total paraffin sections stained with cresyl violet by the Nissl method, the density of total glia, the density of satellite glia, and the density of neurons surrounded by satellite glia were analyzed. The motor speech area of the cortex of the famous writer is characterized by a more complex macroscopic and cytoarchitectonic structure. In Broca's area, the density of total glia, satellite glia, and the neurons surrounded by satellite glia in associative layer III of area 44 were higher than in the control (brains of 5 men aged 59-71 years).

Posterior Intraparietal Sulcus Mediates Detection of Salient Stimuli Outside the Endogenous Focus of Attention.

Visual consciousness is shaped by the interplay between endogenous selection and exogenous capture. If stimulus saliency is aligned with a subject's attentional priorities, endogenous selection will be facilitated. In case of a misalignment, endogenous selection may be compromised as attentional capture is a strong and automatic process. We manipulated task-congruent versus -incongruent saliency in a functional magnetic resonance imaging change-detection task and analyzed brain activity patterns in the cortex surrounding the intraparietal sulcus (IPS) within the Julich-Brain probabilistic cytoarchitectonic mapping reference frame. We predicted that exogenous effects would be seen mainly in the posterior regions of the IPS (hIP4-hIP7-hIP8), whereas a conflict between endogenous and exogenous orienting would elicit activity from more anterior cytoarchitectonic areas (hIP1-hIP2-hIP3). Contrary to our hypothesis, a conflict between endogenous and exogenous orienting had an effect early in the IPS (mainly in hIP7 and hIP8). This is strong evidence for an endogenous component in hIP7/8 responses to salient stimuli beyond effects of attentional bottom-up sweep. Our results suggest that hIP7 and hIP8 are implicated in the individuation of attended locations based on saliency as well as endogenous instructions.

The Brain of an Outstanding Scientist-Inventor: Structural Organization of Area 10 of the Frontal Cortex.

We studied structural organization of cortical area 10 of the prefrontal cortex in the left and right hemispheres of the brain of an outstanding scientist and inventor (age 78 years). To this end, continuous series of 20-µm Nissl-stained frontal slices were compared with cortex sections of the same area from senile men (control group). It was found that the cytoarchitectonic organization of the cortical area 10 of the prefrontal cortex of the brain of an outstanding scientist-inventor is characterized by more pronounced vertical striation, greater thickness of the cortex and association layer III, higher density and size of pyramid neurons and higher density of satellite glia.

Anatomy and cytoarchitectonics of the human hypothalamus.

Due to the complexity of hypothalamic functions, the organization of the hypothalamus is extremely intricate. This relatively small brain area contains several nuclei, most of them are ill-defined regions without distinct boundaries; these nuclei are often connected with each other and other distant brain regions with similarly indistinct pathways. These hypothalamic centers control numerous key physiological functions including reproduction, growth, food intake, circadian rhythm, behavior, and autonomic balance via neural and endocrine signals. To understand the morphology of the hypothalamus is therefore extremely important, though it remains a stupendous task due to the complex organization of neuronal networks formed by the various neurotransmitter and neuromodulator systems.

Cytoarchitectonics of the Rolandic operculum: morphofunctional ponderings.

Constantin von Economo (1876-1931) had a long-standing interest in the cellular structure of the human cerebral cortex. In the present article I highlight a historical paper that von Economo published in 1930 on the cytoarchitectonics of the Rolandic operculum, an English translation of which I provide as supplementary material. I further discuss some morphofunctional aspects of the human opercular cortex from a modern perspective, as well as the clinical relevance to language dysfunctions, the operculum syndrome, and epilepsy.

A detailed comparison of the cytoarchitectonic and myeloarchitectonic maps of the human neocortex produced by the Vogt-Vogt school.

The comprehensive research programme of the Vogt-Vogt (V-V) school, which was active during the period 1900-1970, included detailed cytoarchitectonic and myeloarchitectonic analyses of the human cerebral cortex, with the aim to integrate the data obtained into a map, showing a parcellation of the human cerebral cortex into fundamental structural and potentially functional units. The cytoarchitectonic V-V analyses yielded two maps of the human cerebral cortex, the famous map of Brodmann (Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Barth, Leipzig, 1909), Brodmann (in: Bruns P (ed) Neue deutsche Chirurgie, Enke, Stuttgart, 1914), and the less known, but more detailed map of Sarkisov et al. (Cytoarchitecture of the human cortex cerebri. Medgiz, Moscow, 1949). Sarkisov et al. used in their cytoarchitectonic parcellation of the cortex the same numbering scheme as Brodmann. They confirmed the presence of most of the areas delineated by the latter, but they subdivided several of these areas into two or more separate areas or subareas. Within the realm of the myeloarchitectonic V-V analyses, numerous meticulous studies of the cortex of individual cerebral lobes were carried out, but these were not united into a single map. Consequently, the envisioned integration of cytoarchitectonic and myeloarchitectonic data mentioned above was never realized. Some years ago, we (Nieuwenhuys et al. in Brain Struct Funct 220:2551-2573, 2015a, Nieuwenhuys et al. in Brain Struct Funct 220:3753-3755, 2015b) reanalyzed the V-V myeloarchitectonic data, and succeeded in constructing a complete myeloarchitectonic map of the human neocortex from these data. Because the data provided by the V-V school were derived from many different brains, a standard brain had to be introduced as a template to which all data available could be transferred. As such the MNI305 template was selected. Having made available now the cytoarchitectonic maps of Brodmann and Sarkisov et al. and the recently prepared myeloarchitectonic map, an attempt is made here to realize at last the original aim of the V-V school, viz. the preparation of a single, combined (cyto + myelo) architectonic map of the human cortex. To this end, the following three steps have been made. First, Brodmann's (BR) map, and the map of Sarkisov et al. (SA) were harmoniously transferred to the same template brain as the one used during the construction of our myeloarchitectonic map. Second, the standardized BR and our myeloarchitectonic (NI) map were compared, and the data contained within these maps were integrated into a single standardized combined BR-NI map (Fig. 11). The standardized SA and NI maps were subjected to the same procedure (Fig. 12). Finally, the standardized combined BR-NI and SA-NI maps were united into a single combined BR-SA-NI map (Fig. 13). This map renders it possible to make direct comparisons between the results of the architectonic studies of the V-V school and current parcellations of the human neocortex.

Mapping the Architecture of Ferret Brains at Single-Cell Resolution.

Mapping the cytoarchitecture of the whole brain can reveal the organizational logic of neural systems. However, this remains a significant challenge, especially for gyrencephalic brains with a large volume. Here we propose an integrated pipeline for generating a cytoarchitectonic atlas with single-cell resolution of the whole brain. To analyze a large-volume brain, we used a modified en-bloc Nissl staining protocol to achieve uniform staining of large-scale brain specimens from ferret (Mustela putorius furo). By combining whole-brain imaging and big data processing, we established strategies for parsing cytoarchitectural information at a voxel resolution of 0.33 µm × 0.33 µm × 1 µm and terabyte-scale data analysis. Using the cytoarchitectonic datasets for adult ferret brain, we identified giant pyramidal neurons in ferret brains and provide the first report of their morphological diversity, neurochemical phenotype, and distribution patterns in the whole brain in three dimensions. This pipeline will facilitate studies on the organization and development of the mammalian brains, from that of rodents to the gyrencephalic brains of ferret and even primates.

Cytoarchitectonic Areas of the Gyrus ambiens in the Human Brain.

The Gyrus ambiens is a gross anatomical prominence in the medial temporal lobe (MTL), associated closely with Brodmann area 34 (BA34). It is formed largely by the medial intermediate subfield of the entorhinal cortex (EC) [Brodmann area 28 (BA28)]. Although the MTL has been widely studied due to its well-known role on memory and spatial information, the anatomical relationship between G. ambiens, BA34, and medial intermediate EC subfield has not been completely defined, in particular whether BA34 is part of the EC or a different type of cortex. In order to clarify this issue, we carried out a detailed analysis of 37 human MTLs, determining the exact location of medial intermediate EC subfield and its extent within the G. ambiens, its cortical thickness, and the histological-MRI correspondence of the G. ambiens with the medial intermediate EC subfield in 10 ex vivo MRI. Our results show that the G. ambiens is limited between two small sulci in the medial aspect of the MTL, which correspond almost perfectly to the extent of the medial intermediate EC subfield, although the rostral and caudal extensions of the G. ambiens may extend to the olfactory (rostrally) and intermediate (caudally) entorhinal subfields. Moreover, the cortical thickness averaged 2.5 mm (1.3 mm for layers I-III and 1 mm for layers V-VI). Moreover, distance among different landmarks visible in the MRI scans which are relevant to the identification of the G. ambiens in MRI are provided. These results suggest that BA34 is a part of the EC that fits best with the medial intermediate subfield. The histological data, together with the ex vivo MRI identification and thickness of these structures may be of use when assessing changes in MRI scans in clinical settings, such as Alzheimer disease.

Cytoarchitecture, probability maps, and functions of the human supplementary and pre-supplementary motor areas.

The dorsal  mesial frontal cortex contains the supplementary motor area (SMA) and the pre-supplementary motor area (pre-SMA), which play an important role in action and cognition. Evidence from cytoarchitectonic, stimulation, and functional studies suggests structural and functional divergence between the two subregions. However, a microstructural map of these areas obtained in a representative sample of brains in a stereotaxic reference space is still lacking. In the present study we show that the dorsal mesial frontal motor cortex comprises two microstructurally different brain regions: area SMA and area pre-SMA. Area-specific cytoarchitectonic patterns were studied in serial histological sections stained for cell bodies of ten human postmortem brains. Borders of the two cortical areas were identified using image analysis and statistical features. The 3D reconstructed areas were transferred to a common reference space, and probabilistic maps were calculated by superimposing the individual maps. A coordinate-based meta-analysis of functional imaging data was subsequently performed using the two probabilistic maps as microstructurally defined seed regions. It revealed that areas SMA and pre-SMA were strongly co-activated with areas in precentral, supramarginal and superior frontal gyri, Rolandic operculum, thalamus, putamen and cerebellum. Both areas were related to motor functions, but area pre-SMA was involved in more complex processes such as learning, cognitive processes and perception. The here described subsequent analyses led to converging evidence supporting the microstructural, and functional segregation of areas SMA and pre-SMA, and maps will be made available to the scientific community to further elucidate the microstructural substrates of motor and cognitive control.

Mapping brain structure and function: cellular resolution, global perspective.

A comprehensive understanding of the brain requires analysis, although from a global perspective, with cellular, and even subcellular, resolution. An important step towards this goal involves the establishment of three-dimensional high-resolution brain maps, incorporating brain-wide information about the cells and their connections, as well as the chemical architecture. The progress made in such anatomical brain mapping in recent years has been paralleled by the development of physiological techniques that enable investigators to generate global neural activity maps, also with cellular resolution, while simultaneously recording the organism's behavioral activity. Combination of the high-resolution anatomical and physiological maps, followed by theoretical systems analysis of the deduced network, will offer unprecedented opportunities for a better understanding of how the brain, as a whole, processes sensory information and generates behavior.

[The characteristics of redox-status of peripheral part of erythron under various localizations of neoplasm of organs of female reproductive sphere.]

The study was carried out to evaluate characteristics of redox-status in erythrocytes of peripheral blood of patients with ovarian cancer, uterine body cancer and cervix cancer using evaluation of products of peroxide oxidation of lipids: diene conjugates, ketodienes, Schiff's bases by Volchegorskii, malonic di-aldehyde by L.I. Andreieva, content of products of oxidizing modification of proteins by E.E. Dubinina; activity of anti-oxidant enzymes: superoxiddismutase by Nishikimi, catalase, glutathione-S'-transferase, glutathionereductase and level of reduced glutathione by A.I. Karpischenko. The evaluation of architectonics of erythrocytes and rigidity of membrane was implemented using a scanning probing microscope SolverPro (NT-MDT, Zelenograd, Russia). The statistical processing of obtained data was implemented using non-parametric Mann-Whitney U-test. The increasing of products of initial stages of peroxide oxidation of lipids - diene conjugates and malonic di-aldehyde and decreasing of level of interim (ketodienes) and tertiary ( Schiff's bases) products of peroxide oxidation of lipids have been established. Against this background a multi-directional alteration of superoxiddismutase and decreasing of catalase occurred. Simultaneously, increasing of activity of glutathione-transferase and level of reduced glutathione under all analyzed localizations of neoplasm were noted. The level of products of oxidizing modification of proteins depended on localization of primary tumor and it was minimal in case of cervix cancer. Also such an alteration of cyto-architectonics of erythrocytes was established as development of reversible deformed echinocytes in patients in case of ovarian cancer and irreversible deformed spherocytes in patients with cervix cancer and uterine body cancer and also abrupt increasing of rigidity of membrane of erythrocytes. The obtained data permits to surmise as a capacity of para-neoplastic processes development of oxidative and carbonyl stress in erythrocytes of peripheral blood of patients with ovarian cancer, cervix cancer and uterine body cancer at extensive stage of disease. The mentioned stress is accompanied by formation of echinocytes and spherocytes and significant increasing of rigidity of membrane. However, intensity of these processes is determined by localization of primary neoplasm and it can be applied for characteristic of biological portrait of tumor in case of consideration of schemes of anti-oxidant therapy.

A map of the human neocortex showing the estimated overall myelin content of the individual architectonic areas based on the studies of Adolf Hopf.

During the period extending from 1910 to 1970, Oscar and Cécile Vogt and their numerous collaborators published a large number of myeloarchitectonic studies on the cortex of the various lobes of the human cerebrum. In a previous publication [Nieuwenhuys et al (Brain Struct Funct 220:2551-2573, 2015; Erratum in Brain Struct Funct 220: 3753-3755, 2015)], we used the data provided by the Vogt-Vogt school for the composition of a myeloarchitectonic map of the entire human neocortex. Because these data were derived from many different brains, a standard brain had to be introduced to which all data available could be transferred. As such the Colin 27 structural scan, aligned to the MNI305 template was selected. The resultant map includes 180 myeloarchitectonic areas, 64 frontal, 30 parietal, 6 insular, 17 occipital and 63 temporal. Here we present a supplementary map in which the overall density of the myelinated fibers in the individual architectonic areas is indicated, based on a meta-analysis of data provided by Adolf Hopf, a prominent collaborator of the Vogts. This map shows that the primary sensory and motor regions are densely myelinated and that, in general, myelination decreases stepwise with the distance from these primary regions. The map also reveals the presence of a number of heavily myelinated formations, situated beyond the primary sensory and motor domains, each consisting of two or more myeloarchitectonic areas. These formations were provisionally designated as the orbitofrontal, intraparietal, posterolateral temporal, and basal temporal dark clusters. Recently published MRI-based in vivo myelin content mappings show, with regard to the primary sensory and motor regions, a striking concordance with our map. As regards the heavily myelinated clusters shown by our map, scrutiny of the current literature revealed that correlates of all of these clusters have been identified in in vivo structural MRI studies and appear to correspond either entirely or largely to known cytoarchitectonic entities. Moreover, functional neuroimaging studies indicate that all of these clusters are involved in vision-related cognitive functions.

Mapping dynamical properties of cortical microcircuits using robotized TMS and EEG: Towards functional cytoarchitectonics.

Brain dynamics at rest depend on the large-scale interactions between oscillating cortical microcircuits arranged into macrocolumns. Cytoarchitectonic studies have shown that the structure of those microcircuits differs between cortical regions, but very little is known about interregional differences of their intrinsic dynamics at a macro-scale in human. We developed here a new method aiming at mapping the dynamical properties of cortical microcircuits non-invasively using the coupling between robotized transcranial magnetic stimulation and electroencephalography. We recorded the responses evoked by the stimulation of 18 cortical targets largely covering the accessible neocortex in 22 healthy volunteers. Specific data processing methods were developed to map the local source activity of each cortical target, which showed inter-regional differences with very good interhemispheric reproducibility. Functional signatures of cortical microcircuits were further studied using spatio-temporal decomposition of local source activities in order to highlight principal brain modes. The identified brain modes revealed that cortical areas with similar intrinsic dynamical properties could be distributed either locally or not, with a spatial signature that was somewhat reminiscent of resting state networks. Our results provide the proof of concept of "functional cytoarchitectonics", that would guide the parcellation of the human cortex using not only its cytoarchitecture but also its intrinsic responses to local perturbations. This opens new avenues for brain modelling and physiopathology readouts.

Meta-connectomics: human brain network and connectivity meta-analyses.

Abnormal brain connectivity or network dysfunction has been suggested as a paradigm to understand several psychiatric disorders. We here review the use of novel meta-analytic approaches in neuroscience that go beyond a summary description of existing results by applying network analysis methods to previously published studies and/or publicly accessible databases. We define this strategy of combining connectivity with other brain characteristics as 'meta-connectomics'. For example, we show how network analysis of task-based neuroimaging studies has been used to infer functional co-activation from primary data on regional activations. This approach has been able to relate cognition to functional network topology, demonstrating that the brain is composed of cognitively specialized functional subnetworks or modules, linked by a rich club of cognitively generalized regions that mediate many inter-modular connections. Another major application of meta-connectomics has been efforts to link meta-analytic maps of disorder-related abnormalities or MRI 'lesions' to the complex topology of the normative connectome. This work has highlighted the general importance of network hubs as hotspots for concentration of cortical grey-matter deficits in schizophrenia, Alzheimer's disease and other disorders. Finally, we show how by incorporating cellular and transcriptional data on individual nodes with network models of the connectome, studies have begun to elucidate the microscopic mechanisms underpinning the macroscopic organization of whole-brain networks. We argue that meta-connectomics is an exciting field, providing robust and integrative insights into brain organization that will likely play an important future role in consolidating network models of psychiatric disorders.