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Imagine you were asked to investigate the workings of an engine, but to do so without ever opening the hood. Now imagine the engine fueled the human mind. This is the challenge faced by cognitive neuroscientists worldwide aiming to understand the neural bases of our psychological functions. Luckily, human ingenuity comes to the rescue. Around the same time as the Society for Neuroscience was being established in the 1960s, the first tools for measuring the human brain at work were becoming available. Noninvasive human brain imaging and neurophysiology have continued developing at a relentless pace ever since. In this 50 year anniversary, we reflect on how these methods have been changing our understanding of how brain supports mind., (Copyright © 2020 Nobre and van Ede.)

The technique of microneurography has advanced the field of neuroscience for the past 50 years. While there have been a number of reviews on microneurography, this paper takes an objective approach to exploring the impact of microneurography studies. Briefly, Web of Science (Thomson Reuters) was used to identify the highest citation articles over the past 50 years, and key findings are presented in a decade-by-decade highlight. This includes the establishment of microneurography in the 1960s, the acceleration of the technique by Gunnar Wallin in the 1970s, the international collaborations of the 1980s and 1990s, and finally the highest impact studies from 2000 to present. This journey through 50 years of microneurographic research related to peripheral sympathetic nerve activity includes a historical context for several of the laboratory interventions commonly used today (e.g., cold pressor test, mental stress, lower body negative pressure, isometric handgrip, etc.) and how these interventions and experimental approaches have advanced our knowledge of cardiovascular, cardiometabolic, and other human diseases and conditions.

Research on memory has been a major focus in the neurosciences over the past decades. An important advance was achieved by Wilder Penfield at the Montreal Neurological Institute, who reported from the 1930s to the 1950s about experiential phenomena induced by electrical brain stimulation in humans, implying neuronal causation of memory. Since then, neuroscientists have addressed the topic of memory from a range of subdisciplines; however, these reports by Penfield and his group as well as those on patient H. M. by Brenda Milner at the same institution continue to be referenced as groundbreaking. Further experimental work by Nobel laureates Eric Kandel and John O'Keefe, as well as by Edvard and May-Britt Moser related Penfield's patient documentation to experiential phenomena. However, our reassessment of Penfield's original patient documentation questions the stance that he had uncovered the "storehouse of memories." Human memory must be regarded more as context sensitive and as representative of an active reconstructive process, than as a simple recording of events. Hence, strategies aiming at naturalizing all phenomena of mind (including memory) to cellular and molecular mechanisms cannot convincingly refer to Penfield's electrophysiological studies alone as evidence that memories are solely caused by neuronal firing patterns.

As a primary component of homeostasis, the sympathetic nervous system enables rapid adjustments to stress through its ability to communicate messages among organs and cause targeted and graded end organ responses. Key in this communication model is the pattern of neural signals emanating from the central to peripheral components of the sympathetic nervous system. But what is the communication strategy employed in peripheral sympathetic nerve activity (SNA)? Can we develop and interpret the system of coding in SNA that improves our understanding of the neural control of the circulation? In 1968, Hagbarth and Vallbo (Hagbarth KE, Vallbo AB. Acta Physiol Scand 74: 96-108, 1968) reported the first use of microneurographic methods to record sympathetic discharges in peripheral nerves of conscious humans, allowing quantification of SNA at rest and sympathetic responsiveness to physiological stressors in health and disease. This technique also has enabled a growing investigation into the coding patterns within, and cardiovascular outcomes associated with, postganglionic SNA. This review outlines how results obtained by microneurographic means have improved our understanding of SNA outflow patterns at the action potential level, focusing on SNA directed toward skeletal muscle in conscious humans.

In between Carl Wernicke's locationist aphasia concept from 1874 and Norman Geschwind's new connectionist model of human brain functions in 1965, little notice was taken of the historical debate on aphasia and brain plasticity. Interestingly, Kurt Goldstein made long-forgotten, but highly relevant remarks on the connectionist model and thereby served as an important connecting link between Wernicke and Geschwind. With the original contributions of Goldstein and contemporary authors, we analyzed the historical background of the aphasia debate in the time period between Wernicke and Geschwind, which still influences current aphasia concepts and neurosurgical practice of today.

The year of 2014 is the birth centenary of Aristides Azevedo Pacheco Leão (1914-1993), and also marks seventy years of the publication of his discovery of the novel electrophysiological phenomenon, named by him "spreading depression" (SD), soon designated "Leão's wave" or "Leão's spreading depression". This was a remarkable scientific milestone, and the author must be celebrated for this achievement, as the studies he triggered proceeded worldwide, with new concepts, as spreading depolarization, until the present days. Robust experimental and clinical evidence emerged to suggest that these and related electrophysiological phenomena are involved in the mechanisms of migraine aura, acute cerebrovascular diseases, traumatic brain injury, transient global amnesia, epileptic seizures, and their pathophysiological characteristics come to offer new therapeutic perspectives. He was a remarkable and complex personality, and the authors remit the readers to a paper where his personal life is contemplated.

Claude Bernard (1813-1878) followed two main research paths: the chemical and physiological study of digestion and liver function, along with experimental section of nerves and studies on sympathetic nerves. Curare studies were, for example, of longstanding interest. His profound mental creativity and hand skillfulness, besides methodology quality, directed his experiments and findings, mainly at the Collège de France. His broader and epistemological concerns were carried out at the Sorbonne and later at the Muséum national d'Histoire naturelle. His insight gave clues to define the " milieu intérieur", later known as "homeostasis", and grasp the brain complexity. Bernard followed and surpassed his master François Magendie who also fought against dogmas and laid the foundations of experimental medicine, and its main heinous tool - vivisection. Bernard created the methodological bases of experimental medicine, and collected honors as a renowned researcher.

During his lifetime and a career spanning 42 years, James Watson Kernohan made numerous contributions to neuropathology, neurology, and neurosurgery. One of these, the phenomenon of ipsilateral, false localizing signs caused by compression of the contralateral cerebral peduncle against the tentorial edge, has widely become known as "Kernohan's notch" and continues to bear his name. The other is a grading system for gliomas from a neurosurgical viewpoint that continues to be relevant for grading of glial tumors 60 years after its introduction. In this paper, the authors analyze these two major contributions in detail within the context of Kernohan's career and explore how they contributed to the development of neurosurgical procedures.

Neuroimaging techniques, such as positron emission tomography and functional magnetic resonance imaging are essential tools for the analysis of organized neural systems in working and resting states, both in physiological and pathological conditions. They provide evidence of coupled metabolic and cerebral local blood flow changes that strictly depend upon cellular activity. In 1890, Charles Smart Roy and Charles Scott Sherrington suggested a link between brain circulation and metabolism. In the same year William James, in his introduction of the concept of brain blood flow variations during mental activities, briefly reported the studies of the Italian physiologist Angelo Mosso, a multifaceted researcher interested in the human circulatory system. James focused on Mosso's recordings of brain pulsations in patients with skull breaches, and in the process only briefly referred to another invention of Mosso's, the 'human circulation balance', which could non-invasively measure the redistribution of blood during emotional and intellectual activity. However, the details and precise workings of this instrument and the experiments Mosso performed with it have remained largely unknown. Having found Mosso's original manuscripts in the archives, we remind the scientific community of his experiments with the 'human circulation balance' and of his establishment of the conceptual basis of non-invasive functional neuroimaging techniques. Mosso unearthed and investigated several critical variables that are still relevant in modern neuroimaging such as the 'signal-to-noise ratio', the appropriate choice of the experimental paradigm and the need for the simultaneous recording of differing physiological parameters.

The brain illustrations of Vesalius and Willis were the first in anatomic history with pictorial accuracy. Their illustrations, illustrators, and methods are discussed. Woodcut blocks were used for the prints of figures in the Vesalian anatomy. Figures of the brain appear to be done after external fixation in the work of Willis.

Patricia S. Goldman-Rakic (1937-2003) transformed the study of the prefrontal cortex (PFC) and the neural basis of mental representation, the basic building block of abstract thought. Her pioneering research first identified the dorsolateral PFC (dlPFC) region essential for spatial working memory, and the extensive circuits of spatial cognition. She discovered the cellular basis of working memory, illuminating the dlPFC microcircuitry underlying spatially tuned, persistent firing, whereby precise information can be held "in mind": persistent firing arises from recurrent excitation within glutamatergic pyramidal cell circuits in deep layer III, while tuning arises from GABAergic lateral inhibition. She was the first to discover that dopamine is essential for dlPFC function, particularly through D1 receptor actions. She applied a host of technical approaches, providing a new paradigm for scientific inquiry. Goldman-Rakic's work has allowed the perplexing complexities of mental illness to begun to be understood at the cellular level, including atrophy of the dlPFC microcircuits subserving mental representation. She correctly predicted that impairments in dlPFC working memory activity would contribute to thought disorder, a cardinal symptom of schizophrenia. Ten years following her death, we look back to see how she inspired an entire field, fundamentally changing our view of cognition and cognitive disorders.

This year, the Albert Lasker Basic Medical Research Award will be shared by Richard Scheller and Thomas Südhof for their elucidation of the molecular mechanisms underlying neurotransmitter release. Their discoveries provided insight into the molecular basis of synaptic transmission and enhanced our understanding of how synaptic dysfunction may cause neuropsychiatric disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This article presents historical background preceding writing and publication of Jerzy Konorski book "Integrative Activity of the Brain" followed by a short description of the main topics covered in the book. Two new and original contributions of Konorski are presented in detail, his theory of the motivational processes and the organization of the sensory systems in the brain. Those two contributions are then incorporated in the revised theory of the classical and type II conditioned reflexes which constitutes the core of the book. Conclusions point out at some of the ideas which remained valuable for the present day neuroscientists.

The authors have analyzed the content of a selection of letters written by Dom Pedro II, the Emperor of Brazil, and sent to Doctor Charles Brown-Séquard, the famous neurologist, between 1876 and 1885. The content of those letters focuses mainly on his wife's, Princess Thereza Cristina, health issues and Dom Pedro's personal desire to foster the research into the physiological study of the nervous system.

This article aims to reintroduce two classic papers on motor control published in Brain in 1968, in which Lawrence and Kuypers reported their systematic studies of the effects of lesions to the corticospinal system (Lawrence and Kuypers, 1968a), and subsequently to the descending brainstem pathways (Lawrence and Kuypers, 1968b) in the Old World macaque monkey. They showed that the capacity for independent movements of the digits was permanently lost after a complete, bilateral lesion of the corticospinal system. These studies also revealed that the brainstem pathways contribute to fundamentally different aspects of motor control, with one set of pathways (the ventromedial system) involved in the control of head, trunk and girdle movements, while the other, lateral set of fibres control movements of the extremity such as reach and grasp. There is still much to learn today from these papers. However, an important part of their scientific legacy, the films illustrating the different cases, has long been unavailable. Much of this filmed material is now made available again in video format accessible on the Brain web site, complete with supplementary notes and histological detail. This article summarizes this newly available material for these classic papers in Brain.

Background: Emil Theodor Kocher (1841-1917) was elected as head of the university clinic for surgery in Berne, Switzerland at the age of 31 years. During the 45 years of his professorship he became one of the outstanding surgeons of Europe by using surgical techniques based predominately on physiological and biological ideas. The aim of this article was to highlight his neurosurgical achievements published in the German language., Methods: The illustrations of Kocher's works in the field of neurosurgery are exclusively based on his publications and works published by his co-workers., Results: Kocher received the Nobel Prize in Physiology or Medicine in 1909 because he devoted himself to intense research and development in the pathophysiology and surgical treatment of diseases of the thyroid gland. His particular neurosurgical interests were in cerebral and spinal trauma, operative treatment of epilepsy and the pathophysiology of elevated intracranial pressure., Conclusion: Studies of Kocher's contributions, published exclusively in the German language, lead to the conclusion that Kocher must be designated as the first Swiss neurosurgeon.

In September 1961, the First International Congress of Electromyography (EMG) was held at the University of Pavia. This event proved to be a sort of foundation stone for the further development of EMG as an organized field. Many of the most distinguished clinical neurophysiologists attended this congress and took an active part in it, delivering important lectures and scientific communications on the various aspects of EMG, including electroneurography. They included: Henri Gastaut, Fritz Buchthal, Jean Edouard Desmedt, Eric Kugelberg, Roger W. Gilliatt, John A. Simpson, Albrecht Struppler, Irena Hausmanowa-Petrusewicz, and Howard Edward Lambert. The congress was organized by Paolo Pinelli, at the time a young and brilliant clinical neurophysiologist who had learned the EMG procedure in Copenhagen under the guidance of Fritz Buchthal. Various scientific and social aspects of this important congress are outlined in this paper.

John Newsom-Davis was born in 1932 and died, aged 74, in 2007. After national service in the Royal Air Force, he read Natural Sciences at Cambridge. Following clinical studies at the Middlesex Hospital, he began research into respiratory neurophysiology with Tom Sears at the National Hospital, Queen Square, in London, and spent 1 year with Fred Plum at Cornell University in New York. After neurology specialist training at Queen Square, he became the director of the Batten Unit, continuing his interest in respiratory physiology. There he began to work on myasthenia gravis in collaboration with Ricardo Miledi at University College London and in 1978, after performing the first studies on plasma exchange in that disease, he established a myasthenia gravis research group at the Royal Free Hospital. There he investigated the role of the thymus in this disease and demonstrated an autoimmune basis for the Lambert Eaton myasthenic syndrome and 'seronegative' myasthenia. He was awarded the first Medical Research Council Clinical Research Professorship in 1979 but moved to Oxford in 1987 when he was elected Action Research Professor of Neurology. While at Oxford, he continued to run a very successful multidisciplinary group, researched further into the thymic abnormalities and cellular immunology of myasthenia, identified antibody-mediated mechanisms in acquired neuromyotonia, and began the molecular work that identified the genetic basis for many forms of congenital myasthenic syndrome. Meanwhile, he was also involved in university and college governance and contributed widely to the Medical Research Council, government committees, research charities and the Association of British Neurologists. Among many honours, he was elected Fellow of the Royal Society in 1991, appointed Commander of the British Empire in 1996 and made a Foreign Associate Member of the Institute of Medicine of the United States in 2001. Nearing and following retirement from Oxford, where he continued to see patients with myasthenia, he was the President of the Association of British Neurologists and Editor of Brain, and led a National Institutes of Health-funded international trial of thymectomy.

In the early 1970s, receptors for neurotransmitters acting via second messengers had not been identified biochemically nor were there definitive links to such messengers. The discovery by John W. Kebabian and Paul Greengard of a dopamine-sensitive adenyl cyclase, accordingly, was a giant step forward. The investigators first characterized the enzyme in sympathetic ganglia wherein dopamine-producing cells link pre- and post-synaptic neurons. Then, in the corpus striatum, the brain area enriched in dopamine, they delineated the enzyme\x{2019}s properties and showed that it was inhibited by antipsychotic drugs, leading to a large body of research on dopamine as a mediator of antipsychotic drug action and putative roles for this transmitter in the pathophysiology of schizophrenia.

The history of the representations of the brain is broadly the history of the brain itself, since observations and ideas which concern it are closely linked, and are even depending on each other. These representations are images, but are also materials produced by manipulating, cutting, fixing the brain; they are also the descriptions of these objects. The interpretations, structured by the representations, ultimately organize the knowledge.

The changing use of the clock metaphor serves as a helpful contrast medium to highlight the different concepts of the body-soul-system between 1450 and 1750. This article first relates to the social, political and philosophical functions of the horologium. Then it outlines the different fields of discourse, in which the clock metaphor was mainly invoked. Finally, it examines the writings of a number of significant authors (Cusanus, Ficino, Descartes, Leibniz, Wolff, La Mettrie) with an eye to the evolution of the clock metaphor in various theological, metaphysical and physiological contexts. Surprisingly enough, the clock (or watch) initially represented the life-giving soul and human consciousness, before turning into the well-known symbol for the body-machine, and in particular for its neurophysiological operations.

My professional life over five decades meandered from a high school ambition to be a psychiatrist and understand the "mind" to biochemical studies of neurotransmitters and drugs. Hopefully, the tale of my quirky impatient curiosity about "too many" different areas will be useful for young scientists embarking on their own careers., (Copyright 2009 Elsevier Inc. All rights reserved.)