An Introduction to Neuroscience

Neuroscience, as defined by the Merriam-Webster Medical Dictionary, is “a branch of science that deals with the anatomy, physiology, biochemistry, or molecular biology of nerves and nervous tissue and especially their relation to behavior and learning”. Neuroscience is a broad discipline that studies the nervous system, its diseases, and potential therapies to treat these diseases.

Figure 1. Trend showing the number of published articles that use the term ‘neuroscience’ from the MEDLINE database. (Image Credit: PubMed accessed on March 18, 2022).

Research in neuroscience and related fields continues to gain momentum. A search of the MEDLINE database reveals that the number of published articles using the term ‘neuroscience’ has exploded in the past few years (Figure 1).

This trend is also supported by the increased funding available for research in neuroscience. The National institute of Health (NIH) has consistently reported increased funding for neurological disorders such as dementia (Figure 2). The NIH led, Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, was launched in 2013 to interrogate neural circuits and patterns of activity underlying complex behavior and thought. The multidisciplinary initiative prioritizes funding for research with the goal of understanding the brain and developing informed treatments for neurological and psychiatric disorders.

Figure 2. Increased funding from NIH for Alzheimer’s disease and Alzheimer’s Disease-related dementias in the past five years. (Image Credit: RePORT accessed on March 18, 2022)

Organizations such as Society for Neuroscience, which has for over 50 years been a global community for neuroscientists, facilitate collaborations. Ongoing, multidisciplinary collaborative approaches are underway to tackle the challenges of scale in neuroscience research, as epitomized by the non-profit Allen Institute and are transforming the research landscape.

Given the public interest in neuroscience, it is worthwhile to understand the scope of neuroscience. In this article, a brief overview of the history, scope, and future trends in neuroscience are discussed.

History of Neuroscience

The history of neuroscience informs us about how past failures and past successes have shaped our current knowledge base. The earliest philosophers thought about the brain in a very subjective manner, and through the centuries that followed, this mode of thinking gave way to a more targeted, empirical probing of the brain in finer, finer detail. This was a reductionist approach, based on experimentation that generated copious and increasingly complex variety of data. Researchers applied principles from other rigorous modalities to further analyze and organize these huge datasets, taking advantage of increasingly easier access to computation and faster, more efficient computer systems. These advancements have led to modern attempts of abstracting the essential, simplified, and broadly applicable concepts derived from these experiments. Today these theoretical insights have been consolidated and applied to build models based on neural networks, and to the development of artificial intelligence and machine learning tools.

The oldest medical documentation of the brain and spinal cord, referred to as the Edwin Smith papyrus was ascribed to the 7^th century BC Egyptians, and provides descriptions of features, such as meninges, cerebrospinal fluid, and included cases of brain trauma. The ancient Greeks, in the 4^th century BC would debate that the heart was responsible for what we know to be brain functions, especially issues related to the location of the 'mind'. In this period, Hippocrates, favored the brain and argued for the importance of the brain in perception, memory, and other cognitive functions. During the 2^nd century BC, while it was known at this time that the brain, spinal cord and nerves were connected, the Roman physician Galen, provided anatomical and structural evidence of 7 cranial nerves, and stated "the nerves originate in the brain", he further elaborated on the cerebral localization of perception, cognition and motion. Both Hippocrates and Galen are considered to be forefathers of medicine!

There is evidence from the 4^th century BC Greco-Roman civilization of healers conducting trepanation (derivative of Latin 'trephanon'), or boring a hole in the skull. Trepanation, was deployed therapeutically through the centuries, and evidence from recovered skulls suggest that the Inca's of Peru famously used this technique during 14^th to 16^th centuries. Later, in the 17th century, psychiatric disorders such as hysteria, mania, melancholia were thought to originate in different organs of the body. Hysteria was deemed to be a uterine disease, but Thomas Willis, the physician, whose contributions laid the foundation for clinical neurology, considered hysteria to be a convulsive disorder due to brain dysfunction. Thomas Willis, described numerous brain structures including descriptions of the blood supply to the brain, and the arterial circuit he elucidated at the base of the brain, is known as the 'Circle of Willis'. During this period the study of epilepsy led to the discovery of brain areas related to function, such as the motor cortex, and furthermore it also got scientists interested in the study of speech. The 19th century French physician, Paul Broca, found patients who had lesions in a particular region of the left cerebral hemisphere were unable to produce speech. This loss of expression is now referred to as Broca's aphasia. Similarly, Karl Wernicke, a neurologist in Germany, discovered that lesions to parts of the left temporal lobe, resulted in loss of comprehension, but not production of speech, and this receptive malfunction is referred to as Wernicke's aphasia. These finding's localized language preferentially in the left hemisphere, and this lateralization of brain function is now a widely accepted principle for other brain modalities, and has further enabled the functional mapping of the cortex.

Neuroscience has made rapid progress since the 1900s. The technological progress in microscopy has marshaled the field for rapid discoveries that were previously, literally invisible to the eye and could at best only be inferred.

Figure 3. Drawing of Purkinje cells (A) and granule cells (B) from pigeon cerebellum by Santiago Ramón y Cajal, 1899. Instituto Santiago Ramón y Cajal, Madrid, Spain. (Public domain image accessed on June 13, 2022)

In the late 1800's, the Spanish physician and histologist Santiago Ramon y Cajal improved the silver tissue staining technique that were developed by the Italian Camillo Golgi to visualize individual nerve cells such as Purkinje and granule cells (Figure 3). Cajal used a light microscope to establish the neuron as a discrete entity and not part of a "synctium", a continous reticular network promoted by Golgi. Cajal's, truly beautiful drawings of neurons laid the groundwork for the neuron doctrine—the central organizational and signaling role of the neuron in the nervous system.

Sir Charles Sherrington, in the late 1800's, a proponent of the neuron doctrine, appreciated that individual neurons had to communicate their signal to one another across the space between them, and coined the term 'synapse' to distinguish the neuronal surfaces at the interface of and the cleft between adjacent neurons. These days the light microscope is deployed to provide morphological detail as much as to provide information about the connections formed by cells in a circuit forming the "connectome". The advent of the electron microscopy in the 1930's provided nanometer scale resolution and yielded information on the ultrastucture of the synapse. Confocal microscopy allowed for 3D reconstruction of neurons stained with a variety of fluorescent dyes to distinguish components of the nerve cell. Tunneling microscopes of today, with atomic scale resolving ability have exceeded the theoretical limits of visualization! The 2014 Nobel Prize in Chemistry was awarded to the discoverer's of the super-resolved fluorescence microscopy for 'seeing' structures smaller than 200 nanometers, which has an immediate impact on our ability to further query the cells at the finer, ultrastructural level. What used to be direct visualization of the tissue has been largely transformed, in the 20^th and 21^st centuries into acquiring images digitally, with computational analysis and image reconstruction, and with higher levels of abstraction.

In a collaboration spanning the late 1930's to the 1950's Alan Hodgkin and Andrew Huxley conducted an elegant series of studies on the giant axon of the squid, developing a model to describe how the movement of ions across the axonal membrane drove the excitability of nerve cells, and in doing so laid the foundation of studying the kinetics of voltage-gated ion channels. Hodgkin and Huxley shared the 1963 Nobel prize for their landmark findings, and their work represented a milestone that would lead to future milestones in the field of electrophysiology, including the development of the patch-clamp in the 1970's, that enabled study of single ion-channels, and later in the 2000's, the elucidation of the ion channel structure at the molecular level. In addition, the discovery of now, over a hundred neurotransmitters, including small molecules, amino acids, and peptides, through their receptors are responsible for the chemical gating of ion channels.

The field of neuroscience has greatly benefited form the development of diagnostic techniques. In the 1920s, the invention of the electroencephalogram (EEG) gave scientists a tool to further study brain activity in relation to function, and in clinical settings. Today there is heightened interest in ECG-based brain-computer interface (BCI) systems being utilized for rehabilitation of amputees and stroke victims. The advent of diagnostic techniques, including CT scans and MRIs, advanced the study of complex neuropsychiatric disorders such as dementia, traumatic brain injury, and tumors.

As computing power and genomic science continue to advance, neuroscience will be able to explain the pathophysiology underlying complex multi-factorial diseases such as Alzheimer’s disease, Schizophrenia, and brain injuries.

Scope of Neuroscience

Neuroscience is a broad scientific discipline that incorporates and integrates with other scientific disciplines. This multidisciplinary nature of neuroscience includes under it's purview, neuroanatomy that has a long tradition of exploring the structure and organization—the architecture—of the developing and adult brain; neurophysiology, which is concerned with the behavior of nerves that underpin the functioning of the brain. Additionally, the study of psychiatric conditions, such as depression and bipolar disorders, inform their biological causes.

Depending on the domain of study, neuroscience has further branched out into sub-disciplines. Cognitive neuroscience is a popular discipline where researchers measure neural activity to understand the information processing conducted in the brain. Affective neuroscience measures neural activity underlying emotion and its expression whereas behavioral neuroscience studies neural correlates of human behavior such as language, apathy, or even movement.

Neuroscientists study the brain and behavior at various levels of the human body. For instance, in cellular neuroscience, neurons and glial cells are studied. In systemic neuroscience, the role of the nervous system in regulating other tissues such as muscles is studied. Since interdisciplinary studies and collaborations are useful in advancing science, newer disciplines of neuroscience such as neuroimmunology, neuroendocrinology etc. have emerged.

The huge datasets generated by research in neuroimaging, electrophysiology, amongst other areas of neuroscience research has necessitated increased quantitation. Computational approaches are critical for the acquisition, analysis, modeling, simulation of data and hypothesis testing. These tools for the study of the nervous system and the greater integration of computational technologies allow us to derive insights from ever increasingly complex data. The field of Computational Neuroscience has gained traction, and enlists neural networks to model the electrical and chemical activity in the brain involved in information processing.

Future of Neuroscience

The field of neuroscience is poised to offer fascinating prospects for the future. Cutting-edge technology along with high level computational ability are fueling advances on many fronts of neuroscience research. The integration of these findings in large databases, such as The Allen Institute are contributing to our understanding about the fundamental nature of brain function. The advent of integrated technologies, such as brain-machine and brain-computer interface (BCI) represent the ongoing research and proof-of-concept for direct and bidirectional communication between the brain and a computer or a peripheral device such as prosthetic limbs or robots. This conjunction of the brain with external devices offer's up exciting avenues for rehabilitation involving motor function impairment, and is being tested for its enhancement of cognitive and physical abilities. Switching to another area where neuroscience is providing answers is in stress physiology. We are faced with stress daily, confronting life as our ancestors were confronted with, and we too are equipped with the "flight or fight" evolutionary safeguard against, say being confronted with a predator! Yes the stress axis is a potent and dynamic repository of instructions to reflexively prepare us to protect ourselves. And we follow those instructions! The underlying biology of the axis between body and brain under stressful conditions is complicated and has been and continues to be a highly researched area in neuroscience. Considering that stress can lead to physical disorders such as hypertension, diabetes, and mental disorders such as anxiety, depression, advances in the areas such as post-traumatic stress disorder (PTSD) are providing insights into how the stress handles the body and the brain's ability to handle stress. The stress hormone corticosteroid, has been linked with phenotypic, epigenetic alterations to DNA in the brain. These modifications do not affect the sequence of the DNA, but influence gene expression, thus greatly impacting brain function and plasticity. Studying these epigenetic patterns can help us understand the long-lasting impact of stress on the human body.

Figure 4. White Matter Connections Obtained with MRI Tractography. (Image accessed on June 13, 2022)

Advances in brain imaging have made available innovative tools for leading a massive effort of mapping all the neuronal connections in the brain, a wiring diagram—the connectome. Each individuals connectome is unique and is constantly changing, as neurons change their connections by reweighing, rewiring, reconnecting, and regenerating them. Figure 4 is representative of the complexity and interconnectedness of white matter connections in the human bran. One can appreciate the large number of connections between the two hemispheres made by the axon bundles traveling in the corpus callosum. This kind of research has enormous implications for treating mental disorders—such as depression, obsessive-compulsive disorders, Parkinson's disease, epilepsy—as repairing the connectome to cure these disorders could involve tweaking identified, malfunctioning neural networks. These efforts are already underway with strategies employing deep brain stimulation for alleviating the troublesome motor symptoms of Parkinson's disease, eccentric tremors, dystonia.

Machine learning and artificial intelligence (AI) technologies have been recruited for decades to construct neural networks and systems of general intelligence using the principles of brain mechanisms, structure and function. These efforts continue to be inspired by, and aim to emulate and mimic the perceiving, learning and reasoning brain. There is reciprocity between neuroscience and AI, and deep learning models. These programs have advanced to now being capable of predicting human behavior based on patterns of neural activity. Progress in the use of imaging technologies in psychiatry has generated vast datasets that AI systems use to learn about, profile and potentially treat the disorders. These approaches can reveal much about diseases related to behavior (e.g., dementia) early on and help in investigating associated neural dysfunction. Neuroscience and the AI models will continue to grown and learn from each other, informing our understanding of how the brain computes and functions during development, adulthood, and in diseased, dysfunctional states.

Lastly, the mechanisms underlying neural degeneration and regeneration are poorly understood and are currently being rigorously investigated. As neuroscience advances, scientists will know more about the cellular mechanisms of neural regeneration. This will in turn help in knowing more about the formation of neural circuitry and ultimately rehabilitation after injuries. Injuries involving trauma to the brain, such as Traumatic Brain Injuries (TBI); neurodegenerative diseases, like Parkinson's and Alzheimer's diseases that progressively worsen; spinal cord injuries that lead to paralysis - are a consequence of neuronal degeneration and the limited capacity that neurons have to repair themselves. This however is not always the case. The field of nerve regeneration is growing rapidly, exploiting the advances in technology, using innovative approaches that include, and are not limited to—re-engineering a persons stem cells to facilitate neural regeneration; interventions that promote innate neuronal healing and growth are benefitting from the knowledge of the differences in the intra—and extra-cellular environment in healthy and diseased, and traumatized brain; use of electronic devices to assist in overcoming limb paralysis due to spinal injury. These therapies and interventions represent decades of study of the diseased and dysfunctional brain, and will continue to make great strides into the future.

Recent advances in neuroscience have made it possible to envision potential therapies for diseases that were incurable in the past. On this, the BrainMatrix.com platform, we engender to provide information about neuroscience, diseases of the nervous system, psychiatric illnesses, and current and potential treatments for these diseases. These articles are written by experts in their fields, relying on the latest available scientific evidence.

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