Principles of the Central Nervous System PDF

MOHD2 Principles of the Central Nervous System OBJECTIVES Broadly, for the study of neuroscience in MOHD2: Explain the organization and intricate relationships between structure and function of the human central nervous system Describe the functional anatomy of the major...

MOHD2 Principles of the Central Nervous System OBJECTIVES Broadly, for the study of neuroscience in MOHD2: Explain the organization and intricate relationships between structure and function of the human central nervous system Describe the functional anatomy of the major motor, sensory, and regulatory systems of the human CNS Describe the key components of regions of the CNS – most disorders affect regions! Identify major gross anatomical components of the CNS on whole specimens, dissections, slides, and medical images (MRI, CT) Develop ability to localize lesions of the CNS based on clinical signs Survey the mechanisms of pathological anatomy and physiology underlying common lesions of the CNS Specific to this introductory lecture: Discuss characteristics of the CNS including its autonomy, self-organizing capacity, multi-level information processing, and hierarchical aspects of structure and function List the basic tenets of the modern Neuron Doctrine Describe the modular nature of the CNS and its function as a collection of modular neural networks Explain what is meant by spatial processing of sensory and motor function Think in 3D: in particular, plan your approach to learning three-dimensional neuroanatomy Supplemental: Watch “Anatomy of a Play” (https://youtu.be/Z5TAeD2T4AE) and describe in basic terms the functions of the following brain regions: occipital lobe, parietal lobe, temporal lobe, frontal lobe, brainstem, cerebellum, basal ganglia, amygdala, hippocampus, thalamus, hypothalamus, and spinal cord GENERAL COMMENTS This section of the course is designed with the aim of providing students a solid foundation in basic human neuroscience as it relates to mechanisms of neurological and psychiatric disease. The components of the course provide an integrated core curriculum taking the student from the basic anatomy of the nervous system through more complex systems and clinical applications. Students should be aware that information is presented repeatedly in different course sections, in a spiraling fashion, with different emphases or 1 spin in each section. For example, students will get lectures on the blood supply of the brain, see brains with a variety of strokes in the laboratory, and analyze and discuss case histories of patients who have suffered strokes during integration exercises. Students should expect examinations to cover material presented in all of these course phases, with a strong emphasis on integration. Prior knowledge: It is expected that students already have a basic understanding of muscle tissues, nervous tissues, and glial cells (refer to Dr. Hoffmann’s Foundations lectures), as well as the anatomy of the peripheral nervous system, including peripheral components of the autonomic (visceral) system, dermatomes and myotomes, an understanding of the extra-cranial anatomy and functions of the cranial nerves, eye movements, and knowledge of the vascular system, particularly that of the head and neck (refer to Gross Anatomy). Students lacking confidence in these areas should contact a tutor or course director so that arrangements can be made to reinforce information. I. RULE ZERO The brain is not divorced from the body, or vice versa. As such, the purpose of the brain is to move the body with control. All the other neat stuff, from perception to cognition to memory, is in aid of making controlled, coordinated movements in the world. Said differently, the brain coordinates information to produce behavior (which is movement). Along the way, we experience being alive. Trees sense all sorts of things about the world around them, from photons striking their photoreceptors to the brush of adjacent lifeforms against their mechanoreceptors, and much else. But trees don’t move in a manner requiring centralized coordination of information, and therefore don’t have a brain (or nervous system for that matter). II. INTRO TO THE CNS The nervous system is everywhere With the exception of cartilage, every mm3 of the human body has nerve endings or nerve fibers coursing through it, including the skin, sense organs, bone, and all viscera. This massive peripheral innervation is controlled by the central nervous system (CNS). What is the central nervous system? The CNS may be defined as an autonomous, self-organizing, multi-level information processing and control system – weighing about 3 pounds (1500 grams). 2 Information processing Outside the brain there is just energy and matter, and the brain will never experience it directly. Our sensory organs must act as interpreters, detecting information sources (light particles, sound waves, molecules, mechanical indentations of the skin, temperature, etc.) and translating them into electrochemical signals, the common currency of the CNS. “Information processing” largely refers to the ability of the CNS to process raw sensory information, extract data from the sensory information, and transfer that data to other systems within the CNS. Raw sensory information can be obtained from stimuli that originate: Outside the Body (exteroception): e.g., visual, acoustic, olfactory, or tactile stimuli. Inside the Body (interoception): e.g., proprioceptive component of somatosensory system (from muscles, tendons, joints), viscerosensory (from internal organs, blood, CSF), and vestibular (from the inner ear concerning head position) Illusions: The CNS applies certain rules and assumptions about the external world to the sensory information it receives. Visual illusions are good examples of how the brain makes inferences about the nature of the external world by perceiving patterns that don’t really exist in the sensory environment and “filling in” missing details. These inferences arise from genetic and developmental processes hard-wired into the neural networks of the CNS. Refer to the slides (run in Presentation mode) for demonstrations. Control system This refers to the output of the CNS and its ability to control the musculo-skeletal system (the motor system) and, through the endocrine and autonomic nervous systems, the cardiovascular, gastrointestinal, genito-urinary, thermo-regulatory and secretory (saliva, mucus, sweat, etc.) systems. Multi-level The CNS is a hierarchical structure where sensory information is progressively refined as it is transmitted through different brain structures until it reaches the highest level (generally the cerebral cortex) where complex information can be extracted and transformed into symbols. In the motor system, translating the idea or desire to move into movement requires multiple brain structures. Autonomous This refers to the fact that each CNS is self-governing and self-motivating and not influenced directly by any other CNS. The manifestations of the autonomous nature of the CNS include: 3  Consciousness Self-representation Volition (will) and motivation Emotional states Memory Communication Self-organizing The basic anatomical plan of the CNS is genetically determined and the early stages of CNS development appear to be common to all vertebrates. Similarly, the basic connectivity of the CNS is genetically determined. However, the CNS is adaptive despite the inability of almost all neurons to divide (some new neurons can be generated by stem or other pluripotent cells). This adaptive element largely occurs at the level of the interconnection between neurons, the synapse. Formation of new synaptic contacts by axon and dendritic growth, permanent alterations in synaptic efficiency at the cellular and molecular level, and (very occasionally) generation of new cells contribute to learning and memory, and maintenance and/or restoration of function following cell loss or axonal injury. The strengthening and pruning of axonal inputs during sensory experience provides a good example of this self-organizing principle. In the diagram below, the right eye of a cat has been covered. Over time, axons from the left eye strengthen synapses with postsynaptic cells (increasing the number of synaptic contacts) while those from the right eye prune their synapses, disabling them. 4  ß In the diagram at left, a neuron deploys new dendrites and dendritic processes (spines) during a motor learning behavior. The presynaptic (green) neuron places a behavioral demand on the postsynaptic neuron, which responds by increasing the number of dendritic connections made with the presynaptic cell. How are new synapses formed on a cellular level? – Proteins need to be readily available at synapses to remodel the cytoskeleton – mRNAs are not transported as free molecules, but complexed with RNA-binding proteins in dormant ‘granules’ stored in neuronal processes – Synaptic activation of the dormant granule releases beta-actin mRNA from the masked state – Local translation can now remodel the cytoskeleton, strengthening the synaptic contact Akbalik G and RM Schuman, Science 343 (2014) 5 III. HOW DOES THE CNS WORK? The CNS consists of two basic cell types, the neuron and the glia (please read up on glial cell types as they will not be covered in detail in this course). – Neurons are electrically excitable cells capable transmitting information over long distances to other neurons or other cell types through a thin cell process, the axon. Most neurons possess one or more thicker cell processes termed dendrites that are generally (but not exclusively) the ‘receiving’ end of the neuron. There is such an enormous variation in the number, thickness, length, branching pattern and orientation of dendrites that some 300 distinct neuron types have been described on the basis of this variation. Structurally, there are 3 major classifications of neurons. Multipolar neurons: 3+ dendrites and one long axon. E.g., most CNS neurons, plus all peripheral motor neurons: Pseudo-unipolar neurons: A single neurite arises from the cell body and divides into two branches. One branch projects to the periphery, the other projects to the CNS; both branches have the structural and functional characteristics of an axon. E.g., most peripheral sensory neurons, including all sensory neurons associated with the spinal cord; Bipolar neurons: One process ends in dendrites, the other (an axon) ends in terminals in the CNS. E.g., special sensory neurons (retina, inner ear): 6  – Glia (the most numerous cell type in the CNS) are largely responsible for supporting neuron function by controlling movement of nutrients (including water and O2) to neurons, removing metabolites, neurotransmitters, infectious agents, etc., insulating axons (myelination) and isolating neurons and their connections. In general, glial cells provide a favorable environment for neurons. THREE IMPORTANT CONCEPTS i. Neuron Doctrine (Theory) Originally expounded by Heinrich Wilhelm Gottfried von Waldeyer-Harz (aka Waldeyer) in 1891 from the work of Camillo Golgi and Santiago Ramón y Cajal on the cellular structure of CNS. The modern basic tenets of the neuron doctrine are: – All physiological (and today, psychological) properties of the CNS are determined by the electrochemical activity of neurons. – Neurons are stand-alone processing units and do not form cytoplasmic continuity (syncytia) with other neurons as other electrically excitable cells do (e.g. cardiac muscle cells). – Neurons transfer information to other neurons via cell processes (axons and dendrites). – Transfer of information between neurons is effected through a specialized junction, the synapse, by chemical (neurotransmitter) or electrical means: 7  – Interaction between neurotransmitters and receptors on the receiving neuron determine whether the receiving neuron is ‘excited’ (+) or ‘inhibited’ (–). ii. Functional Localization While early neuroscientists like Thomas Willis (1621-1675) attempted to describe specific functions to different parts of the brain, it was not until the 19th century that the concept of specific CNS regions and systems serving sensory versus motor functions, or visual versus auditory processing, etc., was established. Specialization in the CNS is largely established by: Modularity Modularity or regional specialization is a feature of the CNS of the most primitive vertebrates and is a general feature that has been highly conserved through evolution. All vertebrate nervous systems are composed of many interconnected modules of neurons (and modules within modules), each serving a specific task or subtask in brain function. 8 If you’re familiar with modern computing, this is like the function of subroutines. A subroutine is a sequence of program instructions in a larger program that is organized as a unit to perform a single task. A main program can call upon a subroutine to do something and “branch back” to return instructions after the call. This is a powerful and efficient way to set up a computer program, as it reduces the amount of code necessary to run the program and therefore improves its reliability. Neural modules appear to be set up in a similar manner. Some modules do things you are consciously aware of (like aspects of visual perception). Some do things you have no access to (like sensing the blood gas concentration of CO2 in your carotid arteries). Some of these modules help you read and write, while others inform the way you read and write without their operations being consciously accessible in your mind. Every neural module is not connected to every other module. Such an arrangement would be extremely inefficient, not to mention biologically costly to operate. Modules connect in particular ways to modules within functional groups, and these connections often go in both directions, feed-forward, and feed-backward. This allows interconnected modules to modulate the firing rates of their partners, either by increasing the transfer of information across synapses (excitation) or diminishing this transfer (inhibition). How the various modules connect to each other in the nervous system is often depicted as a kind of wiring diagram. If each pool of neurons in the central nervous system represents a node or “dot” in a “connect-the-dots” drawing, it is our task in this course to explore how the dots are connected and to describe the functional effect of this circuitry. In essence, this is the difference between information (a bunch of dots) and knowledge (how they are connected). You could also think of modules as destinations and pathways as the highways connecting them. We’ll only look at a few of the most important connections in this course, ones directly applicable to clinical practice. Modules come in two levels of organization: 1. Large scale modules – usually referred to as systems – are dedicated to a particular modality, e.g. vision, language. 2. On a smaller scale, each system is composed of many smaller, but similarly organized modules with dedicated functions, e.g., patterns in the visual field, the color and form of objects, their motion, etc. Modules are hierarchical and typically connected to hubs linking together anatomically distinct modules. Brain functions can thus be characterized by: local integration within segregated modules for specialized functions global integration of modules across hubs for perception, cognition, and action Because each module can evolve independent of the others, adaptive changes can occur much more rapidly than if the brain was a single complex module. 9 The core concept: Sense organs transmit information to limited modular populations of neurons which, in turn, only connect with limited populations of neurons: this is the basis of sensory systems; similarly, only a restricted number of neurons are directly connected with the motor neurons that innervate skeletal muscle, and these neurons only receive input from a restricted number of neurons; this is the basis of motor systems. Certain CNS regions (the hippocampus and cerebellum are good examples) have their neurons arranged and interconnected in a highly specialized manner for the extraction of specific information. In contrast, the cerebral cortex is fairly homogeneous, yet one part can extract color information from incoming visual information while another part can exert control over individual muscles. iii. Neural Networks Interconnected networks of neurons form the basic structure of all central nervous systems in all known animals (including e.g. the neural nets of jellyfish!). The most reliable estimates suggest there are 100 billion (1011) neurons in the human brain each forming an average 7,000 synaptic connections with other neurons. The total number of synapses may be between 1014 and 1015. This enormous number of ‘active devices’ and the equally enormous number of possible connected configurations confers certain properties on the CNS. The degree of interconnectivity within and without brain regions is a key element in network function. ‘Small-world’ properties of cortical networks A too-regular pattern makes for low adaptability while random organization is inefficient. Cortical networks use high local interconnectivity with long connections to other cortical areas. Spatial processing Unlike, for example, a digital camera whose sensor scans an image and transmits it linearly over a single wire, the eye transmits the whole image simultaneously over some one million axons. Because of the enormous number of synapses, the original representation of the image can be preserved through subsequent processing stages. Spatial processing occurs in the somatosensory, auditory, gustatory (taste), and olfactory sensory systems. In motor cortex, a topographically organized map of the body, limbs and individual muscles can be maintained. 10 Dynamic properties: Neural networks are dynamic not static systems, and can have their processing capabilities altered by additional inputs that change, for example, the signal to noise ratio of incoming information. A number of systems in the CNS do not carry sensory or motor information per se but are there to alter the properties of neural networks. Learning and memory: It is believed that information (e.g., ‘memories’) is stored in neural networks. Theoretical studies show that neural networks can store information spatially. Predictive processing The brain’s main function is to make predictions about the state of the body and the world, and to match these predictions against “error” generated by the sensory systems, for the purpose of making better predictions. In this sense, the brain can be understood as a prediction machine, organized to minimize prediction error. Predictive processing appears to be a fundamental principle of cognition, underlying how we sense, feel, think, and ultimately do. The better the model, the more accurate the behaviors generated by the brain. E.g., We don’t see with our eyes, exactly. When we open our eyelids, we don’t simply “see” what happens in front of us. Rather, our brain makes predictions about the visual world and constantly refines its internal model of the visual world using error generated by light falling on the retina, adjusting predictions at each hierarchical brain level until the prediction errors between sensory inputs (retina) and predictions (brain) are minimized. What you experience in the mind’s eye at any given time (mental state) is a best-fit prediction of the external visual world, not a facsimile of it. The visual illusions we looked at earlier help demonstrate this idea. We’ll unpack this theory of predictive processing and its importance for understanding cognition in greater detail throughout the course. 11  Emergent properties Many so-called “higher functions” of the CNS like consciousness and cognition have been argued to arise as emergent properties of the predictive neural networks making up the brain. Theoretical studies show that neural networks can perform not only logical and mathematical operations but can manipulate information transformed into symbols. While still largely theoretical, this implies that the ‘mind’ is an emergent property of the brain and the separation of the mind as distinct from the brain (the mind-brain dichotomy) is false. Proponents of emergentism argue, essentially, that many simple operations combine to form something that is more complex than its components parts. Despite this concept, things like consciousness, and the truly amazing mystery of subjective experience (e.g., why are red things experienced as red in the mind’s eye?), are still far from understood. IV. THINKING IN 3D Presented here are a few suggestions to help you get started learning neuroscience and neuroanatomy: 1. Don’t lose sight of the forest for the trees. Learn what each system does (the forest), as well as the neuroanatomical details of how it does it (pathways of information transfer—all the trees). 2. When learning the neuroanatomical details of neural pathways, find a method that works for you to gain confidence with the necessary connections. Some learners prefer to draw cross sections of the spinal cord/brain stem, drawing in the details of pathways under study (information will often be presented this way in lecture). Others prefer to make flowcharts, such as: Neuron I à Neuron II à Neuron III, with each arrow representing a projection and synapse, filling in anatomical details where relevant. E.g., two ways to represent the Fasciculus Gracilis (FG) pathway: 12  There are plenty of other ways this might be done. Whatever approach you take, the goal is the same: to develop a three-dimensional representation of the human CNS, linking anatomy to function. 3. Use blood supply (Lectures #6 & 7, Lab #1B) to scaffold regional anatomical relationships. Understanding how each region is linked to its blood supply helps organize learning, and is a critical skill necessary for interpreting strokes. You should be able to assert how a given pathway is irrigated at any level of the neuraxis through which it passes. 13 V. PUTTING IT ALL TOGETHER Even simple behaviors require participation of multiple parts of the CNS to execute properly. Components of given behaviors will be encountered at different times throughout the course. It’s important to layer this information progressively, making deep connections between new material and material you’ve already mastered. Understanding, for instance, that: A. tongue movements are associated with CN XII function; B. GSE lower motor neurons for CN XII are located in the dorsal medulla; C. the peripheral course of the XII nerve exits the ipsilateral ventromedial medulla at the preolivary sulcus; D. paramedian branches of the anterior spinal artery supply the region described above and therefore also supply the pyramids and medial lemniscus at this level; and that… E. other branches of the vertebrobasilar system such as PICA supply nearby but distinct territories with their own constellations of functions …is the kind of working picture you want to develop, combining your knowledge of the systems organization and regional anatomy into a toolkit you can use to think about function and dysfunction. The more tools in your kit, the better, but it’s important to focus on how to use them. The course is designed in such a way as to facilitate this process, as far as is practicable: 14 VI. SUPPLEMENT: ANATOMY OF A PLAY In December 2018, I recorded a short (30 minute) lecture for the University of Iowa, taking a big-picture look at what goes on inside the brains of athletes during the execution of a single football play (On Iowa!). The finished product is available for viewing on the university’s YouTube page: https://youtu.be/Z5TAeD2T4AE This optional video is intended to serve as a helpful “Lecture Zero” for this course. Those of you without a neuroscience background may find it particularly useful as a 30,000 ft. view of major structures and functions. If you’re not into football, while watching you can substitute virtually any other physical activity of interest to you – the brain will go about the task in similar ways. After watching, describe in basic terms the functions of the following brain regions: lobes of the cerebral cortex: occipital, parietal, temporal, frontal brainstem spinal cord cerebellum basal ganglia amygdala hippocampus thalamus hypothalamus We’ll be taking a closer look at each of these areas in the upcoming lecture on Topography of the CNS, and more deeply thereafter. Your task, moving forward, will be to describe the anatomical relationships, interconnections, and specific functions of each of these brain regions, and others, to describe how these parts work together to generate perceptions and produce behavior. Think about the consequences for a patient if a certain part stops working. Be assured: if you know what a part does, you’re a long way toward figuring out what it doesn’t do if it becomes broken. FAQs What information is considered “important” from each of Dr. Sipla’s handouts? All of it, as indicated by the lecture objectives. This is not meant to be intimidating, but liberating. We, as course directors, have already undertaken the effort to reduce the volume of content in MOHD2 to the level required by a thorough M1/PA1 education. Albert Einstein is quoted as saying, “Everything should be made as simple as possible, but not simpler.” This is the state of our lecture notes. The lecture objectives provided on ICON (and restated in the relevant handouts) for each lecture are the ultimate guide to our expectations as course directors. If you are unclear about what you will be required to do on examination day, refer first to your lecture objectives. 15 Are the handouts authoritative? Yes. If you wish to learn exclusively from my notes, you can. But be advised that learning neuroscience is not an endeavor in memorization. To succeed in this course, you must be able to apply the information you learn in a practical way. Facts (discreet units of information), in and of themselves, have low value when it comes to your grade. Knowledge is what you’re after: how the different units of information are related to each other in functional, clinically-relevant ways. This is the goal, and ultimately the thing you will be held accountable for. What good are the Power Points, then? The study of neuroanatomy focuses in detail on the spatial and functional relationships of neural networks in the central nervous system. The critical ability to localize basic neural lesions (a skill required of all learners in this domain) is best developed by layering concepts in a progressive manner. My lecture slides have been designed in such a way as to facilitate this learning process. I encourage everyone to work with the PowerPoint slides (in presentation mode) when learning new anatomical relationships, especially once we get to the detailed study of neural pathways. Cross-sections of the spinal cord, brainstem, and forebrain (from eNeuroscience) are frequently referenced in the PowerPoints, with core concepts and key anatomic relationships layered in a clear progression. Should I come to lecture, tune in live via Zoom, or watch later on Panopto? I trust you to know what studying routine works best for you, but for those students who choose to participate in-person during lectures or live via Zoom simulcast, I recommend that you read the lecture notes in advance and come unburdened by a desire to “take notes.” Put away your cell phones, close browser windows, and give full attention to the presentation at hand. Hearing/seeing a narrative from the standpoint of your narrator is a powerful learning tool, and learning starts with focused attention. For those participating on Zoom, though we will be physically separated I’ll endeavor to be present and attentive. I will be actively monitoring the chat and responding to questions as able in real time. You can hear my dumb jokes on the Panopto recordings, but you won’t be able to ask me questions as they occur to you. How can I avoid falling behind? Avoid cramming and purging. You need to retain the skills and neuroanatomical knowledge you develop early in this section of the course all the way through to the end (and beyond to MOHD4 and Keystone, and for the medical students your Neurology and Psychiatry core clerkships, Step 1 exam, and eventual practice). Advanced, integrative concepts require mastery of earlier concepts. To keep pace, it is strongly advised that you study new content daily. When studying, foremost, ask yourself the following questions for each lecture: (1) What is this lecture 16 about? (Hint: see the objectives.) (2) How does this information relate to what I have already learned in the MOHD2 course and more broadly within the curriculum? And, (3) How can I vary my approach to learning and “do something” to express my newfound knowledge? This last point is key: Take time to generate information on your own. Rather than repeatedly re-reading the same material from a lecture handout, or copying it in slightly different verbiage, try to generate the information in different ways. Schematize a neural pathway you are learning by drawing out its elements and their relationships on a whiteboard. Label your drawings with anatomical details. Carefully consider how these details are represented in the cross-sectional anatomy you are studying on eNeuroscience. Say the words out loud, forcing yourself to find the best words in your lexicon to describe what you are modeling. You will quickly discover the gaps in your knowledge. Practice with colleagues, out loud, on a screen or on a board. Teach each other during review sessions. As you vary learning techniques – schematizing, verbalizing, social interplay – you reinforce concepts and make stronger associations in your mind, and you become more likely to remember and effectively apply the knowledge later. In a very real sense, learning about neural networks (the immediate task at hand) alters your neural networks. Neuroscientists call that learning. May as well harness the situation to get the job done. Use the weekly quizzes as a benchmark for your readiness to tackle the exams. They were written with this purpose in mind, and each question is appended with a thorough rationale statement explaining the important concepts being evaluated, as well as calling your attention to related concepts and skills not explicitly mentioned. Finally, and most importantly, if you determine that you are falling behind, don’t wait to get help. Contact Student Counseling to arrange a tutor. Schedule a meeting with your enthusiastic and very friendly course directors, who are more than happy to help you clear any logjams on the path to mastery. Any other advice? Have fun! Neuroanatomy is amazing, challenging but learnable, and profoundly useful to you. Let’s do this! 17