2024 Neuro Resources PDF

NEURO-1 Neurophysiology: General Introduction For this section on Neurophysiology you are only responsible for material covered in Lectures. That is, there is no assigned textbook for this part of the course. The function of the Lectures is to broadly explain the relevant physiological concepts. I...

NEURO-1 Neurophysiology: General Introduction For this section on Neurophysiology you are only responsible for material covered in Lectures. That is, there is no assigned textbook for this part of the course. The function of the Lectures is to broadly explain the relevant physiological concepts. I do this using simple visual diagrams or simple demonstrations. The function of this document is to be a record of the diagrams presented and the major points discussed in Lecture. That is, this document serves as an initial set of notes that covers most of the same points presented in Lectures – it does not attempt to explain concepts. It is important to understand that neurophysiology is a rapidly developing discipline with new information constantly replacing the old. Consequently, correct answers to exam questions will come only from the Lectures and this document. They will not come from anywhere else including other courses, the Internet or textbooks. Two up to date textbooks for reference at an advanced level are listed below. Much of the material covered in this course will also be covered in these books albeit at a substantially more advanced level. Kandel et al. Principles of Neural Science, 5th Edition, McGraw Hill, 2013 Purves et al. Neuroscience, 5th Edition, Sinauer, 2012 How to do well on Examinations 1. Attend lectures Each year new material will be presented in Lectures that is not in this document. Sometimes scenarios are discussed in lectures that are used in MCQs. Anything discussed in Lectures or in this document, including diagrams, is examinable! Do NOT fall behind. With 3 lectures/week the amount of material is large, and can become overwhelming if lectures are missed. 2. Read and answer objectives for each lecture Objectives given in this document allow you to test your knowledge. 3. Test yourself with recent exams. Sample questions are representative of those that will be on the exam both in terms of content and in terms of what you will be expected to do with the content. All questions on the exam for this Neurophysiology section will be new.  NEURO-2 Neurophysiology I: The Brain, Neurons and Synaptic Transmission Objectives 1. Draw a diagram of the brain and spinal cord (lateral and sagittal view) labeling the major anatomical features. 2. Name two main types of brain cells and their overall function. 3. Draw a representative neuron, label its parts, and indicate where incoming axons terminate (synapse). 4. Name the feature of electrical and chemical synapses. 5. Describe the ionic mechanisms and the changes in membrane potential associated with an excitatory postsynaptic potential (EPSP) and an inhibitory postsynaptic potential (IPSP). 6. Name the three main differences between synaptic transmission in the central nervous system and that at the neuromuscular junction.  NEURO-3 Objectives (Answers) 1. Draw a diagram of the brain and spinal cord labeling the major anatomical features. 2. Name two main types of brain cells and their overall function. Neurons are the information processing cells (electrically excitable) Glial cells are 10x more numerous than neurons and the provide support for neurons in a variety of ways. o Supplying “back-up” glucose from glycogen (most glucose comes from blood) o Removing neurotransmitters o Removing ammonia (a by-product of metabolism) o Taking up K+ o Providing myelin sheaths for axons 3. Draw a representative neuron, label its parts, and indicate where incoming axons terminate (synapse). A neuron has dendrites (90% of surface area), a soma (cell body), an axon hillock (initial segment), and an axon with collaterals (branches). Incoming axons can terminate (synapse) on dendrites, soma or axon terminal. Most synapses are located on the dendrites.  NEURO-4 4. Name the features of chemical and electrical synapses. Chemical Synapses are most common type of synapse. There is high electrical resistance between presynaptic and postsynaptic cells (therefore electrical currents ahead of action potential do not cross the synapse). Instead, the signal that propagates electrically down presynaptic neurons is conveyed across the synapse by neurotransmitters (i.e. like that at the neuromuscular Junction). This process introduces a brief synaptic delay of approximately 1 millisecond. Chemical synapses allow integration (summation) of inputs over the time scale of milliseconds to minutes. Chemical synapses may exhibit plasticity. Electrical Synapses operate when neurons are very close together and exhibit cytoplasmic continuity via gap junctions. This means that there is low electrical resistance between the cells such that the electrical current ahead of the action potential can cross the gap between neurons. This process is typically bidirectional and has no synaptic delay. Figure from Pereda, Nature Reviews Neuroscience 15, 250-263 (2014).  NEURO-5 5. Describe the ionic mechanisms and the changes in membrane potential associated with an excitatory postsynaptic potential (EPSP) and an inhibitory postsynaptic potential (IPSP). An EPSP is a transient (~15 ms) increase in conductance to small cations, i.e., Na+, K+, and Ca++, but Na+ dominates, thus cell depolarizes. An EPSP at a single synapse is < 1mv in size (in contrast to the EPSP in diagram). The total size of the EPSP depends on how many afferent axons were active and how active each was (Lecture 2). An IPSP is a transient (~15 ms) increase in conductance to Cl-, K+ or both, typically producing hyperpolarization. Note that, in some neurons, ECl- may be close to -70mv so the Cl- mediated IPSP may be very near the resting membrane potential of the cell and, thus, may not act to hyperpolarize the cell. Even if the IPSP does not hyperpolarize the cell, it suppresses action potentials because it tends to keep the cell at the IPSP equilibrium potential, which is far from the action potential threshold. Different chemical transmitters produce IPSPs and EPSPs (Lecture 2). 6. Name the three main differences between synaptic transmission in the central nervous system and that at the neuromuscular junction. 1. There are a variety of transmitters in the central nervous system (Lecture 2). 2. At the CNS, an EPSP at a single synapse is 150 ms. 2. What is an electromyogram (EMG)? An electromyogram (EMG) is the recording of extracellular current flow associated with action potentials in a skeletal muscle. EMG activity can be measured using electrodes placed on the skin above the surface of a muscle. Such recordings are possible because there are relatively large current flows associated with simultaneous action potentials in the hundreds of muscle fibers activated during movement.  NEURO-51 3. Describe what happens when a slow stretch, a medium-speed stretch and a tendon tap is applied to a skeletal muscle of a healthy (normal) person. There is no stretch reflex for slow stretch because the EPSPs do not summate fast enough to produce action potentials. Tendon tap produces rapid excitation that reaches threshold. 4. Define spasticity and explain why it shows velocity dependence. Muscle tone is the passive resistance which occurs when a person is asked to relax and a muscle is stretched. In healthy people, this resistance arises because of the viscoelastic properties of the muscle. In some clinical conditions (e.g. spinal cord injury, stroke), additional resistance arises because of increased sensitivity of the stretch – this abnormal resistance is called spasticity. Spasticity is velocity dependent because the receptor activated by muscle stretch is the Ia afferent, whose discharge is proportional to the velocity of stretch. Note that the resting membrane potential of the alpha motoneuron is closer to threshold in spasticity (due to loss of inhibition from motor cortex). Muscle stretch will produce the same (normal) discharge of Ia afferent neurons, which will cause summation of EPSPs in the alpha motoneuron. In the normal situation, these EPSPs do not reach threshold. In spasticity, the same sized EPSPs will reach threshold, discharge action potentials and thereby produce a stretch reflex to passive stretch.  NEURO-52 5. Draw a diagram illustrating the neural components of the spinal flexion (withdrawal) reflex. 6. Describe 4 characteristics of the flexion (withdrawal) reflex. The flexion reflex is a polysynaptic reflex. It will occur the lower limbs of a person with a severed spinal cord (paraplegic). 1. Contraction of flexors, relaxation of extensors (via reciprocal inhibition). All spinal reflexes have reciprocal inhibition. 2. Ipsilateral flexion; crossed extension. 3. After discharge: period of withdrawal outlasts noxious stimulus period. This occurs because: a. Nociceptors will continue to discharge b. Reverberating activity in the spinal cord circuitry 4. Local sign: exact pattern of withdrawal pattern depends on the site of stimulation. 7. List 2 characteristics of the scratch reflex. 1. Programmed within the spinal cord 2. Site specific (position sense). 8. Name the location of the neural circuits for locomotion (stepping). The neural circuits (pattern generator) for locomotion are located in the spinal cord. This is why a chicken whose head has been chopped off (which causes activation of descending pathways and facilitation of spinal cord circuits) can run around for some time.  NEURO-53 Neuro X: Motor Cortex Objectives: 1. Name three main techniques that have been used to demonstrate the function of a particular brain region. 2. Define the motor cortex. 3. Discuss the evidence for a somatotopic organization of motor cortex. 4. List the evidence that motor cortex representation is for movements, not muscles. 5. Give two pieces of evidence that the somatotopic organization is plastic (modifiable). 6. List three output pathways from the motor cortex. 7. Discuss the corticospinal tract mentioning its phylogenetic development, termination and the effects of lesions. 8. Describe the effects of lesions of the motor cortex in man. 9. Name 3 findings about the discharge of pyramidal tract neurons that come from experiments in behaving monkeys. 10. List the factors that cause time delay between onset of cortical discharge and movement.  NEURO-54 Objectives (Answers) 1. Name three main techniques that have been used to demonstrate the function of a particular brain region. 1. Stimulation – electrical, magnetic, naturally occurring (e.g. epileptic discharge) 2. Lesion – many techniques for destroying neurons, naturally occurring (e.g. stroke) 3. Recording – single cells, evoked potentials, EEG, PET, fMRI. 2. Define the motor cortex. The motor cortex is defined as the part of the cerebral cortex from which low intensity electrical stimulation elicits muscle contractions. It occupies the precentral gyrus in man (in front of the central sulcus). 3. Discuss the evidence for a somatotopic organization of motor cortex. As for the postcentral gyrus (i.e. somatosensory cortex), there exists a somatotopic organization on the precentral gyrus (i.e. motor cortex). From medial to lateral: leg, trunk, shoulder, elbow, hand, face, tongue. Evidence comes from: o The somatotopic map was inferred by Hughlings Jackson from observation of epileptic motor seizures (called the Jacksonian March) o It was confirmed by electrical stimulation in human patients (Penfield) o Lesion (strokes) in this area cause paralysis in severe cases and weakness in lesser cases. For example, a large lesion in the medial side of the right precentral gyrus will cause paralysis in the left leg. o Recording of neural activity in animal models. 4. List the evidence that motor cortex representation is for movements, not muscles.  NEURO-55 1. A particular muscle can be activated by stimulating widely dispersed motor cortical sites 2. Single motor cortical neurons make monosynaptic connections with motoneurons innervating several different muscles 3. Motor cortex micro-stimulation can produce purposeful-like movements (bringing food to 4. mouth and mouth opening, reaching, defensive postures) 5. Give two pieces of evidence that the somatotopic organization is plastic (modifiable). 1. Learning. Using fMRI, the size of the finger representation in motor cortex was measured in a simple finger task. The subjects then learned a complex novel task, e.g., touching thumb to different fingers or a new sequence with the fingers on a keyboard. Subjects practiced sequence for 3 weeks. fMRI was done again with the simple task and an increase was found in the size of finger representation in motor cortex. 2. Studies of experimental injury. For example, a small artery supplying the hand region of motor cortex was blocked in monkeys. Neurons controlling the hand died, the area of hand representation decreased, and monkeys lost movements of hand. Some monkeys were retrained to use their hands and others were not. Those that were trained regained some hand functions whereas the non-trained monkeys did not. The trained monkeys now had hand representation in adjacent elbow/shoulder par of motor cortex. The non-trained animals had no hand representation. 6. List three output pathways from the motor cortex. 1. Corticospinal tract (aka pyramidal tract) 2. Corticorubral tract (to the red nucleus in the brain stem) 3. Corticoreticular tract (to the reticular formation) 7. Discuss the corticospinal tract mentioning its phylogenetic development, termination and the effects of lesions.  NEURO-56 Phylogenetic development o Only occurs in mammals and shows progressive development up mammalian tree especially in primates. Termination o About 10% of axons make monosynaptic connections with alpha motoneurons. Lesion o Monkeys with lesions of the pyramidal tract appear at first sight to be fairly normal, i.e., they can walk, run and climb. This is because they still have i) circuits for locomotion in the spinal cord, ii) descending pathways from the brainstem, and iii) other descending pathways from the motor cortex. The major lasting effect of pyramidal tract lesion (in man and monkey) o Loss of refinement in movements e.g., 1) loss of speed and agility in movements (loss of control of force), and 2) loss of independent finger movements (which is associated with loss of the corticospinal monosynaptic connection). Evolution o The pyramidal tract and dorsal column medial lemniscal system evolved together up the mammalian scale, presumably for the accurate identification and manipulation of objects and tools. 8. Describe the effects of lesions of the motor cortex in humans. A large motor cortex lesion causes weakness (or paralysis) and spasticity (increased muscle tone). Increased muscle tone is an increased resistance to passive movement, caused by an increased spinal stretch reflex, which in turn is partly caused by loss of inhibition from the motor cortex (see also spinal reflexes lecture).  NEURO-57 9. Name 3 findings about the discharge of pyramidal tract neurons that come from experiments in behaving monkeys. 1. Some discharge before movement onset 2. Some discharge preferentially for one direction of movement (tuning to movement) 3. Some discharge proportional to force or rate of change of force The figure above illustrates #1 and #2. The plot shows how a single neuron in the monkey motor cortex responds to different directions of movement. Each plot is a direction of movement and the ‘M’ defines movement onset. Note how the neuron starts to generate action potentials before the movement starts (#1) and also that the neuron generates different numbers of action potentials depending on which way the monkey moves its arm. 10. List the factors that cause time delay between onset of cortical discharge and movement. 1. Conduction time from cortex to spinal cord 2. Time for summation of EPSPs to threshold in alpha motoneurons 3. Conduction time spinal cord to the neuromuscular junction 4. Synaptic delay at the neuromuscular junction (1 ms) 5. Electrical mechanical coupling time a. time from muscle action potential to movement onset, i.e., time for muscle contraction to overcome mass/inertia of limb).  NEURO-58 Neuro XI: Cerebellum Objectives: 1. Draw a simple diagram of the cerebellum. What is the origin of the name cerebellum? Does the cerebellum have many neurons? How many cell types are there in the cerebellar cortex? After a lesion of the cerebellum: What does not change? What changes? 2. Draw a simple diagram illustrating the input-output connections of the cerebellum including the cerebellar cortex, Purkinje cells and deep nuclei. Name five features. 3. List the effects in humans of a lesion in (i) the medial cerebellum; (ii) lateral cerebellum. 4. Give an overall function of the cerebellum. 5. Name and discuss four specific functions of the cerebellum.  NEURO-59 Objectives (Answers) 1. Draw a simple diagram of the cerebellum. What is the origin of the name cerebellum? Does the cerebellum have many neurons? How many cell types are there in the cerebellar cortex? After a lesion of the cerebellum: What does not change? What changes? Cerebellum comes from Latin meaning “little brain”. The cerebellum consists of only 10% of the volume of the brain but contains more half of the number of neurons. The same basic neuronal architecture is present the same way across all regions or the cerebellum. Two separate input streams via parallel fibers and climbing fibers. Lesions in the cerebellum do not cause deficits in sensory perception, sensory threshold or the strength of movements. People can still make movements but they are inaccurate and uncoordinated.  NEURO-60 2. Draw a simple diagram illustrating the input-output connections of the cerebellum including the cerebellar cortex, Purkinje cells and deep nuclei. Name five features. 1. Widespread sensory input. None reaches consciousness. 2. Only output from cerebellar cortex to deep nuclei is via Purkinje cells - always inhibitory. 3. Anatomically/physiologically/neurologically there is a medial and a lateral division. 4. In monkeys and humans there is an increased development of lateral cerebellum. 5. Lateral cerebellum projects to motor cortex and to frontal cortex (cognitive function?). a. Lateral cerebellum is particularly developed in monkeys and humans. 3. List the effects in humans of a lesion in (i) the medial cerebellum; (ii) lateral cerebellum. Lateral cerebellum o Dysmetric limb movements o Intention tremor o Arm ataxia Medial cerebellum o Dysmetric saccades o Disorder of smooth pursuit eye movements o Disorder of equilibrium and balance o Gait ataxia Many of the effects of cerebellar lesions can be mimicked by alcohol (which may act at GABA gated ion channels). These disorders occur because of the failure of the cerebellum to “tune-up” the different functions, e.g., failure to tune-up the generation of saccades (in brainstem reticular formation), limb movements (motor cortex) and balance (vestibular postural reflexes). 4. Give an overall function of the cerebellum.  NEURO-61 The cerebellum is like a computer that automatically (subconsciously) tunes-up reflexes, motor programs and cognition to make them more accurate. 5. Name and discuss four specific functions of the cerebellum. 1. Contributes to the generation of accurate saccades and limb movements. a. Every time a saccade of voluntary limb movement is made, the cerebellum helps start it, helps stop it, and makes it as accurate as possible. 2. Feedforward, anticipatory, predictive movement control. a. When a perturbation is expected, the movements which occur are based on feedforward (anticipatory) control. For example, when catching a ball dropped from a height, visual information is used by the cerebellum to predict (anticipate) the time of ball impact. b. This enables biceps muscle contraction to occur before the ball hits the hand, which prevents excessive hand movement when the ball hits the hand. If only feedback mechanisms occurred (as a result of stretch of the biceps muscle after ball impact) it would take a relatively long time to generate muscle contraction, the hand would be displaced further downwards and the ball may be dropped. 3. Motor recalibration, error correction, motor learning  NEURO-62 a. When encountering changes in the environment or body (e.g. new glasses, heavy coat), the nervous learns to recalibrate how motor commands lead to movements and thus reduce errors. b. One mechanism suggested to cause this recalibration is changing the strenfth of the parallel fiber – Pukinje cell synapse, by means of input from climbing fibers (the teacher). c. Cerebellar patients cannot recalibrate or do so very slowly. For example, in the glasses- throwing experiment, after putting on glasses a healthy participant starts throwing to the left but recalibrates and ends throwing at the target. In contrast, a cerebellar patient, after making 30 throws, would still throw to the left. On taking off the glasses, a healthy participant throws to the right (negative after-effect which demonstrates that recalibration/learning has taken place). However, on taking off the glasses, a cerebellar patient would throw straight ahead because no learning had taken place. 4. Contributions to cognition a. Sensory Discrimination. Cerebellar patients cannot discriminate as accurately the duration of auditory tones or the velocity of moving objects, i.e., they have a defect in ability to judge elapsed time. b. Spatial Cognition. Cerebellar patients do not perform well on spatial tasks, e.g., pegboard puzzles c. Linguistic Processing. Cerebellar patients do not perform well on noun-verb matching task, e.g., dog-bark.  NEURO-63 Neuro XII: Basal Ganglia Objectives: 1. Name 3 areas of cortex that interact with motor cortex in production of movement. 2. Name the nuclei of the basal ganglia, draw a diagram of their connections, and describe six features of this diagram. 3. Name the functions, and the disorders resulting from lesions, in the following loops through basal ganglia: Motor, Oculomotor, Limbic, Cognitive. 4. Describe a possible function of the basal ganglia for motor loops. 5. Name two classic diseases associated with the basal ganglia and list their pathology, features/symptoms, neural discharge and treatments. 6. Describe what happened when drug users mistakenly took MPTP. Name two positive outcomes for the scientific investigation of the basal ganglia that have come from this experience.  NEURO-64 Objectives (Answers) 1. Name 3 areas of cortex that interact with motor cortex in production of movement. 1. Supplementary motor cortex 2. Premotor cortex 3. Parietal cortex 2. Name the nuclei of the basal ganglia, draw a diagram of their connections, and describe six features of this diagram. Nuclei o Caudate and putamen (neostriatum) o globus pallidus internal o globus pallidus external o subthalamic nucleus o substantia nigra pars compacta 1. There are at least four separate circuits (loops) from cerebral cortex, through the basal ganglia, and back to cerebral cortex. 2. There are two inputs to caudate/putamen (from cerebral cortex and substantia nigra pars compacta) 3. The major transmitters in the caudate/putamen are dopamine (can be excitatory or inhibitory), acetylcholine, and glutamate 4. From the caudate/putamen to the internal globus pallidus, there is a direct and an indirect (via subthalamic nucleus) pathway 5. GABA is the inhibitory transmitter 6. One major output is from the internal globus pallidus to the thalamus (inhibitory)  NEURO-65 3. Name the functions, and the disorders resulting from lesions, in the following loops through basal ganglia: Motor, Oculomotor, Limbic, Cognitive. Motor o Limb and face movements (Parkinson’s and Huntington Disease Symptoms) Oculomotor o Eye movements (fewer and slower saccades) Limbic o Emotion (irritability and depression) Cognitive o Planning, working memory, attention (absent-minded, reasoning ability, dementia, tourettes, obsessive compulsive disorder) 4. Describe a possible function of the basal ganglia for motor loops. The basal ganglia exerts continuous inhibition which prevents unwanted movements. When a movement is to be made the basal ganglia selects neural programs by releasing them from inhibition. 5. Name two classic diseases associated with the basal ganglia and list their pathology, features/symptoms, neural discharge and treatments. Parkinson’s Disease – Loss of dopaminergic neurons in the substantia nigra (pars compacta). Changes balance of activity in the direct and indirect pathways. Features of Parkinson’s Disease: a. rigidity (not spasticity i.e.flexors and extensors, not velocity dependent, lead pipe) b. resting tremor (not intention tremor, pill rolling, stops during movement) c. akinesia (poverty of movement) d. bradykinesia (slowed movement) i. shuffling gate e. dementia (involvement of frontal cortex) f. mask-like face There is an increase in discharge in neurons in the globus pallidus in Parkinson’s disease. This will increase inhibition at the thalamus and decrease excitation at the motor cortex. Treatment o The main treatment is to enhance dopaminergic transmission using L-dopa. Neurologists try to change the balance between dopamine and acetylcholine i.e., increase dopamine, decrease acetylcholine (anti-cholinergics). Too little dopamine causes akinesia; too much dopamine causes involuntary movements (dyskinesia). L-dopa is not a cure, it only relieves the symptoms and it loses effectiveness with time or disease progression. o High frequency electrical stimulation (deep brain stimulation) of the internal globus pallidus abolishes low-frequency synchronized oscillations as a result of phasic driving (McCairn K, Turner RS J Neurophysiol 101:1941-1960, 2009).  NEURO-66 o Lesion the internal segment of the globus pallidus. Improvement in specific motor signs depends on lesion position. Huntington Disease – Degeneration of neurons in caudate and putamen. Associated with abnormal repeats of Huntingtin gene. Causes abnormal protein folding and cell death. o The first signs of the disorder are subtle: absentmindedness, irritability, and depression, accompanied by fidgeting, clumsiness, or falls. o Uncontrolled movements, a prominent feature of the disease, gradually increase until the patient is confined to bed or to a wheelchair. Speech is slurred at first, then incomprehensible, and finally stops altogether as facial expressions become distorted and grotesque. Cognitive functions also deteriorate, and eventually the ability to reason disappears. No treatment is available. o Once the disease has begun its course, the patient faces years of gradually decreasing capacity, followed by total disability and certain death. Features of Huntington Disease: o Heritability o Chorea (decreased output from the globus pallidus, motor loop) o Oher movement disorders (e.g. slurred speech) o Dementia (limbic, cognitive loops) o No treatment o Death Other Movement Disorders o Hemiballismus – Violent movement of limb due to lesion in subthalamic nucleus o Tourette’s Syndrome – Inappropriate utterances (can be obscene) and tics (brief, repetitive involuntary movements such as eye blinks, head tosses and facial grimaces), thought to be the result of excessive activity in the cognitive (prefrontal) basal ganglia circuitry. 6. Describe what happened when drug users mistakenly took MPTP. Name two positive outcomes for the scientific investigation of the basal ganglia that have come from this experience. MPTP (1 methyl, 4 phenyl,1,2,3,6 tetrahydropyridine) o In 1982, 7 drug abusers in California took what they thought was an intravenous form of synthetic heroin. Unfortunately, the synthesis had gone wrong and the drug was contaminated with MPTP which depletes the brain dopamine levels. Overnight these people developed Parkinsonian-like symptoms with rigidity, resting tremor and severe akinesia. Two positive outcomes: o MPTP produces an animal model of Parkinson’s disease o The hypothesis was proposed that Parkinson’s disease may result in part from an environmental toxin (recent findings in a large twin study indicate that most cases of Parkinson’s disease are probably the result of an environmental cause). In keeping with this, chronic exposure in rats to rotenone (a common organic pesticide) produced the features of Parkinson’s disease. ▪ The current view is that both genetic and environmental factors are involved. NEURO-67