UNIVERSITY OF JORDAN FACULTY OF MEDICINE DEPARTMENT OF PHYSIOLOGY & BIOCHEMISTRY NEUROPHYSIOLOGY (MEDICAL) Spring, 2014

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1 UNIVERSITY OF JORDAN FACULTY OF MEDICINE DEPARTMENT OF PHYSIOLOGY & BIOCHEMISTRY NEUROPHYSIOLOGY (MEDICAL) Spring, 2014 Textbook of Medical Physiology by: Guyton & Hall, 12 th edition 2011 Eman Al-Khateeb, Professor of Neurophysiology No.1 Introduction, CNS organization: Review of the basic concepts of Neurophysiology: What is Neuroscience? It is the understanding of how the brain functions in both health and disease. Modern neuroscience is not an isolated discipline. It integrates the inputs of, for example, biochemistry, physiology, pharmacology, microbiology, anatomy, pathology, psychology and psychiatry to address the normal and abnormal functioning of the nervous system. Our course emphasises such inputs, and offers a balance between molecular and cellular aspects of the subject and systems and clinical neuroscience. Why study Neuroscience? * Neuroscience is one of the most exciting and dynamic areas of modern biomedical research. The topic ranges from understanding the molecular, biochemical and cellular events that underpin communication between nerve cells, through to the execution of complex behaviours such as playing a piano. Higher cognitive functions, such as learning, memory and emotions ultimately depend upon cellular and neuronal networks that neuroscience endeavours to reveal and explain. The discipline grows in importance to society as the aged proportion of the population increases, bringing new challenges in the treatment and management of neurological disorders. Discovering how drugs influence our mood and behaviour is also essential in developing new treatments for conditions such as anxiety and depression and in the better management of drug addiction. * Neurological symptoms account for high percentage of consultation in general practice. It accounts for 20 % of acute admissions to hospitals, trauma, critical illness, anaesthesia & surgery. * Diagnosis is primarily clinical, based on history and physical examination; any investigation can only supplement but never replace the process of clinical assessment. 1

2 *The symptomatology of nervous diseases; The symptoms of a nervous disease have a negative and a positive aspect. Lesion to a centre in the CNS may diminish or abolish the function of that centre because of tissue damage (negative: paralysis, blindness). Other symptoms (positive) are produced by the activity of the intact centers either because they are liberated from the control of the damaged centre or their activity intensifies to compensate for the missing function or because of unbalanced activities. Examples of positive symptoms include an epileptic focus, spasticity, Babinski sign, rigidity, paraesthesia, and ataxia. Additionally, in acute lesions as in intracranial haemorrhage, there may be a temporary cessation of function of the reticular system causing disturbance or loss of consciousness (cerebral shock and coma). *The diagnosis of neurological diseases: The diagnosis of neurological diseases depends on anatomical and non-anatomical factors. Anatomical factors determine the symptoms, signs, and localization of the lesion, whereas non-anatomical factors may help to determine the etiology. Non-anatomical factors include the speed of development of symptoms and signs (acute, sub-acute, chronic), their course (progressive, fluctuating), and their outcome. It should be remembered that the disturbance of function involves the most recently acquired and the most complex features first. Thus skilled movements and functions as writing, speech, and playing a musical instrument become impaired whereas grasping remains. Native language may be preserved whereas acquired language may be impaired or lost. Most recently acquired and complex functions are the last to recover and recovery may not be complete. *Temporal pattern associated with specific neurological causes: 1. Cerebral hemisphere lesion presented with contralateral weakness, a rapid onset (seconds to minutes or at most hours) and then static subsequent course, ultimately possibly with some improvement, suggest a vascular event (stroke), i.e. haemorrhage or infarction. 2. A slowly progressive course (days, weeks or months) is more indicative of a mass lesion, i.e. a tumor. 3. A relapsing and remitting pattern (with symptoms typically developing and resolving over days or weeks, then perhaps recurring with a similar time course) generally implies a chronic inflammatory or demyelinating process of which multiple sclerosis is the prime example in the central nervous system. Major levels of CNS function: 1. Spinal Cord level: Walking movements, spinal reflexes, and reflex control of local blood vessels, gastrointestinal movements and urinary excretion. 2. Brain levels A. Brain stem and cerebellum; Control subconscious activities. Arterial blood pressure, Respiration (Function of medulla and Pons), Equilibrium (Function of cerebellum, vestibular nuclei and reticular formation) B. Sub-Cortical level (Limbic system): 2

3 Many emotional patterns, motivation and behavior. 3. Cortical level: The cerebral cortex is large memory storehouse, it is also essential for most of our thought processes, intelligence and language. It converts lower brain functions that are imprecise to determinative and precise operations. THE CENTRAL NERVOUS SYSTEM; Contains more than 100 billion neurons, ,000 input to each neuron, Single output (axon) that branches. Dinosaur 1600 Kg (his brain weight = 0.07 Kg) %, Human 70 Kg (his brain weight = 1.4 Kg). 2 %. Although the human brain represents only 2 % of the body weight, it contributes up to 20 % of the body resting metabolism; it receives 15% of the cardiac output, 20 % of total body oxygen consumption, and 25 % of total body glucose utilization. Excitable tissue: Any tissue that its cells are capable of generating rapidly changing electrochemical impulses (AP) and transmit them along their membranes, e.g. Nerve and Muscle cells. 3

4 Resting Membrane Potential (RMP): RMP is the electrical potential across the membrane when the cell at rest or inactivity. It is equal to - 90 mv in large nerve fiber and -60 to -70 mv in neurons. Ionic basis of RMP: 1. Passive outward diffusion of K + : At rest, the membrane is 100 times more permeable to K + than to inward diffusion of Na +. This k + outward diffusion will create a state of electropositivity outside the membrane & electronegativity on the inside & contributes to - 86 mv of the RMP in large nerve fiber. 2. Electrogenic pump (Na + - K + pump): The Na + - K + pump pumps 3 Na+ ions out for every 2 K+ pumped in. It utilizes ATP as a source of energy. For every cycle of the pump the inside losses one positive charge, a process that lead to an excess of positive charges outside. It creates only - 4 mv potential difference across the membrane. Therefore RMP = (- 86) + (- 4) = - 90 mv Action Potential (AP), the nerve impulse: AP is rapid transient change in the membrane potential that spreads rapidly along the nerve fiber membrane. In order to initiate an AP there must be an electrical, chemical or mechanical stimulus. Stages of AP: 1. RMP stage it is - 90 mv in large myelinated nerve fiber. 2. Depolarization stage: Na + influx leading to positive potential. This change in membrane potential is due to opening of voltage gated Na + channels for short period leading to Na + influx in a positive feedback vicious cycle, this means: Change in membrane potential opening of voltage gated Na + channels Na + influx Change in membrane potential and so on. 3. Repolarization stage: It is due to: a. Closure of voltage gated Na + channels preventing Na + influx. b. Opening of voltage gated K + channels which lead to K + efflux. 4. Positive after potential. 4

5 Re-establishing Na + & K + ionic gradients after AP's are completed: The activity of Na + - K + pump is strongly stimulated when excess Na + accumulates inside the cell membrane, when Na + concentration intracellularly is doubled, the activity of the Na + - K + pump increases 8 folds. Properties of AP: 1. Regenerative: once initiated it continues without the need for external input of energy. 2. Threshold: it is the level of membrane potential required to cause an AP. It is between - 50 to -70 mv. 3. All on None nature: The size of the AP is independent on stimulus energy and AP has fixed amplitude. 4. AP propagates. 5. AP has a refractory period. Tetrodotoxin: Is a potent neurotoxin with no known antidote, which blocks AP in nerves by binding to the pores of the voltage gated, fast sodium channels in nerve cell membrane. It can be used medically to treat arrhythmias. Novocaine which is used as a local anesthetic has a similar action of tetrodotoxin. Effect of ionic composition on nerve fiber excitability: 1. Hypercalcaemia decrease nerve fiber excitability. 2. HypoKalemia also decreases nerve fiber excitability. 3. Hypocalcaemia increase nerve fiber excitability due to increase membrane permeability to Na + ions leading to depolarization (Hypocalcaemic Tetany). 4. Hyponatremia is the most common electrolyte disorder encountered in clinical practice and may occur in up to % of hospitalized patients. Rapid Hyponatremia (below mmol/l) lead to seizures, coma and brain damage, however when hyponatremia evolves slowly over several days, the brain respond by transporting sodium, chloride, potassium and organic solutes such as glutamate to the EC compartment. Rapid corrections by hypertonic solutions lead to osmotic injury and demyelination (Central pontine myelinolysis) Chronic hyponatremia can be the result of chronic conditions such as kidney failure (when excess fluid cannot be efficiently excreted) and congestive heart failure, in which excess fluid accumulates in the body. SIADH (syndrome of inappropriate anti-diuretic hormone) is a disease whereby the body produces too much anti-diuretic hormone (ADH), resulting in retention of water in the body. Hyponatremia can also result when sodium is lost from the body or when both sodium and fluid are lost from the body, for example, during prolonged sweating and severe vomiting or diarrhea. Medical conditions that can sometimes be associated with hyponatremia are adrenal insufficiency, hypothyroidism, and cirrhosis of the liver. Finally, a number of medications can lower blood sodium levels. Examples of these include diuretics, vasopressin, and the sulfonylurea drugs. Hypernatremia is much less common than hyponatremia, it occur in patients with hypothalamic injury were thirst is impaired, in infants and elderly with altered mental status. Correction also must be slowly by hypotonic solution because rapid correction will lead to multiple cerebral hemorrhages. 5

6 Stimulus Strength Compound AP: When the strength of the stimulus is very low, we see no response from the nerve. This stimulus strength is subthreshold. If the strength is raised, a tiny response appears in the record and, as the strength is increased even more, the response grows to a maximum value; further increases in stimulus strength do not further augment the response. The stimulus strength that just gives a response is termed a threshold stimulus; any stimulus of greater strength is suprathreshold. The strength that just gives the maximal response is a maximal stimulus; any strength greater is supramaximal. The response of the nerve is called the compound action potential. The compound action potential is graded in nature, in striking contrast to the all-or-none response of single axons and this is because the compound AP represents the summation of many AP s that all of them are all or none. Also it has multiple peaks and is recorded from nerve trunk (Median nerve, ulnar nerve...etc). The nerve trunk contains many myelinated large nerve fibers and even more unmyelinated small nerve fibers. The Conduction velocity varies from 100 to 0.5 m / sec respectively. The appearance of multiple peaks in the potential is due to the presence of families of nerve fibers with varying speeds of conduction. Compound Action Potential, CAP 6

7 Electrodiagnostic tests (EDX); During nerve conduction studies, an electric pulse applied transcutaneously sets up a wave of depolarization, which can be recorded at different points along the course of the nerve allowing estimation of conduction velocity in different segments of the nerve. Each nerve contains axons of different thickness and myelination, so much so conduction of action potentials is not at uniform speed; the larger the axon, the thicker the myelin sheath and faster the conduction. Since it is difficult to ensure that the particular axons stimulated at one spot on the nerve are the same ones stimulated at a different site, it is necessary to stimulate all the axons at each site to obtain accurate estimates of motor conduction velocity; this is achieved by using a stimulus intensity, 10 % more than that produces maximum amplitude of the nerve or muscle action potential (supra-maximal stimulus) How EDX tests are done: Motor NCV: The electrical response to nerve stimulation is recorded over a target muscle using surface electrodes; the active electrode is placed over the motor point of the muscle belly and reference electrode over the tendon. A supramaximal stimulus is applied transcutaneously over the nerve, with the cathode of the stimulator facing the muscle; the resulting contraction of the muscle is accompanied by electric activity, recorded as the 7

8 CMAP (compound muscle action potential). By stimulation of the same nerve distally and proximally, the time interval between the onsets of the CMAPs (onset latency difference) can be measured; the distance between the sites of proximal and distal stimulation divided by the latency difference gives the motor conduction velocity. Compound Motor Action Potential: CMAP Motor nerve is stimulated and muscle response is calculated. Latency includes synaptic transmission etc. By subtracting the two latencies, the conduction velocity can be calculated. Sensory Conduction: Sensory axons may be stimulated at the level of the digital branches and the resulting action potential (SNAP) can be tracked as it passes towards the spinal cord (orthodromic); a limiting factor is the small size of the potential, which makes it difficult to pick it up as the nerve goes deeper and deeper from the surface. Several responses may have to be averaged to separate the response from random electrical noise. One could also stimulate proximally and record the responses over the digits distally (antidromic); in this instance, the digital nerves are closer to the skin and the recording electrodes and hence the SNAPs are larger. 8

9 SNAP: Sensory Nerve Action Potential Figure 2 Median orthodromic sensory study. The index finger digital nerves are stimulated via ring electrodes and the response recorded over the median nerve at the wrist. Mallik, A et al. J Neurol Neurosurg Psychiatry 2005;76:ii23-31ii Abnormal patterns and their significance: General observations: 1. Focal demyelination (FD): There is focal slowing of conduction across the area of demyelination. If the segment is long it is easy to detect; however, if the segment is short, one needs special techniques such as inching study. 2. Axon loss: The portion below the area of axon loss shows no conduction if Wallerian degeneration has already set in (takes a week or more after injury); the muscles show denervation changes. If partial axon loss, there is decreased amplitude of CMAP and also denervation changes. Demyelination is indicated if conduction velocities have fallen below 50% of normal. Even significant loss of axons commonly reduces conduction velocities by only about 30%, based on a loss of the fastest conducting fibers. Repetitive nerve stimulation (RNS): RNS is a modified motor NCS where instead of recording cmaps with single supramaximal electrical stimuli, a train of 8-10 stimuli is applied and the sequential response amplitudes measured. RNS is used in the evaluation of patients that are clinically presented with muscle weakness and neuromuscular transmission disorders is suspected such as: 9

10 1. Myasthenia gravis is an autoimmune disease, where the body produces antibodies targeted against the acetylcholine receptor on the postsynaptic membrane in the neuromuscular junction. Muscle fatigue and weakness (especially in upper arms) that worsened with use and improved by rest, is the hallmark of the disease. Decremental RNS of % is expected. 2. Lambert-Eaton myasthenic syndrome; (LEMS) is a disorder where presynaptic calcium channels are subjected to autoimmune destruction which causes fewer neurotransmitter vesicles to be exocytosed. This causes smaller end plate potentials (EPPs) due to less vesicles being released. Oftentimes the smaller EPPs do not reach threshold which causes muscle weakness and fatigue in patients (especially in the lower limbs). Incremental RNS is expected in LEMS after exercise to 3 or 4 folds in amplitude, this facilitation (strength improvement after exercise) allows LEMS to be distinguished clinically from Myasthenia gravis. Around 60% of those with LEMS have an underlying malignancy, most commonly small cell lung cancer, LEMS is usually manifest before the cancer is evident and data suggests that clinical evidence of LEMS confers a survival advantage in patients with small cell lung cancer an aggressive tumor with poor prognosis. Electrtonic Potential (EP), Graded Potential: 1. It is local potential; arise mainly in dendrites and some. 2. It is graded, and its amplitude varies (1 50 mv) as it depends on the intensity of stimulus 3. It rises rapidly and decays exponentially and fades with distance and has longer duration than AP. 4. It has the capability to summate spatially and temporally. 5. Ligand-gated or mechanically gated channels are involved in EP. 6. Either hyperpolarizing or depolarizing potential. 7. Has no refractory period. Examples of EP: End plate potential, EPSP, IPSP, Receptor Potential, Generator Potential. 10

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