Topamax

By D. Stan. State University of New York College at New Paltz. 2018.

It is trocardiogram is the time between the beginning of ven- likely that many other neuronal (and muscle) disorders of tricular depolarization and the end of ventricular repolar- currently unknown pathology will be identified as chan- ization order topamax 200mg with mastercard. This in- axon generic topamax 100mg amex, more of the adjacent region that is depolarized by crease in Rm increases the space constant. The layers of the inward current accompanying the action potential myelin also decrease the effective capacitance of the axonal reaches the threshold for action potential generation. The membrane because the distance between the extracellular result is that the speed at which action potentials are con- and intracellular conducting fluid compartments is in- ducted, or conduction velocity, increases as a function of creased. Because the capacitance is decreased, the time increasing axon diameter and concomitant increase in the constant is decreased, increasing the conduction velocity. While the effect of myelin on Rm and capacitance are Several factors act to increase significantly the conduc- important for increasing conduction velocity, there is an tion velocity of action potentials in myelinated axons. In myelinated axons, voltage-gated Na CNS wrap themselves around axons to form myelin, layers channels are highly concentrated in the nodes of Ranvier, of lipid membrane that insulate the axon and prevent the where the myelin sheath is absent, and are in low density passage of ions through the axonal membrane (Fig. When an action potential Between the myelinated segments of the axon are the nodes is initiated at the axon hillock, the influx of Na ions of Ranvier, where action potentials are generated. This, in turn, causes axons apparently derives from the axon, and its potency is depolarization of the next node of Ranvier and the even- a function of axon size. In general, axons larger than ap- tual initiation of an action potential. Action potentials are proximately 1 m in diameter are myelinated, and the successively generated at neighboring nodes of Ranvier; thickness of the myelin increases as a function of axon di- therefore, the action potential in a myelinated axon ap- ameter. Since the smallest myelinated axon is bigger than pears to jump from one node to the next, a process called the largest unmyelinated axon, conduction velocity is faster saltatory conduction (Fig. In addition, the faster conduction velocity for myelinated than unmyeli- myelin acts to increase the effective resistance of the axonal nated axons. The conduction velocity in mammals ranges membrane, Rm, since ions that flow across the axonal mem- from 3 to 120 m/sec for myelinated axons and 0. CHAPTER 3 The Action Potential, Synaptic Transmission, and Maintenance of Nerve Function 45 Peak of action ated no matter how much the membrane is depolarized. The absolute re- 1 Inward current fractory period also prevents action potentials from travel- ing in the wrong direction along the axon. Since these channels have returned to their initial resting state, they Axon can now respond to depolarizations of the membrane. Con- Depolarized region sequently, when the membrane is depolarized, many of the channels open their activation gates and permit the influx of Direction of propagation Na ions. However, because only a portion of the Na chan- nels have returned to the resting state, depolarization of the A membrane to the original threshold level activates an insuffi- cient number of channels to initiate an action potential. With greater levels of depolarization, more channels are activated, until eventually an action potential is generated. The K channels are maintained in the open state during the relative refractory period, leading to membrane hyperpolarization. By these two mechanisms, the action potential threshold is in- Axon creased during the relative refractory period. At electrical synapses, passageways known as gap junctions connect the cytoplasm of adjacent neurons (see Fig. Elec- Glial cell potential node Axon trical synapses are uncommon in the adult mammalian here here nervous system. Typically, they are found at dendroden- dritic sites of contact; they are thought to synchronize the activity of neuronal populations. Gap junctions are more common in the embryonic nervous system, where they may act to aid the development of appropriate synaptic connec- tions based on synchronous firing of neuronal populations. The initiation of an action potential in one seg- ment of the axon depolarizes the immediately adjacent section, bringing it to threshold and generating an action potential. The initiation of an action potential in one node of Ranvier depolarizes the next node. After the start of an action potential, there are periods when the initiation of additional action potentials requires a greater degree of depolarization and when action potentials cannot be initiated at all. These are called the relative and absolute refractory periods, respec- FIGURE 3.

The (diplopia topamax 200mg discount, ptosis) buy topamax 200mg lowest price, and in approximately 50% of patients, facial and somatotopy of corticospinal fibers in the basilar pons is less obvious than oropharyngeal muscles are commonly affected ( facial weakness, dys- in the internal capsule, crus cerebri, pyramid, or spinal cord. Weakness may also be seen in limb muscles but al- cussation of the pyramids, fibers originating from upper extremity ar- most always in combination with facial/oral weaknesses. In addition to fibers arising from the somatomotor area (as in the Brown-Sequard syndrome) results in weakness (hemiparesis) or of the cerebral cortex (area 4), a significant contingent also originate paralysis (hemiplegia) of the ipsilateral upper and lower extremities. In from the postcentral gyrus (areas 3, 1, 2); the former terminate pri- addition, and with time, these patients may exhibit features of an upper marily in laminae VI-IX, while the latter end mainly in laminae IV and motor neuron lesion (hyperreflexia, spasticity, loss of superficial abdominal V. Prefrontal regions, especially area 6, and parietal areas 5 and 7 also reflexes, and the Babinski sign). Bilateral cervical spinal cord damage contribute to the corticospinal tract. Unilateral spinal cord lesions in thoracic levels may result in paral- ( ), and substance P ( , plus other peptides) are found in small cor- ysis of the ipsilateral lower extremity (monoplegia). If the thoracic spinal tical neurons presumed to function as local circuit cells or in cortico- cord damage is bilateral both lower extremities may be paralyzed (para- cortical connections. Small lesions within the decussation of the pyramids may result fibers that project to the spinal cord. Glutaminergic corticospinal fibers in a bilateral paresis of the upper extremities (lesion in rostral portions) and terminals are found in all spinal levels but are especially concen- or a bilateral paresis of the lower extremities (lesion in caudal portions) trated in cervical and lumbosacral enlargements. This correlates with based on the crossing patterns of fibers within the decussation. Some corticospinal dromes), or midbrain (the Weber syndrome) all produce alternating fibers may branch and terminate at multiple spinal levels. These present as a contralateral hemiplegia of the tor neurons are influenced by corticospinal fibers either directly or in- upper and lower extremities, coupled with an ipsilateral paralysis of directly via interneurons. Acetylcholine and calcitonin gene-related the tongue (medulla), facial muscles or lateral rectus muscle (pons), peptides are present in these large motor cells and in their endings in and most eye movements (midbrain). Lesions in the internal capsule (lacu- Clinical Correlations: Myasthenia gravis, a disease characterized nar strokes) produce contralateral hemiparesis sometimes coupled with by moderate to profound weakness of skeletal muscles, is caused by various cranial nerve signs due to corticonuclear (corticobulbar) fiber circulating antibodies that react with postsynaptic nicotinic acetyl- involvement. Bilateral weakness, indicative of corticospinal involve- choline receptors. Progressive muscle fatigability throughout the day ment, is also present in amyotrophic lateral sclerosis. Abbreviations ACSp Anterior corticospinal tract LCSp Lateral corticospinal tract Somatotopy of CSp Fibers ALS Anterolateral system ML Medial lemniscus A Position of fibers coursing to APGy Anterior paracentral gyrus MLF Medial longitudinal fasciculus upper extremity regions of BP Basilar pons PO Principal olivary nucleus spinal cord CC Crus cerebri PrCGy Precentral gyrus L Position of fibers coursing to CNu Corticonuclear (corticobulbar) Py Pyramid lower extremity regions of fibers RB Restiform body spinal cord CSp Corticospinal fibers RNu Red nucleus T Position of fibers coursing to IC Internal capsule SN Substantia nigra thoracic regions of spinal cord Review of Blood Supply to Corticospinal Fibers STRUCTURES ARTERIES Posterior Limb of IC lateral striate branches of middle cerebral (see Figure 5–38) Crus Cerebri in paramedian and short circumferential Midbrain branches of basilar and posterior communicating (see Figure 5–27) CSp in BP paramedian branches of basilar (see Figure 5–21) Py in Medulla anterior spinal (see Figure 5–14) LCSp in Spinal Cord penetrating branches of arterial vasocorona (leg fibers), branches of central artery (arm fibers) (See Figure 5–6) Motor Pathways 191 Corticospinal Tracts Thigh Somatomotor cortex Leg APGy Foot Somatotopy of CSp Post. These fibers influence—ei- lesioned side and away from the side of the hemiplegia. In addition to ther directly or through neurons in the immediately adjacent reticular a contralateral hemiplegia, common cranial nerve findings in capsular le- formation—the motor nuclei of oculomotor, trochlear, trigeminal, ab- sions may include 1) deviation of the tongue toward the side of the ducens, facial, glossopharyngeal and vagus (both via nucleus ambiguus), weakness and away from the side of the lesion when protruded and 2) spinal accessory, and hypoglossal nerves. This reflects the fact that corticonuclear (cortico- eas 6 and 8 in caudal portions of the middle frontal gyrus), the precen- bulbar) fibers to genioglossus motor neurons and to facial motor neu- tral gyrus (somatomotor cortex, area 4), and some originate from the rons serving the lower face are primarily crossed. Fibers from area 4 occupy the genu of ticonuclear fibers to the nucleus ambiguus may result in weakness of the internal capsule, but those from the frontal eye fields (areas 8,6) may palatal muscles contralateral to the lesion; the uvula will deviate to- traverse caudal portions of the anterior limb, and some (from areas wards the ipsilateral (lesioned) side on attempted phonation. In addi- 3,1,2), may occupy the most rostral portions of the posterior limb. In contrast to from area 4 terminate in, or adjacent to, cranial nerve motor nuclei ex- the alternating hemiplegia seen in some brainstem lesions, hemisphere cluding those of III, IV, and VI. In addition, it is important to note the following: 1) vertical gaze palsies (midbrain), 2) the Parinaud syn- that descending cortical fibers (many arising in areas 3, 1, 2) project to drome—paralysis of upward gaze (tumors in area of pineal), 3) internu- sensory relay nuclei of some cranial nerves and to other sensory relay clear ophthalmoplegia (lesion in MLF between motor nuclei of III and nuclei in the brainstem, such as those of the posterior column system. VI), 4) horizontal gaze palsies (lesion in PPRF), or 5) the one-and-a-half Neurotransmitters: Glutamate ( ) is found in many corticofu- syndrome. In the latter case, the lesion is adjacent to the midline and in- gal axons that directly innervate cranial nerve motor nuclei and in volves the abducens nucleus and adjacent PPRF, internuclear fibers those fibers that terminate near (indirect), but not in, the various mo- from the ipsilateral abducens that are crossing to enter the contralat- tor nuclei. The cerebral artery occlusion) or the internal capsule (as in lacunar strokes result is a loss of ipsilateral abduction (lateral rectus) and adduction or occlusion of lenticulostriate branches of M1) give rise to a con- (medial rectus, the “one”) and a contralateral loss of adduction (medial tralateral hemiplegia of the arm and leg (corticospinal fiber involve- rectus, the “half ”); the only remaining horizontal movement is con- ment) coupled with certain cranial nerve signs. Strictly cortical lesions tralateral abduction via the intact abducens motor neurons. Abbreviations AbdNu Abducens nucleus OcNu Oculomotor nucleus AccNu Accessory nucleus (spinal accessory nu. Many of brainstem and spinal cord, and the general distribution of tectospinal reticulospinal fibers influence the activity of lower motor neurons. Tectospinal fibers originate from deeper lay- Clinical Correlations: Isolated lesions of only tectospinal and ers of the superior colliculus, cross in the posterior (dorsal) tegmental reticulospinal fibers are essentially never seen.

This provides a rationale for the use of phenytoin and carbemazepine in controlling epileptic discharges effective topamax 200mg. In unmyelinated fibres (including the squid axon purchase topamax 100 mg otc, where the ionic currents responsible for the action potential were first elucidated, see Fig. These may be sustained or transient (inactivating) in kinetic behaviour. However, K‡ channels are normally absent from nodes of Ranvier and action potential repolarisation in myelinated fibres results solely from Na‡ channel inactivation. Thus, blocking K‡ channels with drugs such as tetraethyl- ammonium or 4-aminopyridine (Fig. They can also improve conduction in myelinated fibres following demyelination (e. Cooling the nerve has a similar effect to blocking K‡ channels: hence MS patients are very sensitive to temperature. CALCIUM CHANNELS: TRANSMITTER RELEASE When an action potential arrives at the axon terminal, it induces the release of a chemical transmitter. Transmitter release is a Ca2‡-dependent process (see Chapter 4) and requires a charge of Ca2‡. This is provided through the action potential-induced 38 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Table 2. A variety of Ca2‡ channels have been described, characterised by their kinetics, single-channel properties, pharmacology (especially sensitivity to different toxins) and molecular structure (Table 2. Those primarily responsible for transmitter release belong to the N (a1B), P/Q (a1A) and R classes (a1E). So far, no pharmacological agents capable of uniquely modifying Ca2‡ channels involved in transmitter release have been described (other than polypeptide toxins). These, and other (L-type, T-type), Ca2‡ channels are also variably present in neurons somata and/or dendrites, where they contribute to the regulation of neural activity in other ways (see below). REGULATION OFCa2‡ CHANNELS BY NEUROTRANSMITTERS N and P/Q channels are susceptible to inhibition by many neurotransmitters and extra- cellular mediators that act on receptors coupling to Pertussis toxin-sensitive G-proteins (primarily Go) Ð for example, noradrenaline (via a2 receptors), acetylcholine (via M2 and M4 muscarinic receptors), GABA (via GABA-B receptors), opioid peptides (via m=d receptors) and adenosine (via A2 receptors) (see Fig. Inhibition results from the release of the bg subunits of the trimeric (abg) G-protein following its activation by the receptor. The bg subunit then binds to the Ca2‡ channel in such a way as to shift its voltage sensitivity to more positive potentials, so that the channels do not open as readily during a rapid membrane depolarisation. One interpretation of this is that the binding of the bg subunits is itself voltage- dependent. This is thought to provide the principal mechanism responsible for presynaptic inhibition, whereby neurotransmitters inhibit their own release (autoinhibition) during high-frequency synaptic transmission. This process can be replicated by applying exogenous transmitters or their analogues (see Fig. Records show intra- axonal recordings from (a) a regenerating sciatic nerve axon following nerve crush; (b) a normal sciatic nerve axon; and (c) a demyelinated ventral root axon after treatment with lysopho- sphatidylcholine. Note that 4-AP prolongs the action potential in (a) and (c) but not in (b). Thus, current through 4-AP-sensitive K‡ channels contributes to action potential repolarisation in premyelinated or demyelinated mammalian axons, whereas in normal myelinated axons repolarisation is entirely due to Na‡ channel inactivation. Ion Channel Organization of the Myelinated Fiber, p 48±54 (1990) with permission from Elsevier Science 40 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Figure 2. Currents were evoked by two successive 10 ms steps from 770 mV to 0 mV, separated by a prepulse to ‡90 mV. Note that the transient inhibition produced by NA (mediated by the G-protein Go) and the tonic inhibition produced by the G-protein b1g2 subunits were temporarily reversed by the ‡90 mV depolarisation. Note that pretreatment with Pertussis toxin (PTX), which prevents coupling of the adrenoceptor to Go, abolished inhibition. Reproduced with permission) CONTROL OFNEURONAL ACTIVITY 41 and suppressed by blocking the presynaptic receptors with antagonist drugs, which thereby selectively enhance the release of individual transmitters. ION CHANNELS AFFECTING THE PATTERN AND FREQUENCY OF ACTION POTENTIAL DISCHARGES The opening of Na‡ ion channels for the initiation of neuronal depolarisation and action potential generation, as described above, can be induced by excitatory neuro- transmitters acting on receptors that are directly linked to cation channels. These include glutamate AMPA receptors (Chapters 3 and 10) and ACh nicotinic receptors (Chapter 6). The inhibitory neurotransmitter GABA has an opposing effect through receptors (GABAA) that are directly linked to the opening of chloride channels, inducing an influx of Cl7 ions and subsequent hyperpolarisation (Chapters 1 and 11).