Neurobiology Flashcards

Question

The pupillary light reflex is located in the ipsilateral Answers: A. Edinger-Westphal Nucleus B. Medial Geniculate Nucleus C. Optic Tract D. Calcarine Cortex E. Optic Canal

Answer 1

Edinger-Westphal Nucleus ## Footnote Discussion: The Edinger-Westphal nucleus is responsible for ipsilateral pupillary constriction. These nuclei of CN III receive projections from the pretectal nucleus in the brainstem. The axons of these preganglionic parasympathetic neurons send signals along the oculomotor nerve to the postganglionic nerve fibers of the ciliary ganglion, resulting in stimulation of the pupillary sphincter muscle and pupillary constriction. The optic nerves bilaterally leave the orbit through the optic canal, and meet at the optic chiasm in front of the pituitary gland. The optic tract contains ipsilateral temporal fibers and contralateral nasal fibers. The calcarine cortex is the primary visual cortex in the occipital lobe. The medial geniculate nucleus is not involved in the visual pathway. References: Yoo H, Mihaila DM. Neuroanatomy, Pupillary Light Reflexes and Pathway. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan Pubmed Web link: https://www.ncbi.nlm.nih.gov/books/NBK553169/ Kardon R. Pupillary light reflex. Curr Opin Ophthalmol. 1995 Dec;6(6):20-6. doi: 10.1097/00055735-199512000-00004. PMID: 10160414. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/10160414/ Cranial Nerves: Anatomy and Clinical Comments. Linda Wilson-Pauwels, Elizabeth Akesson, and Patricia A. Stewart. B.C. Decker Inc, 1988

Answer 2

Acetylcholine receptor ## Footnote Discussion: The acetylcholine receptor is associated with the post-synaptic membrane potential of the neuromuscular junction. The alpha adrenergic receptor is the target of norepinephrine in smooth muscle sphincter contraction. The beta adrenergic receptor is the target of norepinephrine in detrusor relaxation. The GABA receptor is a primary receptor for inhibitory signals in the CNS. The glutamate receptor receives predominantly excitatory neurotransmitters in the CNS. References: Fundamentals of Neuroscience. 3rd edition. Squire, Berg, B.,oom, Du Lac, Ghosh, Spitzer. Chapter 29. Pgs 681-685, and Chapter 18, 416-419. Rudolf R, Khan MM, Witzemann V. Motor Endplate-Anatomical, Functional, and Molecular Concepts in the Historical Perspective. Cells. 2019 Apr 27;8(5):387. doi: 10.3390/cells8050387. PMID: 31035624; PMCID: PMC6562597

Answer 3

Spontaneous release of vesicles containing Acetylcholine across synaptic cleft ## Footnote Discussion: Miniature end plate potentials (MEPP) are spontaneous occurring depolarizations that occur with release of vesicles containing Acetylcholine (ACh) into the synaptic cleft in absence of stimulation of the presynaptic neuron. These MEPP are not large enough to cause a postsynaptic action potential due to low quanta of release of ACh. The summation of ACh release seen with stimulation of the pre-synaptic neuron causes depolarization and EPPs that lead to action potentials at the post-synaptic membrane. Inhibition of the ACh vesicle binding on postsynaptic membrane causes paralysis as seen in certain toxins. The same is seen in inhibition or release of these vesicles from the presynaptic membrane. Increased acetylcholinesterase activity can increase the response at the postsynaptic membrane but is not related to isolated MEPP. References: On the factors which determine the amplitude of the miniature end-plate potential. Katz B, Thesleff S.J Physiol. 1957 Jul 11;137(2):267-78. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/13449877/ Neuroscience, 4th Edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2008

Answer 4

fibers from nodose/superior ganglion (CNX) ## Footnote Discussion: The spinal trigeminal tract is primarily located in the pons, rostral and caudal medulla and is part of the ventral trigeminothalamic tract which carries pain, temperature and poorly-localized touch information from the head and neck regions to the VPM of the thalamus and eventually the somatosensory cortex. Fibers from CN V (trigeminal/semilunar ganglion), CN VII (geniculate ganglion), CN IX (petrosal ganglion), and CN X (nodose/superior ganglion) merge together to form the spinal trigeminal tract. Fibers from the nodose ganglion of CN X merge with the trigeminal tract at the upper cervical region and synapse at the spinal trigeminal nucleus (STN). Fibers from the secondary neurons then decussate and form part of the medial lemniscus which ascends and synapses with the tertiary neurons in the VPM of the thalamus. References: Patel NM, M Das J. Neuroanatomy, Spinal Trigeminal Nucleus. 2021 Oct 14. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30969551. Adam Fisch. Chapter 15 - Clinical Examination of the Cranial Nerves. Editor(s): R. Shane Tubbs, Elias Rizk, Mohammadali M. Shoja, Marios Loukas, Nicholas Barbaro, Robert J. Spinner, Nerves and Nerve Injuries, Academic Press, 2015, Pages 195-225, ISBN 9780124103900. Pubmed Web link: https://doi.org/10.1016/B978-0-12-410390-0.00016-0

Answer 5

C fibers ## Footnote Discussion: There are two main classes of nerve fibers involved in transmitting pain signals. C fibers are unmyelinated small-diameter fibers that convey thermal pain. These fibers therefore have the slowest conduction velocity. A fibers are myelinated and fast conductors. The conduction speed of a C fiber is 0.5-2 m/s whereas A-delta fibers are 5-40 m/s. A-delta fibers respond to mechanical stimuli and produce the sensation of localized and sharp pain. A-alpha fibers carry proprioceptive information. A-beta fibers carry touch sensations. References: McGlone F, Wessberg J, Olausson H. Discriminative and affective touch: sensing and feeling. Neuron. 2014;82(4):737-755 Pubmed Link: https://pubmed.ncbi.nlm.nih.gov/24853935/ Lawson SN. Phenotype and function of somatic primary afferent nociceptive neurones with C-, Adelta- or Aalpha/beta-fibres. Exp Physiol. 2002;87(2):239-244 Pubmed Link: https://pubmed.ncbi.nlm.nih.gov/11856969

Answer 6

Cochlear nerve ## Footnote Discussion: The superior olivary nuclei are most closely related to the cochlear nerve. This complex of nuclei contains binaural neurons that receive input from both ears. Ipsilateral afferents are excitatory, while contralateral inputs are inhibitory. The inhibitory effect is mediated by interneurons located in the nucleus of the trapezoid body. The superior olivary complex responds to intensity and temporal differences that exists between the ipsilateral and contralateral ears. Sound entering the ipsilateral ear stimulates the cochlear nucleus more intensely and earlier than sound entering the contralateral ear. That small difference is emphasized through crossed inhibition and provides spatial information about where that sound stimulus is coming from. References: Christov F, Nelson EG, Gluth MB. Human Superior Olivary Nucleus Neuron Populations in Subjects With Normal Hearing and Presbycusis. Ann Otol Rhinol Laryngol. 2018 Aug;127(8):527-535. doi: 10.1177/0003489418779405. Epub 2018 Jun 4. PMID: 29862839. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/29862839/ Sanes DH, Friauf E. Development and influence of inhibition in the lateral superior olivary nucleus. Hear Res. 2000 Sep;147(1-2):46-58. doi: 10.1016/s0378-5955(00)00119-2. PMID: 10962172. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/10962172/ Cant NB, Casseday JH. Projections from the anteroventral cochlear nucleus to the lateral and medial superior olivary nuclei. J Comp Neurol. 1986 May 22;247(4):457-76. doi: 10.1002/cne.902470406. PMID: 3722446. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/3722446/

Answer 7

GABA ## Footnote Discussion: Purkinje cells form a single layer at the interface of the granular and molecular layers in the cerebellum and give rise to an elaborate dendritic tree that radiates into the molecular layer. Purkinje cell axons project either to the cerebellar nuclei (cells arising from all areas of the cerebellar cortex), or to the vestibular nuclei (cells arising from the vermis and flocculonodular lobe) and exhibit an inhibitory effect via use of GABA. The synthesis of acetylcholine occurs in the terminal ends of axons. Serotonin is a monoamine neurotransmitter that is synthesized and stored in presynaptic neurons and located in cell bodies in the pons and midbrain. Dopamine is synthesized in neurons and cells in the adrenal glands from phenylalanine through tyrosine, DOPA, and then to dopamine. References: D.E. Haines and G.A. Mihailoff. The Cerebellum. Fundamental Neuroscience for Basic and Clinical Applications, Chapter 27, 394-412.e1 Zorrilla de San Martin J, Trigo FF, Kawaguchi SY. Axonal GABAA receptors depolarize presynaptic terminals and facilitate transmitter release in cerebellar Purkinje cells. J Physiol. 2017 Dec 15;595(24):7477-7493. doi: 10.1113/JP275369. Epub 2017 Nov 21. PMID: 29072780; PMCID: PMC5730858

Answer 8

Connexin Protein ## Footnote Discussion: Gap junctions are channel-like structures that allow for electrical and metabolic communication between cells. Multiple proteins make up gap junctions. These include connexin proteins, mCX36, mCX45, and MCX57. mCX12 and mCX4 are not involved in gap junctions. Glial Fibrillary Acidic Protein (GFAP) is a member of the intermediate filament family of proteins. It is expressed in astrocytes and ependymal cells. Orexin (hypocretin) is a hypothalamic neuropeptide involved in arousal, wakefulness, and appetite. References: Sohl G, Maxeiner S, Willecke K. Expression and functions of neuronal gap junctions. Nat Rev Neurosci. 2005 Mar;6(3): 191-200. Pubmed Link: https://pubmed.ncbi.nlm.nih.gov/15738956/ Maday S, Twelvetrees AE, Moughamian AJ, Holzbaur EL. Axonal transport: cargo-specific mechanisms of motility and regulation. Neuron. 2014 Oct 22;84(2):292-309. doi: 10.1016/j.neuron.2014.10.019. Epub 2014 Oct 22. PMID: 25374356; PMCID: PMC4269290. Pubmed Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269290/

Answer 9

Osteoinduction ## Footnote Discussion: Osteoinduction is the process of inducing osteogenesis and occurs during bone healing. It involves the recruitment of immature cells and the stimulation of these cells to develop into pre-osteoblasts. An example of an osteoinductive material is bone morphogenic protein (BMP). Osteoconduction is the process of bony growth on a surface and is affected by the threedimensional properties of a material. Osseointegration is the process of direct fusion of the implant and bone without intervening tissues. Differentiation is the process of multipotent stem cells developing into specialized cell types. Osteogenesis is the process of providing cells for bone formation which may be achieved by stem cells, osteoblasts, and/or osteocytes. References: Albrektsson T, Johansson C. Osteoinduction, osteoconduction and osseointegration. Eur Spine J. 2001 Oct;10 Suppl 2(Suppl 2):S96-101. doi: 10.1007/s005860100282. PMID: 11716023; PMCID: PMC3611551. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/11716023/ Maji, K., & Pramanik, K. (2021). Electrospun scaffold for bone regeneration. International Journal of Polymeric Materials and Polymeric Biomaterials, 1–16. Pubmed Web link: https://doi.org/10.1080/00914037.2021.1915784 Maslak, J.P., Casper D.S., Pelle, D. (2022) Spine Fusion: Biology and Biomechanics. In Steinmetz, M.P., Berven, S.H., Benzel, E. (Ed), Benzel’s Spine Surgery, Techniques, Complications Avoidance, and Management (5th ed., pp 122-129). Elsevier, Inc

Answer 10

Locus coeruleus ## Footnote Discussion: The locus coeruleus, located near the pontomesencephalic junction, is the major noradrenergic nucleus of the brain, and plays a central role in the regulation of arousal and autonomic activity. Activation of the locus coeruleus produces an increase in sympathetic activity and a decrease in parasympathetic activity via numerous excitatory projections to the majority of the cerebral cortex as well as the basal forebrain, thalamus, dorsal raphe, and spinal cord. The dorsal motor nucleus of the vagus nerve receives afferent input from the GI tract, heart, and bronchi of the lungs and receives indirect projections from the locus coeruleus. The locus coeruleus also projects to other nuclei that influence the autonomic nervous system, including the nucleus ambiguus, which is involved in the regulation of cardiovascular activity, and the EdingerWestphal nucleus, involved in pupillary constriction. The paraventricular nucleus of the hypothalamus also receives projections from the locus coeruleus and contains oxytocin and vasopressin neurosecretory cells that project to the posterior pituitary gland. References: Samuels ER, Szabadi E. Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr Neuropharmacol. 2008;6(3):235-253. doi:10.2174/157015908785777229. Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687936/ Berridge CW, Waterhouse BD. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev. 2003 Apr;42(1):33-84. doi: 10.1016/s0165-0173(03)00143-7. PMID: 12668290. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/12668290/ Berridge CW. Noradrenergic modulation of arousal. Brain Res Rev. 2008 Jun;58(1):1-17. doi: 10.1016/j.brainresrev.2007.10.013. Epub 2007 Dec 4. PMID: 18199483; PMCID: PMC2517224. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/18199483/

Answer 11

Supratrigeminal nucleus ## Footnote Discussion: Mastication involves a complex series of events. The majority of primary proprioceptive neurons of the muscles of mastication are located in the supratrigeminal nucleus. Proprioceptive information comes from the spindle-rich muscles of mastication (temporalis, masseter, medial pterygoid) and periodontal ligaments. This nucleus controls mastication directly through excitatory and inhibitory inputs to the trigeminal nucleus. Tactile and nociceptive information from food in the mouth is provided to the pontine and spinal nuclei, respectively. The mesencephalic nucleus contains cell bodies of primary unipolar sensory neurons, which receive information from neuromuscular spindles in the masticatory muscles and Ruffini endings in the suspensory periodontal ligaments of the teeth via the mandibular division and the maxillary/mandibular divisions of the trigeminal nerve, respectively. Most of the mesencephalic fibers descend in the small tract of Probst and terminate in the supratrigeminal nucleus. The pontine nucleus processes discriminative tactile information from the face and oronasal cavity. The spinal nucleus is divided into two minor nuclei (pars oralis and pars interpolaris) and one main nucleus (pars caudalis), which receive nociceptive and thermal information from the face. References: Yoshida A, Inoue M, Sato F, Morita Y, Tsutsumi Y, Furuta T, Uchino K, Akhter F, Bae YC, Tachibana Y, Inoue T. Efferent and afferent connections of supratrigeminal neurons conveying orofacial muscle proprioception in rats. Brain Struct Funct. 2022 Jan;227(1):111-129. doi: 10.1007/s00429-021-02391-9. Epub 2021 Oct 5. PMID: 34611777. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/34611777/ Luo P, Moritani M, Dessem D. Jaw-muscle spindle afferent pathways to the trigeminal motor nucleus in the rat. J Comp Neurol. 2001 Jul 2;435(3):341-53. doi: 10.1002/cne.1034. PMID: 11406816. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/11406816/ Price S, Daly DT. Neuroanatomy, Trigeminal Nucleus. 2021 May 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30969645. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/30969645/

Answer 12

potassium ## Footnote Discussion: The resting membrane potential of a neuron results from several ion species crossing the plasma membrane through a variety of ion channels and transporters. As the ions move across the membrane, so do their charges. The resting membrane potential is defined as the difference in charge across the cell membrane when it is in a non-excited state. It is calculated using the Nernst Equation. Sodium and potassium ions play a key role in resting membrane potential. Potassium ion concentration is higher inside of the neuron compared to the extracellular space. Because potassium ions will diffuse out of the cell when at rest, this creates a negative resting potential. References: Fundamentals of Neuroscience. 3rd edition. Squire, Berg, B.,oom, Du Lac, Ghosh, Spitzer. Chapter 6. Pgs 120-127. Chrysafides SM, Bordes S, Sharma S. Physiology, Resting Potential. [Updated 2021 Apr 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538338/

Answer 13

Dorsal upper medulla ## Footnote Discussion: Baroreceptor afferent fibers from the carotid sinus synapse onto medially placed cells of the solitary nucleus (the baroreceptor center, which is located within the upper medulla oblongata) via the glossopharyngeal nerve. Baroreceptor neurons of the solitary nucleus respond by stimulating cardioinhibitory neurons in the dorsal (motor) nucleus of the vagus nerve. Preganglionic, cholinergic parasympathetic vagal fibers synapse on mural ganglion cells on the posterior wall of the heart. Postganglionic, cholinergic parasympathetic fibers reduce sinoatrial node pacemaker firing, thus decreasing the heart rate. References: Iskander AJ, Naftalovich R, Yang X. The carotid sinus acts as a mechanotransducer of shear oscillation rather than a baroreceptor. Med Hypotheses. 2020 Jan;134:109441. doi: 10.1016/j.mehy.2019.109441. Epub 2019 Oct 18. PMID: 31726427. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/31726427/ Porzionato A, Macchi V, Stecco C, De Caro R. The Carotid Sinus Nerve-Structure, Function, and Clinical Implications. Anat Rec (Hoboken). 2019 Apr;302(4):575-587. doi: 10.1002/ar.23829. Epub 2018 May 2. PMID: 29663677. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/29663677/ Shoukas AA. Overall systems analysis of the carotid sinus baroreceptor reflex control of the circulation. Anesthesiology. 1993 Dec;79(6):1402-12. doi: 10.1097/00000542-199312000-00032. PMID: 8267213 Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/8267213/

Answer 14

Arachidonic acid ## Footnote Discussion: Prostaglandins are lipid mediators that act upon platelets, endothelium, uterine and mast cells. Prostaglandins play a key role in inflammation. Additionally, they regulate platelet aggregation as well as blood vessel constriction/dilation. Prostaglandins are synthesized from arachidonic acid, which is created from diacylglycerol via phospholipase-A2. Then, arachidonic acid is converted to different prostaglandins via the cyclooxegenase pathway. Substance P, a neurotransmitter in the pain pathway, is a neuropeptide made of 11 amino acids. Glutamate is an excitatory neurotransmitter in the CNS and is a nonessential amino acid. Nitric oxide, which can be used as a medication, exists in a gaseous state composed of 2 atoms. Acetylcholine, which serves as a neurotransmitter at the neuromuscular junction, is derived from choline and an acetyl group derived from coenzyme acetyl-CoA. References: Thomas D. Pollard MD, William C. Earnshaw PhD, FRS, Jennifer Lippincott-Schwartz PhD and Graham T. JohnsonMA, PhD, CMI. Second Messengers. Cell Biology, Chapter 26, 443-462. Nathanson, J. A., & Greengard, P. (1977). “Second Messengers” in the Brain. Scientific American, 237(2), 108–119. http://www.jstor.org/stable/24954007

Answer 15

Ca2+ ## Footnote Discussion: Glutamate receptors are classified as ionotropic or metabotropic. Ionotropic receptors respond to glutamate binding by allowing for flow of Na+, K+, and Ca2+. However, with excessive glutamate binding, excitotoxicity occurs leading to an increased influx of Ca2+ and neuronal damage. Zn2+ and Mg2+ can lead to modulation of electric potentials in particular receptors such as NMDA but do not play a role in excitotoxicity. References: Neuroscience, 2nd Edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001. Glutamate receptor ion channels: structure, regulation, and function. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. Pharmacol Rev. 2010 Sep;62(3):405-96. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/20716669/ Wang Y, Qin ZH. Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis. 2010 Nov;15(11):1382-402. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/20213199

Answer 16

Protein kinase A ## Footnote Discussion: Protein kinase A mediates most cyclic adenosine monophosphate (cAMP) activities in cells. It is also known as cAMP dependent protein kinase. cAMP transforms protein kinase A from its inactive form to active form, allowing for it to perform numerous cellular functions throughout the body. Protein kinase B (Akt) and Protein kinase C are activated by hormones, phospholipids, or other ligands as component of cell signaling but is not directly activated by cAMP. Caspases 3 and 8 are involved in the apoptosis pathway and not associated with cAMP. References: Cyclic AMP, protein kinase A, and phosphodiesterases: proceedings of an international workshop. Stratakis CA. Horm Metab Res. 2012 Sep;44(10):713-5 Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/22951901/ Neuroscience, 2nd Edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001

Answer 17

loss of cerebral regulatory signals and hyperexcitability of the reticulospinal and vestibulospinal tracts ## Footnote Discussion: The reticulospinal tract is part of the extrapyramidal system and is primarily responsible for locomotion and postural control via the medial pontine and lateral medullary tracts. Additionally, the vestibulospinal tract is composed of lateral and medial tracts, each responsible for increasing antigravity muscle tone in response to the head being tilted to one side. These fibers are directly associated with the cerebellum allowing an indirect cerebellar influence on the spinal cord. Fibers descend ipsilaterally through the anterior funiculus of the same side of the spinal cord, synapsing on the extensor anti-gravity motor neurons. They function by inciting excitation of the extensor motor neurons controlling muscle tone and anti-gravity posture. Therefore, an injury to the brainstem and subsequent loss of the cerebral (corticospinal) regulatory signals and hyperexcitability of the reticulospinal and vestibulospinal tracts results in severe rigidity and extensor motor neuron activity. References: Zaaimi B, Edgley SA & Baker SN. Reticulospinal and ipsilateral corticospinal tract contributions to functional recovery after unilateral corticospinal lesion. 2009 Abstract Viewer/Itinerary Planner, Programme No. 568.529. Society for Neuroscience, Washington, DC. Fitzgerald MJT, Gruener G, Mtui E. Clinical Neuroanatomy and Neuroscience. Fifth Edition. Philadelphia: Elsevier Saunders, 2007 Crossman AR, Neary D. Neuroanatomy. An illustrated colour text. Third Edition. Philadelphia: Elsevier, 2005

Answer 18

Superior Olivary Nucleus ## Footnote Discussion: The ascending auditory pathway begins with the cochlear nucleus on the dorsolateral side of the brainstem. From there, neurons travel through the superior olivary nucleus in the pons before passing through the lateral lemniscus of the pons and midbrain to the inferior colliculus. The trigeminal ganglion is not involved in this process. The greater petrosal nerve provides innervation to the lacrimal gland. The facial colliculus is located in the floor of the fourth ventricle and contains axons from cranial nerve VII. References: B Biacabe, JM Chevallier, P Avan, P Bonfils. Functional Anatomy of auditory brainstem nuclei: application to the anatomical basis of brainstem auditory evoked potentials. Auris Nasus Larynx. 2001 Jan;28(1): 85-94. doi: 10.1016/s0385-8146(00)00080-8. PMID: 11137368 Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/11137368/ CM Hackney. Anatomical Features of the auditory pathway from cochlea to cortex. Br Med Bull. 1987 Oct;43(4):780-801. doi: 10.1093/oxfordjournals.bmb.a072218. PMID: 3329925 Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/3329925/ Cranial Nerves: Anatomy and Clinical Comments. Linda Wilson-Pauwels, Elizabeth Akesson, and Patricia A. Stewart. B.C. Decker Inc, 1988

Answer 19

Hypocretin/orexin ## Footnote Discussion: Hypocretin/orexin neurons project to and excite wake-promoting brainstem nuclei including the Locus Coeruleus (NE), Dorsal Raphe (Serotonin), Tuberomammilary nucleus of the hypothalamus (Histamine), and dopaminergic neurons in the ventral tegmental area, substantia nigra, and ventral periaqueductal gray. These brainstem nuclei, in turn, modulate the function of the thalamus. GABA is the major inhibitory neurotransmitter in the brain that plays a role in many pathways, particularly in interneurons. Epinephrine and norepinephrine are neurotransmitters in the autonomic nervous system. Serotonin is a monoamine neurotransmitter that functions in the forebrain, brainstem, and cerebellum and helps to regulate temperature, appetite, sleep, emesis, and sexual behavior. References: D.E. Haines and G.A. Mihailoff. The Cerebellum. Fundamental Neuroscience for Basic and Clinical Applications, Chapter 27, 394-412.e1 Sakurai T. Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev. 2005 Aug;9(4):231-41. doi: 10.1016/j.smrv.2004.07.007. PMID: 15961331Samson WK, Taylor MM, Ferguson AV. Non-sleep effects of hypocretin/orexin. Sleep Med Rev. 2005 Aug;9(4):243-52. doi: 10.1016/j.smrv.2004.07.006. Epub 2005 Apr 22. PMID: 16036174.

Answer 20

Post-synaptic hypolarization via Chloride influx ## Footnote Discussion: GABAA receptors are inotropic chloride channels. Opening of the GABAA receptor allows for a chloride influx which hypopolarizes the membrane. GABAA receptors are clustered on the postsynaptic membrane but also exist in extrasynaptic locations and mediate tonic levels of inhibition in the brain. Barbiturates and Benzodiazepines work by modulating the GABAA receptor at a different location than where GABA itself binds. Benzodiazepines increase the frequency that the channel opens, and barbiturates increase the duration of the open state in response to the presence of GABA. NMDA receptors are an example of a Na+/K+/Ca2+ channel and are triggered by Ca2+/Na+ currents. References: M. Neal Waxham. Neurotransmitter Receptors. Fundamental Neuroscience, Chapter 8, 163-187. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. GABA and Glycine Receptors. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10977/

Answer 21

Voltage-gated sodium channels ## Footnote Discussion: Action potentials are driven by channel proteins whose configuration switches between closed and open states as a function of the voltage difference between the interior and exterior of the cell. These voltage-sensitive proteins are known as voltage-gated ion channels. Voltage-gated sodium channels are responsible for the rising phase of action potentials. Voltage-gated potassium channels are sensitive to changes in membrane potential and help the cell return to a depolarized resting state following an action potential. Voltage-gated chloride channels open in response to a neuron’s depolarization. In response to the positive potentials, negative chloride ions flow into the cell to help maintain resting membrane potential. Magnesium can serve as an ion channel ligand. The strength of the stimulus is not related to the individual cell’s response, rather each cell’s action potential is created by the movement of ions across its plasma membrane. References: Henley, Casey. Foundations of Neuroscience. United States, Michigan State University, 2021. Raghavan M, Fee D, Barkhaus PE. Generation and propagation of the action potential. Handb Clin Neurol. 2019;160:3-22. doi: 10.1016/B978-0-444-64032-1.00001-1. PMID: 31277855.

Answer 22

Gasserian or semilunar ganglion ## Footnote Discussion: The trigeminal ganglion, also known as the Gasserian ganglion (Gasser’s or semilunar ganglion), hosts the cell bodies of the trigeminal nerve, which gather sensory information from the face and head and provide motor input to the muscles of mastication. The petrosal ganglion is a peripheral sensory ganglion and part of CN XI that contains neurons that innervate the posterior third of the tongue and carotid sinus. The nodose/superior ganglion and the inferior ganglion of the vagus nerve innervate the concha of the auricle, the external auditory canal, and the tympanic membrane. References: Yu M, Donohoe C. Neuroanatomy, Semilunar Ganglion. [Updated 2022 Jan 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Rubin, Michael (2017). Netter's Concise Neuroanatomy. Safdieh, Joseph E., Netter, Frank H. (Frank Henry), 1906-1991 (Updated ed.). Philadelphia, PA: Elsevier. pp. 253–256. Mercante, Beniamina et al. “Anatomo-Physiologic Basis for Auricular Stimulation.” Medical acupuncture vol. 30,3 (2018): 141-150. doi:10.1089/acu.2017.1254

Answer 23

Influx of Ca2+ into the cel ## Footnote Discussion: NMDA receptors (NMDAR) are glutamate receptors that also require glycine to bind with glutamate for activation. Depolarization allows displacement of Mg2+ within the channel to allow for ion flow. This allows influx of ions including Ca2+ into the cell. NMDAR-mediated Ca2+ influx is implicated in neuronal differentiation, neuronal migration, synaptogenesis, structural remodelling, long-lasting forms of synaptic plasticity and higher cognitive functions. NMDAR-mediated Ca2+ signalling in dendritic spines is not static but can be remodelled in a cell- and synapse-specific manner by NMDAR subunit composition, protein kinases and neuronal activity during development and in response to sensory experience. Recent evidence indicates that Ca2+ permeability of neuronal NMDARs, NMDAR-mediated Ca2+ signaling in spines and induction of NMDAR-dependent LTP (long-term potentiation) at hippocampal Schaffer collateral–CA1 synapses are under control of the cAMP/PKA (protein kinase A) signaling cascade. Thus, by enhancing Ca2+ influx through NMDARs in spines, PKA can regulate the induction of LTP. An emerging concept is that activity-dependent regulation of NMDAR-mediated Ca2+ signalling by PKA and by extracellular signals that modulate cAMP or protein phosphatases at synaptic sites provides a dynamic and potentially powerful mechanism for bi-directional regulation of synaptic efficacy and remodelling. References: Structure, function, and pharmacology of NMDA receptor channels. Vyklicky V, Korinek M, Smejkalova T, Balik A, Krausova B, Kaniakova M, Lichnerova K, Cerny J, Krusek J, Dittert I, Horak M, Vyklicky L. Physiol Res. 2014;63(Suppl 1):S191-203. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/24564659/ Neuroscience, 4th Edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2008. pp 129-131 Lau CG, Takeuchi K, Rodenas-Ruano A, et al. Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity. Biochem Soc Trans. 2009;37(Pt 6):1369-1374. doi:10.1042/BST0371369

Answer 24

protein ## Footnote Discussion: Large elevations in total protein, white cell count, and serum ACE occur in neurosarcoidosis. The elevation of serum and CSF ACE is more controversial across the literature, particularly the role of CSF ACE in diagnosis. Angiotensin-converting enzyme (ACE) is produced by epithelioid cells derived from activated macrophages. ACE level is correlated with the amount of whole-body granuloma (not ones found in the lungs only) and disease severity. ACE level is elevated in other granulomatous diseases, such as leprosy and histoplasmosis, and in non-granulomatous diseases, such as hyperthyroidism and lymphoma. Protein elevation remains the most reliable CSF marker in distinguishing neurosarcoid, but must be coupled with other diagnostic studies. RBCs, Ach antibodies, and nucleated cells are not diagnostic in neurosarcoidosis. CSF oligoclonal bands are diagnostic of multiple sclerosis. References: Fritz D, van de Beek D, Brouwer MC. Clinical features, treatment and outcome in neurosarcoidosis: systematic review and meta-analysis. BMC Neurol. 2016 Nov 15;16(1):220. doi: 10.1186/s12883-016-0741-x. PMID: 27846819; PMCID: PMC5109654. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/27846819/ Arun T, Pattison L, Palace J. Distinguishing neurosarcoidosis from multiple sclerosis based on CSF analysis: A retrospective study. Neurology. 2020 Jun 16;94(24):e2545-e2554. doi: 10.1212/WNL.0000000000009491. Epub 2020 Apr 30. PMID: 32354749. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/32354749/ Nozaki K, Judson MA. Neurosarcoidosis. Curr Treat Options Neurol. 2013 Aug;15(4):492-504. doi: 10.1007/s11940-013-0242-9. PMID: 23703311. Pubmed Web link: pubmed.ncbi.nlm.nih.gov/23703311

Answer 25

Motor endplate, basal nucleus of the forebrain, hippocampus ## Footnote Discussion: Acetylcholine binds to two main receptor subtypes. Nicotinic receptors are found at the neuromuscular junctions and in the hippocampus, which function by allowing an influx of Ca2+ and Na+. Muscarinic receptors are found in the autonomic ganglia, heart, lung, and smooth muscle. Dopamine is the primary neurotransmitter in the Substantia Nigra Pars Compacta (SNc). The Internal Globus Pallidus (GPi) contains GABAergic neurons which allow for its inhibitory function. It also receives inhibitory signals from the External Globus Pallidus (GPe). The Locus Coeruleus is the primary site for norepinephrine in the brain. References: Estomih Mtui MD, Gregory Gruener MD, MBA, MHPE and Peter Dockery BSc, PhD. Transmitters and Receptors. Fitzgerald's Clinical Neuroanatomy and Neuroscience, 8, 89-109. Omar A, Marwaha K, Bollu PC. Physiology, Neuromuscular Junction. [Updated 2021 May 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470413/ Unwin N. Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynaptic membranes. Q Rev Biophys. 2013 Nov;46(4):283-322. doi: 10.1017/S0033583513000061. Epub 2013 Sep 20. PMID: 24050525; PMCID: PMC3820380

Answer 26

Cervical segment 2 ## Footnote Discussion: The spinal trigeminal nucleus is composed of 3 regions: 1) Pars oralis: the most superior part of the nucleus that spans from the pons to mid-medulla 2) Pars interpolaris: middle of the nucleus spanning the mid-medulla 3) Pars caudalis: the inferior most part of the nucleus, which spans from the lower medulla to the upper cervical regions, roughly around cervical segment 2. References: Adam Fisch. Chapter 15 - Clinical Examination of the Cranial Nerves. Editor(s): R. Shane Tubbs, Elias Rizk, Mohammadali M. Shoja, Marios Loukas, Nicholas Barbaro, Robert J. Spinner, Nerves and Nerve Injuries, Academic Press, 2015, Pages 195-225, ISBN 9780124103900. Pubmed Web link: https://doi.org/10.1016/B978-0-12-410390-0.00016-0 Patel NM, M Das J. Neuroanatomy, Spinal Trigeminal Nucleus. [Updated 2021 Oct 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539729/

Answer 27

Pars caudalis ## Footnote Discussion: The spinal nucleus extends from the lower part of the pons to the spinal cord at approximately the level of the C3 segment. The nucleus is comprised of the main spinal nucleus (pars caudalis), and two minor nuclei (pars oralis and pars interpolaris). The primary synapse of pain and temperature sensation is in the main spinal nucleus (pars caudalis), whereas afferents from the mouth synapse in the two minor nuclei (pars oralis and pars interpolaris). The mesencephalic nucleus is the only nucleus in the CNS that contains cell bodies of primary unipolar sensory neurons that supply the muscles of mastication and the suspensory periodontal ligaments of the teeth. The pontine (principal sensory) nucleus processes discriminative tactile information from the face and oronasal cavity. References: Patel NM, M Das J. Neuroanatomy, Spinal Trigeminal Nucleus. 2021 Oct 14. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30969551. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/30969551/ Dauvergne C, Zerari-Mailly F, Buisseret P, Buisseret-Delmas C, Pinganaud G. The sensory trigeminal complex projects contralaterally to the facial motor and the accessory abducens nuclei in the rat. Neurosci Lett. 2002 Aug 30;329(2):169-72. doi: 10.1016/s0304-3940(02)00656-0. PMID: 12165404. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/12165404/ Contreras RJ, Beckstead RM, Norgren R. The central projections of the trigeminal, facial, glossopharyngeal and vagus nerves: an autoradiographic study in the rat. J Auton Nerv Syst. 1982 Nov;6(3):303-22. doi: 10.1016/0165-1838(82)90003-0. PMID: 7169500. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/7169500

Answer 28

Medial longitudinal fasciculus ## Footnote Discussion: The oculocephalic reflex, also known as the doll’s eyes reflex, is part of the neurological examination assessing the integrity and viability of the brainstem, namely CN III, VI, and VIII in the midbrain and pons regions. It is performed in a patient with a stable cervical spine by holding the patient’s eyelid open and moving the head from side to side. A positive oculocephalic response occurs when the patient moves his eyes in the opposite rotation of his or her head. As the examiner rotates the head to the RIGHT, the RIGHT semicircular canal gets activated, sending impulses through the ipsilateral CN VIII to nucleus vestibularis, which in turn will activate the medial longitudinal fasciculus (MLF) fibers. MLF activation will result in the activation of the LEFT (contralateral) CN VI (LEFT lateral rectus), and RIGHT (ipsilateral) CN III (RIGHT medial rectus), and the patient looks to the LEFT. Therefore, the medial longitudinal fasciculus integrates the movement of the eyes and head by creating a link between CN III, IV and VI. References: Dishion E, Tadi P. Doll's Eyes. [Updated 2021 May 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Angelaki DE (July 2004). "Eyes on target: what neurons must do for the vestibuloocular reflex during linear motion". Journal of Neurophysiology. 92 (1): 20–35. doi:10.1152/jn.00047.2004. PMID 15212435. https://doi.org/10.1016/B978-0-12-385157-4.01161-1

Answer 29

600mL ## Footnote Discussion: In a normal human adult, there is 125–150 mL of CSF in the nervous system at a given time, and this is replenished every 6 hours. Approximately 600–700 mL of CSF is produced daily. CSF is predominantly, but not exclusively, secreted by the choroid plexuses. Brain interstitial fluid, ependyma and capillaries may also play a poorly defined role in CSF secretion. Cranial and spinal arachnoid villi have been considered for a long time to be the predominant sites of CSF absorption into the venous outflow system. Experimental data suggest that cranial and spinal nerve sheaths, the cribriform plate and the adventitia of cerebral arteries constitute substantial pathways of CSF drainage into the lymphatic outflow system. References: Ball AK, Clarke CE. Idiopathic intracranial hypertension. Lancet Neurol. 2006 May;5(5):433-42. doi: 10.1016/S1474-4422(06)70442-2. PMID: 16632314. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/16632314/ Markey KA, Mollan SP, Jensen RH, Sinclair AJ. Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions. Lancet Neurol. 2016 Jan;15(1):78-91. doi: 10.1016/S1474-4422(15)00298-7. Epub 2015 Dec 8. PMID: 26700907. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/26700907/ Chan SM, Chodakiewitz YG, Maya MM, Schievink WI, Moser FG. Intracranial Hypotension and Cerebrospinal Fluid Leak. Neuroimaging Clin N Am. 2019 May;29(2):213-226. doi: 10.1016/j.nic.2019.01.002. Epub 2019 Feb 21. PMID: 30926112. PubMed Web Link: https://pubmed.ncbi.nlm.nih.gov/29903905/

Answer 30

Acetylcholine ## Footnote Discussion: Preganglionic sympathetic neurotransmission is facilitated by acetylcholine through nicotinic cholinergic receptor activation. Postganglionic sympathetic innervation of the cardiovascular system is mediated by norepinephrine, renal vessels by dopamine, and sweat glands by acetylcholine (muscarinic receptors). The 2 most common neurotransmitters released by neurons of the autonomic nervous system (ANS) are acetylcholine and norepinephrine. Neurotransmitters are synthesized in the axon varicosities and stored in vesicles for subsequent release. Nerve fibers that release acetylcholine are referred to as cholinergic fibers. These include all preganglionic fibers of the ANS, both sympathetic and parasympathetic systems; all postganglionic fibers of the parasympathetic system; and sympathetic postganglionic fibers innervating sweat glands. Nerve fibers that release norepinephrine are referred to as adrenergic fibers. Most sympathetic postganglionic fibers release norepinephrine. References: Apostolova G, Dechant G. Development of neurotransmitter phenotypes in sympathetic neurons. Auton Neurosci. 2009 Nov 17;151(1):30-8. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/19734109/ McCorry LK. Physiology of the autonomic nervous system. Am J Pharm Educ. 2007 Aug 15;71(4):78. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/17786266/ McCorry LK. Physiology of the autonomic nervous system. Am J Pharm Educ. 2007 Aug 15;71(4):78. doi: 10.5688/aj710478. PMID: 17786266; PMCID: PMC1959222. Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959222/

Answer 31

Stabilization of microtubules ## Footnote Discussion: Tau proteins are synthesized from the gene, microtubule-associated protein tau (MAPT). They are abundant in the CNS. Tau protein is involved in several neuronal functions including stabilization of microtubules, negative regulation of mRNA translation, and facilitation of habituation in the process of long-term memory. Tau proteins are also implicated in disease processes such as Alzheimer’s disease and Parkinson’s disease. Specifically, in neurodegenerative pathologies, aggregates of tau form neurofibrillary tangles. Other cellular proteins such as kinesin and dynein are motor proteins and play a role in the transport of cellular cargo. References: Harada A, Oguchi K, Okabe S, et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. 1994 Jun 9;369(6480):488-91. Meier S, Bell M, Lyons DN, Rodriguez-Rivera J, Ingram A, Fontaine SN, et al. (January 2016). "Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis". The Journal of Neuroscience. 36 (3): 1001–7. doi:10.1523/JNEUROSCI.3029-15.2016. PMC 4719006. PMID 26791227. Pubmed Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719006/

Answer 32

Complete and reversible inhibition of the nicotinic Acetylcholine Receptor ## Footnote Discussion: Curare poisoning leads to muscle relaxation and eventually paralysis. D-tubocurarine is a competitive antagonist for the ACh binding site, though it can be displaced with a high enough concentration of ACh. Thus, the treatment for Curare poisoning is supportive ventilation and administration of an Acetylcholinesterase inhibitor (physostigmine or neostigmine), which can block the degradation of ACh and raise the amount of it in the neuromuscular junction. NMDA receptor antagonism is a common mechanism in anesthetics. Acetylcholinesterase inhibitors inhibit the breakdown of acetylcholine and can be used for treatment of myasthenia gravis, postoperative ileus, bladder distension, glaucoma, and anticholinergic overdose. References: Estomih Mtui MD, Gregory Gruener MD, MBA, MHPE and Peter Dockery BSc, PhD. Transmitters and Receptors. Fitzgerald's Clinical Neuroanatomy and Neuroscience, 8, 89-109. Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 2013;11(3):315-335. doi:10.2174/1570159X11311030006 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648782 /#:~:text=AChE%20inhibitors%20or%20anti%2Dcholinesterases,two%20groups %3A%20irreversible%20and%20reversible.

Answer 33

Nervus Intermedius ## Footnote Discussion: The general visceral efferent component of nervus intermedius, a branch of CN VII, consists of preganglionic parasympathetic fibers that originate in the superior salivatory nucleus and travel to the geniculate ganglion. Nerve fibers then travel along the greater petrosal nerve to synapse in the pterygopalatine fossa, where postganglionic fibers provide parasympathetic innervation to the lacrimal gland as well as the mucosal glands of the nose, palate, and pharynx. The inferior salivatory nucleus is a component of the glossopharyngeal nerve and supplies parasympathetic input to the parotid gland for salivation. The chorda tympani nerve supplies afferent taste receptors from the anterior two-thirds of the tongue. The superior vestibular nerve and the abducens nerve are not involved with this process. References: Nturibi E, Bordoni B. Anatomy, Head and Neck, Greater Petrosal Nerve. 2021 Nov 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 31971760. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/31971760/ Guinto G, Guinto Y. Nervus intermedius. World Neurosurg. 2013 May-Jun;79(5-6):653-4. doi: 10.1016/j.wneu.2012.05.011. Epub 2012 May 24. PMID: 22634468. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/22634468/ Tubbs RS, Steck DT, Mortazavi MM, Cohen-Gadol AA. The nervus intermedius: a review of its anatomy, function, pathology, and role in neurosurgery. World Neurosurg. 2013 MayJun;79(5-6):763-7. doi: 10.1016/j.wneu.2012.03.023. Epub 2012 Apr 3. PMID: 22484073. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/22484073/

Answer 34

6 hours ## Footnote Discussion: In a normal human adult, there is 125–150 mL of CSF in the nervous system at a given time, and this is replenished every 6 hours. Approximately 600–700 mL of CSF is produced daily. CSF is predominantly, but not exclusively, secreted by the choroid plexuses. Brain interstitial fluid, ependyma and capillaries may also play a poorly defined role in CSF secretion. Cranial and spinal arachnoid villi have been considered for a long time to be the predominant sites of CSF absorption into the venous outflow system. Experimental data suggest that cranial and spinal nerve sheaths, the cribriform plate and the adventitia of cerebral arteries constitute substantial pathways of CSF drainage into the lymphatic outflow system. References: Ball AK, Clarke CE. Idiopathic intracranial hypertension. Lancet Neurol. 2006 May;5(5):433-42. doi: 10.1016/S1474-4422(06)70442-2. PMID: 16632314. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/16632314/ Markey KA, Mollan SP, Jensen RH, Sinclair AJ. Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions. Lancet Neurol. 2016 Jan;15(1):78-91. doi: 10.1016/S1474-4422(15)00298-7. Epub 2015 Dec 8. PMID: 26700907. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/26700907/ Chan SM, Chodakiewitz YG, Maya MM, Schievink WI, Moser FG. Intracranial Hypotension and Cerebrospinal Fluid Leak. Neuroimaging Clin N Am. 2019 May;29(2):213-226. doi: 10.1016/j.nic.2019.01.002. Epub 2019 Feb 21. PMID: 30926112. PubMed Web Link: https://pubmed.ncbi.nlm.nih.gov/29903905/

Answer 35

dynein ## Footnote Discussion: Anterograde and retrograde transport of cellular cargo depend on molecular motors, such as kinesin and dynein, that move along microtubules. They can move cargo such as vesicles synthesized in the endoplasmic reticulum. Retrograde axonal transport uses dynein as a protein motor. Retrograde transport means moving cargo towards the minus end of the microtubule. Anterograde transport, on the other hand, uses kinesin as a molecular motor. Orthokinesin is not a molecular motor protein. Amyloid precursor protein (APP) is a transmembrane protein that is cleaved and aggregates in Alzheimer’s disease. Nidogens are glycoproteins that play a role embryologically in organogenesis. References: Kandel ER, Schwartz JH. Principles of Neural Science. 4th ed. McGraw-Hill Medical, 2000: 99-103. Maday S, Twelvetrees AE, Moughamian AJ, Holzbaur EL. Axonal transport: cargo-specific mechanisms of motility and regulation. Neuron. 2014;84(2):292-309. doi:10.1016/j.neuron.2014.10.019

Answer 36

Saltatory Conduction ## Footnote Discussion: Nodes of Ranvier occur along a myelinated axon where the axon is exposed to the extracellular space. Nodes of Ranvier are uninsulated and highly enriched in ion channels. Nerve conduction in myelinated axons is referred to as saltatory conduction due to the manner in which the action potential jumps from one node to the next. This results in faster conduction of the action potential. Nodes of Ranvier exist both in the central and peripheral nervous systems. References: Bloom, Floyd E.. Fundamental Neuroscience. Germany, Elsevier Science, 2008. Lubetzki C, Sol-Foulon N, Desmazières A. Nodes of Ranvier during development and repair in the CNS. Nat Rev Neurol. 2020 Aug;16(8):426-439. doi: 10.1038/s41582-020-0375-x. Epub 2020 Jul 10. PMID: 32651566.

Answer 37

Anterior limb of the internal capsule ## Footnote Discussion: Surgical procedures targeting the anterior limb of the internal capsule (aLIC) can be effective in patients with selected treatment-refractory obsessive-compulsive disorder (OCD). The aLIC consists of white-matter tracts connecting cortical and subcortical structures and show a topographical organization. The hippocampus, subthalamic nucleus, thalamus, and GPi have not been shown to be appropriate targets for ablation in medically refractory OCD. Stimulation of the STN has been reported to decrease activity in the orbital frontal cortex, medial prefrontal cortex, and anterior cingulate cortex, while stimulation of the aLIC has similarly been associated with decreased activity in the orbital frontal cortex, subgenual anterior cingulate cortex, and right dorsal lateral prefrontal cortex. References: Senova S, Clair AH, Palfi S, Yelnik J, Domenech P, Mallet L. Deep Brain Stimulation for Refractory Obsessive-Compulsive Disorder: Towards an Individualized Approach. Front Psychiatry. 2019 Dec 13;10:905. doi: 10.3389/fpsyt.2019.00905. PMID: 31920754; PMCID: PMC6923766. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/31920754/ Kinfe T, Stadlbauer A, Winder K, Hurlemann R, Buchfelder M. Incisionless MR-guided focused ultrasound: technical considerations and current therapeutic approaches in psychiatric disorders. Expert Rev Neurother. 2020 Jul;20(7):687-696. doi: 10.1080/14737175.2020.1779590. Epub 2020 Jun 21. PMID: 32511043. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/32511043/ Lee DJ, Lozano CS, Dallapiazza RF, Lozano AM. Current and future directions of deep brain stimulation for neurological and psychiatric disorders. J Neurosurg. 2019 Aug 1;131(2):333-342. doi: 10.3171/2019.4.JNS181761. PMID: 31370011. PubMed Web Link: https://pubmed.ncbi.nlm.nih.gov/31370011/

Answer 38

antibody test ## Footnote Discussion: Single-fiber electromyography has the highest sensitivity (90%) in the diagnosis of myasthenia gravis. It has proved to be the most sensitive technique in detecting a neuromuscular transmission defect in comparison with the tensilon test, repetitive stimulation, and acetylcholine receptor antibody estimation. Tests for serum antibodies are highly specific but lack sensitivity when there is pure ocular involvement. In this case there is systemic fatigue as well, suggesting generalized myasthenia gravis. Computed tomography of the chest is usually ordered to rule out thymoma once a diagnosis of myasthenia gravis has been confirmed. CSF oligoclonal bands help in the diagnosis of multiple sclerosis, with which the patient would have more or different symptoms. Serum hemoglobin, iron studies, and spinal imaging do not play a role in the diagnosis of myasthenia gravis. References: Bourque PR, Breiner A. Myasthenia gravis. CMAJ. 2018 Sep 24;190(38):E1141. doi: 10.1503/cmaj.180656. PMID: 30249760; PMCID: PMC6157498. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/30249760/ Morrison BM. Neuromuscular Diseases. Semin Neurol. 2016 Oct;36(5):409-418. doi: 10.1055/s0036-1586263. Epub 2016 Sep 23. PMID: 27704495. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/27704495/ Sieb JP. Myasthenia gravis: an update for the clinician. Clin Exp Immunol. 2014 Mar;175(3):408-18. doi: 10.1111/cei.12217. PMID: 24117026; PMCID: PMC3927901. Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927901/

Answer 39

RIGHT medial longitudinal fasciculus ## Footnote Discussion: The medial longitudinal fasciculus is a myelinated fiber bundle that connects the ipsilateral oculomotor nucleus to the contralateral abducens nucleus. The ipsilateral oculomotor nucleus innervates the medial rectus, while the abducens nucleus controls the lateral rectus. Injury to the MLF causes internuclear ophthalmoplegia, which is impairment of contralateral gaze due to inability to adduct the ipsilateral eye and nystagmus during abduction of the contralateral eye. The paramedian pontine reticular formation (PPRF) controls horizontal saccadic eye movements and receives input from the contralateral frontal eye fields. The PPRF projects to the abducens nucleus and contralateral oculomotor nucleus. Unilateral injury to the PPRF impairs ipsilateral horizontal gaze. The abducens nucleus projects to both the ipsilateral lateral rectus and contralateral oculomotor nucleus. Injury to the abducens nucleus induces an impairment of ipsilateral horizontal gaze, similar to that of PPRF injury. References: Fiester P, Baig SA, Patel J, Rao D. An Anatomic, Imaging, and Clinical Review of the Medial Longitudinal Fasciculus. J Clin Imaging Sci. 2020 Dec 18;10:83. doi: 10.25259/JCIS_49_2020. PMID: 33408958; PMCID: PMC7771398. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/33408958/ Kochar PS, Kumar Y, Sharma P, Kumar V, Gupta N, Goyal P. Isolated medial longitudinal fasciculus syndrome: Review of imaging, anatomy, pathophysiology and differential diagnosis. The Neuroradiology Journal. 2018;31(1):95-99. doi:10.1177/1971400917700671 Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/28541157

Answer 40

Dysnomia ## Footnote Discussion: Alzheimer's disease (AD) is the most common cause of dementia. By 65 years of age, roughly 1-2% of people are affected by AD, and that percentage doubles every 5 years until age 85. While the typical inheritance pattern is sporadic, there are rare instances (<1%) that are due to familial autosomal dominant transmission such as mutations in presenilin 1 or 2, or amyloid precursor protein. In addition, there also exist risk factors for the development of sporadic onset AD such as apolipoprotein ε4 alleles. Gross pathology demonstrates diffuse atrophy and is characterized by decreased neurons and synapses in the neocortex and hippocampus. Neurofibrillary tangles and neuritic plaques are pathognomonic findings. Clinically, patients exhibit only mild symptoms of dementia with forgetfulness and decreased speed of mental processing. Over time, the cognitive decline progresses to confusion, deficits in visuospatial memory, decreased judgment, inability to manage finances, dysnomia, and/or akinetic mutism. There are usually no associated major cortical deficits such as hemiplegia, sensory loss, or visual deterioration. Conduction aphasia is characterized by fluent speech with intact comprehension, however the patient is unable to name or repeat. Paraphasic errors are common. This typically occurs as a result of an injury/lesion to the perisylvian region, which impairs transmission through the arcuate fasciculus between Wernicke’s area and Broca’s area. Global aphasia is characterized by complete aphasia including deficits in speech output, comprehension, repetition, and naming. Patients are also unable to read and write. This is often due to damage to both Broca’s and Wernicke’s area Wernicke’s aphasia is a receptive aphasia that is fluent with paraphasic errors. This differs from conduction aphasia, as the patient has decreased comprehension and an inability to repeat words. It is often caused a by a lower branch middle cerebral artery (MCA) stroke with damage to the posterior and superior temporal gyrus. Broca’s aphasia is an expressive aphasia that is slow and non-fluent with impaired repetition. It is often caused by an upper branch MCA stroke with damage to the anterior insula and/or frontal operculum. References: Citow Comprehensive Neurosurgery Board Review 3rd Ed. 2019, p284, 525 Atri A. The Alzheimer's Disease Clinical Spectrum: Diagnosis and Management. Med Clin North Am. 2019 Mar;103(2):263-293. doi: 10.1016/j.mcna.2018.10.009. PMID: 30704681. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/30704681 Afifi, A. K., & Bergman, R. A. (2005) Functional Neuroanatomy text and atlas. The McGraw Hill Companies. (pp 258-261).

Answer 41

At resting membrane potential ## Footnote Discussion: The absolute refractory period is the period immediately following the firing of a nerve fiber when it cannot be stimulated no matter how great a stimulus is applied. The basis for the absolute refractory period is Na+ channel inactivation, when it is impossible to recruit a sufficient number of Na+ channels to generate a second depolarizing stimulus until the previously activated Na+ channels have recovered from activation, which takes several milliseconds. Following the refractory period, a neuronal membrane will shift back to resting potential. At this point, an action potential can be generated based on ion, particularly sodium, influx. References: Fundamentals of Neuroscience. 3rd edition. Squire, Berg, B.,oom, Du Lac, Ghosh, Spitzer. Chapter 6. Pgs 120-127. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. The Refractory Period. Available from: https://www.ncbi.nlm.nih.gov /books/NBK11146/

Answer 42

Nucleus tractus solitarius ## Footnote Discussion: The afferent impulses from the carotid sinus are transmitted to the nucleus tractus solitarius of the medulla through a segment of the glossopharyngeal nerve known as the sinus nerve of Hering. This pathway helps with maintaining a more consistent blood pressure. Cuneate and gracile nuclei are both part of the dorsal column-medial lemniscus pathway carrying fine-touch and proprioception information from the skin and joints to the somatosensory cortex. The dorsal nucleus of the vagus nerve provides efferent parasympathetic motor innervation to the viscera of the thorax and abdomen. References: Alexander AAZ, Groblewski JC, Davidson BJ. Branchial Cleft Cyst Causing Carotid Sinus Syndrome. Arch Otolaryngol Head Neck Surg. 2009;135(10):1045–1047. doi:10.1001/archotol.125.12.1390 Kikuta S, Iwanaga J, Kusukawa J, Tubbs RS. Carotid Sinus Nerve: A Comprehensive Review of Its Anatomy, Variations, Pathology, and Clinical Applications. World Neurosurg. 2019 Jul;127:370-374. Baker E, Lui F. Neuroanatomy, Vagal Nerve Nuclei. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

Answer 43

Magnesium ## Footnote Discussion: Magnesium occupies the NMDA receptor channel at normal resting potential. NMDA receptors are glutamate receptors within neurons. To be activated, NMDA receptors need to have a bound ligand, glutamate or glycine. When bound, the channel opens allowing cations to flow through the cell membrane, termed activation. However, this activation cannot occur while the receptor is “blocked” with a magnesium ion. These ions are only removed when the cell membrane is sufficiently depolarized. Chloride ion current works in inhibitory GABA and Glycine receptors. Na+/K+/Ca2+ ion currents through influx or efflux determine membrane potential, but these ions are not bound to receptors at rest. References: Nolte J. Synaptic Transmission Between Neurons in The Human Brain: An Introduction to Its Functional Anatomy. St. Louis: Mosby; 2002: 189. M. Neal Waxham. Neurotransmitter Receptors. Fundamental Neuroscience, Chapter 8, 163-187

Answer 44

Somatic muscles of the pharynx, larynx, and soft palate ## Footnote Discussion: The nucleus ambiguus supplies fibers to the ipsilateral muscles of the soft palate, pharynx, larynx, and upper esophagus. It is located in the reticular formation in the lateral rostral medulla, posterior to the inferior olive. It is primarily involved in swallowing and speech functions. The nucleus gives rise to the efferent motor fibers of the vagus nerve, which innervates the muscles of the soft palate, larynx, and pharynx, as well as the glossopharyngeal nerve, which innervates the stylopharyngeus and pharyngeal constrictor muscles. In addition, the nucleus is involved in parasympathetic cardiac regulation. The dorsal motor nucleus of the vagus nerve is an elongated nucleus located in the medulla. The nucleus provides parasympathetic motor innervation the viscera of the thorax and abdomen. The nucleus solitarius is divided into rostral and caudal nuclei. The rostral nucleus solitarius (gustatory nucleus) carries information about taste from the anterior two-thirds of the tongue via the facial nerve. The caudal nucleus solitarius is involved in cardiovascular, respiratory, and gastrointestinal system control through the glossopharyngeal and vagus nerves. The nucleus also provides afferents to the limbic system and amygdala, mediating emotional responses to changes in cardiorespiratory values and contributing to memory, respectively. The inferior salivatory nucleus supplies preganglionic fibers to the otic ganglion, which ultimately sends secretomotor fibers to the parotid gland. The spinal trigeminal nucleus supplies fibers to the contralateral thalamus and relays information about pain and temperature. References: Petko B, Tadi P. Neuroanatomy, Nucleus Ambiguus. [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547744/ Pubmed Web link: https://www.ncbi.nlm.nih.gov/books/NBK547744/ Baker E, Lui F. Neuroanatomy, Vagal Nerve Nuclei. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545209/ Pubmed Web link: https://www.ncbi.nlm.nih.gov/books/NBK545209/ AbuAlrob MA, Tadi P. Neuroanatomy, Nucleus Solitarius. [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549831/ Pubmed Web link: https://www.ncbi.nlm.nih.gov/books/NBK549831/

Answer 45

Skeletal muscle cell ## Footnote Discussion: Acetylcholine receptors occur throughout the nervous system and body. There are nicotinic and muscarinic receptor subtypes. These both respond to acetylcholine but are present in different quantities depending on the cell. The neuromuscular junction ending on skeletal muscle has nicotinic type acetylcholine receptors. The receptors on smooth muscle, cardiac muscle, sweat and salivary glands are predominantly muscarinic. References: Nicotinic acetylcholine receptors: from structure to brain function. Hogg RC, Raggenbass M, Bertrand D. Rev Physiol Biochem Pharmacol. 2003;147:1-46. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/12783266/ Nicotinic acetylcholine receptor redux: Discovery of accessories opens therapeutic vistas. Matta JA, Gu S, Davini WB, Bredt DS. Science. 2021 Aug 13;373(6556) Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/34385370/

Answer 46

Glutamate ## Footnote Discussion: It is hypothesized that in Huntington’s disease, excessive glutamate release in the striatum by cortical projections results in an imbalance between the direct and indirect pathways with subsequent hyperkinesia. While dopamine and GABA are involved in this pathway, the primary initial alteration appears to be related to elevated glutamate levels. Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by a triad of symptoms, including pronounced motor abnormalities (e.g. chorea, dystonia and bradykinesia), cognitive impairment and psychiatric disturbances. Symptoms typically appear at middle age and undergo inexorable progression that leads to death 15–20 years after onset. The molecular underpinning of HD is a polyglutamine (polyQ)-repeat expansion in the amino-terminus of the 350-kDa cytosolic protein huntingtin (Htt), which is widely expressed in the brain and in nonneuronal tissues. Release of glutamate from cortical afferents into the striatum depends on the efficiency of transport, vesicular fusion to the plasma membrane and subsequent recovery of synaptic vesicles at axon terminals. Dysfunction of this process is prominent in HD and other neurodegenerative disorders. A suggested role for mutant Htt in disrupting axonal transport first came from findings showing that mHtt microaggregates form in the axons of MSNs from (knock-in [KI]) mice that express full-length mHtt. References: Andre VM, Cepeda C, Levine MS. Dopamine and glutamate in Huntington’s disease: A balancing act. CNS Neurosci Ther. 2010 Jun;16(3):163-78. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/20406248/ Koch ET, Raymond LA. Dysfunctional striatal dopamine signaling in Huntington's disease. J Neurosci Res. 2019 Dec;97(12):1636-1654. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/31304622/ Benjamin Ray Miller and Ilya Bezprozvanny. Corticostriatal circuit dysfunction in Huntington’s disease: intersection of glutamate, dopamine and calcium. Future Neurology 2010 5:5, 735-756

Answer 47

Solitary nucleus in the medulla ## Footnote Discussion: The gustatory (taste) impulses from the tongue travel through the facial (CN VII), glossopharyngeal (CN IX) and vagus (CN X) nerves and primarily synapse at the solitary nucleus in the medulla oblongata. Secondary fibers then travel to the thalamus and finally project to the gustatory cortex located in the anterior insula in the temporal and frontal opercular regions. The dorsal nucleus of the vagus nerve provides efferent parasympathetic motor innervation to the viscera of the thorax and abdomen. References: Basinger H, Hogg JP. Neuroanatomy, Brainstem. 2021 May 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 31335017. Baker E, Lui F. Neuroanatomy, Vagal Nerve Nuclei. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-

Answer 48

Vestibulospinal tract ## Footnote Discussion: A lesion below the level of the red nucleus, located in the rostral tegmentum of the midbrain, leads to inhibition of the rubrospinal tract and excitation of the vestibulospinal tract. This lack of inhibition of the vestibulospinal tract results in extensor posturing when a painful stimulus is applied. The most common cause of a midbrain lesion is due to trauma. Other causes include a midbrain hemorrhage or a basilar occlusion. The spinothalamic tract is an ascending afferent pathway that sends stimulation to the pontine reticulospinal tract. The ventral posterolateral nucleus of the thalamus receives nociceptive fibers from the spinal cord via the spinothalamic tract. The substantia nigra is not involved in decerebrate posturing. References: Davis RA, Davis L. Decerebrate rigidity in humans. Neurosurgery. 1982 May;10(5):635-42. doi: 10.1227/00006123-198205000-00017. PMID: 7099417. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/7099417/ Al-Chalabi M, Reddy V, Gupta S. Neuroanatomy, Spinothalamic Tract. 2021 Aug 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29939601. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/29939601/ Ruchalski K, Hathout GM. A medley of midbrain maladies: a brief review of midbrain anatomy and syndromology for radiologists. Radiol Res Pract. 2012;2012:258524. doi: 10.1155/2012/258524. Epub 2012 May 22. PMID: 22693668; PMCID: PMC3366251. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/22693668/

Answer 49

Coordination of eye movements during horizontal gaze ## Footnote Discussion: The medial longitudinal fasciculus (MLF) are a group of fiber tracts located near the midline of the pons and midbrain. The MLF carries both excitatory and inhibitory neurons from the frontal eye fields, paramedian pontine reticular formation (PPRF), and cranial nerves III, IV, and VI. The MLF is the final common pathway for conjugate eye movements including saccades, smooth pursuit, and vestibulocochlear reflexes. The MLF plays a vital role in coordinating horizontal eye movements by interconnecting the oculomotor and abducens nuclei in the brainstem. The MLF does not play a role in the other functions listed above. References: Kochar PS, Kumar Y, Sharma P, Kumar V, Gupta N, Goyal P. Isolated medial longitudinal fasciculus syndrome: Review of imaging, anatomy, pathophysiology and differential diagnosis. Neuroradiol J. 2018;31(1):95-99. doi:10.1177/1971400917700671 Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789990/ Fiester P, Rao D, Soule E, Andreou S, Haymes D. The Medial Longitudinal Fasciculus and Internuclear Opthalmoparesis: There's More Than Meets the Eye. Cureus. 2020;12(8):e9959. Published 2020 Aug 23. doi:10.7759/cureus.9959 Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510542/ Lee SH, Kim JM, Kim JS. Update on the medial longitudinal fasciculus syndrome. Neurol Sci. 2022 Mar 8. doi: 10.1007/s10072-022-05967-3. Epub ahead of print. PMID: 35258687. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/35258687/

Answer 50

Acetylcholine ## Footnote Discussion: Gamma motor neurons innervate intrafusal muscle fibers while alpha motor neurons innervate extrafusal fibers. Motor neurons release the transmitter acetylcholine to cause depolarization and contraction of the muscle. Glutamate, serotonin, dopamine, and norepinephrine are all neurotransmitters but are not involved with motor neuron transmission. Glutamate is a major excitatory neurotransmitter involved in pathways such as those used in memory. Serotonin, predominantly inhibitory, is used in pathways involved in mood, hunger, sleep, and arousal. Dopamine, both excitatory and inhibitory, is involved in movement, reward, and learning pathways and the major transmitter affected in Parkinson’s Disease. Norepinephrine, excitatory, is used in autonomic pathways for example. References: Neuroscience, 4th Edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2008. pp 401-411 Colón, A., Guo, X., Akanda, N. et al. Functional analysis of human intrafusal fiber innervation by human γ-motoneurons. Sci Rep 7, 17202 (2017). https://doi.org/10.1038/s41598-017-17382-2

Answer 51

contralateral movement ## Footnote Discussion: The supplementary motor area (SMA) syndrome is a frequently encountered clinical phenomenon associated with surgery of the dorsomedial prefrontal lobe and can result in impairments of contralateral movement. The region has a known motor sequencing function and the dominant pre-SMA specifically is associated with more complex language functions; the SMA is furthermore incorporated in the negative motor network. Injury to the SMA involves speech arrest, contralateral weakness, and near-total recovery in weeks to months. A disconnection syndrome is usually a pattern of behavioral symptoms resulting from a disruption of fiber connections between different regions of the brain. References: Pinson H, Van Lerbeirghe J, Vanhauwaert D, Van Damme O, Hallaert G, Kalala JP. The supplementary motor area syndrome: a neurosurgical review. Neurosurg Rev. 2022 Feb;45(1):81-90. doi: 10.1007/s10143-021-01566-6. Epub 2021 May 15. PMID: 33993354. Pubmed Web Link: https://pubmed.ncbi.nlm.nih.gov/33993354/ Samuel N, Hanak B, Ku J, Moghaddamjou A, Mathieu F, Moharir M, Taylor MD. Postoperative isolated lower extremity supplementary motor area syndrome: case report and review of the literature. Childs Nerv Syst. 2020 Jan;36(1):189-195. doi: 10.1007/s00381-019-04362-2. Epub 2019 Nov 9. Erratum in: Childs Nerv Syst. 2020 Apr;36(4):877. PMID: 31705188. Pubmed Web Link: https://pubmed.ncbi.nlm.nih.gov/31705188/ Berg-Johnsen J, Høgestøl EA. Supplementary motor area syndrome after surgery for parasagittal meningiomas. Acta Neurochir (Wien). 2018 Mar;160(3):583-587. doi: 10.1007/s00701-018-3474-3. Epub 2018 Jan 23. PMID: 29362933. Pubmed Web Link: https://pubmed.ncbi.nlm.nih.gov/29362933

Answer 52

normal EMG of the bulbar muscles ## Footnote Discussion: The diagnosis of ALS is based upon clinical criteria that include the presence of upper motor neuron and lower motor neuron signs, progression of disease, and the absence of an alternative explanation (ALS mimics). Although the diagnosis of ALS has improved considerably in recent years, at present, there is no single test that can confirm or entirely exclude ALS. Muscles innervated by the cranial nerves, such as facial, genioglossus, and sternocleidomastoid, may be needed to identify bulbar dysfunction and confirm presence of disease above the level of the cervical spine. References: Lenglet T, Camdessanché JP. Amyotrophic lateral sclerosis or not: Keys for the diagnosis. Rev Neurol (Paris). 2017 May;173(5):280-287. doi: 10.1016/j.neurol.2017.04.003. Epub 2017 Apr 28. PMID: 28461025. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/28461025/ de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, Mills K, Mitsumoto H, Nodera H, Shefner J, Swash M. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008 Mar;119(3):497-503. doi: 10.1016/j.clinph.2007.09.143. Epub 2007 Dec 27. PMID: 18164242. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/18164242/ van den Bos MAJ, Geevasinga N, Higashihara M, Menon P, Vucic S. Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques. Int J Mol Sci. 2019 Jun 10;20(11):2818. doi: 10.3390/ijms20112818. PMID: 31185581; PMCID: PMC6600525. PubMed Web Link: https://pubmed.ncbi.nlm.nih.gov/31185581/

Answer 53

norepinephrine ## Footnote Discussion: Norepinephrine is synthesized in the synaptic vesicle starting with the amino acid tyrosine. It is then stored in the vesicles and eventually released from the neuron. Epinephrine is synthesized in the adrenal medulla, also starting from tyrosine but then through conversion to DOPA. Dopamine is synthesized in the medulla and in neurons; its synthesis starts through phenylalanine then tyrosine then DOPA. GABA, an inhibitory neurotransmitter, is synthesized in the presynaptic neuron from the precursor glutamate. The enzyme glutamate decarboxylase synthesizes GABA from glutamate with the help of Vitamin B6 (pyridoxine) as a cofactor. Serotonin is a monoamine neurotransmitter. The majority is in the gastrointestinal system but in the CNS, it is synthesized in raphe nuclei from tryptophan. It is also present in Merkel cells in the skin and neuroendocrine cells. References: Kandel ER, Schwartz JH. Principles of Neural Science. 4th ed. McGraw-Hill Medical, 2000: 99-103. NorepinephrineD.B. Bylund, K.C. Bylund, in Encyclopedia of the Neurological Sciences (Second Edition), 2014 Link: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/norepinephrine Best J, Nijhout HF, Reed M. Serotonin synthesis, release and reuptake in terminals: a mathematical model. Theor Biol Med Model. 2010;7:34. Published 2010 Aug 19. doi:10.1186/1742-4682-7-34 Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2942809/

Answer 54

Alzheimer’s disease ## Footnote Discussion: Alzheimer's disease (AD) is the most common cause of dementia. By 65 years of age, roughly 1-2% of people are affected by AD, and that percentage doubles every 5 years until age 85. While the typical inheritance pattern is sporadic, there are rare instances (<1%) that are due to familial autosomal dominant transmission such as mutations in presenilin 1 or 2, or amyloid precursor protein. In addition, there also exist risk factors for the development of sporadic onset AD such as apolipoprotein ε4 alleles. Gross pathology demonstrates diffuse atrophy and is characterized by decreased neurons and synapses in the neocortex and hippocampus. Neurofibrillary tangles and neuritic plaques are pathognomonic findings. Clinically, patients exhibit only mild symptoms of dementia with forgetfulness and decreased speed of mental processing. Over time, the cognitive decline progresses to confusion, deficits in visuospatial memory, decreased judgment, inability to manage finances, dysnomia, and/or akinetic mutism. There are usually no associated major cortical deficits such as hemiplegia, sensory loss, or visual deterioration. Parkinson's disease (PD) is characterized by difficulty initiating movements (bradykinesia), cogwheeling rigidity, resting pill-rolling tremor, festinating gait, and dementia. Onset typically occurs at 40–50 years with male predominance, and affects 1% of individuals >50 years. On pathologic examination of the brain, there is decreased neuromelanin found in the pars compacta of the substantia nigra, locus coeruleus, and dorsal motor nucleus of the vagus. In addition, Lewy bodies comprised of α-synuclein are present, and there is decreased dopamine in the caudate and putamen. Pick’s disease, also known as frontotemporal dementia (FTD), is characterized by symptoms similar to Alzheimer’s disease but with prominent frontal lobe dysfunction such as reduced inhibition and poor planning. Onset is typically 40–60 years with female predominance. Pick bodies comprised of intracytoplasmic tau protein form in hippocampal neurons. In diffuse Lewy body disease, dementia symptoms occur prior to motor symptoms. Characteristic cognitive symptoms include dementia, fluctuations in mental status, and hallucinations. Parkinsonian motor symptoms occur later in the disease. Similar to PD, pathologic examination demonstrates Lewy bodies (intracytoplasmic neuronal deposits of α-synuclein). Huntington's disease (HD) is characterized by personality changes, subcortical dementia without aphasia/agnosia/apraxia, and choreiform movements that start in the hands and face. Unlike other forms of dementia, the onset typically occurs in the 30’s. HD transmission is in an autosomal dominant inheritance pattern due to a trinucleotide repeat disorder of CAG on chromosome 4. There is characteristic significant atrophy of the caudate, which causes typical “boxcar” ventricles. References: Citow Comprehensive Neurosurgery Board Review 3rd Ed. 2019, p284-286 Atri A. The Alzheimer's Disease Clinical Spectrum: Diagnosis and Management. Med Clin North Am. 2019 Mar;103(2):263-293. doi: 10.1016/j.mcna.2018.10.009. PMID: 30704681. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/30704681 Geschwind MD, Haman A, Miller BL. Rapidly progressive dementia. Neurol Clin. 2007 Aug;25(3):783-807, vii. doi: 10.1016/j.ncl.2007.04.001. PMID: 17659190; PMCID: PMC2706263. Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706263/

Answer 55

Lateral lemniscus ## Footnote Discussion: Fibers of the lateral lemniscus come from the dorsal and ventral cochlear nuclei and from the superior olivary nuclei. This fiber tract ends in the central nucleus of the inferior colliculus. The inferior colliculus is responsible for integrating spatial, intensity, and pitch information from the superior olivary, ventral cochlear, and dorsal cochlear nuclei, respectively. The central part of the nucleus is organized by tonal lamina, which contain cells that respond differently to different tones. The trapezoid body is made up of neurons that have an inhibitory effect on the superior olivary complex from the contralateral ear. The inferior brachium (brachium of the inferior colliculus) connects the inferior colliculus with the medial geniculate body, which projects to the superior temporal gyrus (primary auditory cortex, Brodmann areas 41 and 42). References: Driscoll ME, Tadi P. Neuroanatomy, Inferior Colliculus. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554468/ Pubmed Web link: https://www.ncbi.nlm.nih.gov/books/NBK554468/ Blackwell JM, Lesicko AM, Rao W, De Biasi M, Geffen MN. Auditory cortex shapes sound responses in the inferior colliculus. Elife. 2020 Jan 31;9:e51890. doi: 10.7554/eLife.51890. PMID: 32003747. Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062464/ Yang Y, Lee J, Kim G. Integration of locomotion and auditory signals in the mouse inferior colliculus. Elife. 2020 Jan 28;9:e52228. doi: 10.7554/eLife.52228. PMID: 31987070; PMCID: PMC7004561. Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004561/

Answer 56

A. A ## Footnote Discussion: A. Facial colliculus B. Stria medullaris C. Hypoglossal triangulare D. Vagaries triangle E. Area postrema Facial palsy is due to interruption of the ipsilateral facial nerve fibers as they loop behind (dorsal to) the abducens (CN VI) nucleus at the facial colliculus of the dorsal pons within the floor of the 4th ventricle. Tumors arising from the floor of the fourth ventricle can additionally disrupt the activity of the abducens nucleus, damaging both motor and internuclear neurons, resulting in paralysis of the lateral rectus muscle ipsilateral to the lesion and failure of the contralateral medial rectus. References: Yoo, Hannah; Mihaila, Dana M. (2022), "Neuroanatomy, Facial Colliculus", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32310367, retrieved 2022-03-26 Pubmed Web link: https://doi.org/10.1016/C2014-0-03718-5

Answer 57

Soma (body) ## Footnote Discussion: The cell body is the metabolic center of the neuron. Proteins and lipids are synthesized in the soma (body) and then incorporated into vesicles. Each neuron has an axon. This is part of the cell that carries signals away from the cell body. Dendrites on the other hand are finger-like structures at the receiving end of neuronal cells. The nucleus is the organelle within the neuron that contains the cells genetic information within chromosomes. The cell membrane forms the boundary of the cell. Movement of ions and proteins across the membrane occurs via diffusion or via transporters. References: Kandel ER, Schwartz JH, Jessell TM, eds. (2000). "Transmitter Release". Principles of Neural Science (4th ed.). New York: McGraw-Hill. ISBN 978-0-8385-7701-1. Augustine GJ, Burns ME, DeBello WM, Hilfiker S, Morgan JR, Schweizer FE, Tokumaru H, Umayahara K. Proteins involved in synaptic vesicle trafficking. J Physiol. 1999 Oct 1;520 Pt 1(Pt 1):33-41. doi: 10.1111/j.1469-7793.1999.00033.x. PMID: 10517798; PMCID: PMC2269560.

Answer 58

Dopamine and GABA ## Footnote Discussion: The nigrostriatal pathway is a dopaminergic pathway connecting the substantia nigra pars compacta (SNc) in the midbrain and the dorsal striatum (caudate nucleus and putamen). The SNc also receives GABAergic inhibitory projection from the striatum and feeds back to the striatum as part of the basal ganglia motor loop. Degeneration of dopaminergic neurons in the SNc occurs in Parkinson’s disease. Glutamate is involved in cortical brainstem and corticostriatal pathways, as well as thalamocortical pathways. In the peripheral nervous system (PNS), acetylcholine works at the neuromuscular junction. In the central nervous system (CNS), acetylcholine is important in lateral tegmental and other striatal pathways. Most serotonin is found outside the brain. However, serotonin within the CNS is predominantly produced in the raphe nuclei of the brainstem. References: Kurt A. Jellinger. Neuropathology of Movement Disorders. Youmans and Winn Neurological Surgery, 83, e540-e580. Schwartz, Thomas & Sachdeva, Shilpa & Stahl, Stephen. (2012). Glutamate Neurocircuitry: Theoretical Underpinnings in Schizophrenia. Frontiers in pharmacology. 3. 195. 10.3389/fphar.2012.00195. Pubmed Link: https://pubmed.ncbi.nlm.nih.gov/23189055/ Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355-366. doi:10.1146/annurev.med.60.042307.110802 Pubmed Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864293/

Answer 59

The movement of potassium ions out of the cell ## Footnote Discussion: The resting membrane potential of a neuron results from several ion species crossing the plasma membrane through a variety of ion channels and transporters. As the ions move across the membrane, so do their charges. The resting membrane potential is defined as the difference in charge across the cell membrane when it is in a non-excited state. It is calculated using the Nernst Equation. Sodium and potassium ions play a key role in resting membrane potential. Potassium ion concentration is higher inside of the neuron compared to the extracellular space. Because potassium ions will diffuse out of the cell when at rest, this creates a negative resting potential. References: Henley, Casey. Foundations of Neuroscience. United States, Michigan State University, 2021. Chrysafides, Steven M., Bordes, Stephen, Sharma, Sandeep. Physiology, Resting Potential. StatPearls [Internet]. Accessed 2022. Pubmed Link: https://www.ncbi.nlm.nih.gov/books/NBK538338

Answer 60

Inability to recruit voltage-gated sodium channels ## Footnote Discussion: The absolute refractory period is the period immediately following the firing of a nerve fiber when it cannot be stimulated no matter how great a stimulus is applied. The basis for the absolute refractory period is Na+ channel inactivation, when it is impossible to recruit a sufficient number of Na+ channels to generate a second depolarizing stimulus until the previously activated Na+ channels have recovered from activation, which takes several milliseconds. References: Bloom, Floyd E.. Fundamental Neuroscience. Germany, Elsevier Science, 2008. https://www.elsevier.com/books/fundamental-neuroscience/squire/978-0-12-385870-2 Quandt FN, Davis FA. Action potential refractory period in axonal demyelination: a computer simulation. Biol Cybern. 1992;67(6):545-52. doi: 10.1007/BF00198761. PMID: 1335294.

Answer 61

In response to a nerve impulse (Depolarization) ## Footnote Discussion: Action potential is a transient reversal in membrane potential (from negative to positive) in response to a stimulus. There are three stages: depolarization, repolarization, and hyperpolarization. After a response to a nerve impulse, i.e. during depolarization, the neuronal membrane is more permeable to sodium ion than others. This is because sodium channels are open. Repolarization occurs when sodium channels close. Hyperpolarization occurs when potassium leaves the cell through open potassium channels. A plateau potential is the point at which a membrane potential is sustained within a neuron due to intrinsic properties rather than external stimulus. References: Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, McNamara JO, White LE. Neuroscience. 4th ed. Sunderland, MA: Sinauer Associates, Inc.; 2008. Fundamentals of Neuroscience. 3rd edition. Squire, Berg, B.,oom, Du Lac, Ghosh, Spitzer. Chapter 6. Pgs 120-127. (2009) Plateau Potential. In: Binder M.D., Hirokawa N., Windhorst U. (eds) Encyclopedia of Neuroscience. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-29678-2_4617

Answer 62

Pupillary light reflex ## Footnote Discussion: The most common cause of cortical blindness is bilateral occipital lobe infarctions in the posterior cerebral artery (PCA) vascular territories. Other causes include posterior reversible encephalopathy syndrome (PRES) secondary to a hypertensive crisis or immunosuppressive medications. Anton’s syndrome is a rare manifestation of bilateral cortical blindness characterized by visual agnosia, anosognosia, and confabulation. Pupillary light reflexes are preserved with cortical blindness, as are extraocular movements. Visual acuity is affected with cortical blindness, and can range from partial vision loss including a homonymous hemianopsia, to a complete lack of light perception. Optokinetic nystagmus (OKN), elicited on physical exam with a rotating drum with alternating stripes, is when the eye smoothly follows a line (pursuit) and then returns to fix on the next line (saccade). Pursuit is controlled by the ipsilateral parietal lobe and is therefore affected with cortical blindness. References: Flanagan C, Kline L, Curè J. Cerebral blindness. Int Ophthalmol Clin. 2009 Summer;49(3):15-25. doi: 10.1097/IIO.0b013e3181a8e040. PMID: 19584619. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/19584619/ Chaudhry FB, Raza S, Ahmad U. Anton's syndrome: a rare and unusual form of blindness. BMJ Case Rep. 2019 Dec 3;12(12):e228103. doi: 10.1136/bcr-2018-228103. PMID: 31801772; PMCID: PMC7001702. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/31801772/ Sarkar S, Tripathy K. Cortical Blindness. 2022 Feb 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32809461. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/32809461/

Answer 63

Wilson’s disease ## Footnote Discussion: Wilson’s disease (WD) has varied clinical symptoms and may include classic “flapping tremor” coupled with dysarthria; onset occurs around 20 years. The dystonic tremor in WD is often irregular, but may also be similar to resting, action, or intention tremors. In addition to motor symptoms, patients with WD also exhibit psychiatric symptoms such as personality changes and irritability. Inheritance occurs in an autosomal recessive fashion, often due to a ATP7B (copper transporting gene) mutation on chromosome 13. Pathologically, patients have hepatic findings in additional to neuronal findings (hepatolenticular degeneration). There is accumulation of copper in the brain, decreased serum ceruloplasmin, and increased serum-free copper and urinary copper excretion. Radiographically, this copper deposition manifests as hypodensity of the basal ganglia and clinically as Kayser–Fleischer rings with copper deposition in the deepest corneal layer around the iris. Pathologic examination demonstrates Alzheimer II astrocytes with large vesicular nuclei in the cerebrum, cerebellum, and brainstem. Parkinson's disease (PD) is characterized by difficulty initiating movements (bradykinesia), cogwheeling rigidity, resting pill-rolling tremor, festinating gait, and dementia. Onset typically occurs at 40–50 years with male predominance and affects 1% of individuals >50 years. On pathologic examination of the brain, there is decreased neuromelanin found in the pars compacta of the substantia nigra, locus coeruleus, and dorsal motor nucleus of the vagus. In addition, Lewy bodies comprised of α-synuclein are present, as well as decreased dopamine in the caudate and putamen. Hallervorden-Spatz is characterized by extrapyramidal and corticospinal dysfunction with dementia. It is an autosomal recessive disease where onset occurs in late childhood and progresses to death in early adulthood. Radiographic findings include hypodense basal ganglia on CT, giving a classic “eye-of-the-tiger sign.” Iron deposition in the globus pallidus and substantia nigra appears as brownish atrophy on pathologic examination. Huntington's disease (HD) is characterized by personality changes, subcortical dementia without aphasia/agnosia/apraxia, and choreiform movements that start in the hands and face. Unlike other forms of dementia, the onset typically occurs in the 30’s. HD transmission is in an autosomal dominant inheritance pattern due to a trinucleotide repeat disorder of CAG on chromosome 4. There is characteristic significant atrophy of the caudate, which causes typical “boxcar” ventricles. Essential tremor (ET) is the most common movement disorder characterized by rhythmic shaking that is most prominent in the hands during actions such as eating or writing. It can be differentiated from a Parkinsonian tremor as it does not occur at rest. ET has a variable inheritance pattern and may be inherited through an autosomal dominant fashion. Onset may occur in early adulthood and may involve the head and voice, but it does not often manifest in the lower extremities. Over time, the tremor rate decreases, and the amplitude increases with aging. References: Citow Comprehensive Neurosurgery Board Review 3rd Ed. 2019, p285, 543 Bandmann O, Weiss KH, Kaler SG. Wilson's disease and other neurological copper disorders. Lancet Neurol. 2015 Jan;14(1):103-13. doi: 10.1016/S1474-4422(14)70190-5. PMID: 25496901; PMCID: PMC4336199. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/25496901 Srinivas K, Sinha S, Taly AB, Prashanth LK, Arunodaya GR, Janardhana Reddy YC, Khanna S. Dominant psychiatric manifestations in Wilson's disease: a diagnostic and therapeutic challenge! J Neurol Sci. 2008 Mar 15;266(1-2):104-8. doi: 10.1016/j.jns.2007.09.009. Epub 2007 Sep 27. PMID: 17904160. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/17904160

Answer 64

Meniere disease ## Footnote Discussion: Meniere disease (MD), named for French physician Prosper Menière, is a condition characterized by episodic vertigo, tinnitus, and hearing loss. A clinical diagnosis of MD is made based upon the following criteria: A. Two or more spontaneous episodes of vertigo, each lasting 20 minutes to 12 hours B. Audiometrically documented low- to mid-frequency sensorineural hearing loss in the affected ear C. Fluctuating aural symptoms (reduced or distorted hearing, tinnitus, or fullness) in the affected ear D. Symptoms not better accounted for by another vestibular diagnosis BPPV occurs with specific movements of the head such as lying down, turning the head a certain direction or hanging the head upside down, whereas MD is not positional. Acoustic neuroma and temporal bone fracture would likely have findings on imaging. References: Gibson WPR. Meniere's Disease. Adv Otorhinolaryngol. 2019;82:77-86. doi: 10.1159/000490274. Epub 2019 Jan 15. PMID: 30947172. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/30947172/ Weber PC, Adkins WY Jr. The differential diagnosis of Meniere's disease. Otolaryngol Clin North Am. 1997 Dec;30(6):977-86. PMID: 9386235. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/9386235/ Chan Y. Differential diagnosis of dizziness. Curr Opin Otolaryngol Head Neck Surg. 2009 Jun;17(3):200-3. doi: 10.1097/MOO.0b013e32832b2594. PMID: 19365263. PubMed Web Link: https://pubmed.ncbi.nlm.nih.gov/19365263/

Answer 65

Coordination of fine motor movements ## Footnote Discussion: The inferior olivary nuclei are located in the superior medulla. The inferior olivary nuclei provide the main source of cerebellar climbing fibers, which project through the contralateral inferior cerebellar peduncle to terminate on Purkinje cells in the cerebellar cortex as well as on the deep cerebellar nuclei. The inferior olivary nuclei receive information from both the spinal cord and the motor cortex and serves as a relay station between the spine and cerebellum. The superior olivary nuclei integrate motor and sensory information to provide feedback to cerebellar neurons. The superior olivary nucleus participates in sound localization and analysis. The inferior olivary nucleus is not known to have a role in expressive or receptive speech. Eye abduction is carried out via abducens nerve (CN VI) innervation of the lateral rectus muscle. References: Paul MS, M Das J. Neuroanatomy, Superior and Inferior Olivary Nucleus (Superior and Inferior Olivary Complex) [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Pubmed Web link: https://www.ncbi.nlm.nih.gov/books/NBK542242/ Ruigrok TJ. Cerebellar nuclei: the olivary connection. Prog Brain Res. 1997;114:167-92. doi: 10.1016/s0079-6123(08)63364-6. PMID: 9193144. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/9193144/ Bengtsson F, Hesslow G. Cerebellar control of the inferior olive. Cerebellum. 2006;5(1):7-14. doi: 10.1080/14734220500462757. PMID: 16527758. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/16527758/

Answer 66

Apolipoprotein E4 allele ## Footnote Discussion: While many forms of dementia may demonstrate neurofibrillary tangles, such as Pick disease, progressive supranuclear palsy, and corticobasal degeneration, the pathognomonic findings of neurofibrillary tangles and neuritic plaques are only associated with Alzheimer's disease (AD). AD is the most common cause of dementia, and the ε4 allele of apolipoprotein E (APOE) is a major genetic risk factor for Alzheimer’s disease (AD). Superoxide dismutase 1 (SOD1) mutation is associated with amyotrophic lateral sclerosis. CAG trinucleotide expansion is associated with Huntington’s disease. ATP7B mutation is associated with Wilson’s disease. GAA trinucleotide expansion is associated with Friedreich’s ataxia. References: Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013 Feb;9(2):106-18. doi: 10.1038/nrneurol.2012.263. Epub 2013 Jan 8. Erratum in: Nat Rev Neurol. 2013. doi: 10.1038/nmeurol.2013.32. Liu, ChiaChan [corrected to Liu, Chia-Chen]. PMID: 23296339; PMCID: PMC3726719. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/23296339 Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer's disease. Neuron. 2009 Aug 13;63(3):287-303. doi: 10.1016/j.neuron.2009.06.026. PMID: 19679070; PMCID: PMC3044446. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/19679070

Answer 67

Spinal Trigeminal Nucleus ## Footnote Discussion: The ventral trigeminothalamic tract conveys information via axons from cell bodies located in the spinal trigeminal nucleus and the chief sensory nucleus of the trigeminal nerve. This tract then conveys fast pain and temperature from one side of the face to the contralateral ventral posteromedial nucleus of the thalamus. From there, fibers pass to primary sensory cortex. A lesion affecting the ventral trigeminothalamic tract would result in sensory changes in the contralateral face. The dorsal trigeminothalamic tract conveys information on proprioception, 2-point discrimination, vibration, and fine touch from the ipsilateral chief sensory nucleus to the ipsilateral VPM thalamus. The trigeminal ganglion is located in Meckel’s cave lateral to the internal carotid artery and the posterior portion of the cavernous sinus. References: Price S, Daly DT. Neuroanatomy, Trigeminal Nucleus. [Updated 2021 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Pubmed Web link: https://www.ncbi.nlm.nih.gov/books/NBK539823/ Henssen DJ, Kurt E, Kozicz T, van Dongen R, Bartels RH, van Cappellen van Walsum AM. New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input. Front Neuroanat. 2016;10:53. Published 2016 May 10. doi:10.3389/fnana.2016.00053 Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861896/ Walker HK. Cranial Nerve V: The Trigeminal Nerve. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths; 1990. Chapter 61. PMID: 21250225. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/21250225/

Answer 68

Riluzole ## Footnote Discussion: Amyotrophic lateral sclerosis (ALS) is progressive motor neuron disease with a median survival of 2-3 years following initial symptom onset. Characterization of the disease is variable due to a number of different genotypes and phenotypes. Typically there is sporadic inheritance, however there are also genetic variants such as an autosomal dominant inherited form of superoxide dismutase 1 (SOD1) mutation that is linked to a rapidly progressive phenotype in the USA. Classically, ALS manifests with insidious asymmetric weakness in a single limb. Neuronal denervation is manifested as atrophy and fasciculations in the hands, and can often be seen in the bulbar muscles leading to impairment in facial and tongue movements as well as swallowing and chewing. Definitive diagnosis includes EMG/NCS which demonstrate both fasciculations and fibrillations. Due to notable corticospinal involvement, there is significant spasticity as well as hyperreflexia. Eventually, there is development of the hallmark feature of the loss of both upper and lower motor neuron function. It should be noted that sensory changes are absent, as degeneration is limited to the lateral corticospinal tract, preserving the dorsal columns and spinothalamic tract. Histological examination demonstrates this degeneration of the lateral corticospinal tracts and the anterior horn of the spinal cord, as well as Bunina bodies. Riluzole (Rilutek) is a glutamatergic neurotransmission inhibitor and is the only drug approved by the USA Food and Drug Administration for ALS treatment with modest benefits on survival. Riluzole may increase median survival by about 2-3 months in patients with ALS. Tetrabenazine (Xenazine) may be used in the treatment of Huntington disease to control chorea symptoms. It is a reversible inhibitor of monoamine uptake into presynaptic neuron vesicles that selectively binds to VMAT-2 (vesicle monoamine transporter-2). Monoamine degradation is upregulated and leads to a decrease in available monoamines, particularly dopamine. Bevacizumab (Avastin) is an anti-angiogenesis agent which binds to vascular endothelial growth factor A (VEGF-A) to prevent interaction with endothelial cell surface receptors, hence reducing vascular growth of tumors. Bevacizumab has been shown to inhibit the growth of human tumor cell lines, including GBM in mice. Idarucizumab (Praxbind) is a reversal agent for dabigatran (Pradaxa). It is a monoclonal antibody fragment which binds Pradaxa with an affinity significantly higher than that of dabigatran-thrombin. IVIg therapy may be used in the treatment of ALS, however there are no controlled studies that demonstrate a reduction in disease progression or increase in life expectancy. References: Citow Comprehensive Neurosurgery Board Review 3rd Ed. 2019, p288 Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012 Mar 14;2012(3):CD001447. doi: 10.1002/14651858.CD001447.pub3. PMID: 22419278; PMCID: PMC7055506. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/22419278/

Answer 69

Gracile fasciculus (tract of Goll) on the left ## Footnote Discussion: The dorsal column medial lemniscus pathway carries information about discriminative touch, joint position (or proprioception) and vibration from specialized receptors in the skin and joint capsule. Axons enter the spinal cord and ascend via the direct dorsal column pathway. Fibers entering below the sixth thoracic spinal segment (T6) form the gracile fasciculus (tract of Goll), which contains afferents from the lower trunk and lower extremities. Fibers entering above the sixth thoracic spinal segment (T6) form the cuneate fasciculus (tract of Burdach), which contains afferents from the upper trunk and extremities. The gracile and cuneate tracts ascend between the dorsal horns and form the dorsal column. The first synapse in this pathway occurs in the nuclei gracilis and cuneatus, which are found in the lower medulla. Axons emanate from those nuclei and ascend as the internal arcuate fibers in the brainstem. Internal arcuate fibers coalesce and form the medial lemniscus, which changes orientation and position as it ascends through the pons and midbrain. The medial lemniscus terminates in the ventral posterolateral nucleus of the thalamus (VPL). Third order neurons from the VPL group form fibers that enter the posterior limb of the internal capsule and travel to the somatosensory cortex, terminating along the post-central gyrus (areas 1, 2, and 3). A lesion of the dorsal column in the spinal cord will cause a loss on the ipsilateral side; whereas, after crossing in the lower brainstem, any lesion of the medial lemniscus will result in deficit occurring on the contralateral side. Lesions occurring in the midbrain and internal capsule will usually involve the fibers of the anterolateral pathway, as well as the modalities carried in the trigeminal pathway. With cortical lesions, the part of the body affected will be determined by the area of the post-central gyrus involved. References: Kuczynski AM, Carlson HL, Lebel C, Hodge JA, Dukelow SP, Semrau JA, Kirton A. Sensory tractography and robot-quantified proprioception in hemiparetic children with perinatal stroke. Hum Brain Mapp. 2017 May;38(5):2424-2440. doi: 10.1002/hbm.23530. Epub 2017 Feb 8. PMID: 28176425. Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866749/ Schneide RJ, Kulics AT, Ducker TB. Proprioceptive pathways of the spinal cord. J Neurol Neurosurg Psychiatry. 1977 May;40(5):417-433. doi: 10.1136/jnnp.40.5.417 PMID: 28176425. Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC492717/ Hughes A. The development of the dorsal funiculus in the human spinal cord. J Anat. 1976 Sep;122(Pt 1):169-75. PMID: 977478. Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1231939/

Answer 70

Loss of fine touch, vibration pressure, two-point discrimination and proprioception from contralateral skin and joints ## Footnote Discussion: The dorsal column-medial lemniscus pathway, also known as the posterior column, is a major sensory pathway of the central nervous system. It carries fine touch, vibration pressure, two-point discrimination and proprioception from the skin and joints. Sensory fibers originating from the pseudo unipolar cells of the dorsal root ganglia carry afferent information to the spinal cord. These fibers ascend ipsilaterally through the dorsal column and synapse with the secondary neurons of the gracile (lower torso) and cuneate (upper body) nuclei in the caudal medulla. Secondary neurons then decussate and form the medial lemniscus tract, which ascends to synapse with the tertiary neurons at the VP of the thalamus. Therefore, a lesion of the medial lemniscus results in the loss of fine touch, vibration pressure, two-point discrimination and proprioception from contralateral skin and joints of the body. References: Haines, D. E. (2012). Neuroanatomy: an atlas of structures, sections, and systems (8th ed.). Philadelphia, PA: Wolters Kluwer/ Lippincott Williams & Wilkins Health. Kunam VK, Velayudhan V, Chaudhry ZA, Bobinski M, Smoker WRK, Reede DL. Incomplete Cord Syndromes: Clinical and Imaging Review. Radiographics. 2018 Jul-Aug;38(4):1201-1222. doi: 10.1148/rg.2018170178. PMID: 29995620. Schoenen J, Grant G. CHAPTER 8 - Spinal Cord: Connections. Editor(s): Geore Paxinos, Jurgen K. Mai. The Human Nervous System (Second Edition), Academic Press, 2004, Pages 233-249. https://doi.org/10.1016/B978-012547626-3/50009-0

Answer 71

transmitter to be released, diffuse across the cleft, and bind with receptors on the postsynaptic membrane ## Footnote Discussion: Synaptic delay is the time between peak inward current through the presynaptic membrane and the start of inward current in the postsynaptic membrane. The synaptic delay is due to the time necessary for transmitter to be released, diffuse across the cleft, and bind with receptors on the postsynaptic membrane. The post-synaptic membrane must only receive the transmitter as part of the synaptic delay timing and therefore postsynaptic membrane synthesis is not involved. Similarly, pre-synaptic synthesis of neurotransmitter happens prior to the time of the synaptic delay. Channels opening and ions diffusing across the cell membrane is involved in an individual cell’s activation and action potential, but not in synaptic delay. References: Byrne, John H.. Essential Medical Physiology. Netherlands, Elsevier Science, 2003. Lin JW, Faber DS. Modulation of synaptic delay during synaptic plasticity. Trends Neurosci. 2002 Sep;25(9):449-55. doi: 10.1016/s0166-2236(02)02212-9. Erratum in: Trends Neurosci 2002 Oct;25(10):539. PMID: 12183205.

Answer 72

Anti-Yo ## Footnote Discussion: This question requires you to know the commonly detected onconeural antibodies. A. Anti-Yo (PCA-1): this is the most commonly detected onconeural antibody in paraneoplastic cerebellar degeneration (PCD) and is commonly associated with breast cancer and ovarian cancer B. Anti-Hu: most commonly detected in small-cell lung cancer, prostate cancer, and seminoma testicular cancer. C. Anti-Ri: most commonly detected in breast, ovarian and small cell lung cancers D. Anti-Tr: most commonly detected in Hodgkin lymphoma E. Anti-VGCC: most commonly detected in small cell lung cancer and lymphoma F. Anti-Ma2: most commonly detected in small cell lung cancer and testicular cancer G. Anti-CRMP5 (Anti-CV2): most commonly detected in small cell lung cancer and thymoma H. Anti-mGluR1: most commonly detected in Hodgkin lymphoma References: Venkatraman A, Opal P. Paraneoplastic cerebellar degeneration with anti-Yo antibodies - a review. Ann Clin Transl Neurol. 2016 Jun 30;3(8):655-63. doi: 10.1002/acn3.328. PMID: 27606347; PMCID: PMC4999597. Pubmed Web: https://pubmed.ncbi.nlm.nih.gov/27606347/ Saini V, Dhir A, Rudnick AW, Lukas J, Lizarraga KJ, Margolesky J, Heros DO, Hoffman JE. Paraneoplastic Cerebellar Degeneration in Diffuse Large B-cell Lymphoma and Review of Associated Onconeural Antibodies. Clin Lymphoma Myeloma Leuk. 2020 Jun;20(6):e336-e340. doi: 10.1016/j.clml.2020.02.010. Epub 2020 Feb 19. PMID: 32171690. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/32171690/ Yshii L, Bost C, Liblau R. Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications. Front Immunol. 2020 Jun 2;11:991. doi: 10.3389/fimmu.2020.00991. PMID: 32655545; PMCID: PMC7326021. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/32655545/

Answer 73

Simultaneous stimulation by multiple presynaptic neurons ## Footnote Discussion: Spatial summation is a mechanism of eliciting an action potential in a neuron with input from multiple presynaptic cells and their neurotransmitters. It occurs when multiple stimuli are applied at the same time in different areas and there is a cumulative effect upon the cell membrane. The synapse in each area results in movement of sodium ions and a localized graded potential. At each area, there is an excitatory postsynaptic potential that spreads along the inner membrane and combines with other synapses to result in this cumulative effect. When the membrane potential at the initial segment reaches its threshold, there will be an action potential. References: From Molecules to Networks: An Introduction to Cellular and Molecular Neuroscience. Netherlands, Elsevier Science, 2009. https://www.elsevier.com/books/from-molecules-to-networks /byrne/978-0-12-397179-1 Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Summation of Synaptic Potentials. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11104

Answer 74

Respiration ## Footnote Discussion: The nucleus solitarius is one of the nuclei of the vagus nerve located in the dorsomedial medulla and is divided into a rostral and caudal portion. The rostral nucleus solitaries, or gustatory nucleus, receives taste input from cranial nerves VII, IX, and X. The caudal nucleus has a role in cardiovascular, respiratory, and gastrointestinal system control through baroreceptors and chemoreceptors in the carotid body (cranial nerve IX), as well as the aortic arch (cranial nerve X). The nucleus solitarius controls respiration through input on blood pH and blood oxygen levels as well as stretch receptors present in the lungs. The nucleus solitarius also helps to mediate the cough reflex as well as gag and vomiting reflexes. The nucleus solitarius does not play a role in the other functions listed above, as it is primarily a recipient of visceral afferent fibers. References: AbuAlrob MA, Tadi P. Neuroanatomy, Nucleus Solitarius. [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Pubmed Web link: https://www.ncbi.nlm.nih.gov/books/NBK549831/ Baker E, Lui F. Neuroanatomy, Vagal Nerve Nuclei. 2021 Jul 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 31424793. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/31424793/ Mutolo D. Brainstem mechanisms underlying the cough reflex and its regulation. Respir Physiol Neurobiol. 2017 Sep;243:60-76. doi: 10.1016/j.resp.2017.05.008. Epub 2017 May 24. PMID: 28549898. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/28549898/

Answer 75

Cerebral cortex ## Footnote Discussion: The ventral pontine nuclei primarily receive input from layer 5 of the ipsilateral cerebral cortex via corticopontine fibers, and are estimated to provide over half of the mossy fiber input to the cerebellum via the middle cerebellar peduncle. The ventral pontine nuclei also receive descending input from the superior colliculus. The red nucleus is located in the midbrain and does not provide input to the ventral pontine nuclei. References: Kratochwil CF, Maheshwari U, Rijli FM. The Long Journey of Pontine Nuclei Neurons: From Rhombic Lip to Cortico-Ponto-Cerebellar Circuitry. Front Neural Circuits. 2017;11:33. Published 2017 May 17. doi:10.3389/fncir.2017.00033 Pubmed Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434118/ Brodal P, Bjaalie JG. Organization of the pontine nuclei. Neurosci Res. 1992 Mar;13(2):83-118. doi: 10.1016/0168-0102(92)90092-q. PMID: 1374872. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/1374872/ Mihailoff GA, Lee H, Watt CB, Yates R. Projections to the basilar pontine nuclei from face sensory and motor regions of the cerebral cortex in the rat. J Comp Neurol. 1985 Jul 8;237(2):251-63. doi: 10.1002/cne.902370209. PMID: 4031124. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/4031124/

Answer 76

Eaton-lambert syndrome ## Footnote Discussion: Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder mediated by autoantibodies to voltage-gated calcium channels. The disorder is diagnosed clinically on the basis of a triad of symptoms (proximal muscle weakness, hyporeflexia, and autonomic disturbance), supported by electrophysiological findings and the presence of autoantibodies. Between 40% and 62% of patients diagnosed with LEMS are found to have small-cell lung cancer (SCLC), almost all of whom develop neurological symptoms before their cancer is diagnosed. Prompt identification of LEMS and appropriate screening for SCLC is key to improving the outcome of both conditions. References: Kesner VG, Oh SJ, Dimachkie MM, Barohn RJ. Lambert-Eaton Myasthenic Syndrome. Neurol Clin. 2018 May;36(2):379-394. doi: 10.1016/j.ncl.2018.01.008. PMID: 29655456; PMCID: PMC6690495. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/29655456/ M Saltos A, Shafique M, Chiappori A. Update on the Biology, Management, and Treatment of Small Cell Lung Cancer (SCLC). Front Oncol. 2020 Jul 16;10:1074. doi: 10.3389/fonc.2020.01074. PMID: 32766139; PMCID: PMC7378389. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/32766139/ Cai G, Sun X, Yu J, Meng X, Li J. Non-small cell lung cancer associated with late-onset LambertEaton myasthenic syndrome and paraneoplastic cerebellar degeneration. Neurol Sci. 2020 May;41(5):1277-1279. doi: 10.1007/s10072-019-04139-0. Epub 2019 Nov 18. PMID: 31735997. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/31735997/

Answer 77

intracranial hypotension ## Footnote Discussion: The patient’s symptoms, as well as the MR findings, are most consistent with intracranial hypotension. Brain imaging findings of spontaneous intracranial hypotension include: A. Dural (pachymeningeal) enhancement B. Brain sagging C. Venous distension sign D. Subdural collections E. Pituitary engorgement Subarachnoid hemorrhage would demonstrate acute blood in the sulci on MRI, and a venous sinus thrombosis would demonstrate venous hemorrhage on MRI or an abnormal flow void. References: Kranz PG, Gray L, Malinzak MD, Amrhein TJ. Spontaneous Intracranial Hypotension: Pathogenesis, Diagnosis, and Treatment. Neuroimaging Clin N Am. 2019 Nov;29(4):581-594. doi: 10.1016/j.nic.2019.07.006. Epub 2019 Aug 26. PMID: 31677732. Pubmed Web: https://pubmed.ncbi.nlm.nih.gov/31677732/ Schievink WI. Spontaneous Intracranial Hypotension. N Engl J Med. 2021 Dec 2;385(23):2173-2178. doi: 10.1056/NEJMra2101561. PMID: 34874632. Pubmed Web: https://pubmed.ncbi.nlm.nih.gov/34874632/ Chan SM, Chodakiewitz YG, Maya MM, Schievink WI, Moser FG. Intracranial Hypotension and Cerebrospinal Fluid Leak. Neuroimaging Clin N Am. 2019 May;29(2):213-226. doi: 10.1016/j.nic.2019.01.002. Epub 2019 Feb 21. PMID: 30926112. Pubmed Web: https://pubmed.ncbi.nlm.nih.gov/?term=intracranial+hypotension&filter=pubt.review

Answer 78

Glossopharyngeal (CN IX), vagus (CN X) and spinal accessory (CN XI) ## Footnote Discussion: The nucleus ambiguus is a motor nucleus for the glossopharyngeal (CN IX), vagus (CN X), and spinal accessory (CN XI) nerves. Glossopharyngeal nerve fibers arise from the nucleus ambiguus and exit the jugular foramen to supply the stylopharyngeus muscles. Vagus nerve fibers also arise from the nucleus ambiguus and divide into the pharyngeal, superior laryngeal and recurrent laryngeal branches to supply the intrinsic muscles of the larynx, pharynx, and palantine muscles (except tensor veli palatini). Spinal accessory nerve fibers arise from the nucleus ambiguus but also the nuclei of cranial XI and spinal IX to supply the sternocleidomastoid and trapezius. The hypoglossal nerve fibers arise from the hypoglossal nuclei to supply the extrinsic and intrinsic muscles of the tongue (except palatoglossus, which is supplied by the pharyngeal plexus (X). References: Petko B, Tadi P. Neuroanatomy, Nucleus Ambiguus. [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547744/ Pubmed Web link: https://www.ncbi.nlm.nih.gov/books/NBK547744/ Hisa Y, Sato F, Fukui K, Ibata Y, Mizuokoshi O. Nucleus ambiguus motoneurons innervating the canine intrinsic laryngeal muscles by the fluorescent labeling technique. Exp Neurol. 1984 May;84(2):441-9. doi: 10.1016/0014-4886(84)90240-1. PMID: 6714352. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/6714352/ Brown JW. Prenatal development of the human nucleus ambiguus during the embryonic and early fetal periods. Am J Anat. 1990 Nov;189(3):267-83. doi: 10.1002/aja.1001890310. PMID: 2260533. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/2260533/

Answer 79

Increase ## Footnote Discussion: The resting membrane potential of a neuron results from several ion species crossing the plasma membrane through a variety of ion channels and transporters. As the ions move across the membrane, so do their charges. The resting membrane potential is defined as the difference in charge across the cell membrane when it is in a non-excited state. It is calculated using the Nernst Equation. Sodium and potassium ions play a key role in resting membrane potential. The passive influx of sodium ions into the cell makes the membrane potential more positive, or increase. It is only when the membrane potential crosses a threshold value (usually – 55 mV) that sodium channels open allowing the rapid influx of sodium and depolarization. References: Henley, Casey. Foundations of Neuroscience. United States, Michigan State University, 2021. Chrysafides SM, Bordes S, Sharma S. Physiology, Resting Potential. 2021 Apr 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30855922

Answer 80

CN III, CN IV, CN VI, CN XII ## Footnote Discussion: The brainstem is of ectodermal origin and is responsible for some of the most vital functions such as breathing, regulating heart rate and blood pressure, controlling level of consciousness, and housing the cranial nerve nuclei. The cranial nerve nuclei are distributed into the middle layer of the brainstem and are placed, from medial to lateral, on the basis of their function: somatic motor, visceral motor, visceral sensory, and somatic sensory. There are 4 cranial nerves that are located midline in the brainstem with mainly motor functions: CN III, IV, VI, and XII. On the other hand, cranial nerves V, VII, IX and XI with predominant sensory functions are located in the lateral brainstem. References: Gates P. The rule of 4 of the brainstem: a simplified method for understanding brainstem anatomy and brainstem vascular syndromes for the non-neurologist. Intern Med J. 2005 Apr;35(4):263-6. doi: 10.1111/j.1445-5994.2004.00732.x. PMID: 15836511. Basinger H, Hogg JP. Neuroanatomy, Brainstem. [Updated 2021 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Angeles Fernández-Gil M, Palacios-Bote R, Leo-Barahona M, Mora-Encinas JP. Anatomy of the brainstem: a gaze into the stem of life. Semin Ultrasound CT MR. 2010 Jun;31(3):196-219. doi: 10.1053/j.sult.2010.03.006. PMID: 20483389.

Answer 81

narcolepsy ## Footnote Discussion: Classical narcolepsy patients display the clinical "tetrad"--cataplexy, hypnagogic hallucinations, daytime sleep attacks, and sleep paralysis. Schizophrenia is a psychological disorder described by hallucinations, delusions, and extremely disordered thinking and behavior that impairs daily functioning. Obstructive sleep apnea patients experience pauses in breathing (apnea) during sleep, which are associated with partial or complete closure of the airway. Bipolar disorder is a mood disorder characterized by periods of depression and periods of abnormally elevated mood. Multiple sclerosis is a demyelinating disease resulting in diplopia, blindness in one eye, muscle weakness, and trouble with sensation or coordination. References: Douglass AB. Narcolepsy: differential diagnosis or etiology in some cases of bipolar disorder and schizophrenia? CNS Spectr. 2003 Feb;8(2):120-6. doi: 10.1017/s1092852900018344. PMID: 12612497. Pubmed Web Link: https://pubmed.ncbi.nlm.nih.gov/12612497/ Bassetti CLA, Adamantidis A, Burdakov D, Han F, Gay S, Kallweit U, Khatami R, Koning F, Kornum BR, Lammers GJ, Liblau RS, Luppi PH, Mayer G, Pollmächer T, Sakurai T, Sallusto F, Scammell TE, Tafti M, Dauvilliers Y. Narcolepsy - clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol. 2019 Sep;15(9):519-539. doi: 10.1038/s41582-019-0226-9. Epub 2019 Jul 19. PMID: 31324898. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/31324898/ Kornum BR, Knudsen S, Ollila HM, Pizza F, Jennum PJ, Dauvilliers Y, Overeem S. Narcolepsy. Nat Rev Dis Primers. 2017 Feb 9;3:16100. doi: 10.1038/nrdp.2016.100. PMID: 28179647. Pubmed Web link: https://pubmed.ncbi.nlm.nih.gov/28179647

Neurobiology Flashcards

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