Macroscopic anatomy of the nervous system. PharmDr. Tomáš Rajtík, PhD. Department of Pharmacology and Toxicology Faculty of Pharmacy UK rajtik@fpharm.uniba.sk Imhotep, 3000 b.c. – Egyptians understood the brain mainly as an organ which produces mucus and coordinate the functions of eye and ear Hippokrates, 2400 b.c. – „O zraneniach hlavy“, chápanie mozgu, ako orgánu, ktorý determinuje naše vedomie a intelekt Galen, 2. stor.n.l. – medicínsky experimentátor, ktorý preukázal, že mozog je zodpovedný za tvorby fyziologickej odozvy tela – prerušenie rekurentného layrngeálneho nervu ošípanej spôsobilo stratu hlasu. Popísal, taktiež 4 mozgové komory *Ranní kresťanskí filozofi si adoptovali grécku antickú náuku, avšak pre potreby náboženskej náuky boli niektoré informácie pozmenené, napr., že mozog obsahuje 3 komory, čo lepšie korelovalo s ideou svätej trojice Ibn Síná (Avicenna), 9 stor.n.l. – Popísal pasáž podnetov a myšlienok v rámci mozgu Andreas Vesalius, 1543 n.l. – De Humani Corporis Fabrica, najdôležitejšie medicínske dielo renesancie. Vesalius chápal mozog ako ústredný orgán zodpovedný za vedomie, pamäť, tvorbu myšlienok René Descartes, 17. stor.n.l. – Cogito Ergo Sum, za sídlo duše označil corpus pineale (šuška, mozgový prívesok), ktorý sa podieľa na tvorbe o.i. melatonínu a potenciálne aj N,N-dimetyltryptamínu (endogénny halucinogén) Thomas Willis, 1664 .n.l. – Anatomy of Brain and Nerves, snaha o prepojenie anatomických oblastí a funkcií, je považovaný za otca moderných neurovied Luigi Galvani, 18. stor.n.l. – priekopník bioelektromagnetizmu, vykonával experimenty na izolovaných tkanivách využitím elektromagentizmu John Walsh, 1776 n.l. – na základe experimentov s elektrickým úhorom postuloval ako prvý myšlienku, že ľudský nervový systém funguje vďaka elektrickým výbojom, ktorá zostala v platnosti do dnešných dní Piccolino M, Bresadola M. Drawing a spark from darkness: John Walsh and electric fish. Trends Neurosci. 2002 Jan;25(1):51-7. Mozog ako počítač? Funkcia mozgu ako organizovaného kvantového poľa? Vnútroneurónový prenos väčších štruktúr (dynamin, kinesin) 2017 Nikon Small World in Motion Competition Dr. Jeffrey A.J. van Haren • • 1. 2. 3. 4. Neurons Support glial cells: Astrocytes Oligodendrocytes Microglia Ependymal cells On macroscopic level: 1. Grey matter • • Non-myelinated neuron bodies, dendrites and axon terminals In some brain areas form layers and elsewhere clusters of neuronal cells called nuclei 2. White matter • • Mainly myelinated axons of neurons since myelin give typical white appearance Axon bundles interconnecting different regions of CNS are called tracts – adheres to skull bones and spinal canal and creates ducts (sagital sinuses) which drains venous blood from the brain and spine – adheres to pia mater, doesn’t have blood vessels, but consists of containers filled with cerebrospinal fluid – adheres to brain and spine, nests into fissures and gyruses, its thin and richly perfused by blood vessels • Ependymal cells produce CSF and creates choroid plexus which consist of ependymal cells, endothelium of brain capillaries • Ependymal cells creates epithelium-like lining of brain ventricles • Provides osmotic gradient in brain ventricles (ionic homeostasis) • Ensures physical protection (against shock, impact) • CSF crosses the ventricles into the subarachnoid space and drains • Last protective layer of brain between interstitial fluid and blood • Brain capillaries are selectively permeable (dopamine vs. L-dopa) • Hypothalamus-hypophyseal portal system or emetic center of medulla doesn’t contains BBB Vertebral arteries Perfusion of head and brain from aortic arch - Arteriae carotides - Arteriae vertebrales Circle of Willis • High demand on blood perfusion – cca 15% of all arterial blood • Primary energetic source for ATP production is glucose (cca 50% of all glucose consumption in body*) • Pia mater – place of origin of small veins • Venous canals forms cerebral veins which crosses arachnoid mater to endothelium lined do sinuses – sagittal sinuses • Higher brain areas/cerebral cortex • Subcortical and midbrain areas – brain stem, limbic system and basal ganglia • Spinal cord level 11 of 12 cranial nerves ascend from brain stem They transduce motoric and sensory information from neck and head Medulla oblongata • Blood pressure regulation, respiratory, swelling and emetic center • Reticular formation (serotonin – mood), regulation vital function, pain 2 tracts: 1. Somatic-sensory (ascending) 2. Cortical-spinal (descending) • Interconnects cerebellum s with higher brain centers and spinal cord • Along with medulla coordinates breathing • Dreaming (REM sleep, rely inputs to thalamus) Mesencephalon • Eye movement • Visual and auditory reflexes • Wakefulness Consists of white matter • Coordinates motoric functions and balance • Relays motoric, proprioceptive and visual pathways Hypothalamus Main functions Pre-optical a lower Heat loss – skin vessels vasodilation and sweating Rear Heat preservation – skin vasoconstriction and tremor Lateral Feeding Ventromedial Satiety – feeding execution Supraoptic ADH and oxytocin stimulation – thirst Paraventricular ADH a oxytocin secretion Periventricular Hypophyseal hormones secretion • Melatonin secretion (pineal gland) – circadian rhythms • Thalamus – sensory inputs transmission into higher brain areas 3 main parts: • Cortex • Basal ganglia • Limbic system Regulates and integrate movement Sensory inputs processing – hearing, smell, vision, taste, touch Memory Emotions Decision making and thoughts Self-control Cortical-striatal motoric pathway • Information processing for adequate mental or motoric response occurs • Integration – relay and processing of input signals • When the information is not used immediately – stored into memory 1. Sensory system – monitors inner and outer environment and initiates reflective responses 2. Cognitive system – brain cortex, initiation of voluntary responses 3. Behavioral state – cycle sleeping/wakefulness and internal state of organism (metabolism, homeostasis,…) • Bundle of nerve fibers providing inter-hemisphere communication • Interconnects somatic and sensory cortex → transmission of somatosensory signals • Importance in electrical activity spreading (epilepsy) Interconnection with cortex, thalamus and medulla • Voluntary movements • Learning • Subconscious habits – eye movement, teeth grinding • Cognition • Emotions • Reward system (drug addictions) Dopamine GABA, acetylcholine GABA GABA, glutamate Dopamine Amygdala • Middle part of temporal lobe • Creation and relying of memories and association with emotions • „Fight or flight“ responses – stiffness, tachycardia, hyperventilation, secretion of stress hormones Cingulate gyrus • Receives signals from thalamus and cortex • Important in motivation creations in regards to behavior (eg. some action results into positive emotional reaction which results to learning :) → schizophrenia and depression • Executive and respiratory control Hippocampus • Consolidation of long-term memories • Perception of time and place (navigation) → neuronal plasticity and LTP • *Alzeheimer disease • Area responsible for complex processing of thoughts , thinking, planning, rationalization (prefrontal cortex) • Primary motoric cortex, contains long pyramidal neurons – long axons which leads to brain stem (cranial nerves) and into dorsal horns of spinal cord (cortical-spinal tract) • Integrates subconscious memories often associated with emotional affect from limbic system (*Phineas Gage case) • Broca’s area – mostly located in left hemisphere, coordination of mouth during speech – speech intelligibility • Primary somatosensory cortex – perception of sensory stimuli (touch, pain, proprioception) • Wernicke area – Interpretation of word meaning (association between Broca’s and Wernicke area) • Imagination and dreaming • Auditory cortex – neuronal terminals from ears (not chiasmatic) • Interconnection with Wernicke’s area – area of hearing association with connotation and meaning • Olfactory cortex - terminals from smell organ (close to hippocampus – association with memories and emotions) • Oculomotor reflex • Visual cortex – eyes nerves terminals • Area of visual association – associations of images with meaning • Optic chiasmus (along hypothalamus) Nerve fibers originate in motor cortex and descend to the spinal cord where are synapses with second motoric neuron • Starts with great pyramidal neurons which diverge into multiple fibers (one neuron innervate many muscle fibers) • At the brain level they create extra-pyramidal pathway • Apoptosis of pyramidal neurons – Parkinson disease Homunculus – adherent motoric-sensory areas • Somatosensory pathways provides reflex responses at the level of spinal cord Most important descending pathway governing movements, originates with large pyramidal neurons in substantia nigra (SN) • (1) dopaminergic neurons from SN inhibits neuron activity with D2 receptors (2) in CS • (2) stimulates GABAergic neurons in GP (3) • (3) inhibits thalamic-cortical motor pathways → activation of neurions in GP (3) decreases movement • (4) cholinergic neurons in CS stimulate (2) and hence neurons in GP (3) → tonic inhibition of movement • upon basal condition dopaminergic neurons in SN (1) stimulate voluntary movement via decreased activation of neurons (2) in CS and (3) in GP • These pathways are critical for transduction of mechanical, proprioceptive and nociceptive stimuli • Three-neuronal pain pathway – 3 synapses – in spinal cord, in medulla and thalamus • More subtle and proprioceptive stimuli are transduced via 2 neuronal pathway • Terminated in somatosensory cortex Definition according to IASP: • somatic „An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” - superficial - deep visceral • most frequent cause of medical attention seeking • its different of other stimuli – warmth, cold, touch, pressure • neuropathic (de-afferent) – damage of afferent neurons – polyneuropathies, post herpetic neuralgia, Phantom pain • psychogenic – without detectable histologic damage (less common) • warning against damage of organism and force for restitution • intensive and chronical pain traumatize the patient nociceptive (mechanical, heat and chemical stimuli) • • acute • signalizing and warning function chronical • more than 3 months • not signaling function • accompanied with psychosomatic changes, sleeping disorders Causes • mechanical trauma • chemical factors • physical factors „pain receptors“ = nociceptors = free nerve terminals in skin • • algognostic – pain stimulus as such, character, localization • algothymic – emotional component – unpleasant feeling, suffering, fear density of nociceptors in tissues differs, highest amount is in the skin Tissue injury • immediate pain, production of different mediators which activate or modify stimulus transduction at nerves terminals • Interconnection of medulla, brain and cortical areas • Inhibitory modulation at spinothalamic level – 5-HT, NA, opioids, GABA,... • Excitatory modulation at the level of spinothalamic pathway – substance P, glutamate, aspartate, CGRP,... Three neuron pathway: 1. Periphery neuron - from periphery to substantia gelatinosa (SG) in spinal cord A fibers – myelinates, fast conduction, accompanied with nociceptors with high threshold. Sharp, precise localization of origin. C fibers – unmyelinated, slow conduction (<1m/s). Dull, diffuse and burning pain 3. DAS 2. Spinothalamic neuron - from substantia gelatinosa into thalamus - here is decides if the pain stimulus will be transferred further and processed on central level or will be inhibited and blunted by descendent antinociceptive system (DAS) 3. Thalamic-cortical neuron from thalamus into cortex 2. 1. Meninges – meningitis Brain – encephalitis Spinal cord – myelitis Brain + meninges - meningoencephalitides Based on etiology: • Bacterial • Viral • Molds, fungi • Parasites • Toxic – endo- a exotoxins (diphtheria, tetanus, botulism) • Spirochetes • Sarcoidosis Entering paths: • Directly (pyrogenic) – inflammatory processes around meninges, paranasal sinuses inflammation, middle ear, endocarditis • Hematogenic (blood) – distant lesion • Traumas – mostly fractures • Iatrogenic – non-sterile puncture, needle insertion,... Irritation of membranes and spinal roots by chemical or mechanical factors - stretching of the head, flexion of the lower limbs The most common are inflammatory processes in the subarachnoid space, haemorrhage or tumors • • • • • Spasms of upper and lower limb muscles Headache Nausea, vomiting Photosensitivity and noise Typical position of the patient in later stages → lies on the side, head tilted, stiff neck and inability to touch the sternum Dg. 1. Kerning symptom - the lying person does not sit down with his knees crossed; standing with crossed hands on the breasts does not bend without flexing the knees 2. Amos flag - so called. tripod (especially in children) - with outstretched DK unable to sit without support HK 3. Lumbar puncture - cerebrospinal fluid - presence of PMN bb., ↑ proteins, ↓ sugar, ↑ LDH 4. Biochemistry - blood on blood culture (hemophiles, meningococci, pneumococci) 5. CT, MRI Acute infection of subarachnoid spaces and changes caused by the presence of polymorphonuclear cells (eosinophils, basophils, neutrophils) in cerebrospinal fluid Emergency - development occurs within 24-36h Presence of meningeal syndrome Photophobia High temperature Consciousness disorders - somnolence to coma Sometimes epileptic seizures, cranial nerve disorder - ocular, auditory Treatment - ATB (penicillins, cephalosporins) Etiology Most commonly - Neisseria meningitis, spread from menigogoccal nasopharyngitis by droplet infection (young peo Gradual onset, sometimes petechiae on the skin • Hemofilus influenzae - most often children aged 1-5 years, from HDC inflammation • Pneumoccocus pneumoniae - pneumonia, otitis, sinusitis, often adult (alcoholics, diabetics) Mortality 20-30% Dg. LP, blood - sediment, G + and G- bacteria, serological and immunological tests - caspular antigen in CSF, CT, MRI • Seasonal (!) Viral infectious disease (MayOctober) • Transmission by hosts Ixodes ricinus, sp. - infection by infected animals (arboviruses) • Incubation period - 1-2 weeks Usually 2 phases 1. Influenza-like phase (headache and muscle pain, temperature, malaise → either improve or worsen symptoms 2. Meningeal syndrome, photophobia, consciousness changes, limb paresis • Prevention - Immunization • Treatment only symptomatically - corticoids, diuretics • Transmission by Ixodes ricinus vectors through the skin, spreading to joints and nerve tissue • Epidemiological agent - Borrelia burgdoreferi and others • After curing it can leave immune-mediated chronic problems – fatigue, rheumatic disease Clinical symptoms (days to years incubation) • Most often since the turn of spring / summer - 3 stages 1. Flu-like symptoms, arthralgia, skin rash of wandering concentric circles erythema migrans. In the absence of treatment / complications → 2. Stage (weeks to months) - subacute lymphocyte meningitis / encephalitis, often paresis n. facialis eventually the development of peripheral neuropathies. Recurrent arthritis, peri- or myocarditis occurs 3. Stage (months to years) - chronic encephalitis, focal neuropathy and psychiatric symptoms Dg. Antibiotics treatment – • blood collection - serological penicillin, examination (IgM and IgG antibody cephalosporins titer) • Specific antibodies - WB, ELISA Pain that occurs along a neuron or nerve, initiated or caused by a primary lesion or dysfunction in the nervous system. It is often synonymous with neuropathic pain • However, the very concept of neuralgia does not define the etiology, pathomechanism, or character of pain Localization: • on the skin • in deep somatic structures By type: • constant spontaneous • shooting pain • caused Important neuralgia: • postherpetic neuralgia Neuralgia of cranial nerves such as: • neuralgia n. Trigeminal • glosopharyngeal neuralgia • facial ganglion neuralgia neuralgia n. trigeminus The cause is a recurrence of varicella zoster virus (VZV) associated with inflammation and damage to the dorsal corneal ganglion cells The criterion is pain lasting 3-6 months after shingles episode Most often affected are older people without previous history of chronic pain, the incidence is about 15% Typical symptoms: • steady, deep pain as well as intense, piercing, trigeminal neuralgia-like pain • There is also a dynamic, mechanical allodynia (pain after a stimulus that would not normally be painful as touch, movement, light) of the sharp pain Chronical pain caused by 5th cranial nerve disorder. Its accompanied with strong, stabbing pain, reminiscent of electrical shock on face, cheeks or frontal, mainly unilateral. One of most severe pains Causes: Pressure of vessel on nerve in brain stem area Multiple sclerosis, stroke, trauma or tumor Accompanied with demyelination of trigeminal nerve • Afflicted areas often include temple, low and upper jaw, cheek, nose, eye and frontal • Women are more often afflicted mostly after 50 years of life • Seizures of pain can be triggered by stimuli such as talking, washing your teeth, touching your face, chewing or swallowing Complex, recurrent headache Migraine classification: Without aura With aura Retinal migraine Periodic syndromes in childhood – precursors Migraine complications Vascular theory: Ischemia induced intracranial vasoconstriction followed by vasodilatation and activation of perivascular nociceptors Activation of perivascular neurons results into release of substance P, neurokinin A, CGRP and NO, which results into vasodilation, extravasation and inflammation stimulating trigeminalcervical complex Serotonin cascade • 5-HT1D receptors in trigeminal sensory neurons • 5-HT1B receptors in smooth muscle layer of meningeal vessels – plasma extravasation Hours - days 5-60 min 4-72 hrs 24-48 hrs • • • • • Inability to consolidate Exhaustion Depression Euphoria Lack of comprehension
