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67 Cards in this Set
- Front
- Back
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Dorsal Root Ganglia
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Contain cell bodies of sensory neurons
No synapses |
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Cervical radiculopathies
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C5
-Deltoid weakness -Biceps, pectoralis reflex decreased -Shoulder, upper lateral arm sensory abnormalities -C4-C5 C6 -Wrist extensor, biceps weakness -ECR, biceps, brachioradialis reflex decreased -First and second fingers, lateral forearm sensory abnormailities -C5-C6 C7 -Tricep weakness -Triceps reflex decreased -Third finger sensory abnormality -C6-C7 |
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Deep tendon reflexes
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Biceps: C5, C6
Brachioradialis: C6 Triceps: C7 Patellar: L4 Achilles: S1 |
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Key Dermatomes
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Neck: C2/3
Cephalic upper trunk: C5/6 Middle finger: C7 Basal upper trunk: C8/T1 Nipple: T4 Navel: T10 Inguinal Ligament: L1 High thigh: L2 Knee: L3 Leg: L4 (median), L5 (lateral) Posterior leg: S2 Bottom of foot and little toe: S1 |
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Upper motor neuron lesions
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Weakness
Increased Reflexes Increased Tone Spastic Paralysis/Paresis |
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Lower motor neuron lesions
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Weakness
Atrophy Fasciculations Decreased reflexes Decreased tone Flaccid Paralysis/Paresis |
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Central nervous system divisions
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The forebrain (prosencephalon) is subdivided into a telencephalon (cortex and subcortical structures including the basal ganglia) and diencephalon (the thalamus, hypothalamus and the epithalamus). These areas are distinctive in humans.
The midbrain is the mesencephalon. The hindbrain (rhombencephalon) is subdivided into a metencephalon (pons and cerebellum) and myelencephalon (medulla). The spinal cord is a continuation or tail of the brain. |
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Main long tracts of nervous system
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Dorsal column (vibration) – fasciculus cuneatus (from upper extremity) and fasciculus gracilis (from lower extremity) – upper added last (on the outside of the dorsal column)
Anterolateral (Sharp Pain) Lateral Corticospinal (motor) – descending upper motoneuron |
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Testing vibration
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Vibration information crosses in the medulla
Note the spinal DRG (dorsal root ganglia) contain the primary neurons encoding the sense of vibration (as well as proprioception and discriminative touch) in the body. Their axons ascend in the ipsilateral fasciculi (bundles) of the dorsal column – axons from the lower body ascend in the fasciculus gracilis (slender bundle) while axons from the upper body ascend in the fasciculus cuneatus (wedge bundle). These primary axons synapse in the medulla within the nucleus gracilis and cuneatus respectively. Second order neurons in these nuclei have axons that cross to form the medial lemniscus that ascends to synapse in the VPL (ventral posterior lateral) nucleus of the Thalamus. These thalamic nuclei relay this information to the primary sensory cortex (in the postcentral gyrus). |
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Motor control
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Motor control descends from the motor cortex
Motor Fibers mostly cross in the medulla Upper motoneurons in the prefrontal gyrus (primary motor cortex) have axons that travel down the corticospinal tract to command lower motoneurons in the spinal cord. Fibers descend through the midbrain in the cerebral peduncles, through the base of the pons and through the medullary pyramids before they cross or decussate to the opposite side of the spinal cord. Note the position of the motor cortex and the location of motor control for the lower extremity (supplied by the anterior cerebral artery) versus the face (supplied by the middle cerebral artery) |
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Testing sharp pain
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Sharp Pain information crosses in the spinal cord
Note the cells of origin (primary neuron) for pain and temperature in the body are in the DRG. They enter and immediately synapse in the dorsal horn. The secondary neuron immediately crosses at that spinal segment and ascends through the brainstem to the VPL nucleus of the dorsal thalamus. Fibers ascend in the spinal cord and brainstem in the anterolateral pathway. Thalamic fibers travel to the post central gyrus – the primary sensory cortex. |
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Nervous system development
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The entire nervous system is derived from ectoderm.
Primary neurulation. The neural plate is a specialized region of ectoderm with elongated cells that differentiate under the inductive influence of the notochord. This thickened epithelial plate folds to form the neural fold. Cells in the most dorsal region of the fold loose their epithelial properties to become neural crest cells. These neural cells migrate throughout the body to form many different types of cells including the cellular component of the PNS (Schwann cells and neurons in ganglia throughout the body). The neural folds elevate and converge to form the long neural tube. The neural tube forms the CNS (spinal cord and brain). |
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Nerve anatomy
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The epineurium is the connective tissue that surrounds the outside of the peripheral nerve
Within the nerve are fascicles or bundles of axons. Each individual fascicle is bound together or surrounded by connective tissue called the perineurium. The connective tissue within fascicles is called endoneurium. Finally individual axons in a peripheral nerve can be myelinated by Schwann cells with lipid. The figure at right is a scanning electron micrograph of a peripheral nerve Note the fascicles or bundles of fibers. The nerve also contains blood vessels within the nerve which supply capillaries surrounding within the nerve to support the survival of the nerve. |
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PNS and CNS myelination
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Schwann cells myelinate axons in the PNS. A Schwann cell myelinates only one axon with multiple layers of lipid rapped around the axon. Each axon is myelinated by many schwann cells along it’s length. Between the lipid insulation of the myelin sheath are nodes of Ranvier. Myelination allows axon potentials to jump at faster speeds from node to node – this is called Saltatory nerve conduction.
Oligodendrocytes myleniate axons in the CNS. Oligodendrocytes can myleniate many different axons. Unlike the PNS Schwann cells that are dedicated to only 1 axon. |
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Excitatory and inhibitory neurotransmitters
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Synaptic depolarization allows the release of neurotransmitter at synaptic terminals located primarily on neuronal soma (cell body) and dendrites.
The neurotransmitter is a ligand that binds to a specific receptor (with matching ligand affinity) on the postsynaptic cell. If the ligand binding elicits local postsynaptic membrane depolarization through the receptor mediated events then it is acting as an excitatory neurotransmitter. If instead the ligand binding elicits local postsynaptic membrane hyperpolarization through the receptor mediated events then it is acting as an inhibitory neurotransmitter. Note, the same ligand may have different effects on different cells or at different times in development (because of different receptors or different receptor mediated events that alter membrane depolarization). |
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Lumbo-Sacral Radiculopathies
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L5 Radiculopathy
-Intervertebral Disc L4-L5 usually involved -Dorsiflexion (Anterior compartment leg) weakness -Big toe, Dorsum foot sensory abnormality S1 Radiculopathy -Intervertebral Disc L5-S1 usually involved -Plantar Flexion (Posterior compartment leg) weakness -Achilles tendon hyporeflexia -Small toe, sole or lateral foot sensory abnormality |
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Brachial plexus
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Roots
-anterior primary rami of spinal nerves C5-T1 Trunks -Upper C5/C6 (Injury Erb’s Palsy) -Middle C7 -Lower C8/T1 (Injury Klumpke’s Palsy) Divisions -The anterior divisions innervate the anterior side of the upper extremity via a lateral cord median nerve and medial cord. -The posterior cord innervates the posterior upper extremity (radial nerve). Cords -named by relationship to axillary artery in axilla posterior to pectoralis minor tendon -Lateral – arm flexors (musculocutaneous n.) -Median nerve is from both cords (forearm flexors and thenar compartment of hand) -Medial – intrinsic hand - ulnar nerve Branches -Recall the function of 5 major nerves of the upper extremity that are most useful for the neurological exam. |
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RUM Rapid screening exam
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Radial test – Thumbs up (hitch-hiker sign) thumb extension
Ulnar test – Good Luck (cross fingers) – adduction Median test – O’Kay sign – thumb and digit DIP flexion |
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Median, radial, and ulnar nerve palsies
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Recall that a radial palsy results in wrist drop and dorsal numbness over the radial side. This hand cannot be moved into a functional position (ie to open a door handle).
Median nerve palsy is devastating because of a “blind hand”. The median nerve is the branch impacted by carpal tunnel syndrome producing Weakness in the thenar muscle compartment. Ulnar palsy results in the loss of digit abduction and adduction (interossei making it difficult to grasp a sheet of paper placed between the digits – the paper test). Ulnar injury at the elbow results in the Loss of the powerful wrist adductor. |
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Six nerves of lower extremity
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L3 – Flex Hip - Femoral
L4 – Extend Knee - Femoral L5 – Dorsiflex Ankle –Peroneal (Deep) S1 –Flex Knee – Sciatic S1 – Plantar-flex Ankle - Tibial |
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Autonomics neurotransmitters
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Both systems use acetylcholine as a neurotransmitter between the pre and postganglionic neuron at the synapse within the relay ganglion.
The systems differ in the neurotransmitter used by the postganglionic neuron in commanding the target (something other than skeletal muscle). Sympathetics postganglionics use noradrenaline. Parasympathetics postganglionics use acetylcholine. An important exception is the skin sweat glands that are innervated by Sympathetics postganglionics using acetylcholine. This means that since all skin contains sweat glands – all cutaneous nerves (ie. From all of the spinal nerves to cover all dermatomes) contain postganglionic sympathetic axons. Note there are many different types of receptors for both Ach and NA so different cells respond differently to the same ligands. |
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Autonomics erection
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erection (Point with the Parasympathetic) and ejaculation (Shoot with the Sympathetics).
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Visceral pain
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Angina: - Cardiac n. T1-T4
Epigastric Pain: – Organs supplied by Coeliac A./ Ganglia Greater Spl. N. - T5-T9 Paraumbilical Pain: – Organs supplied by Sup. Mesenteric A./G. Lesser. Spl. N. - T10/11 Hypogastric Pain: – Organs supplied by Inf. Mesenteric A./G. Least Spl. N. T12 |
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Parasympathetic nerves
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Points to remember:
Relate the function (homeostasis – rest and digest) with the anatomy of the system. Note the cranio-sacral origin of the parasympathetic nervous system. Cranial portion includes preganglionic parasympathetic neurons in the brainstem. These preganglionic axons travel out of the brainstem on cranial nerves. They synapse on one of the four cranial parasympathetic ganglia of in the case of the Vagus they synapse in ganglia located near or within the target organs of the body cavities. Cranial preganglionic parasympathetic axons and their cranial parasympathetic ganglia will be studied in detail later when we examine the brainstem and dissect the head and neck. Vagus: (wandering nerve): or Xth Cranial Nerve: This is the major cranial preganglionic parasympathetic output to the body. This nerve innervates ALL Thoracic organs and Abdominal organs up to the colon splenic flexure (midgut/hindgut border). Lots of sensory axons hitch a ride back on the Vagus. These neurons have their cell bodies in a special cranial sensory ganglia located at the base of the brain – the Nodose ganglion. They provide important sensory feedback for homeostasis and visceral reflexes in thoracic (heart and lungs) and abdominal organs. Pelvic Splanchnics: Sacral Output of Preganglionic Parasympathetic Axons from Spinal Segments S2-S4. These Pelvic Splanchnics innervate the hindgut and pelvic organs. Lots of sensory axons hitch a ride on the pelvic splanchnics providing sensory feedback for homeostasis and visceral reflexes. |
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Parasympathetic ganglia in head and neck
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1) Ciliary G. (CN III)
2) Pterygopalatine G. (CN VII) 3) Otic G. (CNIX) 4) Submandibular G. (CNVII) CN X carries preganglionics to ganglia in the organs of the body cavities (up to the splenic flexure of the colon) and pelvic splanchnics provide preganglionic to parasympathetic ganglia in the hindgut and pelvic organs). Note the four parasympathetic ganglia in the head and neck all use a branch of CNV to reach their functional targets. |
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Spinal cord blood supply
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2 dorsal spinal arteries at each dorsal horn
1 ventral spinal artery in the midline Loss of dorsal spinal arteries is likely to impact ascending vibration sensory function while the loss of ventral spinal arteries is likely to impact ascending sharp pain and descending motor pathways. Note the anastomosis of these vessels. |
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Forebrain derivatives and the ventricular system
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1. The telencephalon forms the cerebral cortex (“brain bark”) as well as the large basal ganglia nuclei (caudate, putamen and globus pallidus).
2. The diencephalon forms the thalamus and hypothalamus. Remember also that the diencephalon also produces an evagination, the optic cup that will grow out of the diencephalon toward the embryo surface. The optic cup will form the retina (which in turn induces the lens vesicle) and the optic stalk that is connected to the diencephalon will be filled with retinal axons to form the optic nerve. The retina and optic nerve are CNS (diencephalic derived) structures. Each of the 5 neural tube vesicles will eventually become part of the ventricular system of the brain and virtually all of the cells of the brain are produced from stem cells lining the walls of these neural tube vesicles. Forebrain Vesicles 1 and 2 – lateral ventricles of each cerebral hemisphere surrounded by telencephalon (cortex and basal ganglia nuclei) Vesicle 3 – 3rd ventricle surrounded by diencephalon (thalamic and hypothalamic nuclei) Midbrain Vesicle – Aqueduct of Sylvius surrounded dorsally by the midbrain tectum and ventrally the midbrain tegmentum below Hindbrain Vesicle – 4th Ventricle surrounded dorsally by the cerebellum and ventrally by the pons and medulla. |
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Cortex formation
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Observe that the telencephalon rapidly grows over the brainstem expanding greatly to form a C shaped structure. Stem cells lining the walls of the vesicles produce the cortex and the basal ganglia nuclei. As the cerebral cortex grows it forms 4 cortical lobes surrounding the telencephalic vesicles that become the lateral ventricles of the brain.
The expansive growth of the cortex and the ventricles results in the adult “C-Shaped” structure. Axons bridging the two cerebral hemispheres form the corpus callosum and this structure is also C shaped. The subcortical caudate nucleus develops around the lateral ventricles so it is also formed in the shape of a “C” as are the fimbria and components of the limbic cortex. |
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Lobes of the cortex
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Identify the frontal lobe (blue)
- The inferior frontal gyrus including the portion of the gyrus containing the pars opercularis (operculum) - The precentral gyrus (primary motor cortex) separated from the parietal lobe by the central sulcus Identify the parietal lobe (red) -The postcentral gyrus (primary sensory cortex) -The supramarginal and the angular gyri The Temporal lobe (green) Lateral (Sylvian) Fissure separating the temporal lobe from the frontal and the parietal lobe - the superior, middle and inferior temporal gyrus The Occipital Lobe (tan) |
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Primary cortical regions
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Primary Motor Cortex – precentral gyrus
Primary Somatosensory Cortex – postcentral gyrus Primary Auditory Cortex – region of Superior temporal gyrus within Sylvian fissure Primary Visual Cortex – Striate Cortex (Upper and lower bank of calcarine sulcus) |
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MCA, ACA, and PCA supply to cortex
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(MCA) supplies most of the lateral cortical surface serving face and upper extremity while the anterior cerebral artery (ACA) supplies the medial cortical surface serving the lower extremity.
PCA supplies primary visual cortex |
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Medial surface cortex features
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Note the C shaped white matter in the midline forming the corpus callosum (“callosal body”). The corpus callosum contains a massive bridge of axons communicating between the two hemispheres of the brain. A midsagittal plane cuts these bridging fibers in cross section. Be able to identify the sub-regions of callosal fibers. Observe the genu (“knee or bend”) that is the anterior bend of the callosal bridge, the body and the posterior splenium (“bandage of bridging fibers”).
The cortical region surrounding the corpus callosum is the large cingulate gyrus. This gyrus is defined by the cingulate sulcus. Note the central sulcus from the lateral surface of the brain does not continue onto the medial surface. Instead the precentral and postcentral gyri are combined into a paracentral lobule that crosses the boundary of the frontal and parietal lobes. Identify the parieto-occipital sulcus that forms a boundary dividing the occipital lobe from the parietal lobe. Note the calcarine sulcus on the medial surface of the occipital lobe. The primary visual cortex lies on the upper and lower bank of the calcarine sulcus. Identify the parahippocampal gyrus on the medial surface of the temporal lobe. The fornix (“bridge”) is a band of axons connecting nuclei deep within the parahippocampal gyrus to regions of the basal forebrain and hypothalamus (removed in this figure). The parahippocampal gyrus, cingulate gyrus and regions of the orbital frontal lobe form a C shaped region of cortex called the limbic (border) cortex illustrated on the next slide. The septum pellucidum (“translucent wall”) is a thin dividing wall separating the two lateral ventricles ventral to the corpus callosum. The lateral ventricles drain into the third ventricle. The midsagittal plane passes through the third ventricle so the thalamus is visible on the lateral wall of this chamber. |
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Limbic cortex features
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Identify on the inferior surface of the brain the most medial region of the temporal lobe forming the parahippocampal gyrus. The amygdala and the hippocampal formation are critical subcortical regions required for emotions, motivational drives, memory acquisition and learning that are located deep with the parahippocampal gyrus. The most medial hook like bulge of the parahippocampal gyrus is the uncus (“hook”). Note that the parahippocampal gyrus is divided from the surrounding temporal lobe by the rostral rhinal sulcus and more caudally by the collateral sulcus.
Identify on the medial and inferior surface of the frontal lobe the orbital frontal gyrus and the olfactory sulcus covered in part by the olfactory bulb and tract. On the lateral surface of the brain there is an inner island region of cortex visible by opening up the lateral fissure. This region is called the insular (“island”) region of cortex. The anterior most portion of the insular cortex contributes with the temporal pole and orbital frontal gyrus to the limbic system. |
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Defining brain functional regions
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1. Cortical regions can now be defined by differences in cytoarchitecture as described by Broadman (differences in cortical cell numbers and types within each of the six cortical layers) or more recently by differences in neural chemistry (the cellular distribution of receptors and neurotransmitters).
2. Cortical regions can now be define by differences in cortical network connections. This includes connections among neurons within the 6 cortical layers of a specific cortical region, differences in specific connections between different cortical regions and differences in specific connections with subcortical structures (both cortical inputs and output connections). These are most often defined by connections with the thalamus and with other subcortical structures (as in the cortical spinal tract). 3. Functional properties can be used to identify functional regions. These methods include the experimental recording of neuronal responses to specific stimuli (receptive field properties) or observations from changes in behavior following localized brain stimulation or deficits following well defined focal lesions. Functional maps can also be created based on direct observations of changes in neural activity (or indirect changes in cerebral blood blow) during functional imaging studies (as in functional MRI or PET studies) while patients complete cognitive tasks. |
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Parallel and hierarchical visual processing
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Parallel Processing: Dividing up visual tasks
-Localizing visual stimuli in visual space (“Where”) – Parietal Lobe (dorsal stream) -Determining the significance of stimuli (“ What”) or the percept value – Temporal Lobe (ventral stream) Serial Processing: Projections increase from lower to higher order fields within streams demonstrating hierarchical processing |
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Forming a visual percept
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All of the streams of visual information travel from the retina to the thalamus where they are all relayed to the primary visual cortex (this is a specific region - Brodmann’s area 17 which is topographically located on the upper and lower banks of the calcarine fissure).
Then undergo parallel and serial processing Dorsal stream of parallel: "where" Ventral stream of parallel: "what" |
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Unimodal and heteromodal association cortex
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Observe that the modality specific association cortices or the unimodal association cortex is largely (but not completely) devoted to the integration of information within a specific modality (ie. motor association, somatosensory association, visual association, auditory association to form a percept or complex cognitive function required for an individual modality). These large regions of unimodal association cortex are not surprisingly often located near their respective primary cortex.
A Heteromodal association cortex integrates multiple modalities of information processing across the cortex to achieve higher order complex cognitive functions. These areas associate information from diverse unimodal association cortex and the limbic cortex. For instance, note the frontal heteromodal association cortex in the prefrontal region of the frontal lobe – these regions are important for the regulation of attention and are required for complex cognitive tasks governing impulsivity, planning, decision making and forming judgments. |
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Hemispheres symmetry
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The hemisphere that is most dominant for the production of language is most often but not always the left hemisphere in most people (the cognitive processes of language production and symbolic understanding are lateralized most often in the left hemisphere – ie. in 90% of right handed individuals and in about 70% of left handed individuals). The non-dominant hemisphere processes the emotional content of language or language prosidy to provide through parallel processing more complex meaning.
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Which way is up in the forebrain
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Dorsal (up), ventral (down), rostral (anterior), caudal (posterior)
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Synaptic interactions
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Axo-somatic
Axo-dendritic Axo-axonic Dendro-dendritic En passant |
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Neuronal summation
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Neurons can sum their influences either in space or time. Temporal summation refers to additive signals due to their rapid occurrence, while spatial summation refers to signals from closely synapsing neurons.
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Membrane potential
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Differential distribution of electrical charges across a membrane
-extracellular "grounded," considered zero -resting potential = -40 to -80mV Resting membranes are permeable for K+ and Cl- ions, but are relatively impermeable for Na+ and Ca2+. |
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Na+/K+ pump
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This pump is
stimulated by the presence of intracellular Na+. Three Na+ ions are moved out of the cell at the same time that 2 K+ ions are moved into the cell. The power generator for this process is hydrolysis of ATP. Because the charge swap is unequal, this pump is said to be electrogenic. |
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Nernst Equation
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Vm=(RT/zF)ln(Xo/Xi)
where R=9.315 J/K/mol, z=96,485 coulombs/mol, X=molar concentration of ion (extra and intracellular) |
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Voltage gated ion channel structure
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Ion channels are long integral membrane proteins composed of the following:
1) A pore region. The long proteins span the plasma membrane repeatedly with alpha helical segments, and due to thermodynamic constraints the spanning segments gather together to form a central pore. Ions diffuse through this pore if it is in a favorable conformation. 2) An ion filter. A little reflection will raise the question, “Why aren’t the ion channels that are permeable to the largest ions also permeable to all ions that are smaller?” Such selectivity is achieved by a so-called “pore loop” that lies inside the channel. It provides a barrier to certain ions, but not others that are capable of interacting with it. 3) A voltage sensor. This is a membrane-spanning segment of charged amino acids that actually senses the membrane potential. This segment is called “S4” (for segment 4) on the Na+ channel. Depolarization of the membrane causes this segment to change its conformation, opening up the channel pore. There are 4 protein domains, each of which has an S4 sensor. |
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Voltage gated ion channel activation, inactivation, removal of inactivation
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1) Activation. They are triggered to open at or near a particular threshold membrane potential. This is
either due to rapid depolarization through that potential, or in a few cases, hyperpolarization through that potential. Essentially, as the membrane potential changes, it alters the electrostatic forces holding the channels together and allows subtle changes in the structure of the channel. The peptide sequence of the channel determines the structure and balance of these electrostatic forces. Channel opening, or activation is probablistic in nature. This means that for any individual channel, the voltage trigger may not produce a channel opening on every occasion, and the channel may not open in exactly the same way every time. 2) Inactivation. Many channels once activated do not maintain the open state. For example, Na+ channels begin to inactivate or block, after a few microseconds of opening, even while still activated. In part, this provides for greater temporal resolution in the signals generated by these channels. It also prevents the run down of the ion concentration gradients via prolonged channel opening. Several muscle cell diseases result from genetic mutations in the sodium channel that prolong inactivation. Models for inactivation include specific action of special region of the ion channel (called the II-IV linker region) that swings shut over the channel opening. 3) Removal of inactivation. This clears the block with a membrane voltage change that “resets” the channel within the membrane in preparation for the next impulse. |
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Sequence of action potential
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The following steps are involved in the generation of the action potential:
1) Depolarization of the membrane from rest triggers the Na+ channel S4 voltage sensor; 2) If all S4s respond, Na+ enters the neuron through the channel, resulting in further depolarization toward the equilibrium potential for Na+; 3) Na+ current begins to inactivate, and the driving force on Na+ reduces – the rate of depolarization slows; 4) At about the same time the K+ channels become active, allowing the K+ ions to flow out of the neuron. This reduction of positive charge inside the cell hyperpolarizes the membrane potential, turning off the K+ current and any remaining Na+ current. This process is said to be regenerative, since the initial voltage change starts a self-sustaining cascade that is supported by the intrinsic properties of the channels. In other words, a small depolarization triggers the event, but the additional influx of Na+ causes additional depolarization which sustains it, a bit like an avalanche. |
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Voltage gated ion channel selectivity factor
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The polypeptide chain that connects the two transmembrane helices forms a short a helix (the pore helix) and a crucial loop that protrudes into the wide section of the cone to form the selectivity filter. The selectivity loops from the four subunits form a short, rigid, narrow pore, which is lined by the carbonyl oxygen atoms of their polypeptide backbones.
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Direction of propagation
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The lead time of the Na+ current produces
a wavefront of Na+ entering the neuron, followed by a hyperpolarizing “trough” generated by the K+ - mediated hyperpolarization. The hyperpolarization produces a patch of “refractory” membrane that is resistant to the first step in action potential generation for a period of time called the refractory period. This refractory period also places a constraint on the number of action potentials a neuron can generate per unit time. The rapid inactivation of the Na+ channels also contribute to refractoriness. |
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Saltatory conduction
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Because the voltage sensor of the Na+ channel must be activated by local depolarization of the membrane,
any leakage between two patches of membrane would compromise the effectiveness of one patch of depolarized membrane to activate the next patch. Myelination solves this problem in two ways: 1) It provides insulation through the fatty composition of the myelin. (think of wrapping tape on those leaks) 2) The spaces between the myelin along the axon, called the nodes of Ranvier, are highly enriched in Na+ channels. |
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Patch clamp
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By applying negative pressure the capillary suctions onto the cell membrane with a tight seal (“cell attached”). The small opening through the ion channel within this seal is therefore the only space through which ions can flow. If the pressure is increased enough to breach the membrane, the recording is said to be “whole cell”, reflecting the fact that the recorded currents are through the ensemble of channels across the entire cell’s membrane.
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Blood brain barrier permeability
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Lipophilic (lipid-soluble) drugs are easily adsorbed through the blood-brain barrier.
Hydrophilic (water-soluble) drugs penetrate poorly. Charged drugs, with few exceptions, hardly penetrate at all. However, overly lipophilic drugs can exhibit decreased bioavailability |
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Efficacy and potency
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Maximal effect: efficacy
ED50: Potency |
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Classes of neurotransmitter receptors
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1. Oligomeric ion channel (ionotropic) receptors:
- Example: ACh nicotinic; GABAA - Membrane-bound; oligomeric association of protein subunits to form a receptor-ion channel complex. - Mechanism: open ion channel 2. G protein coupled receptors: - Example: adrenergic; ACh muscarinic - Membrane-bound; forms ternary complex with GTP-binding protein and effector. - Mechanism: activate second messengers (cyclic AMP, phosphoinositol turnover, ion channels |
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Chronic drug effects
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A. Chronic agonist effects:
1. Tolerance: decreased response to drug, usually over a relatively long period of drug use. Metabolic tolerance: increase in drug metabolism (barbiturates). Cellular or pharmacodynamic tolerance: decreased response occurring at the receptor or signal transduction level (opiate tolerance). 2. Tachyphylaxis: rapid tolerance, produced by depletion of neurotransmitter stores (tyramine, ephedrine). 3. Sensitization: opposite of tolerance; increase in response to drug after chronic agonist treatment. Rare (cocaine, amphetamine). B. Chronic antagonist effects: Supersensitivity: increased response to drug, usually caused by increase in number of receptors (tardive dyskinesia: DA receptors). |
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Cholinergic synapse
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Choline+AcCoA form ACh
ACh pumped into vesicle by Vesicular ACh transporter ACh released via exocytosis Muscarinic postsynaptic receptor (G-protein) Nicotinic postsynaptic receptor (ion gated) Acetylcholinesterase degrades ACh back into Choline and acetate Choline transporter transports choline back into axon |
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Cholinergic drug categories
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ACh synthesis / release
-botulinum toxin (Botox): inhibits ACh release 2.ACh metabolism -acetylcholinesterase inhibitors 3.Nicotinic receptor agonists -nicotine; succinylcholine 4.Nicotinic receptor antagonists -curare (tubocurarine) 5.Muscarinic (parasympathetic) agonists -pilocarpine 6. Muscarinic (parasympathetic) antagonists -atropine |
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Dopamine synapse
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Dopamine made from tyrosine
Packaged into vesicle by vesicular monoamine transporter Released via exocytosis Activates postsynaptic receptor Dopamine transporter pumps dopamine back into axon (blocked by cocaine) or out of axon (blocked by amphetamine) Dopamine degraded by MAO |
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Dopaminergic drug categories
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DA synthesis / release
-amphetamine: stimulates DA release -reserpine: blocks DA storage DA metabolism -MAO inhibitors: deprenyl DA uptake inhibitors -cocaine; methylphenidate DA receptor agonists -apomorphine; bromocryptine DA receptor antagonists -typical antipsychotics |
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Norepinephrine synapse
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NE made from dopamine from tyrosine
Packaged in vesicle by vesicular monoamine transporter Released via exocytosis Activates alpha or beta adrenergic receptor Pumped back into axon by NE Transporter Degraded by MAO |
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Adrenergic drug categories
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NE synthesis / release
-ephedrine, tyramine: stimulate NE release NE metabolism -COMT inhibitors (pyrogallol) NE uptake inhibitors -tricyclic antidepressants Alpha receptor agonists -phenylephrine (1); clonidine (2) Alpha receptor antagonists -prazosin (1); idazoxan (2) Beta receptor agonists -isoproterenol Beta receptor antagonists -beta blockers |
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Serotonin synapse
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Made from tryptophan
Packaged in vesicle with vesicular monoamine transporter Released via exocytosis Acts on G protein or ion gated postsynaptic receptor Pumped in and out of presynaptic membrane by serotonin transporter Degraded by MAO |
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Serotonergic drug categories
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5-HT synthesis / release
-Fenfluramine: stimulates 5-HT release 5-HT metabolism -MAO inhibitors 5-HT uptake inhibitors -SSRI’s (fluoxetine) 5-HT receptor agonists -5-HT2 hallucinogens (DOM) 5-HT receptor antagonists -5-HT2 (ketanserin); 5-HT3 anti-emesis (odansetron |
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Glutamate synapse
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Glutamate from alpha-KG or glutamine
Packaged in vesicle by Vesicular glutamate transporter Released via exocytosis Acts on AMPA, kainate, or NMDA postsynaptic receptor (excitatory) Reuptake by glutamate transporter |
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Glutamatergic drug categories
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1.Glu receptor agonists
-NMDA -AMPA -Kainate 2.Glu receptor antagonists -Neuroprotective agents (MK-801) |
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GABA synapse
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Made from glutamate
Packaged in vesicular GABA transporter Released via exocytosis Activates GABA postsynaptic receptors (ion or g-protein) Reuptake via GABA transporter Degraded |
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GABAergic drug categories
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1.GABA synthesis / release
-isoniazid: convulsant side effect; blocks GABA synthesis 2.GABAA receptor agonists -benzodiazepines and barbiturates (allosteric agonists) 3.GABAA receptor antagonists -bicuculline, picrotoxin: convulsants 4.GABAB receptor agonists -baclofen: muscle relaxant |
