Block 7 Brain Sciences 1 - Marcus

Factors Contributing to Seizure Generation Note: *impairment of GABA- or glycine-mediated inhibition* can cause hyper-excitability syndromes (anxiety, epilepsy, etc.)

*Too much excitation by glutamate receptors* -Inward Na+ and Ca2+ depolarize the neuron *Too little inhibition by GABA receptors* -Inward Cl- and outward K+ currents hyper-polarize the neuron

Which artery? Stroke affecting lower limbs (think about homunculus on cerebral hemisphere)

ACA Stroke. Medial portion of brain.

Gyri vs. Sulci vs. Fissures

*Gyri:* folds *Sulci:* valleys *Fissures:* deep furrow/elongated cleft *Folding:* increases the surface area of the superficial cerebrum (cortex) to allow more room for neurons, which allows for more integration (processing power).

Stroke Types

"Burst" (hemorrhagic): blood vessel bursts, bleeds into the brain "Block" (obstructive/ischemic): blood vessel is clogged and blood can't flow to its associated brain regions Treatment: IV tissue plasminogen activator (tPA) within 3 hours (tPA converts plasminogen into plasmin, which cleaves fibrin into FDPs)

Glymphatic Circulation

"The Brain's Drain" removes metabolic waste and discarded proteins (2-3x as we sleep, leaving us refreshed in the morning).

General artery supply regions of the brain. ACA: mesial (midilne): frontomedial and superior cerebrum MCA: traverses the lateral sulcus to supply the lateral cerebrum PCA: inferior surface of temporal; mesial surface of occipital

*Anterior Circulation:* *Anterior Cerebral Artery:* located medially and frontally; supplies frontomedial and superior cerebrum (affects lower extremities and trunk) *Middle Cerebral Artery:* traverses the lateral sulcus (Sylvian fissure) to supply the lateral cerebrum. In the sulcus, the artery passes the insular cerebral lobe (deep to the Sylvian fissure) (affects face and upper extremities) *Posterior Circulation:* *Posterior Cerebral Artery:* located medially; supplies inferior and posterior cerebrum (perfuses the "eloquent"/visual cortex)

Benzodiazapines vs Barbituates Hint: ben*z*o ≈ H*z* = frequency

*Barbituate* Mechanism of CNS Depression: *Enhance inhibition* by *increasing the open time of GABAa channels* (allowing more Cl- influx) in the presence of GABA. Note: Barbituates *do not open* GABAa channels themselves, except at very high doses. CNS-Depressant Drugs (reduce neural excitability): 1. Barbituates: *Longer GABA channel open duration* (more Cl- influx) 2. Benzodiazepines: *Higher GABA channel open frequency* (more Cl- influx) Additionally: Gaseous anesthetics (e.g., enflurane) enhance GABAaR currents in a *dose-dependent* manner, resulting in IPSPs and depression of the CNS.

Glutamate (AA)

*Excitatory in CNS* -More permeable in infants (blood-brain barrier) -Involved in cognition functions (learning and memory) in the hippocampus

Dendritic spine shape, number, and biochemistry are affected by:

*Genetics:* -Fragile X babies have a change in spine morphology (more thin and wispy), making it more difficult to make connections with axons from another neuron. -Tay-Sachs patients lack HexA to degrade gangliosides (lipids), resulting in *meganeurites* on cortical pyramidal cells that cause seizures and intellectual disability. *Membranous cytoplasmic bodies* form as lipid molecules accumulate in neuronal cell bodies (see image). *Environment:* -Spine density increases 20-30% during estrogen cycles. -Cortisol (stress) reduces spine density *Age:* spine density decreases with age

Receptor Pharmacology

*Gly-R:* Agonist: glycine Antagonist: strychnine (Indian tree) Sites in CNS: spinal cord, brainstem *GABAaR:* Agonist: GABA, muscimol (mushroom) Antagonist: bicuculline (plant-derived), picrotoxin (East Indian shrub), penicillin Sites in CNS: everywhere *GABAbR:* Agonist: GABA, Baclofen Antagonist: phaclofen Sites in CNS: everywhere

PNS Demyelination

*Guillain-Barré Syndrome:* also known as acute inflammatory demyelinating neuropathy (AIDP) -Demyelinated axons in the PNS -Result of an autoimmune response (which attacks Schwann cells) to a virus (molecular mimicry) -*Rapid onset* (acute) -*Starts peripherally* (fingers/toes) and moves more centrally. This is because longer neurons (most myelin) are most susceptible (distal extremities).

Glutamateric Excitotoxicity

*Hypoxia/ischemia and neurodegenerative disorders (e.g., Alzheimer's, Parkinson's, Huntington) lead to excessive release of glutamate.* Excess release of glutamate leads to: 1. *Ca2+ Overload* -Enters through certain subtypes of glutamate receptors (e.g., NMDA) -Increases intracellular Ca2+; binds to calmodulin; leads to activation of Ca2+/calmodulin-dependent protein kinases and other proteins (see image) -This leads to the destabilization of cell membranes (lipid peroxidation products) and ROS synthesis → cell death 2. *Mitochondrial Dysfunction* -Release of free radicals (superoxide and hydrogen peroxide) -Reduced supply of ATP (impaired energy production)

GABA (γ-aminobutyric acid)

*Inhibitory in CNS* (decarboxylated glutamate)

Glycine (AA)

*Inhibitory in brainstem and spinal cord* Reminder: AA can only be used as neurotransmitters (and not hormones) because they are obtained through food and must be isolated

Cerebellar Lesions -Disrupt fine coordinated movements, equilibrium, posture, and motor learning (ipsilateral) -Induce ataxia (lack of order): irregular, uncoordinated movements (trunk or limbs)

*Lateral* Lesions: -Affect voluntary movement of extremities (*limbs*) -When injured, propensity to fall toward injured (*ipsilateral*) side. *Medial* Lesions: -Affects *midline* structures (vermal cortex, fastigial nuclei) and/or flocculonodular lobe *truncal ataxia* (wide-based cerebellar gait), nystagmus, head tilting. -Generally result in bilateral motor deficits affecting axial and proximal limb musculature.

Fiber-Rich Region Terms

*Lemniscus: ascending sensory channel* *Funiculus: white "column" of spinal cord* Fasciculus: slender bundle of axons Commissure: white matter nerve tract that bridges the two hemispheres Decussation: site where tract crosses the midline

Local Anesthetics BLOCK Na+ channels

*Lidocaine:* 1. Crosses lipid membrane 2. Enters Na+ channel from inside the cell, where it can bind to binding sites on the S6 alpha helix of the voltage-gated Na+ channel 3. Extracellular Na+ blocked from entering

CNS Demyelination

*Multiple Sclerosis* -Plaques of demyelinated axons are visible on staining of brainstem -The central portion of the brainstem (anterior to 4th ventricle and posterolateral to the inferior olivary nuclei) is no longer myelinated (white on myelin stain)

Action Potential Requirements and Channel States

*Na+ and K+ channels are essential for APs. Gating of channels is regulated by voltage and time.* *Na+ Channel States (faster):* -Open -Closed -Inactivated (must be reset by hyperpolarization/reducing Vm/K+ coming into the cell) *K+ Channel States (slower):* -Open -Closed At rest, cells have a high permeability to K+ (leaky). Thus Vm → E(K+) = -90mV ≈ -65 mV (due to open Cl- channels etc.; GHK). Threshold is ≈ -50 to -55mV.

Cerebellar Blood Supply

*PICA*: branch off of vertebral a. (which travels in front of the midbrain): perfuses inferior cerebellum *AICA*: branch off of (low) basilar a.: perfuses anterior inferior cerebellum *Superior cerebellar a.*: branch off of basilar a. that supplies most of cerebellum (from posterior) The "watershed" is the vascular territory of the posterior cerebellum that may be perfused by more than one major artery.

*Sensory Processing Pathway* (parietal lobe) 1. First order neurons in PNS to dorsal horn 2. Second order neurons up spinal cord to thalamus 3. Third order neurons from thalamus to primary somatosensory cortex 4. Primary somatosensory cortex (type? from where?) to somatosensory association area (what is it?)

*Pathway:* 1. Receptors sense stimuli and produce APs that move along axons of somatic sensory *first order neurons of the PNS*. 2. Axons of these first order neurons travel through a spinal nerve (into a dorsal root) and synapse in the dorsal horn of the grey matter of the spinal cord. 3. *Second order neurons* relay the somatosensory APs up through the *spinal cord* via a nerve tract to the thalamus. 4. From the *thalamus*, a *third order sensory neuron* relays the AP to the post-central gyrus (primary somatosensory cortex) 5. Neurons in the *post-central gyrus* determine what part of the body the sensation is coming from (location) and what type of sensation it is. 6. Sensation then moves to the *somatosensory association area*, where information is further processed, and, based on prior experience and other incoming sensory information, a determination is made of how that sensory information should be interpreted. Somatic sensation comes to the brain mainly through the skin: -Heat/cold -Pain -Light touch/pressure -Limb position/movement

Strokes in the cerebellum most likely result from which artery?

*Posterior-inferior cerebellar a. (PICA)*

Mature Spinal Cord Organization

*Somatic Sensory:* -General: touch, pain, pressure, vibration, temperature, and proprioception in the skin, body wall, and limbs -Special: hearing (VIII), equilibrium (VIII), vision (II) *Visceral Sensory:* -General: stretch, pain, temperature, chemical changes, and irritation in the viscera -Special: taste (VII, IX), smell (I) *Visceral Motor:* -Motor innervation of smooth muscle, cardiac muscle, and glands (autonomic nervous system: sympathetic and parasympathetic) *Somatic Motor:* -Motor innervation of all skeletal muscles

Inhibitory Synaptic Function: from presynaptic spike to IPSP

*Stops APs and Signal Propagation:* 1. Local anesthetic (prevents Na+ channels from depolarizing cell) 2. Demyelination (reduced saltatory conduction) 3. Ca2+ entry into presynaptic terminal (activates SNARES of inhibitory NT vesicles as secondary messenger → vesicles fuse with the membrane of the presynaptic cell → NT dumped onto postsynaptic dendrite → NT binds to Cl- channels and opens them, allowing Cl- ions to enter the cell) ∴Vm → E(Cl-) = -65mV (anchors Vm below threshold) → prevents depolarization → *IPSP* Note: GABA and glycine are examples of NTs that increase Cl- conductance (opened Cl- channels on post-synaptic dendrite), leading to inhibitory post-synaptic potentials.

Lobes of Cerebrum

*Superficial Lobes* 1. Frontal (somatic motor): cognition, planning, decision making 2. Parietal (somatic sensory): integrating sensory modalities 3. Temporal (audition): houses Wernicke's area (39) 4. Occipital (vision): processing and integration of visual information *Interior Lobes:* 1. Limbic (cingulate gyrus): emotion formation and processing, emotional perception of one's own suffering, learning, and memory 2. Insular: gustation (taste), visceral sensation, consciousness, emotion, homeostasis (wraps above corpus callosum)

Telencephalon Components 1. Cerebral cortex 2. Cerebral lobes 3. Commissures 4. Specialized cortical centers (Brodmann) 5. Limbic system 6. Basal ganglia

1. *Cerebral cortex* -Gray (neuron cell body) and white (myelinated axons) matter -Central (Rolandic: frontal/parietal) and lateral (Sylvian: frontal/temporal) fissures -Precentral (motor) and postcentral (somatosensory) gyri 2. *Lobes of the Cerebrum* -Outer: frontal (motor), temporal (audition), parietal (sensory), and occipital (vision) -Inner: insula (beneath lateral sulcus: taste, visceral sensation, social and emotional functions) and limbic (cingulate gyrus above corpus callosum: attention, drive, emotional perception of one's own pain = "suffering") 3. *Commissures*: white matter tracts that connect the hemispheres. 4. *Specialized Cortical Centers* -Primary Cortex: auditory (41/42), visual (17), motor (4), and somatosensory (1/2/3) -Language Centers: Broca's area (45; left temporal lobe; production of speech; expressive aphasia: can't articulate what they want, but know what they want to say) and Wernicke's area (39; left temporal lobe; comprehension of speech; fluent aphasia: speaks non-sensically, but fluently) 5. *Limbic System*: hippocampus, amygdala, limbic cortex, fornix, mammillary body (5 Fs: feeding, feeling, fighting, fleeing, and fornication) 6. *Basal ganglia*: modulates voluntary motor control, procedural learning, eye movement, and cognition

Regions of Cerebellum and Roles

1. *Cerebrocerebellum (Lateral):* -Regulates highly-skilled *voluntary movements* with the cerebral cortex (especially those involving complex spatial/temporal sequences and the *distal extremities*) -Dentate nucleus (*motor planning* to pre-frontal cortex) 2. *Spinocerebellum (Medial/Intermediate):* includes vermis -Uses proprioceptive information (i.e., where the body is in space) from the spinal cord to coordinate the *trunk and limbs* (e.g., *posture, gait, balance*) -Interposed nuclei: emboliform and globose (*motor execution* to lateral descending systems) -Fastigial nucleus: (in vermis) and *motor execution* to medial descending systems 3. *Vestibulocerebellum:* nodulus and flocculus -Interacts with the vestibular system to regulate *balance (axial muscles) and eye movement (extra-ocular muscles)*

Local Anesthetics Preferential Action (on small axons)

1. *Local anesthetics block small axons better than large axons* (differential nerve block due to the number of nodes affected by the drug). -Pain and temperature sensation (C fibers) is blocked more easily than fine touch discrimination and motor axons (Aβ, Aα fibers) -*Local anesthetics only spread a given distance.* Since smaller axons have more nodes per given distance, APs can be blocked more easily. In larger axons, there are fewer nodes in a given distance, and if 3 or more are not "blocked", signal propagation can continue and the AP is only slowed down in the region of anesthetic, but not stopped. -Hypoxia works in the opposite direction (large axons have greater requirements for diffusion of oxygen) 2. *Local anesthetics more effectively block rapidly firing axons* (e.g., pain-carrying) than slowly firing or resting axons (e.g., autonomic). -In the presence of local anesthetic, *Na+ channels cannot open as frequently* (blocked from inside the cell); spikes cannot fire as often (fewer APs); painful signals are reduced and less pain is perceived.

3 Planes of Section

1. Coronal: vertical plane perpendicular to midline 2. Sagittal: vertical plane parallel to the midline of the body. 3. Horizontal (axial): a plane perpendicular to the coronal and sagittal planes; parallel to the floor for a standing person

Roles of CSF

1. Cushions the CNS from contact with the skull 2. Lavages (rinses) the CNS, bringing waste material back out to the blood, which helps maintain homeostasis (glymphatic system) 3. Lends buoyancy to the brain (the brain's effective weight is only 2% of its actual weight), allowing it to maintain high density without weighing itself down (or cutting off it's blood supply from its weight in the skull)

Two ways to increase current velocity

1. Larger diameter axons (decrease internal resistance) 2. Increase myelination (allows for spacing nodes of Ranvier further apart) Explained: -Inward Na+ current at nodes is relatively *slow* (ions diffusion facilitated by channels) -Conduction of current down an axon between nodes is relatively *fast* (ions bump into neighboring ions inside axon) -Fewer nodes of Ranvier between points A and B = faster conduction velocity because you have to "wait" at fewer nodes. -Larger diameter of axon and thicker myelin allow for greater spacing between nodes

The internal carotid a. branches into which three arteries to provide anterior circulation to the brain?

1. anterior cerebral a. (ACA): medial aspect of cerebral hemisphere; results in lower extremity and trunk neurologic deficits if occluded 2. middle cerebral a. (MCA): lateral aspect of the cerebral hemisphere; results in face and upper extremities deficits if occluded 3. posterior communicating a. (PCA): rise laterally to the mammillary bodies of the hypothalamus to meet the ICA of the anterior circulation. The left and right ACA are joined by the anterior communicating aa.

The vertebral aa. rise through the transverse processes of the cervical vertebrae to the skull where they give off which three aa.? Note: the vertebral arteries fuse into the basilar a. at the pons, and give off the AICA. The PICA is off of each vertebral a. inferior to that junction.

1. anterior inferior cerebellar aa. (AICA): just below pons, wraps around cerebellum 2. posterior inferior cerebellar aa. (PICA): wraps around and under cerebellum at medulla 3. superior cerebellar a. The 2 vertebral aa. fuse at the level of the brainstem to form a single, midline *basilar a.*.

Neural Tube Differentiation

A single layer of cells post-neurulation derived from ectoderm collectively referred to as the neuroepithelium (ventricular layer/germ cells for the entire CNS). Eventually, the outer neuroepithelial cells will differentiate into *neuroblasts*, which mature into neurons. *Neuroblasts organize into "plates" that become horns*, setting up the basic organization of the spinal cord. 3 Zones/Layers of the Developing CNS: 1. *Ventricular layer* (ependymal zone): lines the central canal (deepest layer); eventually ependymal cells produce CSF 2. *Mantle Zone:* gray matter, neuron cell bodies -*Alar plate: dorsal horn*; cell bodies of interneurons receive input from sensory neurons -*Basal plate: ventral horn*; cell bodies of somatic motor neurons. At T1-L2, pre-ganglionic sympathetic neurons will also form (lateral horn). 3. *Marginal Zone:* white matter, axons (outer-most layer)

Cerebellar Histology

3 Layers of Cerebellar Cortex (gray matter): 1.* Molecular:* cell poor; mostly axons and dendrites 2. *Purkinje:* monolayer of pyramidal efferent neurons 3. *Granular:* densely packed granule neurons with synaptic globules Folia = ridges of cerebellar cortex matter (similar to gyri of the cerebral cortex)

Medications to Control Seizures

Actions: 1. Enhance GABA (increase IPSPs / inhibition) 2. Block Na+ channels (only when AP frequency is high; localized anesthetic blocks rapidly firing axons (e.g., pain-carrying) more so than slowly firing axons (e.g., autonomic); spikes cannot fire as often (fewer APs); painful signals are reduced and less pain is perceived.) 3. Block Ca2+ channels (t-type); less cellular depolarization 4. Block glutamate receptors (stop excitation)

Draw and Label Circle of Willis

An anastomosis that joins the anterior and posterior circulations in the brain. Depending on the pressure within arterial circulation, blood flow can change direction and somewhat compensate for insufficient perfusion of a region of brain tissue.

Blood Circulation in the Brain

Anterior circulation comes from the *internal carotid a. (ICA)*, a branch of the carotid a. (bifurcates at C3). Left CCA from aorta; Right CCA from brachiocephalic trunk. Posterior circulation comes from the *vertebral a.*, a branch of the subclavian artery that travels through the transverse foramina of the cervical vertebrae (C2-C6) and then the foramen magnum.

Action Potentials

Approximately 100mV, 1 mS "spikes" of membrane potential change that occur at the *initial segment* (axon hillock: high density of Na+ channels) when synaptic potentials (EPSPs) are summed up. Membrane depolarization causes Na+ channels to open up and carry inward current that further depolarizes the membrane. Na+ channels are present at the initial segment and nodes of Ranvier. After a spike starts at the initial segment, it triggers Na+ channels to open up at the next segment of axon not covered in myelin (*regeneration* of AP at node of Ranvier), and so on...

Venous Drainage of the Brain

Arterial circulation drains into capillaries and then into the venous circulation. The dural venous sinuses form within the dura (thick, fibrous covering of the brain; pachymeninges)

Other *Sensory* Lobes (not parietal) 1. Temporal lobe (auditory) 2. Occipital lobe (visual)

Audition: 1. Stimulation of cochlear receptors produce APs in the first order sensory neurons that are relayed to second and third order sensory neurons before reaching the primary auditory cortex of the *temporal* lobe. 2. Integration of AP inputs begins in the primary auditory cortex (below Sylvian fissure), where the fundamental nature of sounds is interpreted. 3. Signals are then sent to the *auditory association area* (inferior), where prior experience and other current sensory information plays into your interpretation of what the sound is. Vision: 1. Stimulation of rods and cones of the retina produce APs that enter the primary visual cortex of the *occipital lobe*, where initial integration begins (colors/shapes). 2. Impulses then travel to the *visual association areas*, where further integration occurs and specific objects are recognized (e.g., faces of people you know)

*Alterations in GABA Receptor Function*

Blocking GABAaR can cause seizures by preventing IPSPs from depressing the nervous system (large amplitude; uncontrolled EEG waves; neural excitability not repressed). *Anti-convulsant drugs act by enhancing GABA function (benzodiazapines (higher GABAaR open frequency) and barbituates (GABAaR open longer)) or by blocking GABA breakdown (vigabatrin).* Epilepsy can be caused in various ways by affecting GABA function (reducing its ultimate action on GABAaR): 1. Altered GABA synthesis, reuptake, degradation, and storage 2. Reduced GABA release from synaptic terminals (changes in presynaptic proteins or K+ channel genes) 3. Reduced GABA effects (changes in GABA receptor genes)

CNS vs. PNS

CNS: 1. Brain 2. Brainstem 3. Spinal Cord PNS: 1. Cranial nerves (nerves that exit through the skull) 2. Spinal nerves (nerves that exit through the spine)

Somatotopic Maps (in pre- and post-central gyri)

Certain regions of the pre- and post-central gyri contain upper motor and sensory neurons, respectively, for different parts of the body. Notice that *legs are more medial, and the hands and face are more lateral*. Each hemisphere represents the half of the body on the opposite side. The amount of cortex devoted to a certain region of the obeyed corresponds to how fine the motor control to, and sensation from, that part of the body is.

Transverse Foramina typify what type of vertebrae?

Cervical (C2-C6). This hole allows the vertebral a. (off of subclavian a.) and v. to travel up to and down from the brain.

Funiculi

Columns of spinal white matter (a bundle of nerve fascicles, myelinated axons) that carry motor and sensory information up and down the spinal cord. *Dorsal funiculus/column:* carries ascending sensory information from somatic mechanoreceptors. *Lateral funiculus (lateral corticospinal tract):* descending motor signals from the brain down the spinal cord and to the target muscle or organ *Ventral funiculus:* ascending (pain and temp); descending (posture modulation)

Brainstem

Components: 1. Mesencephalon → midbrain 2. Metencephalon → pons and cerebellum 3. Myelencephalon → medulla

Pons (bridge) Origin: Metencephalon -Repiration

Contains a respiratory nucleus that works with the respiratory nuclei of the medulla. Mainly composed of nerve tracts (peduncles) that connect the cerebrum to the cerebellum (comparator function of the cerebellum, fine motor control, and motor learning).

Midbrain Origin: Mesencephalon -Subconscious control of voluntary motor functions

Contains nuclei that function in *subconscious control of voluntary motor functions*. -Colliculi: auditory and visual reflexes -Red nucleus -Substantia Nigra: produces dopamine that inhibits postural muscles (not functional in Parkinson's)

Mechanism: Glutamate → GABA

Decarboxylation of glutamic acid by glutamic acid decarboxylase (GAD). Glutamate: *excitatory* neurotransmitter in the brain GABA: *inhibitory* neurotransmitter in the brain

Dendrite Purpose and Characteristics

Dendrite Roles: 1. Act as the site of neuronal inputs (synapses) that occur on dendrite spines. 2. Generate excitatory and inhibitory post-synaptic potentials (EPSPs and IPSPs). 3. Conduct synaptic events (PSPs) to the soma (cell body) and axon (for summation). Dendrite Characteristics: 1. Lengths of dendrites vary 2. Some dendrites span multiple layers of cortex to collect various synaptic inputs 3. Some dendrites are short to limit synaptic input 4. *In the cerebral cortex, dendrites come off of pyramidal cells (the principal neurons that run through the cerebral cortex)*. Reminders: 1. Synapses closer to the soma have a greater effect than do those farther away (due to leakage of current down the dendrite). 2. Nissl staining is useful to localize the cell body, and it can be seen in the soma and dendrites of neurons, though not in the axon or axon hillock 3. *Dendritic spines* (microfilaments protruding from dendrites that provide shape and a post-synaptic density) are the *input sites for synapses*, compartmentalizing synaptic molecular machinery to keep it separate from that of adjacent synapses.

Aβ axon fibers (Group II)

Diameter (um): 2nd largest (6-12) Speed (m/s): 2nd fastest (25-75) Sensory Receptors: *Mechanoreceptors of skin (touch and pressure)*

Aδ axon fibers (Group III)

Diameter (um): 3rd largest (1-5) Speed (m/s): 3rd fastest (5-30) Sensory Receptors: *Fast Pain, Cold Temperature*

Aα axon fibers (Group I) -*Most myelin* -Most responsive to anoxia (low O2); least responsive to local anesthetic

Diameter (um): Largest (13-20) Speed (m/s): Fastest (80-120) Sensory Receptors: *Proprioception of skeletal muscle* Ia: Muscle Spindle (stretch) Ib: Golgi Tendon (force)

C axon fibers (Group IV) -*No myelin* -Least responsive to anoxia (low O2); most responsive to local anesthetic

Diameter (um): Smallest (0.2-1.5) Speed (m/s): Slowest (0.5-2) Sensory Receptors: *Slow Pain, Warm Temperature, Itch*

How do we measure gross cortical activity non-invasively?

EEGs (electroencephalogram) measure voltage fluctuations resulting from ionic current within the neurons of the brain.

Dendritic structure is affected by:

Environment. *Chronic Placental Insufficiency* (decreased uterine blood supply) causes intrauterine growth restriction (IUGR), and stunted hippocampal neurons, which are smaller than normal.

Deep Cerebellar Nuclei (DCN) Mnemonic: *lateral to medial* Don't: dentate (in cerebrocerebellum; lateral) Eat: emboliform (interposed) (in spinocerebellum) Greasy: globose (interposed) (in spinocerebellum) Food: fastigial (in vermis; medial)

Found in the white matter of the cerebellum, which lies beneath the cerebellar cortex. These nuclei receive massive input from the Purkinje cells of the cortex and blend this with signals from other brain areas to coordinate accurate and well-timed movements. DCN are the source of virtually all cerebellar output to other brain areas (brainstem and thalamus). Dentate: (motor planning) to motor and premotor cortices Interposed: (motor execution) to lateral descending systems Fastigial: (motor execution) to medial descending systems

Corticospinal axon trajectory

From primary motor cortex through the internal capsule (white matter of cerebrum) to the spinal cord (where axons meet up with lower motor neurons at ventral horn of gray matter). Decussation occurs at the spino-medullary junction (pyramids).

Glutamate Receptors

Glutamate receptors can be *ionotropic (ion channels)*: 1. NMDA: Na+ and Ca2+ permeable (*fast* excitatory) 2. Non-NMDA: Only Na+ permeable (*fast* excitatory) Glutamate receptors can be *metabotropic (GPCRs)*: -e.g., mGluR1 to mGluR8 -*Slower* excitatory and inhibitory (variety of responses)

Choroid Plexus

Highly vasucular tissue inside the lateral, 3rd, and 4th ventricles that produce 500cc CSF per day. The total volume of CSF in the ventricular system is 150cc, and water and solutes (ions and proteins) from the blood enter the choroid plexus via *fenestrated capillaries*. Blood-CSF barrier is between choroid capillary endothelium and choroid epithelium. O2 and CO2 can diffuse across epithelium, but most substances must be actively transported across the choroid epithelium to enter ventricular CSF.

Ventricular System 1. *Lateral:* C-shaped spaces within cerebral hemispheres 2. *Foramen of Monro:* paired narrow channels connecting each lateral ventricle to the third ventricle 3. *Third Ventricle:* single midline chamber separating the diencephalon on the left from that on the right 4. *Cerebral aqueduct:" single midline narrow tube at the level of the midbrain that connects 3rd and 4th ventricle 5. *Fourth Ventricle:* midline, has choroid plexus (also found in 3rd ventricle and lateral ventricles)

In the brain, the central canal (hollow portion of nerve tube) grows and changes shape to become the ventricular system, which produces and contains CSF. In particular, ependymal cells form gland-like structures (choroid plexuses) in the lining of the ventricles that produce CSF. CSF flows through the ventricles via cilia moving it along. Organization: 1. Lateral ventricles (I and II) form deep to the cerebrum (telencephalon). 2. Interventricular foraminae (Foraminae of Monro) connect the 1st and 2nd ventricles to the 3rd ventricle. 3. The 3rd ventricle forms between the thalamic lobes / hypothalamus (diencephalon) 4. The cerebral aqueduct (Aqueduct of Sylvius) connects the 3rd and 4th ventricles, passing through the midbrain (mesencephalon). 5. The 4th ventricle forms between the pons and the cerebellum (metencephalon) 6. Central canal of the spinal cord CSF exits the 4th ventricle into the subarachnoid space in 3 places: 1. Median Aperature (Magendie) (single) 2. Lateral Aperatures (Luschka) (paired) -This CSF eventually drains into the venous system (through arachnoid granulations into the superior sagittal sinus) and is returned to the blood. At arachnoid granulations, arachnoid villous cells transport CSF through giant vacuoles into the venous sinus. -Since there is *no monitoring of total CSF pressure or volume*, if more CSF is produced than is drained back into the venous system, pressure will build up in the ventricles → *hydrocephalus*

Brain Development

In the cerebrum and cerebellum, neuroepithelial cells produce an additional population of daughter cells that migrate out through the white matter and form a second, outer layer of grey matter, the cerebral and cerebellar cortex. In addition to the neurons of the CNS, the *neuroepithelial cells also give rise to the neuroglia (support)* cells of the CNS, with the exception of the microglial cells (macrophages), which develop in the bone marrow.

(Downward) Cerebellar Tonsillar Herniation

Increased pressure in the posterior cranial fossa (where the cerebellum sits with the brainstem) can lead to herniation of the tonsil through the foramen magnum. The cerebellar tonsils can compress the brainstem and cause the medullary respiratory centers to cease to function, leading to apnea or abnormal breathing (respiratory arrest).

Ventricular System (image)

Individual horns and atria of the ventricular system are outlined in the image.

Ventricular System Blockages

Internal (*non-communicating/obstructive*) hydrocephalus: -*CSF outflow obstruction* -Cerebral/Sylvian aqueduct External (*communicating/non-obstructive*) hydrocephalus: -*Impaired CSF resorption by arachnoid granulations* due to damage following infection (e.g., meningitis), inflammation, or hemorrhagic events (e.g., rupture of cerebral aneurysm causing subarachnoid hemorrhage)

Cerebellar hemispheres control _________ side of the body

Ipsilateral. Therefore, lesions affect the ipsilateral side of the body.

Where does the spinal cord end (at which vertebral segment)?

L2 (called the conus medullaris). Caudal to this, the hollow of the vertebral column contains only spinal *roots* coursing to lower vertebral levels. These roots comprise the *cauda equina* (horses tail) and are bathed in CSF of the lumbar cistern.

Language Areas

Language is localized to one "dominant" hemisphere (usually left). Perfused by the MCA (lateral). *Left hemisphere lesion:* aphasia *Right hemisphere lesion:* neglect (can't see left side, ignore it) *Language Centers:* 1. *Broca's area* (45): frontal lobe (production of speech) -Expressive aphasia: can't articulate what they want, but know what they want to say) 2. *Wernicke's area* (39): posterior, superior temporal lobe (comprehension of speech) -Fluent aphasia: speaks non-sensically, but fluently)

CSF Cisterns

Larger, focal spaces within the CSF circulation pathway. 1. Perimesencephalic Cisterns -Interpenduncular: anterior to midbrain, above pons -Ambient: around midbrain -Quadrigeminal Plate : superior to cerebellum, posterior to midbrain (after cisterna magnum CSF makes it around cerebellum) 2. Prepontine: in front of pons 3. Cisterna Magna: at the junction of the medulla and inferior cerebellum (median aperture empties here) 4. Lumbar: space around cauda equina where CSF is obtained during a lumbar puncture (spinal tap at L3/L4)

How to differentiate the 4 spinal cord levels

Lumbar and lower cervical spine cross sections have lateral enlargements of the ventral horn (due to the need for more processing for the upper and lower limbs as compared to the neck or torso). Thoracic levels don't have lateral enlargements of the ventral horn (gray matter is "skinny" and looks like an H), but they do have an *intermediolateral cell column (levels T1-L2) that look like little spikes on the lateral sides of gray matter (comprised of sympathetic neurons). Cervical: big ventral horn, lots of white matter Thoracic: small ventral horn, plenty of white matter Lumbar: big ventral horn, less white matter Sacral: gray matter > white matter

Where do lumbar punctures take place?

Lumbar puncture needles are inserted at the level of vertebrae L3/L4 (around iliac crest level) into the lumbar cistern to avoid damaging the spinal cord. The roots will move around the needle as they are suspended in CSF.

Which artery? Stroke affecting face and hands (think about homunculus on cerebral hemisphere)

MCA Stroke. Lateral portion of brain. Weakness and sensory problems: affects the pre-central gyrus (primary motor cortex) and the post-central gyrus (primary somatosensory cortex).

Cephalic Flexure

Midbrain-diencephalon junction (~80° bend between brainstem-forebrain axes)

Brainstem 1. Midbrain 2. Pons 3. Medulla oblongata

Most of the brainstem is composed of ascending and descending nerve tracts that are either *bringing sensory information to the brain* for processing (ascending) or *transmitting action potentials from the brain* that will cause muscles to contract (descending).

White Matter Commissures

Nerve tracts that connect the left and right sides of the brain. a. *Anterior:* connects the two *temporal lobes* of the cerebral hemispheres across the midline b. *Posterior:* interconnects the *pretectal nuclei*, mediating the consensual pupillary light reflex c. Corpus callosum: connects cerebral hemispheres

Nuclei

Neuronal cell bodies located in grey matter regions deep in the brain

Receptor Divergence -Conductance = # of ion channels open -GABA and glycine are both *inhibitory*

One NT can activate multiple receptors and effectors. Examples of IPSP generation: 1. *GABA* binds GABAaR, GABAbR, and GABAcR: a. *(aR) ligand-gated Cl- channel*: increases Cl- conductance (opens Cl- channels) b. *(bR) GPCR:* increases K+ conductance (opens K+ channels); decreases Ca2+ conductance (closes Ca2+ channels) c. *(cR) ligand-gated Cl- channel:* increases Cl- conductance (opens Cl- channels) 2. *Glycine* binds Gly-R → increases Cl- conductance (opens Cl- channels) Note: GABAaR/GABAcR are *ionotropic*; GABAbR is *metabotropic*

Strokes in the pons most likely result from which artery?

Perforating branches of the *basilar a.*

Brain Vesicles Mneumonic: *Tell Di, Mes Met Myel* Divisions of the CNS: 1. Telencephalon: cerebral cortex and basal ganglia 2. Diencephalon: thalamus and hypothalamus 3. Brainstem -Mesencephalon: midbrain -Metencephalon: pons -Myencephalon: medulla 4. Cerebellum (metencephalon) 5. Spinal Cord (neural tube/neuroepithelium)

Primary and Secondary (lettered) Vesicles: 1. *Prosencephalon (forebrain)* 1a. Telencephalon → cerebral hemispheres (cerebral cortex, subcortical white matter, basal ganglia, basal forebrain nuclei) 1b. Diencephalon → thalamic nuclei (thalamus, hypothalamus, epithalamus) 2. *Mesencephalon (midbrain)* → midbrain 3. *Rhombencephalon (hindbrain)* 3a. Metencephalon → pons and cerebellum 3b. Myelencephalon → medulla

Cerebellum -Acts indirectly on the spinal cord by modulating cortex and long descending motor tracts -Coordinates and regulates somatic motor activity

Roles: 1. Coordinates and regulates somatic motor activity initiated in the frontal lobe. -*Frontal lobe:* thought, planning, and execution of somatic motor activity -*Cerebellum:* monitors motor activity and modulates it so that movements are as close to possible as the movements we intend to make (e.g., learning to shoot a basketball) 2. Receives information from: a. Motor: upper motor neurons (pre-central gyrus) (what you want to do) b. Sensory: from the body and sensory organs (what you're actually doing) 3. Fine-tunes movement (precision, coordination, and timing of voluntary movements) -*The cerebellum compares what you want to do with what you're actually doing (comparator function)*, and sends information to the frontal lobe to adjust motor output so that what you're actually doing more closely matches what you're trying to do (e.g., makes your basketball shot closer).

Brain Directionality

Rostral: anterior (nose) Caudal: posterior (tail) Dorsal: superior Ventral: inferior Contralateral: opposite side of body Ipsilateral: same side of body

Medulla Oblongata Origin: Myelencephalon -Survival functions!

The medulla contains nuclei that control *cardiac, respiratory, and vasomotor function, and reflex centers* that control coughing, sneezing, swallowing, gagging, and vomiting. Within the medulla the baroreceptor reflex is integrated, keeping our blood pressure relatively constant. *Injury of the medulla is typically fatal, because of the important survival functions it performs.*

Central fissure

Separates the frontal lobe (somatic motor) from the parietal lobe (somatic sensory). Other names: -Central sulcus -Rolandic fissure

Lateral fissure

Separates the temporal lobe (audition) from the frontal (somatic motor) and parietal (somatic sensory) lobes. Other names: -Lateral sulcus -Sylvian fissure

Demyelination (Axonal Pathology)

Slows and then blocks conduction (if more than 3 nodes lack myelin sheaths between them). In axons lacking myelin, there can be failure of an AP to reach the synaptic terminal as the signal is diminished in time and space. Demyelination also causes cross-talk between demyelinated axons (as they are no longer isolated); this can cause ectopic APs. Adjacent axons can also conduct APs in both directions from the demyelination site.

GABAaR function can be reduced by...

Small AA changes (even just 1) can leave a GABA-gated Cl- channel insensitive to particular drugs, preventing IPSPs. This shows great specificity in GABAaR binding of drugs and GABA itself (with mutations in GABAaR eliminating dose-dependent drug responses). Mutant receptors can be drug-insensitive.

Basal Ganglia -A complex circuit that aids in communication between the cortex, thalamus, and basal ganglia

Subcortical nuclei centers that play a role in *movement and coordination* (modulate voluntary motor control). Also involved in learning, eye movement, and cognition. Telencephalic Components: 1. Caudate: cognition 2. Putamen: motor control 3. Globus pallidus Di/Mes-encephalic Components: 1. Subthalamus (di) 2. Substantia nigra (mes)

*Motor Processing Pathway:* (frontal lobe) 1. Pre-frontal cortex 2. Frontal association area (motor programming) 3. Pre-central gyrus (upper motor neurons) 4. Descending motor control

The most anterior region of the frontal lobe (pre-frontal cortex) is involved in: -Personality -Motivation -Forethought -Judgment After decisions are made there, that information is sent to the *frontal association area*, where movements are *planned and refined* (motor programming). Information from the frontal association area then passes to the most posterior region of the frontal lobe, the primary motor cortex (*pre-central gyrus*). Upper motor neurons form descending nerve tracts that travel down the spinal cord and synapse with lower motor neurons in the *ventral horn of the grey matter* of the spinal cord (motor). The axons of these lower motor neurons travel out of the spinal cord (through the ventral root), and join with sensory neurons of the dorsal root to form spinal nerves.

Limbic System

The "old brain" network crucial for emotion, motivation, and memory. Telencephalic Components: 1. Amygdala (walnut): emotions (fear/anxiety) 2. Hippocampus (seahorse): memory 3. Fornix (arch) 4. Hypothalamus: HAM BEETSS 5. Thalamus (posterior parts) 6. Cingulate gyrus

Diencephalon (thalamic nuclei)

The "tween" brain that bridges the brainstem and cerebrum. Components: 1. *Thalamus:* gateway to cortex -Filters and relays sensory input (*except olfaction*) moving toward the cerebrum -Modulates consciousness and awareness -Lateral geniculate nucleus (LGN): vision (input from the retina to the optic cortex; L=Looking) -Medial geniculate nucleus (MGN): audition (sends input from inferior colliculus to primary auditory cortex; M=Music) -Ventral posterior (VP) nucleus: somatic sensation (can be medial or lateral) 2. *Hypothalamus:* neuroendocrine and autonomic control -Mnemonic: *HAM BEETSS*: Hunger, ANS, Memory, Behavior, Endocrine, Emotion, Temperature, Sleep-Wake Cycle, Sexual Urges 3. *Posterior pituitary:* derived from neuroectoderm, extensions from the hypothalamus -Secretes ADH (water retention) and oxytocin (lactation and uterine contraction) formed in hypothalamus -Can be reached via a *transphenoidal* approach through the nasal cavity and sphenoid sinus to *remove a pituitary tumor* 4. *Epithalamus:* dorsal diencephalon -Pineal gland (secretes melatonin at night to regulate circadian rhythms) -Habenular nucleus (modulates visceral/emotional responses to odors; involved in sleep and reward processing) 5. *Subthalamus* (subthalmic nuclei of basal ganglia)

Cerebellar Sectors

The 2 cerebellar hemispheres are joined at the *vermis* (midline ridge). 3 Cerebellar Lobes: 1. Anterior Lobe (superior) 2. Posterior Lobe (inferior) 3. Flocculo-Nodular Lobe (under vermis, adjacent to the 4th ventricle and brainstem): responsible for balance and eye movement

Stroke

The sudden onset of local neurologic deficit (e.g., weakness, inability to speak or to understand language) from a vascular cause such as a vessel occlusion (80%) or hemorrhage (20%). Stroke is the 3rd leading caused of death in the US.

Corticocortical axon trajectories

Through the corpus callosum and subcortical white matter (to the same or opposite hemisphere of the cerebral cortex)

Myelin Advantages: 1. *Speed*: conduction velocity of a 10um diameter axon with myelin ≈ 500um axon without myelin) 2. *Space*: the space occupied by one 500um axon is about equal to that of 2500 axons of 10um diameter 3. *Economy*: metabolic cost of axons is greatly reduced

Tightly wrapped spirals of *glial membrane* around the axon that ensure current travels down an axon by increasing distance between intra- and extra-cellular fluid, speeding up conduction velocity. CNS: produced by oligodendrycytes (which myelinate multiple axons) PNS: produced by Schwann cells (which myelinate a single axon) In unmyelinated axons, APs are continuous. In myelinated axons, APs are saltatory.

Cerebellar Peduncles

Trio of white matter tracts that allows the *cerebellum to communicate with other parts of the brain (brainstem)*. 1. *Superior:* outputs signals *from* the cerebellum to the midbrain and thalamus 2. *Middle:* inputs signals *to* the cerebellum from the pons 3. *Inferior:* inputs signals *to* cerebellum from medulla and spinal cord

GABAaR -Structurally similar to nicotinic ACh receptor -5 subunits to form a channel (2α, 2β, 1γ)

When GABA binds to GABAaR, it changes the conformation of the GABA-gated Cl- channel (allowing Cl- influx). Cl- ions think they they are hydrated and are transported across the membrane through an aqueous pore. This Cl- influx maintains a negative polarization (inhibitory) of the post-synaptic neuron (IPSP).

Nernst Potential E(Na+) = +61 mV Meaning: 1. Restates the equilibrium potential in electrical terms 2. Concentration at which there is no net movement of Na+ (equilibrium) 3. Where Vm is drawn toward when Na+ ions are open

When the membrane is in thermodynamic equilibrium (i.e., no net flux of ions), the membrane potential (Vm) must be equal to the Nernst potential. However, in physiology, due to active ion pumps, the inside and outside of a cell are not in equilibrium. In this case, the resting potential can be determined from the GHK equation (which takes into account more than one ion). *The potential across the cell membrane that exactly opposes net diffusion of a particular ion through the membrane is called the Nernst potential for that ion.* The magnitude of the Nernst potential is determined by the ratio of the concentrations of that specific ion on the two sides of the membrane. The greater this ratio, the greater the tendency for the ion to diffuse in one direction, and therefore the greater the Nernst potential required to prevent the diffusion.