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2. Cerebral Cortex MHD – Neuroanatomy Module February 8, 2016
Gregory Gruener, MD, MBA
Senior associate dean, SSOM
Department of Neurology
LUHS/Trinity Health and Catholic Health East

3. Objectives (a lot of them)
Describe general details and functions of the cerebral cortex
Identify the major cerebral gyri
Define the neocortical layers, role of pyramidal and non-pyramidal cells, Brodmann areas
Define and name commissural and association bundles
Describe neocortical, primary, unimodal and multimodal association cortex functions
Describe language localization and predict clinical deficits based on site of injury
Describe the reticular formation and its roles
Describe the diffuse neuromodulatory system and its roles
Define consciousness, sleep, REM and non-REM sleep and their characteristics/functions
Describe sleep cycle regulation (roles of the suprachiasmatic nucleus, preoptic area and medullary reticular formation)

4. Cerebral cortex - Generalities
“Role” of cerebral cortex
Cerebral cortex – analyzes, plans, initiates response
sensory pathways – “brings” in information
Reticular Formation & Diffuse modulatory system – adjusts it’s level of responsiveness
Types of cortex
Neocortex – most of the cerebral cortex (6-layers)
Archicortex – hippocampus (3-layers)
Paleocortex – telencephalon base, olfactory (3-5 layers)
Neocortex “factoids”
Human brain ~ 86 billion nerve cells (19% in cerebral cortex)
Cerebral cortex (GM + WM) ~ 82% brain mass
80% are pyramidal cells, 20% non-pyramidal

5. Cerebral cortex - Neocortex
Pyramidal cells
Long apical dendrite and a basal dendrite
Axons leave cortex; excitatory (glutamate)
Dendritic spines - selectively modified by learning
Non-pyramidal cells
Various morphologies
Axons don’t leave the cortex; inhibitory (GABA)
“interneurons” of the cerebral cortex
Neocortex has six layers (histologic appearance)
“Agranular areas” – predominantly large pyramidal cells
“Granular areas” (or koniocortex) – predominantly small neurons

6. Neocortex Layers & Columnar Organization
Hustler J, Galuske RAW. Trends in Neuroscience 2003;26:

7. Cerebral Gyri & Brodmann Areas
“Granularity” =
Localization in Clinical Neurology. Brazis PW, Masdeau JC, Biller J; Lippincott, 2007

8. “Connections” Splenium Body Genu Rostrum Anterior Commissure
Corpus callosum - Projects from cortical area to mirror image (+ other areas)
Genu – frontal lobes
Anterior body – frontal lobe
Posterior body – parietal lobe
Splenium – occipital and temporal lobe
Anterior commissure - Interconnects temporal lobe & component's of olfactory system
Genu
Splenium
Body
Rostrum
Anterior Commissure

9. Association bundles or fasciculi
Cingulum
Corticocortical connections in the same hemisphere
None are discrete point-to-point
Fibers travel in both directions, leave and enter
Superior occipitofrontal
fasciculus
Inferior occipitofrontal
Uncinate fasciculus
Superior longitudinal
Fasciculus (Arcuate)
Guevara P, et al. Neuroimage 2012;61:
Nolte. Essentials of the human brain. Mosby, 2010

10. Neocortical areas Injuries in certain areas → “specific” deficits
Areas are “specialized” for different functions
Sensory, motor, association and limbic areas
“Relationship” between Brodmann’s number and function
Areas differ in neocortical structure/connections
Function may be localized there, participates in or it facilitates that function within other structures

11. Primary neocortical areas
“Direct link to the world” - Inputs from thalamic nuclei and outputs to brainstem and spinal cord. Contains precise, but distorted body map(s)
Primary motor: precentral gyrus (4)
Primary somatosensory: postcentral gyrus (3,1,2)
Primary visual: calcarine (17)
Primary auditory: transverse temporal gyrus (41)
Primary gustatory: anterior insula?
Primary vestibular: posterior insula?

12. Primary neocortical areas
Localization in Clinical Neurology. Brazis PW, Masdeau JC, Biller J; Lippincott, 2007
Nolte. Essentials of the human brain. Mosby, 2010

13. Unimodal association areas
“More complex response functions”: Adjacent to primary cortical areas, same “function, but less precise” body map(s). Injury can cause an agnosia
Premotor (6): involves larger groups of muscles in an activity
Supplementary motor (6): assumption of postures or using muscles on both sides of the body
Somatosensory (5, 7)
Visual (18, 19, + others?)

14. Unimodal association areas
Localization in Clinical Neurology. Brazis PW, Masdeau JC, Biller J; Lippincott, 2007
Nolte. Essentials of the human brain. Mosby, 2010

15. Multimodal association areas
“High level intellectual functions”: Association areas send converging inputs; may respond to multiple stimuli or under particular circumstances. Injury can cause an apraxia (motor) or neglect (sensory)
Parieto-occipital-temporal region
Surrounded by sensory areas and also receives input form the pulvinar
Injury to the right inferior parietal lobule can cause contralateral neglect
Injury to the left parietal area can cause an apraxia

16. Multimodal association areas (cont.)
Prefrontal area – working memory & decision making
Dorsolateral - more important for working memory, attention, and logical aspects of problem solving
Ventromedial – has extensive limbic connections and are more important for emotional aspects of planning and decisions
Executive functions of the brain – Planning, insight, foresight and basic aspects of personality
Limbic area – emotional and “drive” related behaviors

17. Multimodal association areas
Localization in Clinical Neurology. Brazis PW, Masdeau JC, Biller J; Lippincott, 2007
Nolte. Essentials of the human brain. Mosby, 2010

18. Multimodal association areas
Localization in Clinical Neurology. Brazis PW, Masdeau JC, Biller J; Lippincott, 2007
Nolte. Essentials of the human brain. Mosby, 2010

19. Classical language “localization”
Ross ED. Neuroscientist :222

20. Reticular Formation Roles
“Coordinates” motor and sensory brainstem nuclei:
Pattern generator
Eye movements; horizontal (PPRF) and vertical (riMLF)
Rhythmical chewing movements (pons)
Posture and locomotion (midbrain and pons)
Swallowing, vomiting, coughing and sneezing (medulla)
Micturition (pons)
Respiratory control (medulla)
Cardiovascular control (medulla)
Afferents from baroreceptors (carotid sinus and aortic arch), chemoreceptors (carotid sinus, lateral reticular formation chemosensitive area in the medulla) and stretch receptors (lung and respiratory muscles)
Efferents from neurons within the pons and medulla
Sensory modulation or “gate” control of pain (nucleus raphe magnus)
The term “gating” refers to modulation of synaptic transmission from one set of neurons to the next.

21. Reticular Formation - nuclei locations
Raphe nuclei (e.g. nucleus raphe magnus)
Raphe nuclei
“Medial tegmental field”
“Lateral tegmental field”
Central nucleus of the medulla oblongata (e.g. one of the reticular nuclei)
“Medial tegmental field”
Origin of the reticulospinal pathway; nuclei in this group predominantly have a role in coordinating posture, eye and head movements
“Lateral tegmental field”
Nuclei within this area predominantly coordinate autonomic or limbic functions (e.g. micturition, swallowing, mastication and vocalization)
********************************
Midline Zone → part of the diffuse neuromodulatory system
Raphe nuclei are aminergic neurons (not part of the reticular formation) – modulate neuronal signal transfer
Fitzgerald MJT, Gruener G, Mtui E. Clinical Neuroanatomy and related Neuroscience, 5th Ed., W. B. Saunders 2012

22. Reticular Formation afferents & efferents
Afferents (Primarily to neurons in the pons, “lateral tegmental field”)
Corticoreticular – Motor and premotor cortex origin
Tectoreticular – superior colliculi origin
Cranial nerves - V, VII, IX & X
Cerebelloreticular – primarily from the fastigial nucleus
Spinoreticular – receives collaterals from spinothalamic tract, widespread bilateral distribution, no somatotopy
Efferents (Primarily from neurons in the pons, “medial tegmental field”)
Spinal cord termination – Pontine and Medullary reticulospinal tracts
Descend bilaterally, terminate in intermediate gray of spinal cord
Effect on axial muscles of posture and locomotion
Brain stem termination – Reticulobulbar tract and Central tegmental tract
Indirect to cranial nerve motor/sensory nuclei, direct to dorsal column and parasympathetic nuclei
Thalamus, hypothalamus, basal forebrain nuclei, amygdala, medial septal nuclei.

23. The diffuse neuromodulatory system
Located around the borders of the Reticular Formation
Extremely long projections covering wide areas of the brain (e.g. whole cerebral cortex)
Neurons within specific nuclei in brainstem and forebrain, characterized by different neurotransmitters for example:
Raphe nuclei – serotonin
Ventral tegmental area – dopamine
Pontine tegmental area - acetylcholine
Modulate signal transfer by altering cell properties (e.g. excitability)
Modulates arousal, sleep, learning, memory, cognition, locomotion and pain
The cerebral cortex projects to this system
influences alertness (as can visual, auditory and mental imagery)
inhibits other sensory input, allows focusing of attention.
Gives rise to the Ascending Reticular Activating System (ARAS) - role in level of alertness, sleep-wake rhythms and alerting (startle) reactions

24. Diffuse neuromodulatory system
Magnus raphe nucleus
(Locus Ceruleus) *
Function of the serotonergic and adrenergic systems:
Sleep-arousal mechanisms
Integrative behavioral and neuroendocrine functions
Modulate actions of other neurotransmitters
Brain growth and development
Pain suppression *
Fitzgerald MJT, Gruener G, Mtui E. Clinical Neuroanatomy and related Neuroscience, 5th Ed., W. B. Saunders 2012

25. An example – Raphe nuclei & their serotonergic projections
Largest Territorial distribution of any CNS neurons
Midbrain – projects to cerebral cortex
Pons – ramifies in brainstem and cerebellum
Medulla – Projects to the spinal cord.
Fitzgerald MJT, Gruener G, Mtui E. Clinical Neuroanatomy and related Neuroscience, 5th Ed., W. B. Saunders 2012

26. Consciousness
“A state of self-awareness in which it is possible to direct attention and manipulate abstract ideas”
Content – reflects activity/interactions of different cortical areas
Level – dependent on diffuse modulation projections
Diffuse neuromodulator system maintains consciousness
Raphe nuclei (serotonin) → Cortex & Thalamus
Locus ceruleus (norepinephrine) → Cortex & Thalamus
Midbrain reticular formation (acetylcholine) → Thalamus
Tuberomammillary nucleus (histamine) → Cortex & Thalamus
Lateral hypothalamus (Orexin) → Cortex & Thalamus
Basal nucleus of Meynert (acetylcholine) → Cortex

27. Diffuse neuromodulatory system
1 = serotonin
2 = norepinephrine
3 = acetylcholine
4 = histamine
5 = orexin
6 = acetylcholine
Nolte. Essentials of the human brain. Mosby, 2010

28. Sleep – potential roles
Restoration and recovery
Consolidation of memory and daily experiences
Brain growth and development
Brain anabolism (e.g. synthesis of glycogen)
Tissue repair
“Rest” for the body and brain
Energy conservation
Strategies for prey and predator
Programming of innate behavior

29. Electroencephalogram (EEG) Stages of sleep
Fitzgerald MJT, Gruener G, Mtui E. Clinical Neuroanatomy and related Neuroscience, 5th Ed., W. B. Saunders 2007

30. Characteristics of non-REM and REM sleep
Non-REM Sleep
REM Sleep
EEG
Large amplitude, slow frequency, synchronized
Low amplitude, fast frequency, desynchronized
Muscle tone
Decreased
Almost abolished
Arousal level
Progressively higher
Highest
Mental activity
Vague dreams
Detailed, visual, emotional dreams
Autonomic activity
Increased parasympathetic
Slow, regular pulse and respiration
Increased sympathetic
Irregular pulse and respiration

31. “Regulation” of sleep-wake cycles
Flip-Flop switches - Two pathways that inhibit one-another so when one side gains control it turns the other off and stabilizes its own firing. This allows the production of two stable states and repaid transitions between each.
Suprachiasmatic nucleus
“clock for circadian rhythms”
Approximately 10,000 neurons in the hypothalamus use retinal inputs to adjust to the day-night cycle
“Flip-Flop” switch #1
Neurons within the preoptic area and medullary reticular formation “turn-off” wakefulness.
The flip-flop analogy represents the rapid and complete transitions between wake and sleep states
“Flip-Flop” switch #2
Nuclei in the pons generate the REM sleep stage and different nuclei in the pons terminate REM sleep; they have a mutually inhibitory relationship. The REM-off neurons are further regulated by excitatory inputs form Orexin, locus ceruleus and dorsal raphe nuclei.
The flip-flop switch analogy represents the transitions between wake and sleep states
Orexin secreting neurons (lateral hypothalamus) through their innervation of other brain & brainstem areas, play a key role in promoting wakefulness and arousal, motivation and emotions.
In the syndrome of narcolepsy, there is a loss of these neurons and resulting in excessive daytime sleepiness, disordered REM sleep and episodes of skeletal muscle (not respiratory) paralysis (cataplexy)
Nolte. Essentials of the human brain. Mosby, 2010