Neuroanatomy of Reticular Formations OS 202 PDF

OS 202: HUMAN BODY AND MIND 1: INTEGRATION AND CONTROL SYSTEMS NEUROANATOMY OF THE RETICULAR FORMATION UPCM 2029 | Dr. Leonard Pascual | LU3 A.Y. 2024-2025 2 OUTLINE I.​ Introduction...

OS 202: HUMAN BODY AND MIND 1: INTEGRATION AND CONTROL SYSTEMS NEUROANATOMY OF THE RETICULAR FORMATION UPCM 2029 | Dr. Leonard Pascual | LU3 A.Y. 2024-2025 2 OUTLINE I.​ Introduction III.​ Other Components of A.​ Location the Reticular Formation B.​ Description A.​ Midbrain C.​ Significance B.​ Pons II.​ Nuclei of the Reticular C.​ Medulla Formation IV.​ Recall A.​ Rostral raphe nuclei V.​ References B.​ Noradrenergic nuclei C.​ Medial nuclei D.​ Lateral nuclei I. THE RETICULAR FORMATION A.​ LOCATION ​ The location of the Reticular Formation (RF) is around the core of the brainstem ○​ “Bandang gitna ng brainstem” ​ It is located in the tegmentum or floor of the ventricle TEGMENTUM OF THE BRAINSTEM Figure 2. Longitudinal Zones of the RF. Raphe Nuclei (Gray), Medial Zone (Fuschia), ​ General Morphology of the brainstem Lateral Zone (Cyan). ○​ Tectum ○​ Tegmentum C.​ SIGNIFICANCE ○​ Base ​ Wakefulness ​ Lower borders[2028 trans] : ○​ Basic level of consciousness comes from here ○​ Level of the pons: Basis Pontis ​ Movements ​ Sandwiched by the Cerebellar Vermis and Basis Pontis ○​ Integration of movements, to understand the basal ganglia ○​ Level of the midbrain: Cerebral Peduncle circuitry comes from here ​ Has a Y-shaped configuration ○​ Gray matter in pons midbrain structure, the pedunculopontine ○​ Level of the medulla: Pyramid nucleus, moves extremities [2028 trans] ​ Dorsolateral: Sensory fibers/Nuclei ​ Pain ​ Ventromedial: Motor Cranial Nuclei ○​ Perception of pain ​ In between: Reticular Formation ​ Autonomics ○​ Control of autonomics i.e. control of pupils and blood pressure ​ Essentially, you do not want you RF to be damaged because without it you are not a living person anymore D.​ HISTOLOGY OF THE RF ​ Zoomed in, they are a mesh work of gray matter and a bunch of neurotransmitters ○​ "Reticular formation" means network or meshwork ​ Neuroanatomy question: Where is the extent of the RF? ○​ Between the midbrain and upper pons ​ ARAS is also here ○​ Ascending Reticular Activation System ○​ Most rostral portion connects to the thalamus and cerebral cortex Figure 1. Tegmentum at the Level of the Pons. Sensory fibers (orange), motor cranial nuclei (red), and reticular formation (purple). B.​ DESCRIPTION ​ Central core of the brainstem ○​ Diffusely organized connectivity, with connections throughout the brain and the body ​ A network of gray and white matter ○​ Big mess of fibers criss-crossing all over the place because everything is tightly woven together ​ Central core of the brain stem but is hard to see because it is widespread ​ These reticular formation form a cylinder within a cylinder Figure 3. Neurotransmitters along the RF. ○​ Raphe Nuclei is something along the midline ​ 3 Longitudinal Zones ○​ Raphe Nuclei (Center) ○​ Medial Zone (beside Raphe Nuclei) ○​ Lateral Zone (most lateral) ​ A single RF neuron can have several connections with several areas in the brainstem ○​ Down to the spinal cord ○​ Up to the thalamus to cerebral hemisphere [2028 trans] ​ Appearance of RF [2028 trans] ○​ In medulla: small and jam packed ○​ In pons: dorsal and smaller space ○​ In midbrain: jam packed again Figure 4. Histology of Reticular Formation. Trans 12 TG8: Cortez, Costillas, Covar, Cruz, Cuenco, Daroca, de Castro TH: Ilagan 1 of 8  II. NUCLEI OF THE RETICULAR FORMATION SLEEP AND WAKEFULNESS ​ Midbrain - rostral pons reticular formation reticular formation ○​ ARAS, in physiology ○​ From upper pons to the midbrain ​ Lesion below lower pons means no problem with the level of consciousness ​ Cut in the pons-midbrain leads to coma [2028 trans] ​ Cut in medulla leads to paralyzed but awake [2028 trans] ○​ Projects to the thalamus and cerebral cortex ​Sustain wakefulness Figure 5. Parts of the RF in a Cut Section of the Pons and the interconnections between them. Table 1. SECTIONS OF THE PONS AND THEIR CORRESPONDING NEUROTRANSMITTERS SECTION NEUROTRANSMITTER Norepinephrine Locus coeruleus (upper blue) (activating system) Dorsal Raphe Nucleus Figure 8. 3-D anatomy of brainstem source nuclei of ARAS. (middle teal) Serotonin Retrieved from Batch 2026 and 2028 Median Raphe Nucleus (green) ​ Reticular formation projects to the intralaminar nuclei of the Pedunculopontine Nucleus thalamus, which project to widespread areas in cerebral cortex Acetylcholine (ACh) (locomotion system) (lower blue) ○​ Thalamus relays input to wake up to the cerebral cortex ​ Activates ARAS Parabrachial Complex (yellow) Glutamate (excitatory) ○​ During a state of excitement and/or fear ​ ARAS Retrieved from Batch 2026 and 2028 ○​ NOT visible to the naked eye in a cut section of the brain ​ Dorsal Raphe Nucleus ○​ Located in the tegmentum of the midbrain and the rostral pons ○​ Better seen with myelin stain (Figure 6A) rather than a specimen in ○​ In charge of putting you to sleep formalin ​ Sleep is an active brain process ○​ Resides in center core of brainstem tegmentum RF ​ People who have difficulty in sleeping have dysfunction in the ○​ Neurotransmitter: Serotonin ARAS mechanism ○​ Related to mental health & sleep-wake patterns ​ Sustain wakefulness by stopping sleepiness ​ Median Raphe Nucleus ○​ Targets the intralaminar nuclei of the thalamus which then targets ○​ Ventral half of the dorsal raphe nucleus the cerebral hemispheres to wake you up ○​ Neurotransmitter: Serotonin ​ In order to be put to sleep, medication must be given to shut ○​ Different target organ from the dorsal raphe nucleus down ARAS ​ At the lower part of the pons ​ If certain stimulants are taken, ARAS will be sent to overdrive and ○​ Has myelin sheaths of crossing pontocerebellar fibers you will be up and awake for several days ○​ Corticospinal tracts cut cross section’ ​ Connections will give rise to various reactions/state of arousal NOTE: Included in the ppt but was not further discussed. F.​ CAUDAL RAPHE NUCLEI Figure 6. (A) Myelin Stained Specimen (B) MRI, (C) DTI E.​ ROSTRAL RAPHE NUCLEI Figure 9. Caudal raphe projections in the brainstem ​ Caudal raphe nuclei project downward to the cranial nerves and spinal cord PAIN ​ Nucleus raphe magnus ○​ Raphe nuclei in the medullary reticular formation ○​ Large nucleus in the midline that projects to the pain pathway ○​ Projects to the dorsal horn of the spinal cord as part of the pain control pathway ○​ Neurotransmitter: Serotonin ​ Involved in dampening physical, mental, or emotional pain [2028 trans] ​ Lack of serotonin results in amplification of pain (e.g. in depression) Figure 7. Rostral raphe nuclei projections in the brainstem ​ Upper (rostral) half of raphe nuclei that projects upwards to the forebrain, frontal lobe of cerebral hemisphere OS 202 Neuroanatomy of Reticular Formations 2 of 8  Figure 10. Serotonin found in the Raphe magnus nucleus. Figure 14. Relative location of gigantocellular nuclei in cross-section of caudal ​ Enkephalin medulla. ○​ Produced from the periaqueductal gray matter ○​ Targets the raphe magnus nucleus ​ Induces serotonin production ○​ Neurotransmitter that keeps away the pain and gives enjoyment ​ Works together with serotonin Figure 15. Histology of gigantocellular nuclei under a light microscope. ​ Have connections with the hypoglossal nerve (CN XII), descending control pathways, and expiration ○​ involved in some important basic functions which are eating, swallowing, and breathing ​ Send down reticulospinal tracts to the spinal cord via the central tegmental tract (CTT) Figure 11. Periaqueductal gray matter UPRIGHTNESS ​ Reticulospinal Tract ○​ A primitive motor tract(Kang and Im, 2023) ○​ Involved in the control of posture and gait-related movements (Blumenfeld, 2021; Vanderah, T & Gould, D., 2016) ​ Posture and coordination when standing or upside down (i.e. handstand) ○​ Sent to the spinal cord by the medial nuclei via the central tegmental tracts (CTT) Figure 12. Periaqueductal gray matter and the production of serotonin. G.​ MEDIAL NUCLEI Figure 16. Pontine (Medial) and Medullary (Lateral) Reticulospinal Tract ​ Afferent connections from the basal ganglia, substantia nigra, vestibular nuclei, and the motor cortex ○​ Serve several purposes for coordination and postural control Figure 13. Medial nuclei in the brainstem ​ e.g. Performing a handstand ​ Contain the largest neurons (gigantocellular nuclei) ​Substantia nigra: secretes dopamine which turns off ○​ Tiny area with gigantic neurons inside switches in the basal ganglia ○​ Column at the sides ​Vestibular nuclei: for knowing the position of the head and ○​ Lateral to both sides of the raphe nuclei [2025 Trans] legs ​Motor cortex: for sending commands to put legs up in the air OS 202 Neuroanatomy of Reticular Formations 3 of 8  ○​ e.g. disconnection of white matter, removal of myelin, accident ​ Dominance of parasympathetic nervous system ​ Will result in pseudoptosis, miosis and anhidrosis (less common) (Blumenfeld, 2021) ○​ Pseudoptosis: apparent drooping of the upper eyelid ​ NOT caused by weakness of the levator palpebrae superior muscle unlike in ptosis ○​ Miosis: decreased pupillary size ​ Opposite of mydriasis which is the dilation of the the pupil ○​ Anhidrosis: loss of sweat of the ipsilateral face and neck Figure 17. Gross anatomy of the basal ganglia (cyan) and the substantia nigra (purple). Figure 21. Pseudoptosis (left), miosis (middle), anhidrosis (right) ​ Efferent connections from the red nucleus to the inferior olivary I.​ NORADRENERGIC NUCLEI nucleus ​ Includes locus coeruleus, nucleus solitarius of CN X (vagus nerve), ○​ Allow coordination with the cerebellum for fine-tuning of and dorsal motor nucleus of CN X (vagus nerve) movements ○​ Has connections with the dentatorubral pathways [2025 Trans] LOCUS COERULEUS ​ Fibers from dentate nucleus in cerebellum → Red nucleus in the midbrain → Inferior olive in the medulla → original dentate nucleus (forms a triangle) (Goyal, et al., ) Figure 22. Anterior view of the brainstem in a 3D reconstruction. Locus coeruleus is highlighted in green. Figure 18. Locations of the hypoglossal nerve (yellow), descending pain control pathways (green), expiration (light blue), CTT (orange), and inferior olivary nucleus (dark blue) relative to the medial nuclei (red). H.​ LATERAL NUCLEI ​ Mediate cranial nerve reflexes (e.g. corneal, cough, gag reflexes) and autonomic functions (e.g. splashed with cold water makes you stop breathing for a while) ○​ Loss of reflexes is a criterion for brain death Figure 23. Cross section of the pons. Locus coeruleus can be seen as the 2 black pigmented spots in the dorsal area. ​ Located in the pons ○​ Visible to the naked eye as 2 black pigmented spots in the dorsal area ​ Produces norepinephrine ○​ Some people have more norepinephrine ○​ Keeps people active, even hyperactive sometimes ​ Innervates virtually the entire CNS, from spinal cord to cerebral cortex ○​ Wakes up the brain and the spinal cord [2028 Trans] NUCLEUS SOLITARIUS OF CN X Figure 19. Lateral nuclei in the brainstem. ​ Sympathetic tract descends into the thoracic spinal cord and forms synapses with neurons in the intermediolateral horn of the spinal cord Figure 20. Sympathetic tract descending into the thoracic spinal cord. HORNER’S SYNDROME Figure 24. Anterior view of the brainstem in a 3D reconstruction. ​ Can be caused by injury or disease to thoracic spinal cord Nucleus solitarius of CN X (vagus nerve) is highlighted in yellow green. OS 202 Neuroanatomy of Reticular Formations 4 of 8  Figure 28. Cross section of the medulla along the floor of the 4th ventricle. Dorsal motor nucleus of CN X (vagus nerve) outlined in blue, lateral to CN XII (hypoglossal nerve) outlined in purple. ​ NOT visible to the naked eye ○​ Seen histologically ○​ Reconstructed using 3D technology Figure 25. Cross section of the medulla. Nucleus solitarius of CN X is outlined in dark red and tract of the nucleus solitarius is outlined in red. ​ Principal parasympathetic nucleus in the CNS ○​ Slows down heart rate, breathing [2028 Trans] ​ NOT visible to the naked eye ○​ Brings digestive system back to life [2028 Trans] ○​ Seen histologically ​ Located in the floor of the 4th ventricle, lateral to CN XII (hypoglossal ○​ Reconstructed using 3D technology nerve) ​ NOT white matter, and does NOT darken with myelin stain ○​ Located next to the area postrema ​ Located in the medulla ○​ In vomiting, tongue protrudes, palatoglossal arches rise, forms orifice ○​ Located in the same area as the locus coeruleus BUT in the medulla to eject vomit [2028 Trans] [2028 Trans] ​ Sends motor fibers to the viscera ○​ Located dorsolaterally which is sensory in nature ○​ Lungs ​ Inputs of viscerosensory signals to the primary autonomic center, the ○​ Stomach nucleus of the solitary tract (NTS) ○​ Vocal cords ○​ NOT voluntary, has to be off-center AREA POSTREMA (AP) Retrieved from Batch 2028 ​ Converges at the area of the obex ○​ Because the vomit center is located in the obex ​ Tract goes down to GI system ○​ Push button for when you need to vomit ○​ Motor part of vomiting ​ Subserves taste and sensations in the abdomen when nervous or when there is need to go to the bathroom ​ Subserves sensation in the viscera ​ Inputs of viscerosensory signals to the primary autonomic center, the nucleus of the solitary tract (NTS) ○​ Stimulus comes from the stomach, which in turn stimulates/irritates the AP ○​ Signal goes down to the dorsal motor nucleus ​ Leads to vomiting ​To eject whatever is inside the stomach ​ When one feels nauseous, NTS sends signal to the dorsal motor nucleus of the vagus to vomit ​ The NTS works together with what is inside the viscera ​ The feeling, which is mediated by the vagus nerve, is there in the RF in the solitary tract and solitary nucleus of the vagus nerve ○​ Vagus nerve in action: feeling very tense, emotional, and nervous ​ Via RF Figure 29. Cross section of the medulla. Area postrema (pink), Nucleus solitarius (red), and tract of nucleus solitarius (dark red). ​ “All about vomiting” ​ Located anterior to the obex in the floor of the fourth ventricle ​ Contains specialized ependymal cells ○​ Does NOT produce CSF but line the CSF cavities ○​ Sensitive to substances floating in the CSF ​ Since there is no blood brain barrier (BBB), it is sensitive to changes in the blood ​ Reflex to protect from ingesting poisonous substances ○​ If one is pregnant, levels of human chorionic gonadotropin hormone (HCG) are elevated ​ High HCG levels stimulate the area postrema ​ Results in morning sickness Figure 26. Cross section of the medulla. DORSAL MOTOR NUCLEUS OF CN X Figure 30. Specialized ependymal cells of the AP. ​ Has chemoreceptors ○​ Allows CN X to monitor sensory information from the viscera Figure 27. Anterior view of the brainstem in a 3D reconstruction. Dorsal motor nucleus of CN X (vagus nerve) is highlighted in pink. OS 202 Neuroanatomy of Reticular Formations 5 of 8  Figure 31. Typical capillary vs brain capillary (with astrocytic feet constituting the BBB). The AP lacks the BBB. ​ Has sensory afferents ○​ Overstimulation can induce vomiting because of the connections of the vagus (CN X) and glossopharyngeal (CN IX) ​ i.e. Afferent input to the AP from the ff. come from CN IX & X[Mirza & Das 2023] Figure 34. Ventral 3Dl anatomy of the brainstem source nuclei of the ascending ○​ Afferent signals arousal network. Source nuclei abbreviations are as follows: LC, locus coeruleus; DR, ​ Excessive coughing dorsal raphé; MR, median raphé; PBC, parabrachial complex; PPN, pedunculopontine ​ Overstimulation of the ear nucleus; and VTA, ventral tegmental area. Neuroanatomic landmarks are provided ​ Heart attack for reference: IC, inferior colliculus; SC, superior colliculus ​ Stomach problems A.​ MIDBRAIN Retrieved from Batch 2028 ​ Pedunculopontine nucleus (PN) ​ When you feel nervous, you will feel nauseous, chest pain, ○​ Part of the ARAS palpitations, shortness of breath, butterflies in the stomach ​ In terms of movement (e.g. when you hear something loud/ ○​ Because of the vagus and its connections to the dorsal motor surprising; when house is burning, you jump out of bed and run nucleus, and the solitary nucleus outside; arms flailing when thrown into the pool)[Batch 2028] ​ May present in neuromyelitis optica (NMO) where patients vomit for ​Eyes widen no apparent reason ​Breathe fast ○​ MRI reveal loss of myelin in the area ​ Reason why you sometimes get startled when you get woken up by a classmate ​ Connected to arousal centers and the basal ganglia[Batch 2028] ○​ Responsible for arousal, attention, learning, reward and locomotion ​ Deep brain stimulation in Parkinson’s disease ​ Resides on top on medial lemniscus ​ Cholinergic: secretes ACh ○​ PN is composed of two groups of neurons:[Lee & Marsden, 2000] ​ Cholinergic neurons: containing acetylcholine ​ Non-cholinergic neurons: (GABA, glutamate) Figure 35. Right: Posterior view of the brainstem showing pedunculopontine Figure 32. Connections of the area postrema (afferents). nucleus (orange). Left: Cross section of the pons showing the PPN (blue) which secretes ACh. III. OTHER COMPONENTS OF THE RETICULAR FORMATION B.​ PONS The following notes were skipped during sir’s lecture but were part of his slides. Locations of the ff. are seen in Fig X. Retrieved from Batch 2028 BARRINGTON’S MEDIAL MICTURITION NUCLEUS AND LATERAL MICTURITION NUCLEUS ​ Parasympathetic function ○​ e.g. Bladder incontinence[2026 Trans] ​ Can only control sphincters to stop from dripping out, but is very difficult to stop the act of urination PONTINE ATTACK CENTER ​ Aggressive behaviors have nucleus in this area ​ Stimulating this area may cause thrashing Figure 33. Nuclei in the midbrain (yellow), pons (red)[2026 Trans] ○​ e.g. Basketball player that hit everyone onsite ​ Pontine attack center was on overdrive ​ Action of swinging is automatic PONTINE SWALLOWING CENTER ​ Control of vagus nerve ○​ One of the many automatic centers in the midbrain[2026 Trans] NUCLEUS OF KÖLLIKER-FUSE ​ Regulates respiratory rate ○​ If the brainstem is still intact, then there is no need to take out the ventilator (Don't give up on your patient.) OS 202 Neuroanatomy of Reticular Formations 6 of 8  NOTE: This was included in Doc Pascual's PPT though not discussed during the lecture. BREATHING CENTERS IN THE MEDULLA ​ Full set of gray matter that controls breathing ○​ Bötzinger Complex ○​ Pre-Bötzinger Complex ○​ Dorsal Respiratory Group ○​ Ventral Respiratory Group Figure 36. Nucleus of Kolliker-Fuse PARABRACHIAL COMPLEX ​ In the sensory area of the brainstem ○​ Dorsolaterally located (2026 Trans) ​ Part of the parasympathetic nervous system ○​ For special sensation (2026 Trans) Figure 39. Breathing centers in the medulla (1). Medial Parabrachial Nucleus ​ Relays taste stimuli from the nucleus solitarius up to the insula NOTE: Doc Pascual said we do not need to memorize this. Just note and the amygdala that “for breathing to occur, we need our medulla.” ​ Urge to eat (2026 Trans) ○​ Informs the hypothalamus during state of hunger ​ Related to appetite ○​ Plays a role in mental health, particularly in conditions like eating disorders (e.g. obesity) Lateral Parabrachial Nucleus ​ Relays signal from nucleus solitarius for thirst, salt intake, and blood pressure to the hypothalamus and cerebrum ○​ Primarily for automatic actions (2026 Trans) ​ Reaction of the body to a state of hydration ○​ Informs the hypothalamus when you are in a state of thirst Sub-parabrachial Nucleus (Nucleus of Kölliker-Fuse) ​ Connects with the nucleus solitarius to regulate breathing Additional info from Trans 2028 ​ Personal mechanical ventilator: controls the diaphragm (2026 Trans) Figure 40. Breathing centers in the medulla (2). ​ Downwards, it connects to medulla respiratory center (2028 Trans) NOTE: This was included in Doc Pascual's PPT though not ○​ Medulla: lets you breathe discussed during the lecture. ○​ Pons: controls how your breath is ​ Chemosensitive neurons (2026 Trans) VENTROLATERAL PONTINE BRAINSTEM ○​ Checks for pH of blood ○​ Triggers mechanism to breath ​ Sympathetic input to the heart rate ​ Above the superior olivary complex Retrieved from Batch 2028 PARABRACHIAL KÖLLIKER-FUSE COMPLEX ​ Has receptors outside of the medulla, below the pia matter of the medulla ○​ Receptors for what is floating in the CSF ​ Internal CO2 monitor ​ If ↑ CO2, need to breathe faster to blow it off ​ If ↓ CO2, need to breathe slower ​ “Ondine’s Curse” ○​ When you sleep, you stop breathing ○​ Breathing is a voluntary action ○​ Patient has no significant problems (e.g. no tumor in lungs) but upon sleep, would stop breathing (2028 Trans) ​ Oxygen would go down every time she slept Figure 37. Ventrolateral Pontine Brainstem. ​ Had to wake her up and had to be in a ventilator for quite some time Additional info from Trans 2026 ○​ Needed to stay alive. If removed, will revert to the basic rhythm CAUDAL VLM of heart (30 bpm) which is NOT compatible with living ○​ In charge of making the heart race ​ E.g. standing up, running C.​ MEDULLA VENTROLATERAL MEDULLA Figure 41. Caudal VLM NOTE: This was included in Doc Pascual's PPT though not discussed during the lecture. MEDULLARY SWALLOWING CENTER ​ Swallowing is automatic, NOT voluntary Figure 38. Ventrolateral medulla. ○​ Once you swallow, you cannot stop the swallowing action OS 202 Neuroanatomy of Reticular Formations 7 of 8  RETROAMBIGUUS NUCLEUS Figure 42. Medullary swallowing center and retroambiguus nucleus NOTE: This was included in Doc Pascual's PPT though not discussed during the lecture. IV. RECALL Exercise: Name the parts of the reticular formation and their corresponding neurotransmitters Figure 43. Parts of the reticular formation in a cut section of the pons * see Figure 5 and Table 1 above for the answers. V. REFERENCES Blumenfeld, H. (2021). Neuroanatomy Through Clinical Cases (3rd ed.). Sinauer Associates/Oxford University Press. Goyal, M., Versnick, E., Tuite, P., Cyr, J. S., Kucharczyk, W., Montanera, W., Willinsky, R., & Mikulis, D. (2000). Hypertrophic olivary degeneration: metaanalysis of the temporal evolution of MR findings. AJNR. American journal of neuroradiology, 21(6), 1073–1077. Kang, J. H., & Im, S. (2023). Functional Anatomy of the Spinal Tracts Based on Evolutionary Perspectives. Korean journal of neurotrauma, 19(3), 275–287. https://doi.org/10.13004/kjnt.2023.19.e43 Lee, M. S., Rinne, J. O., & Marsden, C. D. (2000). The pedunculopontine nucleus: its role in the genesis of movement disorders. Yonsei Medical Journal, 41(2), 167. https://doi.org/10.3349/ymj.2000.41.2.167 Mirza, M., & M Das, J. (2021). Neuroanatomy, Area Postrema. PubMed; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK544249/ Vanderah, T. W., & Gould, D. J. (2016). Nolte's The human brain: an introduction to its functional anatomy (7th ed.). Elsevier. OS 202 Neuroanatomy of Reticular Formations 8 of 8