OS 202 Past Paper PDF - Blood-Brain Barrier, Cerebral Metabolism, Sleep

OS 202: HUMAN BODY AND MIND 1: INTEGRATION AND CONTROL SYSTEMS BLOOD-BRAIN BARRIER, CEREBRAL METABOLISM, SLEEP UPCM 2029 | Dr. Delfin Darwin A. Dasig | LU3 A.Y. 2024-2025...

OS 202: HUMAN BODY AND MIND 1: INTEGRATION AND CONTROL SYSTEMS BLOOD-BRAIN BARRIER, CEREBRAL METABOLISM, SLEEP UPCM 2029 | Dr. Delfin Darwin A. Dasig | LU3 A.Y. 2024-2025 ○​ Posited as the main restorative portion of sleep OUTLINE ​ Person goes through progressively deepening degrees of sleep I.​ Sleep III.​ Cerebral Circulation, (stages 1 to 4) A.​ Electroencephalogram Cerebral Metabolism, ○​ EEG shows different patterns depending on the depth of sleep B.​ Patterns of Sleep Blood-Brain Barrier ​ Characterized by C.​ Different States of A.​ Vasculature of the ○​ Decreased skeletal muscle activity Consciousness Human Brain ○​ Less body movements D.​ Distribution of Sleep B.​ Blood-Brain Barrier ​ More stable vital signs Stages C.​ Cerebral Blood Flow & ○​ Heart rate E.​ Sleep and Age Metabolism ○​ Breathing frequency II.​ Chronobiology: Internal D.​ Regulation of Cerebral ○​ Body temperature Clock Blood Flow ○​ Blood pressure A.​ Biological Rhythms IV.​ References ​ Absence of REM B.​ Zeitgebers and V.​ Appendix ​ Minimal mental activity Entrainment ○​ Individuals awoken from this state rarely report vivid, complex C.​ SCN story-like dreaming ​ Period when most body and brain processes are restored or recuperated I.​ SLEEP ​ Stages of nREM sleep ​ Normal (physiologic), cyclic, temporary loss of consciousness ○​ Stage 1 ○​ Readily, promptly, and completely reversed by appropriate stimuli ​ Characterized by drowsiness ​ Results from an interaction between reticular formation and the ​ Low-amplitude high frequency background with an hypogenic (sleep-producing) centers of the brain attenuation of rhythmic activity (alpha dropout) ○​ The brain does NOT stop functioning. ​Begins when a person closes their eyes, with the EEG showing alpha dropout and loss of posterior rhythmicity A.​ ELECTROENCEPHALOGRAM ​Very light sleep where the person can be easily awakened ​ Procedure that records cortical activity of the conscious system ○​ Applied over the scalp via electrodes ​ Consists of numerous waveforms from different cortical areas ○​ Represent summations of postsynaptic dendritic potentials [excitatory and inhibitory postsynaptic potentials (EPSPs & Figure 2. EEG of Stage 1 nREM sleep IPSPs)] ​ Generated near the surface in response to the intrinsic, neuronal ○​ Stage 2 activity of the cerebral cortex ​ Sleep is light to medium in depth ○​ Modified by input from subcortical structures ​ EEG features: ​ Provides information on: ​Sleep spindles: 1-2 second burst of 12-15 Hz ○​ Cortical functioning ​Vertex sharp waves: intermittent high amplitude with ○​ Activity throughout the consciousness system central-parietal sharp slow wave complexes ○​ Stages of sleep and its clinical characteristics of each ​K-complexes: formed by the overlap of vertex sharp waves ​ Patient lie down and close their eyes losing stimulation from the and sleep spindles. visual environment, allowing more arithmetical summation of the EPSPs & IPSPs (more prominent on the posterior part, area of vision). ​ Limitation: presence of scalp and bone serves as barrier affecting the sensitivity of the test EEG WAVEFORMS ​ Alpha: 8-13 Hz, 50-100 μV amplitude ○​ Fairly regular pattern ○​ Prominent posteriorly ○​ Associated with decreased levels of attention ​ Beta: 13-30 Hz, low voltage activity ○​ Irregular pattern ○​ When attention is focused on something and when using certain drugs ​ Gamma: 30-80 Hz ○​ When individual is aroused and focuses attention on something ​ Theta: 4-7 Hz ​ Delta: 0.5-3 Hz ○​ Theta and delta are more pathological Figure 3. Sleep spindles and Vertex sharp waves ○​ The lower the function of the brain, the lower the pattern is. ​ Sleep spindles: 12-14 Hz, sinusoidal waves ​ Obstructive sleep apnea often becomes evident in this stage, ​ K complexes: high voltage biphasic waves presenting with loud snoring, pauses in breathing, and ○​ Large negative followed by large positive deflection airway obstruction caused by tongue relaxation. B.​ PATTERNS OF SLEEP ​ Two distinctive patterns alternating throughout its duration seen in normal persons: ○​ Rapid eye movement (REM) ○​ Non-rapid eye movement (nREM) Figure 4. EEG of Stage 2 nREM sleep ​ Experimental data have shown that NREM and REM sleep are produced by different anatomic and physiologic systems. ○​ Stage 3 ​ Awake state ​ Deeper sleep with increased difficulty to wake up ○​ Relaxed wakefulness with eyes closed ​ Slow wave activity ○​ Posterior alpha waves of 9-11 Hz ​Lower frequency ○​ Intermixed with low voltage fast activity of mixed frequency ​Increased amplitude ​Highly synchronized ​Constitutes 20-50% of total EEG activity with occasional delta spikes (large 1-2 Hz bursts) Figure 1. EEG of an awake person; posterior alpha waves of 9-11 Hz intermixed with low voltage fast activity of mixed frequency nREM SLEEP ​ Initial stage of sleep Figure 5. EEG of Stage 3 nREM sleep ○​ Predominant type of sleep during the first half of the whole sleep cycle Trans 9 TG6: Carena, Carinugan, Carranto, Carreon, Carurucan, Caugma TH: Santos, A. 1 of 11  ○​ Stage 4 ​ GABA: Inhibition of preoptic neurons in hypothalamus ​ Deepest sleep SLEEP ​ EEG shows maximum slowing with large waves ​Lower frequency ​ Increased GABA levels ​Increased amplitude ​ Decreased Orexin and Histamine levels ​Highly synchronized ​ Disinhibition of preoptic neurons in hypothalamus by GABA ​More than 50% of EEG dominated by delta spikes ​ Inhibition of posterior hypothalamic neurons by Histamine ○​ Often seen in children, who are difficult to wake even nREM SLEEP when moved. ​ Reverse, with cholinergic predominance ​ Levels of 5-HT, NE, and dopamine are higher than ACh ​ Dominant activity of Locus Coeruleus (norepinephrine) and Raphe nuclei (serotonin/ 5-HT) ​ Decreased activity of pontine reticular formation (ACh) Figure 6. EEG of Stage 4 nREM sleep REM SLEEP REM SLEEP ​ Reverse of occurrences in nREM sleep ○​ High levels of predominant ACh ​ General Features ​ Flip-flop switch model of sleep-wake regulation ○​ Also called paradoxical, active or dream sleep ○​ Fluctuation of ACh levels ○​ Brain activity levels and EEG patterns resemble waking state: ​ nREM (low) ​ Rapid, low-amplitude, desynchronized waves ​ REM (high) ○​ Skeletal muscles are completely inactive ​ Muscle paralysis prevents acting out dreams but can persist D.​ DISTRIBUTION OF SLEEP STAGES briefly after waking (normal, not pathological) ​ Throughout the whole period of sleep, the cycle alternates between ​ REM Sleep Behavior Disorder (RBD): Occurs when muscle nREM and REM paralysis is lost, leading to acting out dreams. ​ No standard amount of sleep ​Linked to neurodegenerative conditions like Parkinson’s ​ There are people who need more and people who can function well or dementia with Lewy bodies with less ​Symptoms include falling out of bed, waking in unusual places, or experiencing vivid, frightening dreams TYPICAL NIGHT OF SLEEP IN YOUNG ADULT ○​ Sleep is not easily interrupted ​ First enters nREM sleep ○​ Observed in all studied mammals and birds but likely absent in ○​ Passes through stages 1 and 2 other classes of mammals ○​ Spends 70 to 100 minutes in stages 3 and 4 ​ Autonomic Functions ○​ Sleep then lightens and a REM period follows ○​ Rapid conjugate eye movements ​ Cycle is repeated at intervals of about 90 minutes throughout ○​ Fluctuations in body temperature, heart rate, blood pressure, the night and respiration ​ During the first half of sleep, nREM sleep periods are longer and ○​ Decrease in muscle tone prevents acting out dreams reach up to deep stages ○​ Muscle twitches ○​ REM sleep periods are shorter ○​ Penile erection ​ Towards the latter half of sleep, REM sleep periods become longer ​ Helps differentiate physiological from psychological causes of ○​ nREM periods tend to be less deep impotence ​ Stages 1 and 2 are predominant ○​ Occurrence of dreams ​ Cycles are similar ​ Humans woken during REM often report dreaming ○​ Less stage 3 and 4 sleep ​ Bruxism (teeth-grinding) is associated with dreaming ○​ More REM sleep toward the morning ​ Triggering Mechanisms and Neural Activity ​ Total night’s sleep ○​ Pontine Reticular Formation: Site of triggering mechanism for ○​ 4 to 6 REM periods per night REM sleep ○​ Arousal threshold by sensory stimuli and reticular formation E.​ SLEEP AND AGE stimulation is sometimes elevated during REM sleep, making ​ Sleep patterns change with age the individual less responsive to external disturbances ○​ nREM and REM sleep decrease with increasing age ○​ Presence of Ponto-geniculo-occipital (PGO) spikes ​ REM is less affected ​ Large phasic potentials that play a crucial role in triggering ​Slow wave sleep is maximal in children and maintaining REM sleep ​Decreasing steadily with age ​ Characteristics: ​ Proportion of REM sleep falls rapidly with age ​Occur in groups of 3 to 5 ​Plateaus at about 25% until old age ​Originate in the pons (specifically, the lateral pontine DISTRIBUTION OF SLEEP BY AGE GROUP tegmentum) 1.​ Neonates ​Rapidly pass to the lateral geniculate body and occipital ​ 16 hours/day cortex ​ REM sleep is dominant ​Mediated by cholinergic neurons from the pontine reticular ○​ 80% of total sleep in prematures formation ○​ 50% of sleep in full-term neonates ​ Effects on the medulla: 2.​ Infants ​Activate the reticular inhibiting area in the medulla. ​ Transition rapidly from wakefulness into REM sleep ​Reduce stretch and polysynaptic reflexes through both ○​ Stage 3 nREM sleep is dominant pre- and postsynaptic inhibition ​ Makes children harder to wake ​Lead to hypotonia (reduced muscle tone), ensuring skeletal ​ Sleep Cycle: 50-60 minutes long muscle paralysis during REM sleep ​ Have more sleep in general than adults ​ Clinical Relevance 3.​ Adults ○​ REM sleep places high metabolic demands on the body, ​ 7 to 9 hours of sleep causing fluctuations in autonomic functions ​ nREM sleep is predominant ○​ These fluctuations may increase the risk of cardiovascular ○​ 80% nocturnal sleep pattern events (e.g., strokes) during the night ○​ 20% REM sleep ○​ Frequent waking during REM leads to vivid dream recall, while 4.​ Older Adults uninterrupted REM results in little or no dream recall ​ Earlier nREM sleep is dominant ○​ Hardly reaches stages 3 and 4 ○​ Makes elderly susceptible to more Figure 7. EEG of REM sleep frequent awakenings C.​ DIFFERENT STATES OF CONSCIOUSNESS ​ Sleep-wake cycle involves an active process of regulation AWAKE ​ Increased levels of the neuropeptide Orexin ○​ This strongly excites brain nuclei that secrete transmitters with important roles in wakefulness ​ Histamine, dopamine, norepinephrine (NE), acetylcholine (ACh) ○​ Inhibits release of GABA ​ Histamine ○​ Main chemical keeping us awake ○​ Excitation of posterior hypothalamic neurons: ​ Dominant activity of: ○​ Locus Coeruleus: produces norepinephrine ○​ Raphe nuclei: produces serotonin/5-HT OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 2 of 11  Adenosine ​ Inhibitory neuromodulator in CNS ​ Caffeine: Antagonist of adenosine receptors with potent stimulating effects ​ Increased adenosine levels ○​ Reduced ATP production ○​ Signal of reduced brain energy reserves during waking ​ Sleep is induced as energy restorative state ○​ Reason why those who exercise tend to sleep earlier or more due to need to restore metabolic reserves Oxidative Stress ​ Combats natural buildup of free radicals ○​ Products of enhanced metabolic activity during waking states ​ Reduced metabolism during sleep ○​ Enable repair of cellular and tissue damage caused by free radicals Figure 8. Distribution of sleep among age groups. ○​ Hence the need to sleep when sick for faster recovery ​ If awakened during REM stage then permitted to sleep without Sleep & Immunity interruption ​ Sleep deprivation increases susceptibility to illnesses such as ○​ Humans would show a great deal more than normal amount of infection REM sleep for a few nights ​ During bacterial infection = higher death rates ​ Arousal Threshold ​ Sleep-related suppression of immune function ○​ Ability to wake from sleep ​Prolonged sleep deprivation in rats increases occurrence of ​ Nearly impossible to arouse young child from Stage 3 or 4 specific bacteria in blood ​ Easy to awaken elderly restless sleep ​ Sleep helps in recovery from illnesses IMPORTANCE OF SLEEP ○​ Experimental animals with induced infection show increased level of non-REM sleep Critical for Survival ​ Elevation of key immune mediators ​ All birds and mammals (? insects) sleep ​ Proinflammatory cytokines with sleep-promoting properties ○​ Extended sleep deprivation in mammals and fruit flies leads to death Sleep & Brain Plasticity ​ As if you deprived them of hunger ​ Sleep may function to fortify or enhance synaptic plasticity ○​ Duration of survival of sleep-deprived rats comparable to totally ○​ Conserves energy food-deprived rats ○​ Regulate synaptic overload that the brain and its cells endure ○​ Swimming mammals exhibit unihemispheric nREM sleep during wakefulness ​ Cannot sleep completely, otherwise they will drown ○​ Important in learning and memory ​ Only half of their brain is asleep at a time ​ Without sleep, it would be difficult to retain any learning activity ​ Putative functions ​ Sleep maintains synaptic homeostasis ○​ Energy conservation ○​ Waking cognitive performance is maintained ○​ Thermoregulatory control ​ Possibly: sleep-dependent processes important aspect of memory ○​ Decreased oxidative stress formation ○​ Support for immunity ○​ Promotion of brain plasticity Sleep & Protein Synthesis ○​ Promotion of protein synthesis ​ Daily sleep quota varies greatly across mammalian species (4 to 20 ​ Neonates need at least 50% more sleep than adults hours) ○​ Suggests that sleep play a role in growth and development ​ Length of sleep is positively correlated with metabolic rate ​ In rats, sleep deprivation leads to a 60% reduction in the ○​ Animals that sleep for shorter periods are generally large (e.g. number of new neurons being produced elephants and giraffes) ​ Suppression of cell proliferation after sleep restriction ○​ Long-sleeping animals are usually small (e.g. rodents and fruit ○​ Brain protein synthesis is increased in non-REM sleep vs flies) waking and REM state ○​ Rationale: Due to small animals having a higher metabolic rate, II.​ CHRONOBIOLOGY: INTERNAL CLOCK they expend energy more quickly → thus, longer periods of sleep helps restore energy levels ​ Study of biological timing among living things ○​ chronos (time) NOTE: ○​ logos (study) ​ For the next part, most details were glossed over for the interest ​ It examines how internal clocks and rhythms influence behavior, of time during the actual lecture. physiology, and overall health. ​ However, Dr. Dasig still encouraged us to read through the slides ​ Rhythm: regularly repeating process and lecture notes. ​ Two drives of sleep: metabolic and circadian rhythms A.​ BIOLOGICAL RHYTHMS Sleep and Energy Conservation ​ Positive correlation between daily sleep and metabolic rate ○​ Sleep serves as an energy conserving state ​ Humans have decreased whole body and cerebral metabolic rates ○​ Lowering motor activity ○​ Reduced heat loss ​ Nesting ​ Insulating methods ​ Sleep postures ​ Piloerection ​ Human sleep onset: associated lowering of body temperature ○​ Sleep is increased when body temperatures is low ​ Reduced energy expenditure by reducing body temperature and metabolism ○​ Enable body and brain recuperation Thermoregulatory Control of Sleep Figure 9. Spectrum of Biological Rhythms in a Human Body ​ Thermoregulatory process orchestrates sleep by: ○​ Coordinating suppression and arousal systems ​ Biorhythm ○​ Lowering temperature and metabolism ○​ Rhythm occurring in a living thing ​ Hypothalamic mechanisms underlying control of sleep ○​ Advantages in organisms ○​ Preoptic area: Subregions with sleep active neurons containing ​ Circadian Rhythm GABA projecting to hypothalamic & brainstem neuronal groups ○​ Process that repeatedly occurs over the span of 24 hours ○​ Lesions of preoptic area reduce or eliminate sleep ○​ Circum (“around”) + Dies (“day”) ​ Local warming of preoptic area in rats triggers non-REM sleep ​ Sleep-wake cycle ​ Mild cooling of preoptic area suppresses non-REM & REM sleep ​ Endocrine rhythms (ACTH, GH, Prolactin) ​ Warm-sensitive neurons are “sleep-active” ○​ Almost everything occurs under circadian control ​ Cold-sensitive neurons are “wake-active” ​ Because life evolved under influence of cosmic time OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 3 of 11  Figure 10. Biological factors following circadian rhythm Figure 11. Entrainment: Three processes synchronize differently to a Zeitgeber. ​ Diurnal Rhythm ○​ Entrainment by light ○​ Two processes/events involved in cycle occurring within the ​ Through changing nature of light at dawn and dusk same duration ○​ Pittendrigh (1960) Experiment ​ Ultradian (Ultra/Beyond) ​ Light pulses given at different times ○​ Recur in period shorter than 24 hours (seconds to hours) ​ When an animal “thinks” it is the day has little effect on clock ○​ e.g. breathing, beating of heart ​ If given during first half of subjective night, activity of the ​ Infradian (Infra/Below) following day is delayed ○​ Recur beyond 24 hours (week, month, year) ​ If given during second half of subjective night, effect is ​ Circaseptan (Septem/Seven) advancing the clock ○​ Recur every 7 days ​ To correct jet lag, you should expose yourself to the time of ○​ Levels of 17-ketosteroid dawn and dusk (not necessarily the sun) ​ Circa Triginta (Triginita/Thirty) ○​ Circadian Rhythm ○​ Recur every 30 days ​ Self-sustained inherent rhythm ○​ e.g. menstrual cycle ​ Independent from external signals ​ Circannual (Annus/Year) ​ Synchronized in real life to 24 hours by zeitgebers ○​ Seasonal systems (e.g. mood) (entrainment) Advantages of Biological Rhythms C.​ SUPRACHIASMATIC NUCLEUS ​ Tuning and synchronization of rhythms saves energy (body ​ Small paired nucleus found in the anterior hypothalamus just lateral working efficiently) to the third ventricle and on top of the optic chiasm ​ Temporal compartmentalization allows polar events to occur in ​ Consists of a few neurons the same space unit ○​ Light receptors but not for vision ​ Homeodynamics: Self-calibration of control circuits in body leads ​ Receives environmental light-dark information to organismic stability ​ Does NOT perceive light ○​ Master circadian clock: The internal pacemaker that determines B.​ ZEITGEBERS & ENTRAINMENT the circadian rhythm ​ Zeitgebers ​ All cells have natural rhythmicity but the SCN sets the pace ○​ “time givers” and synchronicity for all cells to follow circadian rhythm ○​ External cues that act to adjunct internal cycle ​ When SCN perceived darkness, it sets nearby pineal gland to ​ Light secrete melatonin ​Strongest cue: If light/dark cycle is presented to an ​Initiates sleep-wake cycle organism, most will entrain to light and ignore others SCN and Local Clocks ​ Change in temperature ​Temperature fluctuations reinforce rhythms ​ Vertebrate body is composed of billions of independent clocks (local ​ Availability of food clock) ​The timing of meals influences metabolic processes ​ Only transplanted SCN cells can store rhythmicity to an ​ Humidity SCN-lesioned animal ​ Social contact ​ SCN regulates a temporal programme ​Communication and activities help regulate rhythms ○​ Circadian organization based upon multiple oscillators (“standard ​ Entrainment: process of adjusting the internal clock to the time” environment ○​ Factors Influencing Entrainment ​ Light exposure ​ Meal timings ​ Social and environmental context ○​ EX. When you travel to another country with a different time zone ​ Not following our biology clock is associated with increased pathology ​Increased sleep problems, headache, cardiopulmonary, gastrointestinal problems, and cancer[2027 Trans] ○​ Chronotype: Temporal relationship between external and internal time ​ Related to phase of entrainment ​Early chronotypes: shorter or more advanced circadian cycle (FRP < 24h), thus tend to sleep earlier ○​ Can be problematic when made to sleep late (e.g. night shifts) Figure 12. Pathway for SCN of the hypothalamus to process light signals and dictate biological internal clock ​Late chronotypes: longer circadian rhythm (FRP > 24h), thus tend to sleep later Retina and Retinohypothalamic Tract (RHT) ○​ Have a greater need for extra sleep in the morning ​ Retina: Contain rods and cones for phototransduction ○​ More likely to be sleepy during morning class ○​ Not required for entrainment ​ Change and differ with age and sex ○​ Melanopsin ganglion cells (MG): Non-rod & non-cone ​Teenagers have a later chronotype photoreceptor ​Males have later chronotypes than females ​ RHT ○​ Small number of distinct ganglion cells (~1% of total) ○​ Distributed evenly over entire retina ○​ Sends unmapped (random) projection to SCN ○​ Information about general brightness of environmental light ○​ Neurotransmitter: glutamate ​ Pathway: Light → Melanopsin Ganglion cells → Retinohypothalamic tract → Suprachiasmatic nucleus Coupling of the body to the internal clock ​ Clock genes: intracellular transcriptional and translational feedback loops ○​ Negative feedback: Per1-3, Cry1-2 ○​ Positive feedback: Bmal1 & clock ​ Melatonin: Major output of SCN from pineal gland OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 4 of 11 Melatonin ​ Effector of SCN ○​ Ultimately dictates circadian rhythm ​ Secretion with circadian rhythm ○​ Stimulated by darkness (peak at night) ○​ “Daily clock”: diurnal changes of light intensity of melatonin ○​ “Seasonal clock”: seasonal changes ○​ “Age clock”: reduction of melatonin observed in aging Circadian Clock ​ Governs most biological systems ​ Regulates physiological processes ​ Affects human health & behavior ​ Evolution of biological clock in natural selection ○​ Circadian (night and day) activities of an organism developed as evolutionary strategy to success ​ Adaptation to a predictable environment ​ Encoded in genes ○​ We have evolved to be day-oriented creatures, hence most biological processes are more active during the day ​ Unlike predators, who have evolved to be more active at night to hunt down prey ​ Circadian Rhythm ○​ Rotating repertoire of drive and their concomitant behaviors (controlled by the internal clock) ○​ It is only with unexpected fluctuations in the local environment does homeostasis take place, acting as a fine tuner against the biorhythm as main controller Figure 15. Blood supply of the brainstem (Dasig) III.​ CEREBRAL CIRCULATION, CEREBRAL METABOLISM, BLOOD-BRAIN BARRIER A.​ VASCULATURE OF THE HUMAN BRAIN ​ Circle of Willis: multiple anastomoses connect branches of the 4 major arteries that supply the intracranial contents ○​ Explains how the circulation of the brain comes from the heart ○​ Has 2 systems of circulation connected to the Circle of Willis ○​ Can help localize lesion or where the stroke happened ​ 40% of total vascular resistance in CNS in penetrating parenchymal arteries (< 200 μm in diameter) ○​ Small arteries coming from major arteries ​ Whatever blood comes from major arteries is transmitted to the smaller, thus whatever the effect of hypertension is strongest there Figure 16. Major branches of the anterior cerebral artery (Dasig) ​Prone to stroke; smaller but have the same blood pressure from where they are coming from ​ Unlike the branches of anterior cerebral and middle cerebral; branching part do not have the same blood pressure ​ Blood-brain barrier Figure 17. Major branches of the posterior cerebral artery (Dasig) Figure 13. Major arteries supplying the supratentorial and posterior fossa levels (Dasig) Figure 18. Blood supply of the homunculus (Dasig) ​ Arterial input and venous drainage only ​ No lymphatic vessels in CNS ​ Perivascular sheath-like extensions of subarachnoid space around arteries and veins: Virchow-Robin spaces ○​ Act as lymphatic vessels ○​ Source of movement of infection in meningitis ​ All intracranial veins drain into dural sinuses B.​ BLOOD-BRAIN BARRIER ​ Noted when they injected dyes to cadavers and noticed that it Figure 14. Circle of Willis (Dasig) spread everywhere except for the brain ○​ Thus, brain is generally protected from anything outside of it ​ Capillaries of organs outside nervous system ○​ Have fenestrated capillaries ○​ Pores and channels between individual endothelial cells ​ Water and solutes can pass from blood to extracellular space OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 5 of 11 ​ Capillaries of the central nervous system ○​ Single layer of endothelial cells surrounded by a basement membrane, invested by a nearly continuous layer of astrocytic extensions called foot process ○​ Adjacent endothelial cells joined by continuous tight junctions formed by fusion of external layers of the plasma membrane Figure 19. Capillary of the central nervous system (Dasig) Figure 20. Factors Regulating Cerebral Blood Flow TIGHT JUNCTIONS ​ Substances to enter extracellular space or interstitium of brain: Information directly taken from 2027 Trans(2027 Trans) ○​ need to pass through plasma membrane of capillaries rather than ​ Any decrease in CBF will compromise brain function between endothelial cell ​ Beyond 6 minutes or more of decreased CBF, there will be ​ Function as continuous bilipid layer irreversible brain damage ​ No fenestra ​ Most important are the cerebral autoregulatory mechanisms ○​ Strongest driving force to increase CBF is increased carbon BILIPID LAYER dioxide or decreased pH (acidity) ​ Lipid-soluble substances can pass the plasma membrane with ease ○​ Increased CO2 → increased lactic acid → decreased pH → ​ Rule: only lipid-soluble drugs can reach therapeutic acidic environment → blood vessels dilate → increased CBF concentrations in the brain ○​ Drugs needs to be at higher dose to reach the brain like in EXTRACEREBRAL FACTORS meningitis; 2-4x higher for the medicine to penetrate ○​ In tumors, there is a rapid production of neoplastic cells resulting ​ Factors outside the cranial cavity that modify or regulate CBF to impaired tight junctions which may result to vassoprenic ​ Primarily related to the cardiovascular system edema ○​ Systemic blood pressure ○​ In stroke, sodium potassium pump cannot do its job resulting to ○​ Efficiency of cardiac function intracellular swelling ○​ Viscosity of blood ​ Systemic blood flow BRAIN AREAS WITHOUT BBB ○​ e.g. hypovolemic shock, bleeding, cardiac arrest, septic shock ​ There are areas of the brain without BBB allowing to monitor if (rearrangement of blood flow) the brain is being poisoned and can be sampled: ○​ Principal force in maintaining cerebral circulation ​Anterior 3rd ventricle ○​ Pressure difference between arteries and veins ​Tuber cinereum of the hypothalamus ○​ Normal condition: Cerebral venous pressure is low (5 mmHg) ​Pineal gland ○​ Arterial blood pressure ​Area postrema of the caudal 4th ventricle ​ Most important factor in maintaining CBF ○​ The absence of BBB allowed the brain to sample noxious ○​ Systemic arterial blood pressure depends on: stimuli and induce vomiting. ​ Efficiency of cardiac function (cardiac output) ASTROCYTIC FOOT PROCESSES ​ Peripheral vasomotor tone or resistance ​ Both governed principally by autonomic control from the ​ NOT functionally for the BBB vasomotor center in the medulla ○​ But improve the environment of the neuron ​ Cardiovascular function ​ Previously thought to contribute to BBB function ○​ e.g. arrhythmia, orthostatic hypotension (i.e. blood flow cannot ​ Presently appears that it does not exclude substances from compensate from lying down to standing due to impaired entering ECS of brain vasopressor receptors), loss of sinus and aortic arch reflexes ​ Main function: rapid transfer of ions from extracellular environment ○​ Changes in cardiac output caused by: of neurons to region of capillary wall ​ Alterations in cardiac rhythm and myocardial function C.​ CEREBRAL BLOOD FLOW & METABOLISM ​ Presence of cardiac disease ​ Brain is a very demanding organ. ○​ Reflexes that mediate cardiovascular tone and help maintain a ○​ It only makes up 2% of total body weight (1.2-1.5kg) yet it constant BP involve: receives 15% of cardiac output and utilizes 20% of oxygen ​ Baroreceptors in carotid sinus and aortic arch consumed in the basal state. ​ May be altered by advancing age, presence of atherosclerosis, ​ Normal blood flow through brain: 50-55mL/100g brain tissue per and certain drugs minute (750 mL/min) ​ Blood viscosity ○​ Decreased blood supply/Hypoperfusion → ischemia → ischemic ○​ Severe anemia cascade → cerebral infarction/stroke → ischemic necrosis(2027 ​ May increase CBF as much as 30% ​ High output failure Trans) ​ Total oxygen consumption: 3.7mL/100g brain tissue per minute ○​ Polycythemia (50 mL/min) ​ May decrease CBF as much as 50% ​ Brain relies mainly on glucose for energy(2027 Trans) ​ Can be intrinsic (e.g. polycythemia vera) or secondary (e.g. smoke, sudden high altitude) CEREBRAL BLOOD FLOW ​ Directly proportional to perfusion pressure INTRACEREBRAL FACTORS ​ Inversely proportional to total resistance of the system ​ State of cerebral vasculature ​ CBF = (MAP - CVP) / CVR ○​ Widespread intracranial arterial disease increases CVR ○​ CBF: Cerebral Blood Flow ​ Leads to decrease in CBF ​ Mainly dependent on MAP ​ e.g. atherosclerosis causing stenosis ○​ MAP: Mean Arterial Pressure ○​ Pathologic processes associated with rapid shunting of blood ​ “presyon” from arteries to veins ​ Driving force of CBF (i.e. generally, increased MAP increases ​ Increase in total CBF or local reduction in tissue perfusion CBF, unless there resistance of blood vessels or CVR) ​ e.g. arteriovenous malformation (AVM; abnormal congenital ​ Decreases if there is defect whereby artery goes directly into the vein without ○​ CVP: Central Venous Pressure intervening arterioles, capillaries, nor venules) ​ Very small, almost insignificant under normal circumstances ​ Intracranial CSF pressure ​ Increases if there is intracranial mass ​ Increase in intracranial pressure ​e.g. tumor, hemorrhage ○​ Transmitted directly to low-pressure venous system ○​ CVR: Cerebrovascular Resistance ​ Increase in CVP ○​ similar to Ohm’s Law: current = electromotive force/resistance ​ Decrease in CBF D.​ REGULATION OF CEREBRAL BLOOD FLOW ​ Pathologic states frequently accompanied by increased ICP ​ Why do we want to maintain CBF? ​Reduction in blood flow may further accentuate signs and ○​ To ensure that the brain receives its needs (i.e. adequate oxygen symptoms produced by the primary lesion and nutrients) to sustain its normal functioning. ​ Cerebral autoregulatory mechanisms ○​ Neurogenic control ​ Both extrinsic and intrinsic to brain OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 6 of 11  ​ Extracranial and intracranial arteries are richly supplied by a ​ Increase pH (alkalosis): vasoconstriction neural network AUTOREGULATION ​ Not with as great a role in regulation of CBF (as chemical & metabolic factors) ​ Ability of an organ to maintain its blood flow constant for all but the widest extremes in perfusion pressure Cerebral Autoregulation ​ Ability of normal brain to regulate its own blood supply in response to: ○​ Changes in arterial BP ○​ Metabolic demand ​ Occurs in CBF when mean arterial BP is between 60-150 mmHg ​ Mechanisms for cerebral autoregulation ○​ Myogenic, neurogenic, chemical-metabolic ○​ Occurs in both large and small arterioles ​ Primarily a pressure-controlled myogenic mechanism ○​ Operates independently but synergistically with other neurogenic and chemical-metabolic factors ○​ Does not have to wait for effects of carbon dioxide ​ Major homeostatic and protective mechanism ​ e.g. High blood pressure does not necessarily produce headache Figure 21. Effects of neurogenic factors on arteries. ​ e.g. Determining brain death in comatose patients(2027 Trans) ○​ Myogenic factors ○​ Loss of spontaneous/autonomic respiration ​ Cerebral vessels can alter their diameter in response to ​ Absence of cerebral and brainstem function intraluminal pressure via a myogenic mechanism ​Like all other hollow organs that contain smooth ​ Increase pressure → vasoconstriction (via sympathetic control) ​ Decrease pressure → vasodilatation (via parasympathetic control) ○​ Biochemical-metabolic factors: Carbon Dioxide ​ Strongest driving force ​ End product of cerebral metabolism ​ Rapidly diffuses across BBB ​ Most potent physiologic and pharmacologic agent that influences CBF ​Cerebral blood vessels react rapidly to any change in local CO2 tension Figure 24. Cerebral autoregulation ​ Increase PaCO2: vasodilation with increased CBF ​ Decrease PaCO2: vasoconstriction with decreased CBF Metabolic Regulation ​e.g. Hyperventilation ​ Brain relies mainly on glucose for its energy source ○​ Blow off more CO2 than bring in O2 → decrease PaCO2 ​ Normal conditions: CBF coupled directly to neuronal metabolic blood vessels → vasoconstrict → feel dizzy after activity hyperventilating for a long time (for emergency only) ​ Linear increase/decrease in CBF results from corresponding ​Tumor increasing ICP and impending herniation change in brain metabolic activity ○​ Fastest way to prevent herniation is hyperventilate patient ​ Coupling of 1-2 seconds ○​ Decrease parenchyma → spare blood flow(2027 Trans) ○​ Strictly regional effect ○​ Produces little alteration in overall blood flow ​ Brain does not tolerate lack of oxygen[2026 Trans] ○​ Mainly aerobic metabolism ○​ e.g. meningitis → bacteria anaerobic metabolism → increased lactic acidosis → cerebral edema Figure 22. Response to CO2 ○​ Biochemical-metabolic factors: Oxygen ​ Reaction of cerebral circulation to local oxygen tension (PaO2) in reverse manner Figure 25. Metabolic-flow coupling ​ Increase PaO2: vasoconstriction ​ Decrease PaO2: vasodilation ​ Driving force is not as strong as PaCO2 in altering CBF Figure 23. Response to O2 ​ Carbon dioxide and oxygen may act: Figure 26. Glucose metabolism ​Directly on smooth muscle of the vessel wall IV.​ REFERENCES AND CITATION ​Indirectly via neurogenic chemoreceptors Dasig D. (2025). OS 202 Physiology of the Blood Brain Barrier, Cerebral Blood Flow ​By producing alterations in brain hydrogen concentration and Metabolism [Powerpoint Presentation]. ○​ Biochemical-metabolic factors: pH Dasig D. (2025). OS 202 Handout for Sleep [Powerpoint Presentation]. ​ Very strong UPCM 2027 Trans. (2020). Basic Mental Control, Consciousness and Sleep ​ Lactic acid: potent vasodilator UPCM 2027 Trans. (2020). Physiology of the Blood Brain Barrier, Cerebral Blood Flow and Metabolism ​ Decrease pH (acidosis): vasodilation OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 7 of 11  APPENDIX Figure 13. Major Arteries Supplying the Supratentorial and Posterior Fossa Levels Figure 14. Major Arteries Anastomosing to Form the Circle of Willis OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 8 of 11  Figure 15. Blood Supply of the Brainstem Figure 16. Major Branches of the Anterior Cerebral Artery Figure 17. Major Branches of the Middle Cerebral Artery OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 9 of 11  Figure 18. Distribution of the Blood Vessels and their corresponding Parts in the Homunculus Figure 19. Circle of Willis OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 10 of 11  Figure 19. Structure of Capillaries of the CNS Figure 21. Factors Regulating Cerebral Blood Flow Figure 26. Glucose Metabolism OS 202 Blood-Brain Barrier, Cerebral Metabolism, Sleep 11 of 11