Final Exam NB (Powerpoints) PDF

NSG 7430 Week 8 Lecture 1 Weekly Objective/Topic List ◦ Drives and Emotions ◦ Limbic System Functional A & P ◦ Hypothalamic Pituitary Adrenal (HPA) Axis ◦ Sleep & Wakefulness ◦ Selected pathophysiology ◦ Limbic System Dysfunction ◦ The Stress Response BALANCE ...

NSG 7430 Week 8 Lecture 1 Weekly Objective/Topic List ◦ Drives and Emotions ◦ Limbic System Functional A & P ◦ Hypothalamic Pituitary Adrenal (HPA) Axis ◦ Sleep & Wakefulness ◦ Selected pathophysiology ◦ Limbic System Dysfunction ◦ The Stress Response BALANCE  Homeostasis ◦ Remember our physiological body has set interthreshold ranges ◦ Outside of these ranges our biochemistry does not function optimally… examples are: ◦ Temperature, pH, perfusion pressures (MAP autoregulation), body water volume, blood glucose, neuroendocrine function, osmotic regulation, ECF ionic concentrations ◦ Sodium, Potassium, Calcium among others ◦ Oxygenation and ventilation thresholds * This Phot o by Unknown Author is licensed under CC BY ◦ ETC. What Do I Mean by the term “Drives”? Our physiological needs produce a desire for action… some would say a primal desire for action (Drive) ◦ The drive for action is often seeking a way to restore balance to a bodily system or function, with the two overarching goals being survival and reproduction ◦ The autonomic system creates situations favorable to restoring homeostatic balance in many aspects ◦ The SNS essentially creates energy for needed action to remedy a deficit in a more phasic manner ◦ The PSNS uses gained resources to created NRG stores and sets many system tonic states plus “breed/feed” ◦ The initial aim is to return efficiently to a homeostatic equilibrium ◦ Reaching balance will satiate the drive for a finite period of time, as defined by normal interthreshold ranges ◦ The goal is maintenance of health, life, growth and feelings of well-being ◦ These goals drive behaviors… and are deeply influenced by emotions and memories applied to them HOMER “A hungry stomach will not allow its owner to forget it, whatever his cares and sorrows.” ~ Circa 800 B.C. By Lawrence Alma-Tadema - fAFfW9CzajZAaA at Google Cultural Institute maximum zoom level, Public Domain, https://commons.wikimedia.org/w/index.php?curid=21886584 Differentiation Basic Physiological Needs/Drives Psychological Needs/Drives Promotes immediate surviving/thriving Promotes both short- and long-term behaviors ◦ Hunger ◦ Drive to Acquire or Seek ◦ Thirst ◦ Drive to Bond ◦ Sex ◦ Drive to Learn (Comprehend) ◦ Aggression/Fear ◦ Drive to Defend ◦ Sleep (Circadian Rhythm) ◦ Drive to Feel ◦ Pleasure, pain, reward, etc. What else? https://www.thoughtco.com/thmb/AjKcgMjVzPE4irF_ZrNlj2cozmc=/1500x0/filters:no_upscale():max_bytes(150000):strip_icc()/maslow-s-hierarchy-of-needs--scalable-vector-illustration-655400474-5c6a47f246e0fb000165cb0a.jpg Emotion…how does that tie in? ◦ Emotions are tied into our behaviors to lend motivation to the necessary drives ◦ Emotions can supply NRG, attention, vigilance, reactions to events or physiologic needs ◦ Emotions can decrease NRG, attention, vigilance, reactions to events/physiologic needs ◦ Emotions can motivate or demotivate a human to cope with events and circumstances ◦ They are integrally tied into our everyday life, and tempered by the other portions of the CNS that lend balance (the PFC, the insula, the BN and others) The Seat of Drives, Emotion and Memory? ◦ The Limbic System and its interactions with multiple other areas... ◦ The insular lobe ◦ The association cortices ◦ The basal nuclei ◦ The prefrontal cortex ◦ The diencephalon The Limbic System ◦ A complex set of structures for a complex set of functions ◦ Limbus = Latin, for “border” ◦ Mostly gray matter structures that lie b/w the cerebral cortex and the diencephalon proper, just superior to brainstem, forming an intracerebral border of sorts ◦ Bridge between the neocortex and the hypothalamus ◦ Composed of both cortical and subcortical structures ◦ Lack of consensus on what exactly constitutes the limbic system THE LIMBIC SYSTEM  Limbic System Components Limbic Cortex Thalamus ◦ Cingulate gyrus / Parahippocampal gyrus ◦ Anterior & Lateral Dorsal nuclei ◦ Other regions of cortex (Subcallosal area) ◦ Dorsomedial nuclei Hippocampus Basal Nuclei Fornix ◦ Ventral striatal portion ◦ Nucleus accumbens and olfactory tubercle Hypothalamus* ◦ Reward/reinforcement/addiction ◦ Limbic interconnections ◦ Pathway of treatment for refractory depression ◦ Regulatory inputs on pituitary function Amygdala ◦ Connections with varied motor/ sensory nuclei in ◦ Stria terminalis – major output pathway for amygdala brainstem & spinal cord ◦ Connected to thalamus, PFC and sensory processing, ◦ Autonomic interconnections olfactory system, hypothalamus/autonomic system ◦ Numerous brainstem nuclei Mammilary bodies and Septal nuclei Olfactory apparatus/pathway Insular lobe ? Portions of the Midbrain ? Limbic Gyrus Cingulate Gyrus Parahippocampal Gyrus ◦ The gyral fold at its anterior tip = uncus ◦ Anterior Division → amygdala; helps to ◦ Channels information both to and from the mediate attention, motivation, behavior hippocampus ◦ Posterior Division → hippocampus:; helps to ◦ Memory processing/ consolidation center mediate learning and memory ◦ A functional and efficient parahippocampal gyrus is mandatory for efficient memory processing Intralimbic Gyrus Hippocampus Amygdala ◦ The main memory processing and ◦ Corticomedial group → olfactory, consolidation center hypothalamus, autonomic function ◦ Basolateral group → thalamus and PFC, involved in visual, auditory and somatosensory processing This Photo by Unknown Author is licensed under CC BY Limbic System Interpretative Function Memory and emotive associations Drives & motivations r/t survival ◦ Nostalgia ◦ Fear ◦ Bonding ◦ Anger ◦ Romance ◦ Hunger ◦ Repulsion ◦ Circadian rhythm ◦ Sexual behavior Why some physical things evoke pleasure or Higher cognitive functions displeasure ◦ Memory ◦ Songs ◦ Adaptive Associations ◦ Smells ◦ Learning ◦ Aversive stimuli ◦ Avoidance of negative consequences ◦ Seeking out repeatable pleasurable experiences Takotsubo Cardiomyopathy AKA stress cardiomyopathy (broken heart) ◦ Interconnections with the limbic system can show how some medical conditions can be exacerbated or even caused by mental stress ◦ This is an acute heart failure syndrome brought on by intense psychological or physiologic stress ◦ Theorized to be related to powerful, sustained limbic activation of the HPA axis and the sympathetic nervous system causing a sustained catecholamine overload ◦ The sustained excess of catecholamines are a result of intense excitation of the locus coeruleus-adrenomedullin axis and hypothalamus- pituitary-adrenocortical (HPA) axis Limbic Networking The Limbic System ◦ Basis for emotions, memory and conscious awareness of the same, plus mediating bodily responses towards these For these complex functions/interactions to happen: ◦ Must be a structural, coherent subsystem ◦ Must be connected to afferent sensory information: this implies afferent evocation of perception/emotion ◦ Must be connected to efferent motor/action system in some manner ◦ Needs connections to cortical processing centers Therefore, the limbic system needs capabilities in multiple systems ◦ Must serve as a bridge between the autonomic and conscious, voluntary responses to a changing environment How does this work? Coordinated response to a cold room: ◦ ANS response, coordinated by the hypothalamus ◦ Cutaneous vasoconstriction and shivering ◦ Conscious awareness of the sensation of being cold and being averse to this condition ◦ Cognitive decision to seek more clothing and/or sources of warmth ◦ Negative emotion associated with the feeling of being too cold encodes the memory and stimulates the planning activity of the PFC to dress warmly in the future  LIMBIC NETWORKING ILLUSTRATION ONLY Limbic System Functions Mnemonic Main Functions of the Limbic System (H O M E) ◦ Homeostasis: Bodily function regulation ◦ Homeostasis via endocrine regulation ◦ Homeostasis via autonomic regulation ◦ Thermoregulation ◦ Drives: sleep/wake/circadian rhythm, hunger, thirst, sexual ◦ Olfaction ◦ Memory functions: Storage and consolidation of memories ◦ Associative learning, short- and long-term memory formation ◦ Emotions: stimuli and interpretation of emotional responses ◦ Associative learning, short- and long-term memory formation Simplification of the Limbic System ◦ These are the KEY structures involved in these basic functions of the limbic system ◦ Not the ONLY structures involved in them… ◦ Multiple feedback circuits must operate simultaneously for the limbic system to function normally ◦ Closely connected structures must also function normally DITKI HOMEOSTATIC BALANCE HYPOTHALAMUS Yes, again!!  It is a Diencephalon Structure ◦ 0.3% of total brain mass, or 4cc of tissue volume ◦ Forms the walls and floor of the inferior portion of the 3 rdventricle Anatomical ◦ Lies posterior to the optic chiasm ◦ The anterior border is the lamina terminalis Facts ~ ◦ The posterior structure in the hypothalamus = mamillary bodies Hypothalamus ◦ The column of the fornix descends through the hypothalamus and connects with the mamillary bodies ◦ Laterally is in contact with the internal capsule ◦ The inferior border is the tuber cinereum ◦ Inferiorly is exposed to subarachnoid space ◦ Controls both lobes of the pituitary gland  The hypothalamic sulcus separates it from the thalamus ◦ Mammilary bodies: pair that form much of the posterior hypothalamus ◦ Tuber cinereum: “gray swelling”: bulge b/w the optic chiasm and the mammilary bodies Anatomical ◦ Infundibulum: arises from the tuber cinereum and forms the pituitary stalk which is continuous with the posterior pituitary lobe Facts ~ together forming the neurohypophysis ◦ The neurohypophysis is neurally connected to the hypothalamus via the Hypothalamus hypothalamohypophyseal tract (white matter, axonal projections) ◦ Median eminence: anteroinferior area of the tuber cinereum: funnel for collection and release of regulatory chemicals from the hypothalamus → adenohypophysis ◦ Anatomical fact: the adenohypophysis is actually NOT a diencephalic structure, but instead is an outgrowth of the roof of the mouth ◦ Connected to hypothalamus by a venous portal system (hypothalamohypophyseal venous portal system) Functional Facts - Hypothalamus ◦ Major forebrain afferent input to the hypothalamus arise from limbic structures ◦ Hypothalamic output influences pituitary function ◦ Interconnections to visceral and somatic nuclei of both sensory and motor function in both the brainstem and the spinal cord ◦ Anteromedial region = PSNS activity, satiety, sleep... and dissipation of heat (response to hyperthermia) ◦ Posterolateral region = SNS activity, hunger, wakefulness... and conservation of heat (response to hypothermia) Hypothalamic Main Functions Remember “H E A L” = Homeostasis: Endocrine: Autonomics: Limbic To perform these functions, the hypothalamus is also connected to: ◦ The limbic system ◦ The reticular formation ◦ Autonomic centers in brainstem and spinal cord ◦ Connected via neurohumoral control and vascular (hypophyseal) portal system to endocrine function ◦ Can release secretions into the ECF or into CSF (exposed inferiorly to the interpeduncular cistern, and medially to the third ventricle) ◦ Blood supply: surrounded by the Circle of Willis ◦ Flow is derived from an extensive network of small perforating branches of multiple main arterial systems: ◦ FYI only… Anterior and posterior communicating arteries, proximal posterior cerebrals, proximal middle cerebrals & the lenticulostriate, and the anterior choroidal Hypothalamic Inputs (Afferent Info Received) ◦ Thalamic and neocortex inputs ◦ Notably the frontal lobe, PFC ◦ Visual input ◦ Spinal cord and brainstem inputs ◦ Visceral and sensory input ◦ Somatic afferent information ◦ Autonomic centers ◦ Olfactory information (minor but present) ◦ Limbic system inputs ◦ Septal nuclei ◦ Amygdala ◦ Hippocampus Hypothalamic Outputs (Efferent Info Sent) Many hypothalamic efferents mirror, or Cerebral cortex efferents reciprocate, the afferent connections ◦ Thalamic and neocortical ◦ Not focused only on limbic cortex ◦ Spinal cord and brainstem ◦ Widespread cortical projections ◦ Autonomic ◦ Histaminergic ◦ Limbic ◦ Orexin, or hypocretin (arousal, ◦ Septal nuclei wakefulness, appetite) ◦ Amygdala ◦ Mammillothalamic tract: memory ◦ Hippocampus Basics of Homeostasis Many physiologic parameters must be kept within a narrow range of interthreshold values for normal function of the body and mind, with a perfect goal of a SET POINT ◦ Changes in neuroendocrine, visceral and autonomic functions strive to re-balance the parameter towards the set point, or at least a normal range (mostly negative feedback systems) ◦ The hypothalamus functions as a command/control center, integrating input & output from limbic & other centers ◦ It projects to pregang ANS motor neurons and to central pattern generators ◦ Nucleus of the solitary tract (NST): principal visceral sensory brainstem nucleus supplying afferent information to visceral reflex arcs and also to the rostral CNS, assisting with autonomic regulation (mechanoreceptor and chemoreceptor information, among others) ◦ Parabrachial nuclei: visceral sensory information in less specific way… receives inputs from spinothalamic tract and from the NST and then coordinates w/ hypothalamus, amygdala, the insula and the thalamus to generate a general sense of well-being (or not!) ◦ Ventrolateral reticular formation (rostral medulla): CV and pulmo fxn, micturition/defecation, sexual function ◦ Periaquectuctual Gray (PAG): Descending pain control origin: organizing complex behaviors to external threats *  OSMOTIC HOMEOSTASIS ~ ONLY FOR ILLUSTRATION OF COMPLEXITY AND NOT FOR EXAM  Homeostasis Examples – Know These Temperature Thirst (H2O and Na+ balance) ◦ Set point 37 degrees C (?): sensing neurons (medial ◦ Decreased H2O volume leads to a decreased preoptic neurons) feed afferent information to... plasma volume and increased osmolality ◦ Central pattern generators to handle decreased or increases in body temperature, either heat dissipation ◦ Baroreceptors sense volume change via pressure (anteromedial hypothalamus) or heat conserving detection (mechanoreceptors) (posterolateral hypothalamus) ◦ Information transmitted to CNS and to kidneys pH (indirectly via decreased blood flow) ◦ Multiple avenues for pH control (extracellular fluid) ◦ Increases in angiotensin II (sensed in CNS neurons) ◦ Chemical, respiratory and metabolic pathways ◦ Afferent stimuli lead to the medial preoptic ◦ Main Chemical trigger is CO2 in arterial blood & in CSF nucleus that then stimulates ADH secretion Appetite ◦ Cerebral cortex stimulated to cause thirst ◦ food intake, glucose and metabolic balance ◦ Complex balance between ghrelin and leptin MENTAL BREAK... LAKE ATITLÁN LIMBIC FUNCTION ~ OLFACTORY SENSATION Limbic Function ~ Olfaction Very small area, especially compared to other vertebrates ◦ Smell sensation contributes to both odor detection and to the sense of taste ◦ Olfactory receptor neurons are free nerve endings connected to unmyelinated axons ◦ These traverse the cribiform plate behind the nose ◦ After going through this the axons terminate in the olfactory bulb ◦ Synapsing on tufted and mitral cells ◦ Axons from these cells form the olfactory tract which transmits information to the olfactory cortex ◦ No thalamic relay but there are some projections from the tract to thalamus and limbic cortical areas Entorhinal cortex: association of smells and related memories Just a reminder... ◦ Intracranial invasion with a medical device has a reported mortality of greater than 64% ◦ Rarely is there an absence of neurological complications ◦ Beware of insertion of NGT or a nasopharyngeal airway in patients with: ◦ Dx'd basal skull fractures ◦ Suspected CSF leak via nose or ears ◦ Severe craniofacial trauma ◦ History of transsphenoidal surgery (sinus or pituitary surgeries) Limbic Function Memory Two Main General CNS Areas for Memory Medial Temporal Lobe Medial Diencephalic Memory Areas Hippocampal formation ◦ Thalamus: DM and anterior nucleus ◦ Hippocampus, parahippocampal ◦ Mammillary bodies gyrus, dentate gyrus and others ◦ Septal nuclei White matter connections Basal forebrain cholinergic projections For anatomical reference only NOT ON EXAM… Memory ~ Temporal Lobe Structures Hippocampal Formation – Temporal lobe structures ◦ Dentate gyrus: connections to the entorhinal cortex, ◦ Plays a role in formation of memories: Can also play a role in depression ◦ Subiculum: transition zone b/w the dentate gyrus and the hippocampus proper ◦ Two different cortical tissue types ◦ Major source of output fibers from the hippocampal formation ◦ Hippocampus proper: lies close to the amygdala ◦ Key in functional consolidation of short-term memory transforming into LT memory ◦ Some function in memory retrieval ◦ Spatial memory contributing to navigational abilities ◦ Long term potentiation (plasticity) via certain high frequency activity causing a long-lasting increase in synaptical strength Hippocampal Connections  Parahippocampal Gyrus: area of cortex curved around the hippocampus ◦ Memory encoding and retrieval Associated ◦ Forming/storing new memories Cortical Cingulate gyrus: just above the corpus callosum Memory ◦ Connected to cortical association areas, thalamic anterior nucleus, somatosensory areas of the cortex Structures ◦ Emotion formation/processing, learning and memory, central role in attention, pain/emotion processing and regulation ◦ Drives body to avoid unpleasant experiences, avoid negative consequences Memory ~ Diencephalic Structures Mammillary bodies ◦ These 2 groups of nuclei have extensive connections to both the amygdala & hippocampus ◦ Possible integration of memory and emotion Septal nuclei ◦ These groups of nuclei are also extensively interconnected in the limbic system ◦ Key in pleasure, reward and reinforcement… plus the memory of the same Fornix: receives output fibers from the subiculum, and these continue the major hippocampal output tract ◦ White matter information conduit ◦ Projects to the mammillary bodies, the thalamus, and questionably some projections to the hypothalamus Memory Terminology Declarative (Explicit) memory ◦ Conscious recollection of specific facts or occurrences Nondeclarative (Implicit) memory ◦ Non-conscious learning of skills, habits or acquired behaviors: unconscious or automatic memories, used or applied w/out thought Anterograde amnesia ◦ Deficit in forming new memories* Retrograde amnesia ◦ Deficits in pre-existing memories* Bilateral damage to medial temporal lobes = Patient HM s/p temporal lobe resections for epilepsy was unable to learn new facts or store and recall new experiences (Also see the excellent movie "Memento”) Guy Pierce in “Memento” LIMBIC FUNCTION EMOTIONS Emotions Amygdala – Temporal Lobe Structure ◦ Considered the seat of emotions and survival motivation ◦ Mediates fear, anxiety, anger and associative learning with situations that provoke these states ◦ Bilateral collections of nuclei, shaped like almonds = Amygdala ◦ Lies in the temporal lobe, within the uncus, above the inferior horn of the lateral ventricles ◦ Lies at the anterior end of the hippocampus ◦ Receives a large array of sensory afferent input, including visual and auditory info ◦ Sends out a large array of efferent connections ◦ Has a hand in a very large number of integrative functions Afferent Input to the Amygdala Sensory information Input routes ◦ Sight, sound, touch, smell, taste ◦ Stria terminalis General levels of physical and emotional ◦ Thalamus comfort ◦ Hypothalamus ◦ Orbital and cingulate cortical areas ◦ Cingulate cortex (amygdalofugal path) ◦ Insula ◦ Olfactory cortex ◦ Visceral sensory areas ◦ Temporal lobe structures including the ◦ Hypothalamus hippocampus ◦ PAG ◦ Parabrachial nuclei  EFFERENT OUTPUT OF THE AMYGDALA (NOT ON THE EXAM)  ◦ Provides a general window of the current status of a person’s thoughts and situation in the environment Amygdala through the interplay of the limbic and cortical areas ◦ Behavioral awareness: matching the propriety of behavioral responses/actions ◦ Situational awareness… vigilance and attention ◦ Involved in emotionally related parts of learning Functional ◦ Self-preservation via coordinated responses to Effects environmental and emotional threats ◦ Feeding and drinking: Fighting behavior: Mating and maternal care (DRIVES) ◦ Response to physical or emotional stress  LIMBIC SYSTEM DYSFUNCTION  Neurodegenerative disease most commonly associated with the limbic structures ◦ Deposition of amyloid proteins leads to the formation Alzheimer's of amyloid plaques (outside neuronal cells) ◦ Development of neurofibrillary tangles within neuronal cells Disease ◦ The disease preferentially focuses on bilateral hippocampal, temporal and basal forebrain structures ◦ Anterograde amnesia is a cardinal, early sign ◦ As other cortical areas become involved, then retrograde amnesia begins, followed by dementia  Neurobehavioral syndrome associated with bilateral medial temporal lobe lesions or damage, especially in Klüver Bucy the amygdala (bilaterally) ◦ Fearlessness, placid affect Syndrome ◦ Not responsive to threats, social gestures ◦ Facial expression blunting, or inappropriate to the situation ◦ Loss of avoidance ◦ Hyperphagia, hyperorality and hypersexuality ◦ Inordinate attention to all sensory stimuli ◦ Visual agnosia  Caused by severe and sustained thiamine deficiency ◦ D/t damage of mammillary bodies & thalamic dorsomedial nucleus ◦ Seen in alcoholics, patients on long-term TPN, hemodialysis Wernicke- patients, gastric carcinoma ◦ Acute = ataxia, eye movement abnormalities and confusion Korsakoff Chronic Syndrome ◦ Temporal lobe aspects ◦ Antero- and retrograde amnesia, remote memory affected more than immediate recall ◦ Lacking awareness of memory deficit ◦ Frontal lobe aspects ◦ Executive function deficits: impaired judgment, initiative, impulse control, task sequencing, confabulation PSYCHIATRIC IMBALANCES Schizophrenia Neuropsychological disorder Neuro-anatomical changes ◦ Thought abnormalities ◦ Abnormalities in frontal lobe, PFC, basal nuclei and the limbic system ◦ Delusions and hallucinations hallmark sx ◦ Reduced limbic structure size and volume, ◦ Flat affect, +/- catatonia especially hippocampus and amygdala ◦ Disorganized speech ◦ ? Excess dopaminergic activity, reduced ◦ Cognitive deficits glutamate transmission** even given glutamate ◦ Working memory impaired excitotoxicity damage that is often present ◦ Altered GABA, 5HT and norepinephrine activity Ketamine diminishes overall glutamatergic transmission NOT the agent for patients w/ schizoaffective psychiatric diagnoses or borderline personality disorder patients  Can be thought of as a failure of top-down regulation in the limbic system ◦ Failure of the cingulate gyrus (anterior cingulate) and the hippocampus to regulate the activity of the amygdala Anxiety ◦ Storage and creation of emotions is thought to play a States role in all anxiety-related information processing ◦ So, in anxiety states, the amygdala predominates on the basis of noradrenergic and serotonergic transmission ◦ Enhancing GABAA transmission seems to help (BZDs) ◦ This is especially true of situational anxiety, less so in chronic anxiety states QUESTIONS...? NSG 7404 or NSG 7204 WEEK 8 LECTURE 2 Weekly Objectives - - ·Drives and Emotions ·Limbic System Functional A & P ·Limbic System Dysfunction ·Sleep & Wakefulness ·Hypothalamic Pituitary Adrenal (HPA) Axis The Stress Response Sleep & Wakefulness Loading… Melatonin (Happy Thanksgiving!) · Tryptophan, an essential amino acid, is the initial precursor in the synthesis of melatonin · Through mitochondrial enzymatic biosynthesis, tryptophan is transformed first into serotonin · Serotonin is then synthesized further into melatonin · Hormonal secretion of melatonin into the bloodstream occurs via the pineal gland · Major influence in sleep-wakefulness cycle, circadian rhythm, and in BP regulation · It has significant utility as an antioxidant; its roles in supporting the immune system, as an anti-  A reminder of the pineal gland that is at the back of the epithelmas, right? It is derived from the roof of - the diacephalon and again, it's part of the Reminder – Pineal Gland epithelmas. It synthesizes both melatonin and it does some serotonin synthesis as well. It's mostly known for melatonin and that is the predominant thing that it synthesizes. · Structure developed from the roof of the G oodiencephalon, part of the epithalamus · Synthesizes both melatonin and its precursor, serotonin Loading… ⑳ · The pineal gland releases melatonin into both the systemic circulation and into the CSF of C the third ventricle · Circulating melatonin levels inform brain regions about both 24-hour light/dark cycles and seasonality light cycles · Especially key in the induction of sleep  EXAM D- D So functional anatomy, this is a really nice and simple diagram Functional Anatomy – Melatonin Release from Draw It to Know It. It does explain things really well. Suprachiasmatic nucleus (SCN) Anterior hypothalamus "Master timekeeper" Adjusts production & release of melatonin Acts in concert w/retinohypothalamic pathway which transmits light that excites the SCN Works to inhibit the Paraventricular nucleus during the Light phase... which in turn inhibits melatonin release And the other relays that can be involved in this are in the cervical spinal cord and in the superior cervical ganglion, which you Paraventricular nucleus might remember is either sympathetic or parasympathetic. It would be a useful thing to Anterior hypothalamus remember on future exam. Dark phase: this removes the inhibition of the SCN Stimulates the pineal gland to release melatonin after relays in the cervical spinal cord and the superior cervical ganglion (BTW… is this ganglion sympathetic or parasympathetic?) Orexin (Hypocretin) and the Flip-Flop Switch* This happens alt production of orexin ↑ - ⑧ which stabilizes · Once a desired state (sleep or wakefulness) is obtained, a way to stabilize each portion of the biphasic state is necessary · The sleep center is located in the hypothalamus and works during sleep to inhibit wakefulness cells · Wakefulness cells are located in the frontal lobe, hypothalamus, and multiple brainstem areas Recall the reticular activating system of the brainstem Multiple neurotransmitters involved in the wakefulness cells · Wake-promoting cells work in the hypothalamus and function to inhibit the sleep center structures Sleep Properties of Common Medications - Ex - O · TCAs inhibit BOTH cholinergic - & histaminergic transmission ( resulting in sleepiness) ① - Amitriptyline, nortriptyline Very commonly given in lower doses as sleep aid · Benadryl is an antihistamine (causing sleepiness)* · Amphetamines promote wakefulness (NeRI) O -· Cholinesterase inhibitors promote wakefulness O O · Dopamine agonists counterintuitively can cause O sleepiness subtypesapet rempyr & · SSRIs counterintuitively can cause sleepiness These last two facts likely reflects that other factors  and receptor subtypes play into complexity Summary Table – Direct Pharmacologic o Corollaries Wakefulness We said Benadryl and we're listing the dopamine agonist and Amphetamines (noradrenergic reuptake inhibitors) the SSRIs as counterintuitive. So just a nice summary table to provide for study. Combined serotonin-norepinephrine reuptake inhibitors Cholinesterase inhibitors (donepezil) Sleep-Inducing Tricyclic antidepressants (anticholinergic/antihistamine) Diphenhydramine (antihistamine and antimuscarinic) Dopamine agonists and SSRIs counterintuitively cause sleepiness… even though they can enhance wakefulness mediators Phases of Sleep and EEG Terminology - Wakefulness = alpha waves Non-REM Sleep = theta and delta wave sleep (mixed frequency and slow wave patterns) REM Sleep = saw tooth waves: occur every 90 minutes or so and there should be 4 cycles per night This sleep type only occurs in mammals and birds bodies Is the predominant sleep type in newborns and infants, and decreases with age olivary With normal sleep, each REM cycle should be longer in length than the previous one > - REM sleep is associate with dreaming and muscle atonia (olivary inhibition) but has similarities to wakefulness states Dreams are hard to remember due to absence of normal levels of neurotransmitters needed for adaptive memory storage REM is an ACTIVE state: the brain utilizes equal or more O2 and glucose during REM sleep than during wakefulness REM sleep is highly integral to normal neurological function, especially cognitive function Current research indicates that propofol interferes with REM sleep Sleep Pathology - Narcolepsy a -tapexy complete) Type 1 Narcolepsy Extensive loss of hypothalamic neurons that produce orexin, so the wakeful state is not Type 1 narcolepsy is able to stabilized once established be pinned to a specific problem. It is extensive loss Type 2 Narcolepsy Loading… of the anterior hypothalamic neurons that produce orexin. Idiopathic, cause unknown Type 2 narcolepsy is we don't know why it's happening. You can do Can interfere Chronic tremendously sleep in personal disorder functional MRIs and see and Cataplexy**professional Highly lives attacks disordered the loss of signal in the (partial or regulation complete) of REM Sudden Significant sleep · Diagnosis is challenging area of the hypothalamus paroxysms daytime of drowsiness irresistible sleep and you can surmise that those hypothalamic neurons are damaged. · Rx combination of behavioral and medications · Combination of amphetamines or similar drugs plus additional meds, especially if significant cataplexy symptoms are present Normal Neurobiology with Perioperative Stress Hypothalamic Pituitary Adrenal Axis HPA Axis  - Summary Review of Hypothalamic Pituitary Control EXAM Anterior E need to know anterior vs. posterior  EXAM The HPA Axis - Corticotropin Releasing Hormone (CRH) from the hypothalamus · Stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH) oo ACTH release is excitatory to the adrenal cortex · Stimulates the release of cortisol (glucocorticoid) and to a lesser extent aldosterone (mineralocorticoid) Glucocorticoids, on the other aldosterone hand, promote glucose mobilization into the ECF. Mineralocorticoid Effects eg : - They are also anti- inflammatory in all tissues and can influence both immune · Maintains stable BP via both fluid balance & vascular tone and reactions. So by and mobilization large, cortisol is · Controls electrolyte balance immunosuppressive and it is used Na+ and H2O retention, excretion of K+ and protons Usually, systemic level of cortisol 3 functions as a negative feedback loop Glucocorticoid Effects to modulate the release of CRH/ACTH · a Perioperatively, we are particularly interested in Anesthesi (HPA-ax) a this ① Cortisol * Release Cortisol pathophysiology… too much, too little ⑭ O  Sustained HPA Axis Response ↑ - r/t Perioperative Stress Pathophysiology It can obviate or blunt this normal feedback mechanism Of The Adrenal Medulla (SNS Mediation) Tes O The adrenal medulla is internal to the cortex G · This area is under direct control of the preganglionic sympathetic neurons · Releases - epinephrine and norepinephrine These mediators stimulate the Sympathetic Nervous System · Not only does this alter physiologic vital signs but initiates a positive feedback loop because the adrenal gland as a whole functions as a stress transducer · Modulates neuro-immunologic responses Sustaineda & & · Regulates cardiovascular responses in crisis mode  Injured Tissues (Inflammatory – Immune Response) BOARDS When tissue is injured, there is the ↓ · Histamine causes the "triple flare of Lewis" = G inherent reaction of vascularized tissue to & redness (rubor), heat and swelling - O - - limit bleeding by reflex vasoconstriction... this is very time-limited · The combination of all of this causes pain but is functionally intended to deal with the injury · However, to initiate healing, an - inflammatory response must then quickly · Histamine leads to increased blood flow into the injured tissue, bringing immune cells in for follow - cleanup and healing · Injured cells immediately release · Chemokines stimulate functional WBC arachidonic acid * chemotaxis from systemic circulation to the · Injured cells stimulate the downstream release cytokines and chemokines from leukocytes site of injury rese · The WBC then follow with a liberal release of  cytokines Adrenal Medullary Sustained Stress Response - ⑳ diagram wontbetested On but its a , good summary  Controlled Chaos THE STRESS RESPONSE T O S U R G I C A L O R T R A U M AT I C I N J U RY This Photo by Unknown author is licensed under CC BY-NC-  Anesthesia - The Perioperative Surgical Stress Response - Is a two-pronged response (Neuroendocrine-Metabolic & Inflammatory-Immune) · The extent of the overall response is mediated by: Magnitude, invasiveness and duration of the surgical procedure Pathophysiologic state of the patient (comorbidities, physiologic reserve) - Perioperative interventions to mitigate the surgical stress response · The worst offenders are major open vascular and abdominal surgery, joint replacement surgery, and cardiac surgery utilizing cardiopulmonary bypass · The stress response can be needed but should be controlled for best results in M&M · All the body's homeostatic mechanisms are again intended for time-limited interventions · When sustained beyond usual limits can lead to SIRS, hyper-metabolism, impaired healing, tissue failure and /or systemic organ failure Inflammatory-Immune Response ALREADY COVERED REVIEW SLIDE #19 SNS Responses Periop monitoring (part of the Neuroendocrine/Metabolic Response) · HypothalamicG PVN detect hypotension and/or inflammation via endogenous markers · Fibers activate the limbic system and pituitary secretion · SNS is strongly activated leading to adrenal medullary - positive release of epinephrine feedback · Epinephrine releaseO reinforces the SNS activation and mobilizes CHO and fat stores Inhatabout o? · Sustained increases in both epinephrine and norepinephrine are facilitated · Increased HR and vascular tone  Endocrine System Response BOARDS-SAVE THIS f Unfortunately, surgical stress induces hyper- normal increases in both ACTH and cortisol · Plasma cortisol levels remain increased an o o average of 7 days post-op when finally, negative feedback loops impose a return to homeostasis · Minimally invasive surgical techniques both delay and limit the peak of cortisol surge - - · Effective multimodal analgesia and adequate O overall depth of anesthesia also mitigates the cortisol stress response · Chronic activation* of the HPA axis prior to surgery impairs mitigation of the physiologic stress response t blunts any return to homeostasis stress response and blunts any return to Cortisol – An independent predictor of M&M · Basal cortisol levels measured within 24 hours have been correlated to in-patient mortality and 28-day survival rates in both surgical and sepsis patient populations · This is true... BUT · This literature is not as clear-cut as it used to be, as we are able to safely anesthetize much more frail and critically ill patients than even just a few years ago, and with different agents and improved anesthetic techniques · And so large sustained surges in the HPA axis and in cortisol and other end mediators is still to be mitigated to the extent possible · CAVEAT: totally blunted ability of the HPA axis to respond to the healing challenges of surgery also greatly impacts survival in frail or critically ill populations  Metabolic Response to Surgical Stress What matters to anesthesia practice? p fro · Propofol is excellent at minimizing or abolishing the stress response, particularly in relation to cortisol and aldosterone levels (the HPA axis response to the adrenal cortex) Differential effects are noted with single dose vs. sustained infusions O · Etomidate is an induction agent that imparts hemodynamic stability but is known to suppress Loading… adrenocortical function: is known to suppress cortisol and aldosterone for up to 8 hours after a single dose Unfortunately, no cortisol is just as bad (or worse) than too much in the long run in an unstable patient This induction agent has certain specific indications and does not have broad usage anymore · Volatile anesthetics are nearly as good as propofol with stress response surge suppression, if not O actually better: no major differences in outcomes are seen between TIVA and volatile maintenance techniques in relation to the degree of surgical stress response · However… volatiles do interfere with both platelet aggregation and immunomodulation significantly more than propofol What matters to anesthesia practice? Stress Dosing of Glucocorticoids Back to Balance, or Homeostasis What to do Requires Provider Judgment The Goals of Excellent Perioperative Care · Optimizing the patient’s preoperative medical condition if feasible · Avoidance of excessive/prolonged periods of fasting · Mitigate the adverse effects of the Neuroendocrine Stress Response to the extent possible · Multimodal pain management · Multimodal symptom management (e.g., PONV) · Facilitate early mobilization of the patient · Earlier resumption of enteral nutrition (minimize postoperative ileus) Can anesthetic techniques and practices influence all of these?? The Evolution of Liverpool Technique (Neonatal Anesthetics) · Until the 1960-80s, common A story about unintended consequences of the HPA Axis anesthetic technique for stable or especially ill neonates was known as the "Liverpool Technique" · This consisted "light" general anesthesia maintained with nitrous oxide and paralytics – and nothing else · At the time, it was justified by the theory that neonates' neurological systems were “too immature” to feel pain · The stress and pain kept catecholamines in systemic circulation and helped maintain vital signs at acceptable ranges during surgery giving the appearance of a successful anesthetic · Seminal research in the 1980s (Anand, et al. 1987) showed withholding analgesia in these types of cases lead to  exaggerated and sustained stress responses, which then led to So... what is best anesthetic practice?  Good Summary - Balanced Anesthesia with Multimodal Analgesia Combination of agents for induction that have the goal of reasonable suppression of sustained surges of the HPA axis Strong recommendation for inclusion of adrenergic alpha2 agonists in plan of care Maintenance agents: volatile agents vs. TIVA (some advantages to HPA stability from TIVA is strongly suggested in the literature( The control of pain with multimodal techniques and medications The use of regional or neuraxial anesthesia whenever feasible Consideration of glucocorticoid supplementation in elderly, frail or critically ill patients or in surgical procedures known to induce extreme inflammatory responses m The Development of ERAS Protocols u Food for Thought… Laughter, Tragedy and the Limbic System  tested The Power of the Limbic System Connections ·“While it is well known that both not laughter and humor can have deep and long- Louie D, Brook K, Frates E. The Laughter Prescription: A Tool for Lifestyle Medicine. Am J Lifestyle Med. 2016;10(4):262-267. Published 2016 Jun 23. doi:10.1177/1559827614550279  lasting psychological Respectful Treatment of Others Can Alter Limbic Function · Limbic associations proceed whether we wish them to, or not. They are deeply instinctual and embedded · So… my admonition to treat people well and engender positive thoughts is not just altruistic · It works just as well, and usually better than aversive conditioning · Patients This Photo by Unknown Author is licensed under CC BY-ND · Colleagues/Interprofessional Colleagues Post-Lecture Mental Break Elephant Rehabilitation and Care · Elephant Sanctuary and Discovery Center in TN: https://www.elephants.com · https://youtu.be/TlE73DZ4QME? si=Ry5PoCs4UEdSR8Wr · The story of Bella and Tarra · https://youtu.be/brbZie9kZlQ? si=WcQRdXGgqOOaifFI · Elephants and caretaker reunion Questions… ? NSG 7430 We ek 9 Le ctu re 1 W E E K LY O B J E C T I V E S / T O P I C S Functional A&P of the Sensory System Review Further detail Nociception Pathways Acute Pain Epidemiology & Impact Acute Pain Interventions Selected Pathophysiology: Risk Factors for Acute Pain Persistence/Transformation RE V I E W M AT E RI A L S I M P L I F I E D N E U RO N A L S C H E M AT I C N E U RO N A L I N F O R M A T I O N P RO C E S S I N G Transduction A transducer accepts NRG in one form and transmits or gives back that NRG in a different form Neurological receptors transform specific stimuli they detect into electrochemical messages (receptor potentials) that are then conveyable to the neurological systems Transmission The movement of the messages by electrochemical propagation by axonal and synaptic transmission A single axon can synapse with as many as 1000 other neurons Perception/Reception Occurs in cortical or subcortical areas of the CNS Modulation A physics term → the variation of a property in an electromagnetic or chemical wave or signal A functional fluctuation of neuronal cells responding to a changing environment That change can occur either in the internal or external environments… or both Can be inhibitory or facilitory, long- or short-term, fast-acting or slow Can happen anywhere, at any level, along the neurological pathways/tracts  S E N S O RY PAT H WAY S Terminology Reminder: First order = primary Second order = secondary Third order = tertiary S E N S O RY S Y S T E M Sensory Nervous Division (AKA the “Special Senses”) Mediates vision, touch, taste, smell, hearing and balance Consists of highly specialized sensory receptors, neurons, reflex arcs, neural pathways or tracts, and CNS perception/reception centers Somatosensory Nervous Division Mediates the senses of crude and fine touch, temperature, pain, pressure, vibration, and proprioception Mediates visceral sensory information: usually chemical changes or stretch/pressure information Consists of sensory receptors, neurons, reflex arcs, neural pathways/tracts, and CNS perception/reception centers Includes thermoreceptors, mechanoreceptors, chemoreceptors, nociceptors, muscles spindle fibers, GTOs, proprioceptors, stretch receptors S O M A T O S E N S O RY S Y S T E M R E V I E W S E N S O RY A N A T O M Y R E V I E W Peripheral sensory system: specialized neuronal receptors, primary afferent neuron, peripheral nerves, peripheral nerve plexuses, dorsal root ganglia, spinal nerves (cranial nerves) Transduction, Transmission, Modulation CNS sensory system: synapse in dorsal horn SC laminae (brainstem nuclei), secondary and tertiary afferent neurons, decussations, ascending tracts, brainstem passages and projections, thalamic synapses (VPM and VPL), cortical and subcortical terminal transmission endpoints with association projections Transmission, Perception, Modulation TERMINOLOGY REVIEW Stimulus: A detectable change in internal or external environment Adequate stimulus: The type and quantity of energy a specific receptor requires to respond to stimuli by transduction signal production Modality/mode: The qualitative aspect of a stimulus after the stimulus is perceived Special senses Somatosensory (pressure, temperature, crude touch, fine touch, proprioception) Noxious or non-noxious stimuli, or noxious or non-noxious levels of stimuli P roduction of receptor potentials: the change in membrane potential resulting from a stimulus: can be related to the structural characteristic of the receptor involved (brief, maintained, intermittent) Adaptation: the tendency of a receptor to become less sensitive in the face of a maintained stimulus Slow vs. fast adaptation → E.G. static position sense (tonic) vs. position change or movement (phasic) Response: The amount of neurological transduction/transmission invoked by the stimulus TERMINOLOGY REVIEW Threshold: The minimum intensity stimulus that provokes a receptor response Sensitivity: The innate capacity of a receptor to respond to a stimulus: indirectly proportional to the threshold. The lower the receptor threshold, the higher the receptor sensitivity, and vice versa Receptive field: The area of tissue, or space on a sensory surface, innervated by a neuron or specialized receptor Receptive field size differs d/o how discrete the sensation Cutaneous pain/temperature receptors typically have generous receptive fields Cutaneous vibration/fine touch typically have much smaller receptive fields Localization of stimuli more difficult the larger the receptive field: more typically found in the sensations of temperature, pain, itching * P E R I P H E R A L S E N S O RY N E RV E S Peripheral sensory nerves (pr imary afferent neurons) are bundles of individual sensory nerve fibers that transmit the stimuli that have been transduced by the sensory receptors Nerve plexuses: outside the vertebral column these per ipheral nerve fibers are organized into intricate networks for convergence and collation of sensory information Cervical Plexus Brachial Plexus Lumbosacral Plexus Facial Plane Bundles These feed into the mixed spinal nerves (31 pair) that transmit innervation from specific anatomical ter ritories: dermatomes, myotomes and osteotomes The cell bodies for the sensory pr imary afferent neurons reside in the dorsal root ganglia at each level of the spinal column The primary afferents continues in the dorsal rami at each level of the spinal column which car ry the primary afferent fibers into the spinal cord The primary afferents synapse with CNS secondary afferent neurons at different levels depending on sensory modality mediated and the ascending tract used: dorsal column tract vs. anterolateral tract I M P O RTA N T C O N C E P T Remember that the dorsal root ganglion represents the cell body of the primary sensory neuron that is transmitting afferent information It is pseudounipolar … This means it sends neuronal fibers both towards the spinal cord and towards peripheral targets This is important later in sensory modulation and in overall function S P I N A L C O R D P E R I P H E R A L I N N E RV A T I O N C N S T RA N S M I S S I O N D I T K I A S C E N D I N G PAT H WAY S Will not focus heavily on Spinocerebellar tracts Mediates unconscious proprioception integration Afferents from muscle spindles and GTOs At its simplest is a two-neuron system Primary afferent into dorsal horn through the DRG Synapse with second order neurons in SC Projects to ipsilateral cerebellum P O S T E R I O R C O L U M N P AT H WAY S Posterior Column = entire posterior The primary afferent medial division funiculus on one side projections from from the caudal end of the SC to the T6 level and compr ise the gracile Ascending large myelinated first-order fasciculus (lower extremities and trunk) and neuronal afferent fibers synapses in the caudal medullary nucleus Transmits infor mation from low- gracilis with the secondary neuron threshold cutaneous, joint, and muscle The primary afferent lateral division receptors to the cerebral cortex. projections from T6 level and up comprise Spinal first-order (primary) afferent the cuneate fasciculus (upper limbs and fibers have their cell bodies in the trunk) and synapses in the caudal medullary ipsilateral dorsal root ganglion nucleus cuneatus with the secondary neuron The fibers enter the spinal cord and All posterior column second order neurons segregate into medial and lateral decussate in the caudal medulla, coalesce to divisions on each poster ior column side for m the medial lemniscus which then project to synapses in the thalamus and finally the SSC P O S T E R I O R C O L U M N P AT H WAY Know the posterior column sulci landmarks T H E A N T E RO L A T E R A L P A T H WAY The Spi notha la mic Tra ct (STT) T H E S P I N OT H A L A M I C T RA C T Lateral Spinothalamic Tract Anterior Spinothalamic Tract This tract is the one meant when just the In the anterior funiculus, interposed also with STT is used, truly located laterally in the the vestibulospinal tract AL pathway Conveys crude (poorly localized) touch and Pain, temperature, noxious stimuli pressure sensations (protopathic sensation) Uses mostly A-beta fibers, synapses in the Thinly myelinated A-delta and C fibers nucleus proprius Certain peripheral receptors and nerve Secondary neuron decussates in the anterior fibers are routed to the LSTT white commissure as do the secondary neurons of the LSTT Incoming primary afferents can ascend or descend via Lissauer’s tract just prior to dorsal horn entry TH E S PIN OTH AL AMI C TRACT( STT ) Concerned with the tra nsmission of noxious stimuli (pa in, plus temperature & itching) Noxious neurological transmission is broadly termed nociception, and entails typical sensations described as burning, stinging, aching, stabbing, or cutting The STT is connected to multiple pathways and collateral projections in the CNS in order to mitigate and remove sources of har m or injury from our bodies Rapid attention must attend the source of the pain and muscle reflexes to end exposure to the damaging stimuli Emotions, autonomic responses and memory patterns are activated Encodes memory and learning to avoid similar harmful situations in the future Much of the transmission of noxious stimuli begins with free nerve endings or thinly myelinated receptors/fibers in the periphery transducing the stimuli into nociceptive signals These nociceptive signals are transmitted to the SC via primary afferent nerve fibers Much more widespread distribution of the STT signals than in the posterior column system Trigmenothalamic Pathway We will not focus extensively on this, but I do expect that you know: It exists Mediates facial sensation First order neurons enter via the pons Synapse in the trigeminal nucleus Second order neurons cross the midline of the pons Terminate in the VPM thalamic nuclei Third order neurons project to the CC A S C E N D I N G PAT H WAY S Mnemonic: VPM = Trigem M E N TA L B R E A K CONTINUING PLASTICITY NOCICEPTIVE TERMINOLOGY Noxious stimulus: A stimulus that is damaging or threatens damage to normal tissues Nociceptive stimulus: An actually or potentially tissue-damaging event transduced and encoded by nociceptors Nociception: The neural process of encoding noxious stimuli Nociceptor: A high-threshold sensory receptor of the peripheral somatosensory nervous system that is capable of transducing and encoding noxious stimuli Nociceptive neuron: A central or peripheral neuron of the somatosensory nervous system that is capable of encoding noxious stimuli Nociceptive pain: Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors Neuropathic pain: a broad term, which can refer to pain that stems from any somatosensory nervous system lesion or pathologic process.  P E R I P H E R A L N E RV E F I B E R T Y P E S Nerve fiber diameter and myelination is correlated with nerve fiber function and conduction velocity (Please note: there is more than one naming/classification convention!) A fibers: myelinated sensory and motor fibers, listed here from the fastest conduction → the slowest within the A fiber designation A (alpha) fibers = proprioception, muscle spindle fibers(1-a), GTOs (1-b), joint receptors A (beta) fibers = some proprioception, non-noxious touch, pressure (e.g. Pacinian corpuscles) Some small percentage are also ultra-fast nociceptors A (gamma) fibers = motor efferents to muscle spindles A (delta) fibers = some (fast) nociceptors, some cold and visceral receptors B fibers: myelinated visceral afferents: preganglionic autonomic nerve fibers C fibers: unmyelinated fibers: most nociceptors, some touch and visceral receptors, itch receptors, and postganglionic autonomics P E R I P H E R A L P R I M A RY A F F E R E N T S Site of Transduction (receptors) for the Somatosensory System Transmission via: A- fibers (thinly myelinated) C fibers (unmyelinated) These 2 comprise > 70% of the peripheral nervous system Activation and cross-activation is possible Send axons into the SC via the spinal nerves, with the cell bodies residing in the dorsal root ganglia Some C fibers may also potentially enter by the motor nerve root O V E R A L L : A N T E RO L A T E R A L ( S T T ) P AT H WAY The primary sensory neuronal fibers enter the spinal cord matter after projecting from the DRG From entry it is possible that the primary neuronal fibers may ascend or descend 1-2 spinal segment levels within Lissauer’s tract (fasciculus) OR… they may simply carry on within the same level to enter the gray matter of the dorsal horn of the spinal cord In the dorsal horn Rexed’s laminar layers, the primary sensory neuron then synapses with the secondary sensory neuron The secondary STT sensory neuron then decussates within the SC anterior white commissure and ascends in the anterolateral pathway’s STT (can change SC levels here also) The outer portions of the anterolateral pathway carry sensory information from the legs (O my leg!) The inner portions of the anterolateral pathway carry sensory information from the arms R E M I N D E R : D I T K I A S C E N D I N G PA T H WAY S C R I T I C A L R E L AY S TAT I O N : T H E T H A L A M U S Thalamus routes almost all sensory information to and from cerebral cortex Discriminative vs. affective/emotional pain signals routed appropriately to supraspinal structures Some mediation of autonomic responses Is a VERY viable target for analgesic interventions Is literally connected to almost every portion of the brain Which nuclei are the main somatosensory relays?? VPM = Trigem → facial sensation VPL = body sensation (look at relative size of the two) R E V I E W : S O M AT O S E N S O RY C O RT I C A L A R E A S The post central gyrus = S1 Lies at the front of the parietal lobes behind the central sulcus Perception and discrete localization of pain occurs here Discriminative vs. affective aspects of pain r/t interconnections with other centers and association cortices In nomenclature of cortical gyri and sulci, recall you must pay attention to pre- and post suffixes as clues AC UT E PA I N E pidemi ol ogy a nd I mpa ct PA I N Pain: psychological response to a noxious stimulus, a negative emotional state, which serves to protect us from injury through the alteration of behavior Pain: Unpleasant sensory and emotional experience associated w/ actual or potential tissue damage or described in terms of such damage (WHO & IASP) Pain threshold: The minimum intensity of a stimulus that is perceived as painful Pain tolerance level: The maximum intensity of a pain-producing stimulus that a subject is willing to accept in a given situation PA I N T E R M I N O L O G Y Hypo- or hyperesthesia: decreased/increased response to any sensory stimulus Hypo- or hyperalgesia: decreased/increased response to a noxious stimulus Analgesia: the absence of painful sensation with a normally noxious stimulus Allodynia : painful sensation with a normally non-noxious stimulus (bed sheets on feet) Paresthesia : An abnormal sensation, whether spontaneous or evoked, not necessarily unpleasant Dysesthesia: An unpleasant abnormal sensation, whether spontaneous or evoked Neuritis: Inflammation of a nerve or nerves causing pain Neuralgia: Pain in the specific innervation distribution of a nerve, or nerves Neuropathy: A disturbance of function or pathological change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy P RO C E D U R A L PA I N Rarely is the pain we deal with clinically the adaptive physiologic process, or at least not for long… Exposure to the inciting stimuli is prolonged and to a degree, unavoidable Inflammatory and nociceptive chemistry set up a self-perpetuation difficult to interrupt Interplay of unique physiology (single nucleotide polymorphisms = SNPs) Interplay of cognitive and emotive factors… positive or negative Pain always has psychiatric, emotional and behavioral aspects A C C E S S O RY P A I N P A T H W A Y S E P I D E M I O L O G Y O F PA I N 30 million surgical procedures are perfor med annually in the US This exposes patients to the occurrence of post-operative pain, with the incidence of severe post-op pain being somewhere in the 20-40% range Normal physiologic functioning and healing typically make acute pain a self-limited process Effective and proactive analgesic interventions can greatly assist with this process Serves to elicit neuroendocr ine, metabolic, inflammatory and sympathetic nervous system responses geared towards possible need for self-preservation dr ives In large part this response is mediated by the HPA axis and results in increased levels of cortisol Sustained increases in cortisol perioperatively is an independent marker of morbidity and mortality Increased ACTH, ADH, cortisol, aldosterone, angiotensin and glucagon Water and sodium conservation Vasoconstr iction, HTN, tachycardia * and increased O2 demand Increased blood sugar (inhibition of insulin, stimulation of glycogenolysis) combined with catabolic state Suppression of normal levels of inflammatory responses (cortisol) Suppression of the immune system responses Hypercoagulable state O T H E R G E N E R A L S E Q U E L A E O F A C U T E PA I N Poor pulmonary toilet Muscle spasm from guarding Anxiety Cognitive impairment Depression Gastrointestinal inhibition Ileus N &V Delayed discharge from PACU or facility Opioid side effects PA I N A S S E S S M E N T Visual Analog Scale (1-10) Brief Pain Inventory No one single pain scale has Should use a Incorporates mood, function and cognition been shown to be consistent tool for more accurate or the ability to effective than assess and intervene Just because he/she can’t communicate does not another mean the patient is not in pain!! * Multiple facial expression scales exist for Pain interventions pediatric patients or foreign language situations Most effective then should scales include encompass all Facial expression scales are the preferred assessments of aspects of pain mood, cognition phenomena, and medium for pediatric populations and function not just nociception I N D I V I D UA L I Z I N G PA I N R E G I M E N S Individualized assessment re: multiple aspects of pain can be done w/ planned surgical interventions Psychological tendencies can predict pain levels or response to single episodes of acute pain Pre-existing chronic pain states can predispose to less controlled acute pain Individual differences in endogenous opioid functionality Intrinsically low levels of endogenous opioid function can predict a better response to exogenous opioid therapy… and the converse is also true Single nucleotide polymorphisms (SNP) Nucleotides are the components of DNA and RNA (adenine (A), cytosine (C), guanine (G), and thymine (T) SNP is the substitution of a single nucleotide in the genomic sequence A common SNP can alter the function of the Mu ( ) opioid receptor and therefore affect opioid function Both endogenous and exogenous opioid function can be affected r/t ligand receptor affinity Gender-based opioid responses Differential opioid receptor physiology in men and women can alter exogenous opioid efficacy S O, W H AT ’ S N E X T ? ( A L L O F I T ! ) Also, areflexia or moderated reflexia YO U M U S T L E A R N T O M U LT I T A S K AND BE FLEXIBLE… S U M M A RY O F V I A B L E A N A L G E S I C T A R G E T S A & P A N D I N T E RV E N T I O N M E T H O D O L O G Y Peripheral Block signal transduction Block action potential propagation Block action potential transmission Spinal Prevent hypersensitivity Prevent plasticity/windup Restore/augment segmental inhibition Glial cell modulation ? Supraspinal Enhance descending modulation Psychological/Behavioral modulation This P hoto by Unknown Author is license d under CC BY-NC-ND QUESTIO NS…?? NSG 7430 WEEK 9 LECTURE 2 Weekly Objectives/Topics Functional A&P of the Sensory System Review Further detail Nociception Pathways Acute Pain Epidemiology & Impact Acute Pain: Nociceptive Physiology and Interventions Selected Pathophysiology: Risk Factors for Acute Pain Persistence/Transformation  Peripheral Mechanisms Neurobiology: Spinal Mechanisms Pain Pathways & Interventions Supraspinal Mechanisms Targeted Interventions  Peripheral Pain Physiology - Nociceptors The receptor type that transduces noxious stimuli are most often free nerve endings = nociceptors Nociceptors respond to heat/cold, mechanical and chemical stimuli Nociceptors convert (transform/transduce) the energy of the noxious stimuli into an electrochemical signal Analgesic target = receptors This happens via ion channels and if stimulus is large enough (meets the threshold) → results in the generation of an action potential in the peripheral terminal The action potential is propagated (transmitted) along unmyelinated C fibers and/or thinly myelinated A delta- fibers of the primary (peripheral) afferent neuron and transmitted to the spinal cord Analgesic targets = neuronal fiber transmission Primary Somatosensory Afferent Neuronal Fibers A beta- transmits touch & pressure (non-noxious); a small % are ultra-fast nociception fibers A delta- transmits noxious mechanical stimuli and sub-noxious temperature stimuli C fibers respond to only noxious heat, mechanical and chemical stimuli…i.e., noxious stimuli is the modality of the C fiber nociceptor Fiber Summary Explanation for Your Reference The classic lateral spinothalamic tract is primarily served by non-myelinated C fibers (slower transmission) and thinly myelinated A-delta fibers (relative to C fibers, faster transmission) These fibers mediate noxious crude touch (pain), noxious temperature, painful pressure/mechanical distortion and itch sensations The posterior column-medial lemniscus tract is served by thicker, faster myelinated fibers such as A-beta and some unnamed others; due to the cutaneous receptor density, threshold and innate sensitivity these fibers serve to relay proprioception, vibration and fine touch sensation (two-point discrimination, tracking and the discrete sensation of light touch) This is truly FINE touch sensation. A-beta fibers are used in the anterior spinothalamic tract to transmit non-noxious touch sensation into the nucleus proprius in Rexed's laminae III and IV. Compared to the touch sensation relayed by the lateral spinothalamic tract, this A-beta sensation is less crude, more fine and discrete in nature However, compared to the touch sensation relayed by the posterior column system, this A-beta sensation is crude So, this A-beta sensation is normally non-noxious and crude touch as compared to the posterior column system, but more discrete or fine as compared to the lateral STT, so kind of in the middle. Be aware: some A-beta fibers can be recruited... or even genetically transformed, to relay noxious stimuli in the case of inflammation and increased nociception Also, in normal conditions there is already some rather limited participation by A-beta fibers in the lateral STT (also called the pain pathway). Primary Afferent Neurochemistry Targets (Some of them…) TRP Vanilloid Type 1 Channels (TRPV1) Capsaicin and heat receptor Voltage-gated Na+ and K+ channels Na+ → Initiation/transduction and transmission of nociception K+ → sets the resting membrane potential, repolarization Voltage-gated Ca2+ channels Ca 2+ needed for synaptic neurotransmitter release in the CNS synapse of the primary afferent G-coupled protein receptors Nociceptive inflammatory mediators: calcitonin gene-related peptide (CGRP), bradykinin, prostaglandin (excitatory to nociception) Antinociceptive pathway agents: opioids and adrenergic agonists (inhibitory to nociception)  When exposed to the adequate noxious stimulus, these afferents can then release stimulatory chemical messengers Prostaglandins, bradykinin, *5HT*, histamine, substance P, CGRP… This is the first example of facilitory modulation as Primary these messengers all facilitate movement of Nociceptive nociceptive information towards the SC Peripheral Peripheral sensitization: An inflammatory Afferent response in the periphery which leads to a Physiology zone of primary hyperalgesia D/T release of intracellular contents from damaged cells, stimulating histamine and other inflammatory mediators Often marked by a zone of tissue showing the Triple response of Lewis = vasodilation (flare), edema (wheal), and hyperalgesia Primary Peripheral Afferent – Facilitory Modulation Nociceptor stimulation can lead to a neurogenic inflammatory response from the peripheral afferent due to: Release of substance P, neurokinin A, CGRP and neurotrophins (nerve growth factor) Can lead to the recruitment of nociceptors that, under normal conditions, are silent. Consequences of Peripheral Neuronal Sensitization Decreased threshold and latency Increased frequency response Increased receptive field plus overlap After-discharges Increase in excitatory nociceptive transmission within the SC Recruitment of further neurons to ramp up nociception Increased neurotransmitter release locally and upstream Spinal Nociceptive Mechanisms Spinal Mechanisms The primary peripheral afferent transmits its message of noxious stimulus into the SC Plus or minus segmental change in Lissauer’s tract Noxious signals primarily synapse in dorsal horn gray matter, in Rexed’s laminae I, II, III (V) Non-noxious stimuli input in laminae III and IV Glutamate is the major neurotransmitter released by nociceptive afferents and some excitatory(!) interneurons This is an unusual function for interneurons, BTW GABA and glycine are the some of the main inhibitory neurotransmitters released by inhibitory interneurons and descending inputs Substantia Gelatinosa Rexed’s lamina II Principal site for the modulation of nociception in the SC Neurons, glial cells, inhibitory interneurons Mu & Kappa opioid receptors, both pre- & post-synaptic Pre-synaptic means interaction with the primary afferent neuron Post-synaptic means interaction with the secondary afferent neuron Extends the entire length of the SC and into the medulla Plus… Medullary extension in the spinal nucleus of trigeminal nerve Spinal Cord Neuronal Types Primary nociceptive afferents synapse in the SC with secondary afferent neurons Nociceptive-specific neurons (NS) receive noxious input mainly from C fibers Wide dynamic range neurons (WDRs) receive input from A- and A- fibers as well as C fibers WDR neurons are the most prevalent neuronal type in the dorsal horn Have very large receptive fields, and a great facility for “windup” Their recruitment is a likely mechanism → allodynia, hyperalgesia LT (low threshold) neurons are facilitory to both nociceptive and non-nociceptive transmission Cross-talk b/w cell types and fiber types can occur which is faciliatory to nociception Primary afferent neurons may also synapse here with interneurons, SNS neurons and ventral motor neurons Spinal Cord Cascade – Facilitory Modulation C fiber stimulate the release of Flexion reflex: hyper excitability excitatory neurotransmitters in the SC Spinal motor neuron crosstalk Glutamate Positive feedback pain mechanism Substance P (sP) Retrograde increase in peripheral sP Aspartate, CGRP, NO synthetase Recruitment of WDR neurons Activation of Na+ channels and Receptive field expansion and overlap propagation of the action potential Developing knowledge about the Can increase temporal and spatial contribution of glial cells to both nociception and its inhibition neuronal summation If the pain is sustained, genetic change Windup, and long-term potentiation are and expression occurs that is facilitatory now possible with these conditions in to nociception place C-fos expression is a biological marker that this genetic transcription has occurred Spinal Cord Synapse Receptors Key nociceptive excitatory receptors Glutamate: NMDA, AMPA Glutamate: Kainate, MgluR Substance P Nitric oxide NK1 and cAMP Key nociceptive inhibitory receptors GABA (inhibits post-synaptic neuron in the SC by Cl- channels) Glycine *5HT* (serotonin) Alpha2 adrenergic Opioid Glutamate Continued nociceptor activity induces prolonged glutamate release Activates NMDA and non-NMDA receptors These include AMPA, MgluR and kainate receptors Stimulates calcium influx into secondary afferent neurons = ^^ neurotransmitter release Perpetuates excitatory chemical cascade Mediates central plasticity, stimulates NO synthetase, mediates primary and secondary hyperalgesia, and opioid tolerance Surgical trauma and exogenous opiates unfortunately are known to activate NMDA receptors BTW… as previously mentioned, NMDA receptors are also key in memory formation and neuronal plasticity needed for learning: d/o on the pathway Sequence of NMDA Receptor Activation Removal of the magnesium plug by depolarization Calcium influx into the cell and neurotransmitter release Activation or production of intracellular second messengers Direct enhancement of receptor activation and sensitivity Facilitation of neuronal pathway transmission Induction of gene transcription within the cell nucleus Leads to long-term changes in the responsiveness of the cell Production of arachidonic acid (AA) metabolites sP Receptor Activation Activates excitatory amino acid cascade in both the spinal cord and retrograde in the peripheral afferents Acts via NK-1 receptors to mediate peripheral and spinal cord neuronal sensitivity Can be involved in afferent innervation of visceral sensation as well All this perpetuates continued nociceptor activity in BOTH the periphery and in the SC Nociception Supraspinal Structures Supraspinal Mechanisms On its way to the thalamic relay with the tertiary afferent neuron, projections are sent along the way to… The reticular formation The hypothalamus The midbrain (PAG), among others The pain pathway culminates in the SS1 & SS2 plus projections to… The limbic system The insula The prefrontal cortex Double-edged Sword Transmission projections along Transmission projections the way form the ”pain matrix” along the way also lay the → the important divergence of foundation for supraspinal the nociceptive signals to inhibition of nociception multiple critical subsystems Descending inhibitory (modulatory) pathway, AKA Almost always accomplished by Monoaminergic descending glutamatergic transmission or inhibition, most often other excitatory media propagated by serotonergic elaborated transmission to inhibitory structures, but is actually initiated by the presence of glutamatergic signaling Supraspinal Descending Inhibition Pain is PERCEIVED and localized in CNS structures… primarily by supraspinal structures Once it is perceived, the brain and other structures can modulate nociceptive transmission in an inhibitory manner Key cortical structures in the descending inhibition of nociception include the PFC, insula, anterior cingulate cortex, amygdala… Key subcortical structures include midbrain PAG, pontine parabrachial complex and locus coeruleus, the rostral ventromedial medulla (RVM), the raphe nuclei in the RVM, and SC interneurons Descending Inhibition Mechanisms Rostrally, the PAG has reciprocal connections with multiple cortical sites and the amygdala The PAG receives ascending nociceptive signals from the parabrachial nuclei PAG can be both facilitory AND inhibitory to nociceptive signaling: best known for inhibition, however Inflammatory mediator release in the PAG can cause the facilitation of nociception Caudal to the PAG, it is reciprocally connected with the RVM and the locus coeruleus: (1) the PAG activates the raphe nuclei in the RVM via glutamate (2) The RVM then projects to dorsal horn laminae and inhibits nociception via serotonergic, GABAergic and opioid synapses (3) The locus coeruleus projects to dorsal horn laminae and inhibits nociception via presynaptic noradrenergic synapses Neurotransmitters used to initiate and maintain descending inhibition can include glutamate, 5-HT, endogenous opioids, norepinephrine, cannabinoids, GABA and glycine Global Actions – Main Pathway Descending Inhibition Stimulation of the PAG in the midbrain is triggered by inputs from ascending STT projections as well as descending influences from the amygdala, other limbic structures, the insula and PFC The PAG then stimulates the structures in the parabrachial nuclei and the RVM to activate inhibitory projections The RVM raphe nuclei act as a final relay switch for the descending inhibitory system The raphe nuclei send projections down to the inhibitory interneurons in the SC and activate these via 5HT These interneurons then release enkephalins or endorphins, or other inhibitory neurotransmitters In turn these endogenous ligands ramp down the activity of nociceptive fibers and helpfully work to decrease the antegrade and retrograde release of sP Where do we go from here?? Even though the deck is stacked against us Glutamate, aspartate, sP AA metabolites, other facilitory mediators all along the pathway Facilitory neurohumoral transmission via the neuroendocrine stress response SNS activation, inflammatory responses, HPA axis enhancement Other pro-inflammatory mediators Nitric oxide production in the pathway via stimulation of NO synthetase Genetic transcription → long-term potentiation All these can conspire to ramp down nociception inhibitory processes, or even kill beneficial cell types such as interneurons Role of glial cell types Fortunately, quite a few alternatives do exist Mental Break… The Perioperative Goal Balanced Multimodal Pre-emptive Analgesia Balanced & Multimodal, Pre-emptive Analgesics that act on distinct and varied pain pathway components, to increase efficacy and decrease side effects Goal of preemptive analgesia: prevent the induction of CNS plasticity Initiated prior to procedural trauma Modalities or their effects outlive the continued generation of noxious stimuli, or at least the most intense period of the same ** The very best pre-emptive modalities modify noxious afferent input before spinal cord transmission, or at least cortical perception Neuraxial and Regional Techniques Avoidance of large doses of multiple IV medications, particularly opioids Possible avoidance of general anesthesia and its inherent potential complications throughout the perioperative period Less hemodynamic compromise if no GA Less PONV Attenuated neuroendocrine stress response Decreased thromboembolic complications Less time for ambulation and/or discharge, dependent on the block utilized Less use or no use of opioid agents Always prepare for complications or changes due to your chosen technique… Potential longer pre-operative time period Limitations due to proper equipment Limitations due to proper training or experience Complications inherent to each type of blockade Risk of systemic local anesthetic toxicity  Endogenous Opioid Ligands Opioid Neurochemistry Opioid receptors: G-coupled proteins w/ 7 transmembrane helices Peripheral opioid Rs can directly inhibit noxious stimuli, acting on somatic and sympathetic nerves Also acts on GI tract tissue via receptors there Importantly, these receptors work in the substantia gelatinosa, brainstem nuclei, PAG & certain cortical areas In SC pre-synaptic terminals opioids inhibit Ca2+ influx (decreases NT release) In SC post-synaptic terminals opioids promote K + efflux (hyperpolarization of membrane and inhibits nociception transmission) Opioids can also disinhibit the descending modulatory pain