Week 2 (Anxiety, Hearing, Alterations in Consciousness and Sleep) Flashcards
Normal developmental fears
Infancy: strangers, loud noises, separation
Early childhood: separation, monsters, dark
Middle childhood: real-world dangers, new challenges, health, school
Adolescence: social status, relationships, performance, the future
When is anxiety a disorder?
Avoidance
Interference
Distress
Duration
DSM-IV Anxiety Disorders
Generalized anxiety disorder (GAD)
Panic disorder/agoraphobia
Post-traumatic stress disorder (PTSD)/Acute stress disorder
Social phobia
Obsessive compulsive disorder (OCD)
Specific phobia
Seen predominantly in childhood: separation anxiety disorder (SAD), selective mutism (SM)
Prevalence of anxiety disorders
Most common class of mental disorders in general population
Lifetime prevalence of any anxiety d/o >15%
Women > men (except OCD, SoP)
Common in childhood: 75% have first episode by age 21.5; most common class of childhood disorders (10-15% of community children)
Comorbidity of anxiety disorders
Other anxiety disorders
Depression (genetic influence because similar pathways, runs in families, treated by same drugs; environmental influence secondary to anxiety-related disability)
Substance abuse (biological because overlapping risk factors; environmental because of self-medication)
Greater burden of non-psychiatric illness
If no anxiety/depression in childhood, are you likely to become anxious/depressed in adulthood?
Only 5% chance of anxiety/depression if healthy in childhood
Etiology of anxiety
Genetic: high heritability but complex genetics; “behaviorally inhibited” children 3x risk; cognitive biases in processing and attention
Environment: parents of anxious children more likely to model anxious cognitions and behavior, provide negative feedback/behave less warmly, act in a restrictive manner (grant less autonomy)
Agoraphobia
Fear and avoidance of place and activities from which it might be difficult to escape or get help
Commonly avoided places: crowds, school, wide open spaces, restaurants, parties, subway
Commonly avoided activities: leaving house, driving, waiting in line, being alone, travel, shower, exercise, caffeine, drugs, sex
Specific phobia
Intense anxiety/avoidance of specific stimuli, disproportionate to actual danger, which causes functional interference
Common fears: dark, animals, thunderstorms, water, elevators, illness/injury, airplanes, blood/injections, heights, doctor/dentist, choking
Generalized anxiety disorder (GAD)
Anxiety/worry about multiple things more days than not for >6 months
Difficult to control worry
3 or more of these symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance
Distress/impairment
Obsessive compulsive disorder (OCD)
Obsessions: intrusive, unwanted, distresing thoughts or urges that persist despite efforts to ignore or control them; concerns about contamination, illness/somatic, safety, right/wrong (scrupulosity); intrusive thoughts/images could be numbers/words, violent/sexual images
Compulsions: repetitive rituals aimed at neutralizing (but often unrelated to) the obsessive worry; repeating rituals could be cleaning/washing, checking, re-reading/writing, tapping/touching, counting; good/bad clothes, numbers
Compulsions more common in touretic OCD: ordering/arranging/symmetry, hoarding/collecting
Post-traumatic stress disorder (PTSD)
May develop after a person has experienced or witnessed a traumatic or terrifying event in which serious physical harm occurred or was threatened
Symptoms may include flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the event
Anxiety disorder due to a general medical condition
Physical health problem can cause symptoms of anxiety
Ex: cardiac, endocrine, asthma/COPD, neuroendocrine tumor
Anxiety disorder due to a drug/substance
Substance-induced anxiety disorder is characterized by prominent symptoms of anxiety that are a direct result of abusing drugs, taking medications or being exposed to a toxic substance
Ex: inhaled beta-agonists (albuterol), stimulants, steroids, thyroid replacement, caffeine, decongestants, marijuana, cocaine, methamphetamine
Anxiety disorder not otherwise specified (NOS)
Prominent anxiety or phobias that don’t meet the exact criteria for any of the other anxiety disorders but are significant enough to be distressing and disruptive
Separation anxiety disorder (SAD)
Presence of 3 or more of the following:
Distress when separation is anticipated or occurs
Worry about harm befalling others
Worry that an untoward event will result in separaion
Refusal to go to school or elsewhere
Fear or reluctance to be alone at home or in other settings
Refusal to sleep away from attachment figures
Nightmares
Physical complaints at separation
Note: common to have GAD, specific phobia and depression as comorbidities
Developmental considerations with SAD
Ages 5-8: fears of harm befalling attachment figures, nightmares, school refusal
Ages 9-12: excessive distress at separation, school refusal
Ages 13-16: somatic complaints and school refusal, avoidance of developmentally appropriate socialization
Selective mutism (SM)
Consistent failure to speak in specific social situations despite speaking in other situations
Closely related to social anxiety disorder
Symptoms typically become problematic when children enter school
Uncommon (0.71% of K-2nd graders)
Screening questions for different anxiety disorders
GAD: “Would you describe yourself/your child as a worrier?”
Social: “Have you noticed yourself/your child avoiding social situations or feeling uncomfortable or afraid of doing something embarrassing in front of others at school, restaurants, parties, or when meeting new people?”
SAD: “Does your child worry a lot about being away from you; that something bad may happen to you or him/her while you’re apart?”
OCD: “Do you/does your child have intrusive thoughts that s/he can’t get rid of or rituals that bother him/her?”
Cognitive-Behavioral Triad of Anxiety
Thoughts
Feelings
Behaviors
Anxiety builds when “uncomfortable” situation and subsides when “safe” situation
Intervening at all 3 points of the Cognitive-Behavioral triad of anxiety
Thoughts: learn to talk back to your thoughts (“this is just my anxiety, there’s nothing real to fear”)
Behaviors: control your actions (graded exposure, avoidance is the enemy)
Feelings: learn to relax your body (breathing, progressive muscle relaxation, guided imagery, mindfulness/meditation)
Treating children with anxiety disorders
Children with anxiety disorders are highly responsive to therapy, and it is often possible to avoid using meds
CBT is key in children, but needs to be fun, emphasize rewards, and parental support is necessary
Meds can be important if therapy alone not enough, child is severely impaired/distressed, comorbidity, child/parent unable to adequately engage in therapy
SSRIs for treatment of anxiety
SSRIs have strongest support of all agents!
Excellent efficacy across different anxiety disorders
Excellent tolerability with mild-moderate side effects
Sedation: fluvoxamine, paroxetine
Activation: fluoxetine, sertraline (both have more GI side effects)
P450 interactions in fluvoxamine, paroxetine, fluoxetine
Less evidence for citalopram, escitalopram
Sexual side effects :(
Other drugs for treatment of anxiety
SNRIs: not first-line in OCD, serotonergic action key
TCAs: less effective, more side effects; clomipramine as augmenter or as monotherapy in OCD
Neuroleptics: limited efficacy data except in OCD, side effects; frequent augmenter in OCD (especially with tics)
Benzodiazepines: short-term or occasional use (especially in panic), limited by side effects (tolerance, dependence, cognitive impairment, rebound anxiety), paradoxical effects in children (disinhibition)
Benzo alternatives for PRNs: gabapentin/pregabalin (standing or prn), beta blockers (propanolol) in social phobia (prn)
Benzodiazepines
Bind allosteric site on GABA-A receptor-chloride channel complex (distinct from GABA binding site)
Positive allosteric modulators: produce little or no effect on chrloride conductance in absence of GABA, but enhance GABA-mediated increase in chloride conductance (increase efficiency of GABAergic synaptic transmission by membrane hyperpolarization and decrease firing rate of neurons)
All have anxiolytic, sedative and hypnotic properties
Dose-dependent continuum of CNS depression
Anxiolytics, sedatives, “tranquilizers” cause calm, relaxation then drowsy, sleepy; also cause paradoxical disinhibition (inhibitory pathways themselves get turned off so excitation occurs)
Hypnotics produce sleep
Anesthetics cause unconscious
Dose-response curves of barbiturates vs. benodiazepines
Barbiturates have steep response curve so easy to produce undesired effects (like drowsiness)
Benzodiazepines have shallow curve so wide safety margin and takes more drug to produce undesired effects
Pharmacokinetics of benzodiazepines
Absorption: well absorbed after oral administration
Distribution: very lipid soluble; distribute throughout body
Metabolism: primarily hepatic clearance, oxidation and subsequent conjugation (oxidation can produce active metabolites)
Which benzos do and do not have active metabolites?
Diazepam, chlordiazepoxide and clonazepam have active metabolites and long effective half-lives; accumulate with repeated daily administration
Oxazepam and lorazepam are only conjugated (no CYP metabolism) and do not form active metabolites; accumulation is minor
Is the duration of action of benzos based upon their half life?
Not if they have active metabolites!
If drug has active metabolites (diazepam, chlordiazepoxide, clonazepam) then duration of action based on those active metabolites too!
Pharmacologic effects of benzodiazepines
CNS:
Anxiolytic (treatment of GAD)
Sedative (used before medical procedures like endoscopy)
Hypnotic (promotes sleep)
Anesthetic (note: benzos are not analgesic)
Anticonvulsant, muscle relaxant (produces some degree of skeletal muscle relaxation (suppression of spinal and supraspinal motor reflexes))
Adverse effects of benzodiazepines
Common adverse effects are extensions of their pharmacological actions: sedation, decreased intellectual function (confusion), anterograde amnesia (no memory acquisition or recall), psychomotor impairment (for days), withdrawal seizures; fatal OD rare unless combined with ethanol or other CNS depressant
Abuse only in those with a history of abuse
Few drug interactions due to wide safety margin (high TI) and no inhibition/induction of CYP450
Wide individual differences in sensitivity to benzodiazepines
Elderly more sensitive to all effects
In liver disease, increased sensitivity to those drugs that do CYP metabolism in liver (diazepam, etc) so use oxazepam or lorazepam instead for patients with liver disease
Flumazenil
Competitive antagonist at benzodiazepine binding site; used clinically to treat benzo OD
Tolerance, dependence and withdrawal with benzos
Tolerance develops (pharmacodynamic, not pharmacokinetic) to benzos in general (not individual types) for sedative and anticonvulsant activity (not anxiolytic effects)
Cross-tolerance between benzos and other CNS depressants
Physical dependence occurs if chronic use and get withdrawal upon cessation
WIthdrawal more apparent with shorter acting drugs (suddenly stop then immediately “off” drug as opposed to longer tapering built in to longer acting drugs)
Symptoms of withdrawal may mimic anxiety (jitteriness, insomnia, loss of appetite) or may be different (tremor, muscle twitching, paresthesias, seizures)
How do you minimize withdrawal from benzos?
Switch patient from short-acting to long-acting benzo and slowly reduce dosage of drug
Buspirone
Partial agonist of 5HT1A receptors
Structurally different from benzodiazepines, does NOT interact with GABA receptors
Best for previously untreated patients who might require long-term treatment of GAD, or who are abusers of CNS depressants
Not effective in panic attacks
Side effects: low incidence of headache, dizziness
Response occurs only after several weeks of tretment
No bad side effects: produces no sedation (just calming), no anticonvulsant or muscle-relaxant properties, little impairment of cognitive or psychomotor skills, no tolerance or withdrawal upon cessation, little or no abuse potential, no additive effect
Used for dyspepsia or IBS because there are 5HT1A receptors in fundus of stomach
Drug classes with anti-anxiety effects (other than benzos)
TCAs: effective in some patients with panic attacks
MAOIs: effective in some patients with panic attacks
Beta blockers (propranolol): prevent peripheral autonomic manifestations of anxiety (tremor, sweating, tachycardia and palpitations); don’t prevent anxiety itself
Insomnia
Difficulty falling asleep, staying asleep, and/or too early awakening
Caused by stress, emotional upset, aging, medical and psychiatric illness (sleep apnea, nocturnal myoclonus, depression), drugs, jet lag
Characteristics of the ideal hypnotic
Induce sleep rapidly
Produce normal sleep
Reduce number of awakenings
Wake up refreshed (no hangover)
Not cause tolerance or dependence
Safe (high TI, few side effects, no drug interactions)
Effects of hypnotics on sleep
Decrease latency of sleep onset
Increase duration of stage 2, non-REM sleep
Decrease slow-wave sleep (stages 3 and 4)
Reduce REM sleep (this is bad and can produce hangover the next day!)
Prolong total sleep time
Benzodiazepines for treatment of insomnia
All benzos can be used as hypnotics but don’t meet criteria for good hypnotic (have hangover effect, don’t produce normal sleep, have tolerance so only good short-term, produce withdrawal effects (insomnia, REM rebound which can produce nightmares))
Triazolam (Halcion): short half life (1.5 - 5.5 hours), little hangover, less accumulation but can produce increased wakefulness during last 1/3 of night, daytime rebound anxiety and anterograde amnesia for some
Temazepam (Restoril): half life between triazolam and flurazepam but slowly absorbed and sleep onset can be delayed
Nonbenzodiazepine hypnotics
Structure unrelated to benzodiazepines or barbiturates but still interact with GABA-A receptor!
Zolpidem (Ambien): relatively short half life (1.5 - 4.5 hours), no active metabolites
Zaleplon (Sonata): binds subtype of GABA-A receptor, very short duration of action, useful for patients who have difficulty falling asleep or awaken in the middle of the night
Eszopiclone (Lunesta): binds to subtype of GABA-A receptor; intermediate duration of action
How is melatonin synthesized?
5HT is turned to N-acetyl serotonin by NAT in the pineal gland
N-acetyl serotonin is turned to melatonin
Note: synthesis under control of postganglionic sympathetic fibers that innervate the pineal gland
Melatonin
Lipophilic hormone
Mainly produced and secreted at night by the pineal gland
Stimulated by darkness and inhibited by light
Light –> eyes/retinohypothalamic tract –> SCN of hypothalamus –> PVN of hypothalamus –> spinal cord –> preganglionic cell bodies in intermediolateral horn project out sympathetic ganglia –> superior cervical ganglion –> postganglionic sympathetic neurons along internal carotid –> pineal gland
Synthesis and release decreases with age
Ramelteon (Rozerem)
Melatonin receptor agonist
Targets MT1 and MT2 melatonin receptors (expressed in SCN and throughout brain)
Does not show binding to GABA-A receptors
Particularly for delayed sleep onset
Not shown to produce dependence or potential for abuse
Augments ongoing natural melatonin release
Other classes of drugs used as sedative-hypnotic agents
Antidepressants (given at bedtime to facilitate sleep)
Antihistamines (doxylamine, diphenhydramine)
NOT ethanol! Can cause REM rebound
What should people using sedative-hypnotic drugs for insomnia be aware of?
Early morning awakening
Rebound daytime anxiety
Amnesic episodes
Immune response gene regulation for extracellular vs. intracellular pathogens
Extracellular pathogens (bacteria) activate pro-inflammatory gene program: IL1B, IL6, TNF, NF-kB
Intracellular pathogens (viruses) elicit antiviral gene program: IFN genes, TFs such as IRFs (interferon regulatory factors)
Two efferent programs to modulate immune response genes
1) HPA axis: CRH –> ACTH –> GCs from adrenal gland –> GCs enter WBCs and (1) decrease expression of antiviral immune response genes (IFNA, IFNB) and (2) decrease expression of pro-inflammatory immune response genes (IL1B, IL6, TNF) and (3) induces transcription of anti-inflammatory NFKB1A and (4) antagonizes pro-inflammatory TFs (NF-kB and AP1) via protein-protein interactions
2) Sympathetic nervous system: epi from adrenal gland and NE from SNS nerve fibers act on beta adrenergic receptors on WBCs to (1) decrease expression of antiviral immune response genes (IFNA, IFNB) and (2) increase epression of pro-inflammatory immune response genes (IL1B, IL6, TNF) and (3) stimulates tx of TH2-type cytokine genes (IL4, IL5) and (4) suppresses expression of TH1-type genes (IFN, IL12)
Summary: HPA suppresses antiviral and inflammatory response (yet inflam present because reduced levels of GC-mediated gene transcription?); SNS suppresses antiviral but activates inflammation
Are there direct connections between brain and immune cells?
Yes!
Tyrosine hydroxylase nerve terminal in direct contact with lymphocyte
This allows quick regulation of immune cells by epi and NE?
What effect does stress have on disease?
Increased risk of infectious disease (viral?!)
Increased risk of cardiovascular disease
What is the relationship between depression, inflammation and cardiovascular mortality?
In MDD, have increased sympathetic stimulation (?) so have increased pro-inflammatory cytokines and increased cardiovascular mortality
Psychological stress and upper respiratory illness
Poor social ties are associated with increased susceptibility to the common cold
Higher psychological stress increases susceptibility and severity of common cold symptoms
Remember, common cold is a VIRAL illness! Decreased antiviral genes in depression/stress!
Do stress and depression affect vaccine effectiveness?
Yes, stress and depression make viral vaccines (pneumococcal, herpes zoster, hepatitis) less effective!
Association between shyness and HIV/AIDS progression
Social inhibition (shyness) accelerates progression of HIV/AIDS!
Association between stress and metastasis
Stress promotes metastasis!
Beta blockers being studied in Israel to determine whether they can prevent metastasis
Macroenvironmental sensing
Third way to regulate innate immune system and antiviral gene programs
CNS sensing what is going on externally and integrating info regarding general physiological conditions to lead to changes in innate immune system and antiviral gene programs
This is critical because for example, when we’re sleeping, CNS gives DIFFERENT signals to immune system than when we’re awake
Timeline of stress affecting immune system
SNS is fast acting, so initially get increased pro-inflammatory cytokines
GCs act later to suppress pro-inflammatory cytokines
In chronic stress/depression (high GC), why do you have high inflammation?
Because GC response elements (receptors) are downregulated!
Sleep-wake cycles and inflammation
Insomnia and shift work upregulates inflammatory markers
Sleep restriction activates pro-inflammatory cytokine genes and increased NF-kB activity
Molecular pathways between pro-inflammatory signals and neural activity
1) Interaction of circulating cytokines with cytokine receptors in the brain circumventricular organs that lack a functional BBB
2) Stimulation of brain vascular endothelial cells to release second messengers that stimulate subsequent cytokine production within the brain
3) Active transport of cytokines across the BBB via carrier molecules
4) Peripheral inflammatory stimulation of afferent nerves that subsequently stimulate CNS tissues to produce cytokines
Brain structures responding to pro-inflammatory signals
Hypothalamus: key role in the regulation of systemic physiological function and organism-level biobehavioral dynamics (metabolism, sleep, feeding)
Amygdala: mediates fear- or threat-related responses and processes social information
Hippocampus: key role in learning and short-term memory, general information processing, spatial information processing, and navigation and mobility
Pre-frontal cortex: complex information processing and planning
Anterior cingulate cortex: involved in a diverse array of cognitive-emotional interactions
Ventral striatum: involved in positive motivation and reward
What does injecting endotoxin do to mood?
Endotoxin causes inflammation and inflammatory cytokines increase depression
Also inhibits reward activity in the brain (ventral striatum?)
Behavioral interventions that modulate inflammation
Cognitive behavioral therapy
Aerobic exercise
Meditation
Tai Chi Chih: boosts viral immunity and response to vaccination
Effects of group psychotherapy on recurrence and survival of malignant melanoma
Increased coping
Reduced depression
Increased natural killer activity
Lower rates of recurrence and death
Features of personality disorders
Deeply engrained
Inflexible
Maladaptive
Stable
Impairs function
Distresses others
Definition of personality disorder: PDs represent failure to develop a sense of self-identity and the capacity for interpersonal functioning that are adaptive in the context of the individual’s cultural norms and expectations
Personality disorder clusters A, B, C
Cluster A = Mad = odd or eccentric = paranoid, schizoid, schizotypal = social deficits, perceptual distortions, cognitive impairment = psychosis
Cluster B = Bad = dramatic, emotional or erratic = histrionic, antisocial, borderline, narcissistic = impulsivity, aggression, affective instability, emotionality = substance misuse, sociopathy
Cluster C = Sad = anxious or fearful = avoidant, dependent, obsessive-compulsive = anxiety/behavioral inhibition, compulsivity = depression, anxiety disorders, social phobia, somatoform disorders, eating disorders
Schizoid personality disorder
Pervasive pattern of detachment from social relationships and a restricted range of expression of emotions in interpersonal settings
Experience of illness: anxiety because of forced contact with others
Problemati behaviors: delay seeking care, appears unappreciative
Management strategies: provide clear explanations, avoid over involvement in personal and social issues
Schizotypal personality disorder
Pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for close relationships as well as by cognitive or perceptual distortions and eccentricities of behavior
Prominent features: odd beliefs, socially isolative
Experience of illness: odd interpretations of illness
Problematic behaviors: delay seeking care, odd beliefs, odd behavior
Management strategies: tolerate odd beliefs and behaviors, avoid over involvement
Paranoid personality disorder
Pervasive distrust and suspiciousness of others such that their motives are interpreted as malevolent; this begins by early adulthood and is present in a variety of contexts
Prominent features: distrust, suspicion
Experience of illness: heightened sense of fear and vulnerability
Problematic behaviors: feal that physician will harm leads to arguments and conflict
Management strategies: adopt a professional stance, provide clear explanations, be empathetic to fears, avoid direct challenge to paranoid ideation
Narcissistic personality disorder
Pervasive pattern of grandiosity, need for admiration, and lack of empathy that begins by early adulthood and is present in a variety of contexts
Experience of illness: anxiety caused by doubts of personal adequacy
Problematic behaviors: demanding, attitude of entitlement, denial of illness, alternating praise and devaluation of physician
Management strategies: validate concerts, give attentive and factual responses to questions, channel patient’s skills into dealing with illness
Histrionic personality disorder
Pervasive and excessive emotionality and attention-seeking behavior which begins by early adulthood and is present in a variety of contexts
Problematic behaviors: overly dramatic, attention seeking behavior, inability to focus on facts and details, somatization
Management strategies: avoid excessive familiarity, show professional concern for feelings, emphasize objective issues
Borderline personality disorder
Pervasive pattern of instability of interpersonal relationships, self-image, affects, and marked impulsivity that begins by early adulthood and is present in a variety of contexts
Experience of illness: terrifying fantasies about illness
Problematic behaviors: fear of rejection and abandonment of self-destructive acts, idealization and devaluation of physician
Management strategies: avoid excessive familiarity; schedule regular visits; provide clear, non technical explanations; tolerate angry outbursts but set limits; maintain awareness of personal feelings; consult psychiatrist
Antisocial personality disorder
Pervasive pattern of disregard for, and violation of, the rights of other that begins in childhood or early adolescence and continues into adulthood
Experience of illness: anger, entitlement, fear
Problematic behaviors: anger, impulsive behavior, deceit, manipulative
Management strategies: set clear nonpunitive limits
Obsessive-compulsive personality disorder
Preoccupation with orderliness, perfectionism, and mental and interpersonal control, at the expense of flexibility, openness and efficiency which begins by early adulthood and is present in a variety of contexts
Experience of illness: fear of losing control of bodily functions and emotions
Problematic behaviors: fear of relinquishing control, excessive questioning and attention to details, anger about disruption of routines
Management strategies: complete thorough history and examinations, provide thorough explanations, do not overemphasize uncertainty, encourage patient participation in treatment
Dependent personality disorder
Pervasive and excessive need to be taken care of that leads to submissive and clinging behavior and fears of separation which begins by early adulthood and is present in a variety of contexts; the dependent and submissive behaviors are designed to elicit care giving and arise from self-perception of being unable to function adequately without the help of others
Management strategies: provide reassurance, schedule regular check-ups, set realistic limits on availability, enlist others to support patient, avoid rejection of patient
Prominent features: excessive need to be taken care of, submissive and clinging behavior
Experience of illness: fear of abandonment, helplessness
Avoidant personality disorder
Pervasive pattern of social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation that begins by early adulthood and is present in a variety of contexts
Experience of illness: heightened sense of inadequacy, low self-esteem
Problematic behaviors: withholds information, avoids questioning or disagreeing with physician
Management strategies: provide reassurance, validate concerns, encourage reporting of symptoms and concerns
Audition
Perception is not determined solely by what we hear (bottom-up processing) but by higher-level processes (top-down)
McGurk Effect: hear “ba” but when see“ga” at the same time, then hear “da” (vision goes into what you “hear” because brain is integrating information!)
Physical properties of sound waves
Sound waves are compressed air/rarefied air
Pitch (frequency; period)
Loudness (volume/intensity; amplitude)
Phase
Peripheral auditory system
External/outer ear = pinna, external auditory canal
Middle ear = tympanic membrane, stapes (ossicles), incus; middle ear is amplification device because tympanum larger than stapes/oval window
Inner ear = oval window, round window, semicircular canals, cochlea, auditory nerve
Mehcanical “flow” of pressure
Tympanum –> malleus –> incus –> stapes –> oval window –> scala vestibuli –> helicotrema –> scala tympani –> round window
Note: scala media between 2 canals (scala vestibuli and scala tympani) and this is where mechanotransduction and cochlea proper sits
Hair cells
Hair cells transduce mechanical energy to electrical signals: cillia on inner hair cells embedded in gelatinous membrane (tectorial membrane) and when perilymph vibrates, it vibrates reissner (?) membrane and shears tectorial and basilar membrane to move cillia forward and backward which opens/closes K+ channels to let K+ in
Inner hair cells are single row
Outer hair cells are 3-5 rows
Inner hair cells are primarily responsible for hearing
Inner vs. outer hair cells
Inner hair cells: innervated by many fibers so most info comes from inner hair cells; only have 3,500 inner hair cells which is not very many and these die as you age!
Outer hair cells: not innervated by many fibers; sensory neurons but receive efferent innervation from CNS so can change flexibility/physical properties of basilar membrane to help you hear (mechanical amplification/attenuation so contraction of outer hair cells changes physical properties/function of inner hair cells)
Cochlear tonotopy
Areas lined up by which energy vibration (frequency) affects that area
High levels of energy vibrate thicker end of membrane and low levels of energy vibrate thinner end of membrane (apex)
Cochlea all the way to auditory cortex (entire auditory system) has tonotopy, or frequency map
What does the cochlea do?
Decomposes complex sounds to component frequencies
What is hearing?
Hearing is the detection of the vibration of air molecules
Frequency tuning of auditory nerve fibers
Single nerve fiber has a characteristic frequency where it will fire the highest number of spikes
With higher intensity (louder) sounds, still will have the same characteristic frequency but will fire more spikes
Central auditory system
Auditory nerve (CNVII)
Cochlear nerve
Cochlear nuclei
Olivary complex
Nucleus of the lateral lemniscus
Inferior colliculus (all in brainstem)
Medial geniculate nucleus (in thalamus)
A1 (primary auditory cortex: Broadmann’s area 41) (in cortex)
Which side of the brain will noise in right ear stimulate?
Both sides!
Information is bilateral, and becomes bilateral very early on
Tonotopical organization of cortex
Rostral tip of primary auditory cortex has low frequency
Caudal tip of primary auditory cortex has high frequency
Lateralization of sounds in humans
Left auditory areas more responsive to speech
Right auditory areas more responsive to music
Equally responsive to environmental sound
3 independent mechanisms of sound localization
1) Horizontal (azimuth) discrimination based on interaural time delay (20-2,000Hz; low frequency)
2) Horizontal (azimuth) discrimination based on interaural level differences (2,000-20,000Hz; high frequency)
3) Vertical (elevation) discrimination based on shape of pinna
Does shape of pinna alter your ability to tell where sound is coming from?
Up/down is dramatically altered by shape of pinna
Can still tell if sound is coming from left/right if pinna distorted
Interaural time delays
Right ear neurons fire at certain point in phase/cycle but left ear neurons fire slightly later because phase is off because took longer to get there
Compute difference in firing in R vs. L ear and tell which direction sound is coming from
Phase-locking
In a given fiber, the action potential tends to occur at the same phase (ie always at the peak of the sound wave)
Note: this is how we can calculate interaural time delays!
Why can’t we use interaural time delays for high frequencies?
Because if complete cycle or 2 cycles off, you can’t tell which one came “first”
This is why you have to use interaural level differences to tell difference in direction when high frequency waves
“Delay lines” used to detect phase differences
Sound reaches L ear and action potential travels toward medial superior olive (MSO)
Sound reaches R ear a little later and action potential begins traveling toward MSO
APs converge on an MSO neuron that responds most strongly if arrival is coincident
In this way, based on location of AP convergence, can tell which one came first!
Interaural level differences
Used to detect horizontal location when you have higher frequencies
1) Get stronger stimulus to L lateral superior olive (LSO) of olivary complex
2) Stimulis inhibits R LSO via medial nucleus of trapezoid body (MNTB) interneuron
3) Excitation from L greater than inhibition from R so get net excitation to higher centers
4) Inhibition from L greater than excitation from R so get net inhibition on R and no signal to higher centers
If you change the shape of the pinna, how long until you can re-tune and determine elevation?
One month
2 types of hearing loss
1) Conductive (mechanical): otosclerosis (ossification of bones or ligaments of middle ear); otitis media (scar tissue immobilize membrane)
2) Sensorineural: hair cell loss (aging, loud sounds, ototoxic drugs like gentamicin); brainstem lesions (trauma, tumors); more serious
Presbycusis
Gradual loss of hearing in high frequency range
Tinnitus
Ringing in the ear that can be produced by ototoxic drugs or loud sounds
Permanent tinnitus can be due to a phantom sound (like phantom limb) generated in CNS
Acute/permanent damages in cochlea trigger permanent lesion in auditory cortex which decreases amount of input so brain reacts with plasticity to increase activity of cells in auditory cortex so get phantom sound
Definition of pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
Pain classification
Location on the body
Duration: acute, recurent, chronic
Intensity: mild, moderate, severe
Etiology: malignant, nonmalignant
Mechanism: nociceptive, neuropathic
Mechanisms of nociceptive and neuropathic pain
Nociceptive pain: experienced when injury or irritation is detected by receptors that respond to heat, cold, vibration, stretch and chemicals released from damaged cells; note that you can be so focused at another task that you don’t notice nociceptive pain until later
Neuropathic pain: experienced when peripheral, autonomic or central nervous system structures are injured, irritated and/or overactive causing dysfunction in pain signaling
Chronic pain
Pain does not subside even despite healing of the injury
Spontaneous pain
Hyperpathia: more pain than would be expected after a painful event
Hyperalgesia: increased intensity of pain to further noxious stimulus
Secondary hyperalgesia: spreading of sensitivity or pain to nearby uninjured tissue
Allodynia: sensation of pain from a normally innocuous stimulus
Pain and disability risk factors
Biological processes related to pain perception include prior pain experiences and nervous system reactivity and recovery in response to stress and symptoms
Psychological processes include temperamental tendencies, such as attentional biases toward symptom-related stimuli and coping strategies employed
Social environmental factors include chronic stressors and responses of others to symptom behavior
Do past painful experiences influence current pain processing?
Yes!
Sensory receptors can become sensitized to repeated stimulation, thereby causing a decreased threshold for AP firing and allodynia
Prior medical illness, physical injury, trauma and hospitalizations have been found to be related to increased pain sensitivity
Adverse nature of prior pain experiences appears to be more important than the number of past pain episodes
Newborns are more sensitive to pain than older infants/children/adults, repetitive or prolonged pain in neonatal period can cause long-term changes in neural pathways involved in pain processing (including pain sensitivity) and pain does not have to be remembered for it to have had an impact on current pain processing :(
Temperament
Definition: personality traits; the tendency to respond to and cope with stimuli in predictable ways
Ex: activity level, habit regularity (eating, sleeping), tendency to approach or withdraw from novel situations, adaptability, emotional intensity/reactivity, mood (tendency to be optimistic or pessimistic), persistence, distractibility and sensory sensitivity
Behaviorally inhibited children (restrained, wary, fearful) are more likely to activate distress responses to novel stimuli, and to develop anxiety disorders and somatic symptoms (ie anxious child having stomach ache when starting new school)
Attentional focus
Tendency to fixate on pain is related to greater levels of pain and disability
Those with tendency to interpret anxiety-related bodily sensations as dangerous (anxiety sensitivity) and those who catastrophize are more likely to develop anxiety disorders and chronic pain
Coping
Coping inefficacy is associated with increased distress, autonomic arousal, plasma catecholamine secretion (stress hormones)
Accommodative coping (distraction, acceptance, positive thinking, challenging unhelpful irrational thoughts) is correlated with less pain
Passive coping strategies (denial, cognitive avoidance, behavioral avoidance, wishful thinking) are correlated with increased levels of pain
Active coping strategies (problem solving, emotional expression, emotional modulation, decision making) aimed at reducing pain or a specific stressor are helpful, however, active problem-solving behaviors that are not focused on a changeable problem may be ineffective and frustrating
Primitive defense mechanisms of coping
Denial
Regression: reversion to earlier developmental stage
Acting out
Dissociation: losing track of time, self, and/or usual thought processes and memories
Compartmentalization: parts of oneself are separated from awareness of other parts
Projection: misattribution of a person’s undesired thoughts, feelings or impulses onto another person who does not have those thoughts, feelings or impulses
Reaction formation: converting of unwanted or dangerous thoughts, feelings or impulses into their opposites
More mature and mature defense mechanisms of coping
More mature:
Repression: unconscious blocking of unacceptable thoughts, feelings and impulses
Displacement: redirecting of thoughts, feelings and impulses directed at one person, but taken out upon another person or object
Intellectualization: overemphasis on thinking when confronted with an unacceptable impulse, situation or behavior
Rationalization: reframing a situation to reduce cognitive dissonance
Undoing: attempt to take back an unconscious behavior or thought that is unacceptable or hurtful
Mature:
Sublimation: channeling of unacceptable impulses, thoughts and emotions into more acceptable ones (humor, imagining a different future)
Compensation: psychologically counterbalancing perceived weakness by emphasizing strength in other arenas to reinforce a person’s self-esteem and self-image
Assertiveness
How can persistent stressors result in pain?
Sympathetic nervous system activated after stressful/traumatic event
Cortisol released to cause increased BP and blood sugar which reduces immune system’s ability to heal
Beta receptors cause production of pro-inflammatory cytokines, influencing increased pain response
Do people with chronic pain have anxiety?
80% of people with chronic pain have anxiety symptoms (including 15-30% with PTSD)
Anxiety is associated with greater pain, emotional distress and disability
Somatization
Process whereby somatic (physical) symptoms are expressed in response to stress and is not intentional; is an automatic response to stress
Can control symptoms with training and practice, but somatization is not falsifying symptoms
Most frequently reported symptoms are pain, GI and/or neurological but can also include tension headache
Underlying illness or injury can be significant stressor that triggers or exacerbates somatization (child with epilepsy can have non-epileptic seizures)
When do you suspect there is a contributing psychiatric problem in somatization?
Distress
Disability
Interference with recovery
Complex somatic symptom disorder
One or more somatic symptoms that are distressing and/or disrupting daily life
Chronic = 6 months
At least 2 of the following:
1) Disproportionate and persistent concerns about medical seriousness of one’s symptoms
2) High level of health-related anxiety
3) Excessive time and energy devoted to these symptoms or health concerns
DDx for complex somatic symptom disorder
Illness falsification: malingering, factitious disorder
Adjustment disorder: clinically significant psychological response to an identifiable stressor
Psychological factors affecting medical condition
Treatment of chronic pain
Education, physical, behavioral, psychological, academic or work interventions, complementary/alternative therapies, pharmacological
Relaxation
Distraction
Hypnotherapy
Biofeedback: controlled breathing, relaxation or hypnotic techniques with a mechanical device that provides visual or auditory feedback when desired action is approximated
Psychotherapy
Physical therapy
Acupuncture
Yoga
Massage therapy
4 different types of hearing/hearing loss
Mechanical sound: sound to eardrum, hearing bones and delivered to cochlea; problems in mechanical sound transmission is conductive hearing loss
Conversion of mechanical sound waves to electrical signals: occurs by hair cells within the cochlea; problems with hair cell conversion termed sensory hearing loss
Electrical transmission: occurs by cochlear nerve (CN VIII); carries current generated by hair cells to brain; problems with cochlear nerve are neural hearing loss
Auditory perception: occurs by the brain; problems with auditory sound perception are central hearing loss
Pars flaccida
Top part of eardrum in both posterior-superior and anterior-superior area
Natural weak spot
Critical to assess pars flaccida
Conductive hearing loss
Ear canal lesion: foreign bodies (occlusive ear wax, batteries?), otitis externa
Ear drum: tympanosclerosis (healing after trauma), perforations, atelectasis (TM thin and drawn in), cholesteatoma
Middle ear: effusion, otitis media
Ossicles: fixation, erosion, trauma (fracture, dislocation)
Otitis externa
AKA swimmer’s ear
Infection of skin lining ear canal
Can close ear canal entirely
Treated with antibiotics (orally, ear drops) but may need ear canal stent if completely swollen closed
Cholesteatoma
Trapped squamous epithelium (skin) due to flaky dead skin folding onto itself, usually at top part of ear drum
Eardrum becomes retracted into middle ear and folds on itself
Secretes lytic enzymes eroding bone (ossicles, facial nerve canal, skull base, labyrinth)
Locally invasive
Recurrence common (comes back if you don’t get it all out!)
Intracranial complications: meningitis, encephalocele, epidural, subdural or intracerebral abscess, lateral sinus thrombosis, otitic hydrocephalus, cerebrospinal fluid leak
Extracranial complications: conductive hearing loss, sensorineural hearing loss, facial paralysis, vertigo, subperiosteal abscess, petrous apicitis, labyrinthine fistula, Bezold’s abscess, cutaneous fistula
Treatment: no medical treatment, must be surgically removed (tympanomastoidectomy: postauricular incision, drill out mastoid cortex exposing cholesteatoma, 10% risk of recurrence)
Chronic otitis media
Inflammation of middle ear space longer than 6 weeks
Usually bacterial, but often culture negative
Presentation: otalgia (less severe than acute otitis media, may be ear fullness only), otorrhea (concurrent TM perforation), conductive hearing loss
Sensorineural hearing loss
Ototoxic exposures: chemotherapy (cisplatin, carboplatin, vincristine, bleomycin), antibiotics (aminoglycosides/gentomycin, vancomycin, biaxin, chloramphenicol), heavy metals (mercury, lead, arsenic, gold), diuretics (loop), opiates (high doses only); medications have synergistic effects so don’t be on 2 of these!
Genetic causes: non-syndromic (connexin-26), syndromic (Usher’s, Pendred’s, Alport’s, Waardenberg’s)
Infections: prenatal (TORCH, syphilis), postnatal (meningitis: Strep pneumoniae, H. influenzae, N. meningitis)
Neoplasms: acoustic neuromas/vestibular schwannomas
Sudden sensorineural
Presbycusis
Noise induced
Non-syndromic sensorineural hearing loss
Connexin-26
50% of all patients with genetic hearing loss
Autosomal recessive
Gene is GJB-2: produces connexin-26 which is gap junction protein important in cell-cell ion exchange
Variable severity and progression of hearing loss
Treatment: hearing aids or cochlear impant if profound hearing loss
Usher’s Syndrome
Sensorineural hearing loss and visual loss due to retinitis pigmentosa
Leading cause of deaf-blindness
Autosomal recessive (several subsets)
Visual loss usually detected by 10yo (visual field, night blindness)
Variable vestibulopathy
Early cochlear implantation for auditory rehabilitation
Pendred’s Syndrome
Sensorineural hearing loss and thyroid dysfunction
Defect in peroxidase (cannot incorporate iodine into thyroid hormone)
Goiter
Thyroid hormone deficiencies
SNHL is typically progressive
Autosomal recessive
Alport’s Syndrome
Sensorineural hearing loss and kidney dysfunction
Defect in type IV collagen
Kidney failure in teen years
X-linked, so male predominance
Waardenberg’s Syndrome
Sensorineural hearing loss
Defect in neural crest development
Dystopia canthorum
Disorders in skin and hair pigmentation (white forelock)
Autosomal dominant
Acoustic neuromas (vestibular schwannomas)
Benign neuromas (more accurately called vestibular schwannomas)
Very rare (1 in 100,000)
Benign growth of schwann cells lining the vestibular nerve
Occurs wihtin cerebello-pontine angle and into the internal auditory canal
Presentation with unilateral sensorineural hearing loss, tinnitus, and variable dizziness
T1 MRI with contrast is best for diagnosing vestibular schwannoma
Sudden sensorineural hearing loss
Fairly common (1 in 1,000)
Acute unilateral sensorineural hearing loss: will have ear fullness and tinnitus, variable vestibular symptoms
Need to rule out other causes (neoplasms)
Presumed viral infection (can be from vascular or other issues) but not totally known
Treatment is high dose corticosteroids (better to do this within days), now doing injection through TM and pills
Can be noise induced (volume of sound combined with duration)
Presbycusis
Hearing loss with increased age
Quite common
Cannot predict stability vs. progression
Treatment: hearing aid, cochlear implant if severe
Cochlear implants
Externally worn processor picks up sound and codes it into a “map”
Signal sent across the skin by FM radio waves
Computer chip under skin behind the ear sends signals to electrodes in cochlea
Electrodes stimulate auditory nerve
Cochlear implant takes over the mechanical sound transmission (ear drum, hearing bones) and conversion into electrical signals done by the hair cells to stimulate the cochlear nerve directly
Cochlear implants have been around since 1970s
Patient hums and it’s louder in the affected ear
Conductive hearing loss
(Same as Weber test)
What kind of hearing loss do you have to treat right away?
Treat nerve hearing loss right away!
Can wait before treating conductive hearing loss
Features of circadian rhythm
Endogenous
Period close to, but a little longer than 24 hours
Synchronized by light and other environmental cues
Impact almost all biological processes
Strong genetic control
Basic model for how “clock” genes work
1) At dawn, light activates transcription of Per and Cry (clock genes)
2) Message translated into proteins, they dimerize
3) Then at dusk are translocated back into nucleus where they inhibit their own transcription (negative feedback!)
What can happen if clock genes mutated?
You could lose rhythmicity altogether
You could have a shorter endogenous rhythm (like family in Utah that woke up at 3-4am every morning)
What determines whether a person is a “night person” or “morning person”?
If longer cycle length, then a “night person” because can stay up later
If shorter cycle length, then a “morning person” because can wake up earlier
How do we detect light/dark?
Retinal ganglion cells (below photoreceptors in the retina) contain a novel photopigment, melanopsin, which is the circadian photoreceptor
Melanopsin measures only light and dark (NOT image-forming; is a new sensory system!) and sensitive to blue/green wavelength light, and even blind people have functioning circadian rhythm!
Melanopsin is a vitamin A-based opsin photopigment
Melanopsin expressing ganglion cells target the SCN and give the SCN light/dark information
Difference between photoreceptors and retinal ganglion cells
Photoreceptors usually shut off activity when light shines on them
RGCs depolarize and generate APs when stimulated by light
Where in the brain is the circadian clock?
In the suprachiasmatic nucleus (SCN)
How does the SCN generate rhythm?
Individual neurons generate autonomous rhythm (active during day and silent at night)
Oscillations in SCN circuit more robust than single neurons thought (larger amplitude rhythm that is more precise)
How do timing signals get from SCN out to the rest of the body?
Don’t know much about this
SCN targets SON, PVN, ARC which target anterior and posterior pituitary
However, most behavioral and physiological parameters exhibit circadian oscillations: melatonin, core temperature, cortisol
Neuroendocrine pathway of control of melatonin
Melanopsin-containing RGCs directly synapse onto clock cells in SCN then go out through spinal cord then superior cervical ganglion then sympathetic innervation of pineal gland regulates rate limiting enzyme NAT which takes 5HT to produce melatonin
Are there circadian oscillators other than the SCN?
Yes, they’re everywhere!
Lung, liver, fibroblasts, etc
Different genes in different tissues are rhythmically regulated though
How are the other peripheral oscillators regulated?
RGCs sense light via melanopsin –> projections to central clock/SCN –> HPA and ANS –> separate clocks in each different organ system control genes important in each organ
What happens if there is misalignment of the circadian clock?
You get oxidative stress and inflammation
This is because NF-kB pathway is regulated by circadian timing system
Coma
No purposeful response to environment
No conscious arousal
No speech
No purposeful movements
Nearly every aspect of physiology is altered by sleep
EEG
Muscle tone
Eye movements
HR (and variability)
RR (and variability)
Hormonal release
Body temp
Visceral motility
Physiological features used to define sleep status
EEG = brain electrical activity
EOG = eye movements
EMG = muscle tension
Sleep stages across a night
Duration of REM increases across a night and quiet sleep duration decreases
Fewer large slow waves during quiet sleep across the night
Temperature and cortisol release during sleep
Core temperature is low during sleep
Cortisol is low at midnight and increases a few hours before waking up
What happens during REM sleep
Increased eye movement
Muscle atonia
Autonomic storm (erection, transient hyper and hypotension, substantial HR changes)
Why is REM sleep dangerous for babies?
Infants have compliant chest walls because ribs not calcified and its muscle tension that provides thoracic wall rigidity
During REM sleep, no muscle tension so thoracic walls become “floppy” and can be sucked in by negative pressure from descending diaphragm
Infants have dangerously low residual oxygen reserves in REM sleep (chest sucked in instead of air!)
Obstructive sleep apnea
Collapsed upper airway but continued diaphragmatic efforts
Short term memory, spatial orientation deficits, elevated sympathetic levels (even during waking) thus elevated BP
Injury in hypothalamus, cerebellum (CV and breathing coordination, cognition), medial midbrain, cingulate cortex (depression, anxiety), hippocampus and mammillary body (memory), insula cortex (CV, pain, depression, anxiety)
Obese males higher risk, high sensitivity to alcohol intake, upper airway malformations (micrognathia) or functional increased resistance (chronic upper airway inflammation), neural injury/cereballar injury/stroke higher risk
Central apnea or Cheyne-Stokes Breathing
Abnormal pattern of breathing where you get progressively deeper/faster breaths then decreased and temporary stop in breathing (apnea) and pattern repeats every 30 sec to 2 min
A coordination issue: matching peripheral CO2 sensing with central chemoreception
Found in half of heart failure patients and sometimes accompanies OSA
Heart failure patients also show substantial brain injury, possibly resulting from hypoxic damage during apneic periods of Cheyne-Stokes breathing in sleep
Cardiovascular consequences of OSA
3-fold risk for hypertension, even with moderate OSA
High incidence of stroke
Increased incidence of atrial fibrillation
Relationship between OSA and diabetes?
Can’t consider diabetes without considering the potential for OSA!
Interrupt sleep with 2 hours of waking and get elevated glucose by 50 mg/dl
86% of obese T2DM have moderate-to-severe OSA and remainder have mild OSA
Proportion of sleep states by age
Fetus has periods of activity and rest–should not be considered quiet sleep
Neonates spend more time in REM (and more time asleep)
Adolescents spend more time in QS and are difficult to arouse
Elderly sleep less (and sleep is less continuous)
Arousal systems
Cholinergic
Serotonergic (raphe)
Adrenergic (Locus coeruleus)
Histaminergic (TM nucleus)
Orexin (hypocretin)
Orexin (hypocretin) fibers
Promote arousal
Lost in nacrolepsy
Located in hypothalamus
Interact with other systems
Which brain regions responsible for QS and REM?
QS in basal forebrain
REM in dorsolateral pons
Narcolepsy
Excessive daytime sleepiness
Sleep attacks at inappropriate times: can be triggered by affective stimuli (laughter, excitement)
Cataplexy: sudden and transient episode of loss of muscle tone; distinct from sleepiness, unique to narcolepsy
Sleep paralysis (similar, but occurs in normals)
Hypnagogic hallucinations
REM sleep at sleep onset (short REM latency)
Disrupted nighttime sleep
Orexin (hypocretin) involved (loss of hypocretin cells)
Mechanisms underlying insomnia
Depression
Inappropriate sleep habits
Nocturnal myoclonus
Circadian shift
Other issues…
Interventions for OSA
Tracheostomy
Mandibular advancement devices
Surgical advancement, removal of excess tissue
Hypoglassal stimulation
Nasal continuous positive airway pressure (CPAP)
How might trypanosomes alter rhythm in behavior, electrical activity, gene expression?
Release of pro-inflammatory cytokine interferon (IFN-gamma) as well as cytokine TNF-alpha as part of body’s response to infection
How to synchronize to light/dark
Expose yourself to sunlight in the morning (but not before 5am)
Avoid blue/green light during the night
Jet lag
Chronic jet lag could reduce hippocampal volume, cause high cortisol, performance deficits
Jet lag increases mortality in mice
Aging and neurodegenerative disorders and circadian dysfunction
Difficulty with quality and duration of sleep
Shift to earlier bedtime and wake up
Fragmentation
Difficulty with daytime alertness
Difficulty with shifting to changes in LD cycle
Symptoms caused by dysfunction of circadian system
Cognitive dysfunction including memory problems
Trigger affective disorders
Metabolic dysfunctions including increased risk of T2DM
CV disease
GI disturbances
Increased risk for certain cancers
Enteroendocrine (EE) cells
Form the largest endocrine organ even though they make up less than 1% of the total GI epithlial cells
EE cells contain 20 different hormones/signaling molecules
EE cells sense nutrients, bile salts, short chain fatty acids, bitter and sweet tastants, bacterial products and quorum sensing molecules
Gut to brain signaling in the control of food intake
Nutrient related chemical and physical info encoded in the gut
Afferent info transmitted to CNS via vagal, spinal and endocrine pathways
Info integrated in hypothalamus
Integration of various food related into in brain and generation of sensations of hunger and satiingestive behavior
Where is most of the body’s 5HT?
95% in the gut!
Sequestered in neurons, enterochromaffin cells, enteric mast cells, platelets
“Gut feeling”
Gut related interoceptive signals inform CNS about homeostatic (satiety) and non-homeostatic (inflammation, mucosal irritation, lack of nutrients) events = “gut sensations” if require a response of the organism
Activation of brain circuits created by these things can occur on just thought/remembering of particular situation –> create disgust or craving, even in absence of actual gut signal
Gut microbes affecting the brain and vice versa
Only one study showed gut microbes affecting brain circuits in humans
Stress induces changes in microbial environment:
Direct: NE signaling to the gut can influence behavior of intestinal pathogens to increase their virulence; other stress-induced signaling molecules released into gut lumen (5HT, dynorphin, beta endorphin, etc)
Indirect: gastric acid production, GI motility, intestinal fluid and mucus secretion, intraintestinal pH
Mucosal immune system of gut affecting the brain and vice versa
ANS, SNS, HPA axis influence behavior of macrophages, DCs, mast cells
Macrophage secretory products (cytokines) activate vagus to affect brain
Role of intestinal microbiota on development of stress, emotion and pain modulation systems
HPA axis response
Anxiety-like behavior
Neuroplastic changes in emotion regulation regions (BDNF, PSD-95, synaptophysin, NR2B subunit, 5HT1A)
Lack of inflammation induced somatic hyperalgesia
How might intestinal flora early in life be important?
Ecology of intestinal flora early in life may play important role in shaping stress response
Compromised intestinal microbiota = decreased diversity, neonatal antibiotics, infections
Do probiotics influence response to affective stimuli?
So far, no!
Humans that ate probiotics did not have different response to viewing faces with negative affect (anger, fear)
Summary of brain and gut interactions
Interoceptive signals related to the chemical, mechanical, and immune related context of our inner environment are encoded by different cell types in the gut. Gut microbiota in the intestinal lumen are likely to contribute to this information.
Encoded info reaches CNS via vagal and spinal afferent pathways. CNS, including spinal cord and brain responds to this input in various reflex pathways to adjust the body in an optimal way.
Brain responds to these interoceptive inputs via the HPA axis and the ANS, which in turn modulate the activity and sensitivity of the target cells in the gut.
Chronic overstimulation of this gut brain axis by intestinal factors (e.g. chronic inflammation), or by CNS factors (chronic stress) can result in neuroplastic changes at multiple levels, changing the gain and responsiveness of the entire system.
Future studies should explore if activity within the gut brain axis plays a role in cognitive function, mood and affect (currently no evidence for this in humans)
Speculation that bidirectional brain-gut interactions involved in GI and non-GI disorders
GI: functional GI disorders, cyclical vomiting syndrome, IBD, celiac, obesity, metabolic syndrome
Non-GI (microbiota): autism, anxiety, depression, coronary vascular disease
