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The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
The biology of fear
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The biology of fear

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A description of the current neurobiology of disgust, fear, panic, anxiety and related disorders, focussing on the amygdala and the insula. Based on a presentation given in Denmark in September 2010

A description of the current neurobiology of disgust, fear, panic, anxiety and related disorders, focussing on the amygdala and the insula. Based on a presentation given in Denmark in September 2010

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  •  Sacco, T. and B. Sacchetti (2010). "Role of Secondary Sensory Cortices in Emotional Memory Storage and Retrieval in Rats." Science329(5992): 649-656. Visual, acoustic, and olfactory stimuli associated with a highly charged emotional situation take on the affective qualities of that situation. Where the emotional meaning of a given sensory experience is stored is a matter of debate. We found that excitotoxic lesions of auditory, visual, or olfactory secondary sensory cortices impaired remote, but not recent, fear memories in rats. Amnesia was modality-specific and not due to an interference with sensory or emotional processes. In these sites, memory persistence was dependent on ongoing protein kinaseM{zeta} activity and was associated with an increased activity of layers II-IV, thus suggesting a synaptic strengthening of corticocortical connections. Lesions of the same areas left intact the memory of sensory stimuli not associated with any emotional charge. We propose that secondary sensory cortices support memory storage and retrieval of sensory stimuli that have acquired a behavioral salience with the experience.Fig. 1 Primary auditory cortex and fear memories. (A) Histological reconstruction of the smallest (gray) and largest (hatched) excitotoxic lesions aimed at the primary auditory cortex, area Te1. Negative numbers indicate posterior distance from bregma. Plates adapted from the atlas of Zilles (14). Ent, entorhinal cortex; Gu, gustatory cortex; Par, parietal cortex; PRh, perirhinal cortex; Te2 and Te3, secondary and tertiary auditory cortex. (B) Remote fear memories to acoustic CSs in Te1-lesioned (n = 11) and sham-operated (n = 10) animals. Fear response was measured as percentage of total immobility (freezing) both 2 min before (pre-tone) and during (test trial) presentation of seven CSs. All values are means ± SEM. Fig. 5. Role of sensory cortices in emotional memory. (A) Acoustic fear memories in control (n= 10), Oc2L-lesioned (n= 10), and posterior piriform cortex–lesioned (Pir, n= 8) rats. (B) Visual fear memory in control (n= 9), Te2- lesioned (n= 8), or posterior piriform–lesioned (Pir, n= 10)animals. (C) Olfactory fear memory in control (n= 12), Te2-lesioned (n= 8), or Oc2L-lesioned (n= 9) [in this window] rats. (D) Startle habituation during the first day of training, during the retention trial, and during the presentation of a new tone in Te2-lesioned (n= 12) and sham-operated (n= 12) rats and in those untrained (n= 10). (E) Remote fear memories to white-noise CSs were impaired in Te2-lesioned (n= 8) rats relative to sham-operated animals (n= 8). Te2-lesioned animals could form new fear memories (F1,14 = 0.007, P >0.05). (F) Olfactory habituation in the posterior piriform–lesioned animals (Pir, n= 8) and in sham-operated animals (n= 10).
  • The lateral nucleus (LA) of the amygdala, for example, receives auditory inputs from the thalamus and neocortex while spatial information is relayed from the hippocampus to the basolateral nucleus (BLA). The central nucleus serves as an output structure capable of activating a variety of fear responses via its connections with the hypothalamus and periaqueductal grey (Fendt and Fanselow, 1999; LeDoux, 2000; Nader et al., 2001). This compartmentalization is also observed in the genetic anatomy of the amygdala. For example, the α1 subunit of the GABA receptor is highly expressed in the lateral amygdala, moderately expressed in the BLA and completely absent from the central nucleus (Fritschy and Mohler, 1995; Kaufmann et al., 2003; Marowsky et al., 2004; McDonald and Mascagni, 2004). The function of this differential genetic expression pattern is currently unknown. (Wiltgen at al)
  • The NMDAR is a specific type of ionotropic glutamate receptor. NMDA (N-methyl D-aspartate) is the name of a selective agonist that binds to NMDA receptors (the other types are kainate receptors and AMPA (aminopropionic acid) receptors) Matabotropic glutamate receptors are not linked to ion channels but G proteins
  • Akimova, E., R. Lanzenberger, et al. (2009). "The Serotonin-1A Receptor in Anxiety Disorders." Biological Psychiatry66(7): 627-635. The serotonin system plays an important role in the neural processing of anxiety. The involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in dysfunctional forms of anxiety has been supported by findings from a wide range of preclinical research and clinical trials, including treatment studies, genetic research, and neuroimaging data. The following article summarizes preclinical results with a focus on 5-HT1A receptor knockout and transgenic mice as genetic models of anxiety. Behavioral, autonomic, and endocrinological changes in these mice are reported. This article also presents genetic polymorphisms in humans associated with increased anxiety scores and pharmacological data focused on 5-HT1A receptor agonists and antagonists. Furthermore, molecular neuroimaging results are presented. Recent positron emission tomography (PET) studies have reported reduced 5-HT1A receptor binding in patients with panic disorder and social anxiety disorder, but not in posttraumatic stress disorder. In healthy subjects, increased anxiety scores might be associated with lower 5-HT1A receptor binding. This overview of preclinical and clinical data provides strong evidence for the key role of the 5-HT1A receptor in the serotonergicdysregulation of anxiety disorders.
  • : Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampal-prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P = 0.005) and symptoms (depression and anxiety, P < 0.001) in the absence of main effects for BDNF. In addition, significant BDNF-ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippocampal and amygdala volumes (P = 0.013), heart rate elevations (P = 0.0002) and a decline in working memory (P = 0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippocampus (P < 0.001), and associated lateral prefrontal cortex (P < 0.001) and, in turn, higher depression (P = 0.005). Higher depression was associated with poorer working memory (P = 0.005), and slowed response speed. The BDNF Met-ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P < 0.001). In contrast, the combination of BDNF V/V genotype and ELS predicted increases in gray matter of the amygdala (P = 0.003) and associated medial prefrontal cortex (P < 0.001), which in turn predicted startle-elicited heart rate variability (P = 0.026) and higher anxiety (P = 0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF gene and were not evident for the related 5HTT-LPR polymorphism. Overall, these findings are consistent with the correlation of depression and anxiety, yet suggest that partially differentiated gene-brain cognition pathways to these syndromes can be identified, even in a nonclinical sample. Such findings may aid establishing an evidence base for more tail (Gatt, Nemeroff et al. 2009)
  • Cyrano de Bergerac played by David Wenham
  • photograph of the left insular cortex of a human patient. The human insular cortex is a distinct but hidden lobe of the brain. It is disproportionately (approx30%) enlarged in the human relative to the macaque monkey. It has 5–7 oblique gyri, but its morphology is quite variable, even between the two sides. Primary interoceptive representations are located in the dorsal posterior insula and re-represented in a polymodal integrative zone in the mid-insula and again in the anterior insular cortex (AIC). The primary interoceptive, gustatory and vagal representations extend to the anterior limit of the insula in macaques but only to the middle of the insula in humans, which suggests that the AIC of humans has no equivalent in the monkey. The most anterior and ventral (inferior) portion of the human insula that adjoins the frontal operculum is probably the most recently evolved, because this part (as well as the anterior cingulate cortex) contains von Economo neurons. as, anterior short insular gyrus; al, anterior long insular gyrus; ac, accessory gyrus; APS, anterior peri-insular sulcus; H, Heschl's gyrus; IPS, inferior peri-insular sulcus; ms, middle short insular gyrus; ps, posterior short insular gyrus; pl, posterior long insular gyrus; SPS, superior peri-insular sulcus.
  • The Default Mode Network (DMN) is a constellation of brain areas that decrease their activity during a wide number of different goal-oriented tasks as compared to passive "rest" tasks. DMN can be modulated by different factors such as emotional states, cognitive load of the task and psychopathology, including anxiety. Moreover, DMN seems to play a pivotal role in social cognition. For example, the ability to predict another person's behaviour taking his or her perspective modulates the activity of the DMN. Recent data from autistic patients support a role of DMN in social cognition as well. Social Phobia (SP) is an anxiety disorder characterized by an abnormal distress in situations that require social interaction. To date, no study has assessed DMN in Social Phobia. To determine potential differences in DMN activity between Social Phobia patients (SPP) and healthy control (HC) subjects we examined functional magnetic resonance imaging (fMRI) data obtained during a face perception study with emotional and neutral stimuli. As compared to HC, SPP showed a lower deactivation in the precuneus and posterior cingulate regions (PCun/PCC) during task conditions. These regions are part of the so-called "Theory of Mind" circuit and in particular they are involved in the evaluation of one's own emotional state. Because of the role of the PCun/PCC in self-state perception and attribution and, more in general, the role of the DMN in social cognition, we suggest that its impairment in the DMN network in SPP might be relevant in the development of the feeling of wariness of others' judgment and may be related to the so-called self-focused attention. Self-focused attention is the awareness of self-referent information, and is present in many emotional disorders and may additionally prevent individuals from observing external information that could disconfirm their own fears. Moreover, the abnormal modulation of activity in the DMN may reflect persistent rumination or anxiety-related thoughts that are not modulated by the switch from rest to task (Gentili, Ricciardi et al. 2009)
  • Transcript

    • 1. Biology of anxiety
    • 2. Biology of anxiety
      Digby Tantam, Clinical Professor of Psychotherapy, Honorary Visiting Senior Fellow, University of Cambridge
      slides can be downloaded from the Existential Academy at slideshare.net:
      http://www.slideshare.net/djht2
      www.existentialacademy.com
      2
    • 3. slides can be downloaded from the Existential Academy at slideshare.net:
      http://www.slideshare.net/djht2
      www.existentialacademy.com
      3
    • 4. Septimus Ltd
      New School of Psychotherapy and Counselling Ltd
      The Existential Academy Ltd
      Dilemma Consultancy Ltd
      Ask the therapist Ltd
      Dilemma medical assessment
      Dilemma training
      Ask my friends
      Ask the oracle
      Dilemma therapy
      Virtual therapy office
      Dilemma publishing
    • 5. www.existentialacademy.com
      5
      Anxiety
      Stage fright
      Fear
      Shyness
      Separation
      Stress
      Worry
    • 6. Peripherally, many of the symptoms of anxiety and fear are the same
      Biphasic response
      Fight or flight:
      Sympathetic: increased tone of sympathetic nervous system, increased secretion from adrenal medulla, increased heart rate and rise in BP
      Cortisol: increased secretion from adrenal cortex
      Submission: sham death, freezing, ‘panic’: increased parasympathetic secretion, decrease in heart rate, fainting
      But anxiety also includes:
      disgust
      neo-panic or hyperventilation syndrome
      www.existentialacademy.com
      6
    • 7. 1. Cognitive appraisal. Only events are judged or appraised to have significance for our goals, concerns, values, needs, preferences, or well-being elicit emotion.
      2. Subjective feelings. The appraisal is accompanied by feelings that are good or bad, pleasant or unpleasant, calm or aroused.
      3. Physiological arousal. Emotions are accompanied by autonomic nervous system activity.
      4. Expressive behaviours. Emotion is communicated through facial and bodily expressions, postural and voice changes.
      5. Action tendencies. Emotions carry behavioural intentions, and the readiness to act in certain ways
      6. Sartrean transformation of the world: emotions change awareness, attention, perception, reappraisal
      7. Characteristic brain substrates
      a. phasic
      b. dispositional (‘personality’)
    • 8. Fear and disgust are OF something
      Panic is ABOUT something: being suffocated or just dying
      Anxiety is FOR something: a future feeling, a preparedness for the worst
      So anxiety is a disposition
      Neurobiologically, a disposition is
      A genetic endowment
      Permanent change due to early experience
      Memory
    • 9. www.existentialacademy.com
      9
      Tantam, D. (2003). The flavour of emotions." PsycholPsychother. 76(Pt 1): 23-45.
      Sacco, T. and B. Sacchetti (2010). "Role of Secondary Sensory Cortices in Emotional Memory Storage and Retrieval in Rats." Science 329(5992): 649-656.
    • 10. Short-term memories need consolidation in hippocampus over 24 hours or more
      Happens during SWS
      May be disrupted in PTSD
      Battle survivors, but not survivors of civilian disasters, may have reduced hippocampal volumes
      www.existentialacademy.com
      10
    • 11. Amygdala
      Poorly defined ‘nuclei’
      Contain cortex
      Respond to faces, and other external threats
      Enable fear to be linked to new stimuli via conditioning
      Orchestrate ‘arousal response’ may be fear/ anxiety or rage
      www.existentialacademy.com
      11
      GABA ergic inhibitory interneurons, blocked by benzodiazepines


      Endorphin signalling,
      EtOH increases endorphins
    • 12. www.existentialacademy.com
      12
    • 13. www.existentialacademy.com
      13
      Long-term memory blocked by Inhibitors of PKC (protein kinase C, or mitogen activate protein kinase


    • 14. How do alcohol, opium, and diazepam work?
      On endogenous opioid (endorphin) transmitters and on GABAergic inhibitory interneurons, respectively
      However, both systems show considerable pharmacological tolerance presumably because of receptor number changes
      How does propranolol work, peripherally (i.e. not much) and possibly by potentiating serotinergicanxiolytics
      How do these work?
      Probably on 5-HT1A receptor
      But how?
      And where?
      ?
      slides can be downloaded from the Existential Academy at slideshare.net:
      http://www.slideshare.net/djht2
      www.existentialacademy.com
      14
    • 15. Attachment and the amygdala
      Fear triggers attachment behaviour
      Oxytocin reduces amygdala activation in a diazepam-like way via activation of GABAergic inhibitory interneurons
      In people with generalized anxiety disorder shown frightened faces(Labuschagne, I., K. L. Phan, et al. (2010). "Oxytocin Attenuates Amygdala Reactivity to Fear in Generalized Social Anxiety Disorder." Neuropsychopharmacology.
      More oxytocin receptors in women
      Prairie voles bond
      Oxytocin snuff makes men more woman-like in empathizing
      Increases gaze at the eyes of other people, including angry people
      Increase trust in ‘trust games’
      15
    • 16. The role of other peptides
      Pentagastrin and orexin were both discovered as hormones active on the stomach and small bowel during digestion
      Both stimulate the respiratory centre (as does acidosis) but also superior temporal cortex and hypothalamus: these might be associated with fears of death and experience of suffocation i.e. panic.
      Orexin is linked to reward, and is involved in pleasure in the brain
      16
    • 17. Neo-panic
      ‘Shell shock’
      Hyperventilation syndrome
      Not clear whether hyperventilation increases pCO2 sensitivity in respiratory chemoreceptor
      Or other way round
      Hyperventilation produces hypocapnia and respiratory alkalosis and therefore hypocalcaemia
      But vasoconstriction of cerebral arterioles and therefore cerebral hypoxia: so cautious about cognitive advice that you give
      www.existentialacademy.com
      17
    • 18. www.existentialacademy.com
      18
      Self-conscious anxieties
      Dysmorphophobia
      OCD
      Social phobia
    • 19. Disgust, as well as fear contributes to anxiety. Disgust is response to internal threat: the primordium is ‘yukky’: what makes you vomit
      www.existentialacademy.com
      19
      Miles on David Hume:
      ‘In attacking theoretical attempts to supply a rational basis for Christianity,
      Kierkegaard found an unlikely ally in “the great Infidel”, David Hume (1711-76)’
      Only in people
      ? Abstract disgust
      Morality
    • 20. Anxiety is the ‘dizziness of freedom’
      Because it motivates a ‘leap of faith’
      www.existentialacademy.com
      20
    • 21. Psychoanalytic anxiety is two fold
      Two factors influence distance from the parent, and emotional control (that lead to schizoid personality in extremis):
      External threat (‘guilt’): produced by fear of punishment or loss of love
      Internal threat (‘shame’) produced by parental disgust
      Tantam, D. ‘Fairbairn’ 1996 150 Years of British Psychiatry, vol. 2 (eds. H. Freeman and G.E. Berrios)
       
      www.existentialacademy.com
      21
    • 22. www.existentialacademy.com
      22
      Yuk. That’s gross
      It’s a monster
      Tak for Deresopmærksomhed
      Let’s kill it
      I don’t ever want to hear you say that again. And take this thing out of my sight, I never want to see anything like that again, either
      The outline of my next but one book

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