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									 ABNORMAL ACTIVITY IN
    HYPOTHALAMUS AND
AMYGDALA DURING HUMOR
  PROCESSING IN HUMAN
     NARCOLEPSY WITH
        CATAPLEXY
 Sophie Schwartz, Aurelie Ponz, Rositsa Poryazova, Esther Werth,
                Peter Boesiger, Ramin Khatami
                     and Claudio L. Bassetti

               Presented by: Inger Appanaitis
Cataplexy: It’s no laughing
matter!
 Sudden loss of
  muscle tone with
  preserved
  consciousness
  triggered by variety
  of emotions.
   Telling or hearing
    jokes is most
    common trigger of
    cataplectic attack.
Cataplexy

 Respiratory and eye muscles not affected
 Episodes last a few seconds → 30 minutes
 Sleep deprivation increases frequency and
  severity of attack
 Partial or complete
   Slackening of jaw → total collapse
 Affects 1 in 2000 individuals
Narcolepsy:

 Repeated, irresistible
  ‘sleep attacks’
 Cataplexy
 Recurrent intrusions of
  REM sleep into the
  transition period
  between sleep and
  wakefulness.
    (N1, N2, N3, N2, REM)
Characteristics of Narcolepsy

• Affects 0.02-0.16% of adults
  – 70% of people with narcolepsy also suffer from
    cataplexy (NC)
• Genetic inheritance: 5-15% of first-degree
  relatives (DSM-IV)
  • (Siegel et al 2001: Suggest damage to hypocretin
    system)
• Some individuals take naps in order to
  manage sleepiness
  – Average 2-6 sleep episodes/day
Laughter
Anger
Embarrassment
NC caused by reduction or loss of
hypocretin/orexin in hypothalamus
 1998: De Lecea* and Sakurai
 De Lecea- Hypocretin: Hypothalmic location
  and sequence homology to secretin
   Treatment for obesity
 Sakurai- Orexin: Greek ‘orexis’=appetite
   3rd ventricle injections induced feeding in rats
 Hypocretin (HCRT)= Orexin
Hypocretin- First characterization
• 2 distinct hypocretins
  – Hcrt 1 and Hcrt 2
• No difference between
  males and females
• NT found in dorsal and
  lateral hypothalamus
  – Accumulation within axon
    terminals and vesicles
    suggests that they may
    have intercellular signaling
    activity
  – Hcrt 2 is neuroexcitatory
     • Increase in frequency of
       postsynaptic currents
Coincidence or destiny?
 Luis De Lecea and Thomas
  Kilduff
   Former director of narcoleptic dog
     colony at Stanford
 Sakurai group continued
  research w/ knock-out mice
   Hcrt-2 causing cataplexy
 Stanford group (canine
  narcolepsy)- systematic
  chromosome analysis
   Reported mutated, non-functional
     version of Hcrt-2 gene
Role played by Hcrt
                      ← Inhibitory
                      Feedback




                      ← Direct
                      Inhibition



                      ← Mutually
                      Inhibitory
                      Circuit
‘Snorting a Brain Chemical
Could Replace Sleep’- Siegel
               Can cross BBB
               Reduces sleepiness w/out
                causing edginess
               Orexin A reversed the
                effects of sleep deprivation
                in monkeys, allowing them
                to perform like well-rested
                monkeys on cognitive tests
                 Brains looked ‘awake’ in PET
               Possibilities…
Schwartz’s Funny Study

 Suprapontine brain mechanisms- associated
  with the cataplectic effects of emotion in
  human NC- remain essentially unknown
 Assess brain activity in patients while
  observing humorous pictures
   Hypothalamic and amygdalar brain regions
   fMRI
Why amygdala?

• Dogs demonstrated changes of neuronal
  firing in the amygdala during cataplexy;
• Amygdala found to be strongly activated
  during REM sleep in normal humans;
• Involvement in emotional information
  processing in both animals and humans.
• Hypothalamus represents a second main
  suprapontine brain site whose dysfunction
  might contribute to cataplexy in NC
 Objective
• To date, imaging studies failed to reveal consistent
  brain abnormalities in NC patients. Advanced
  neuroimaging techniques could not demonstrate
  any systematic structural or functional change in
  the hypothalamus and/or amygdala.
• Hypothesis: Patients may show abnormal
  processing of external emotional inputs within
  limbic circuits or increased activation of efferent
  motor systems
  – Use fMRI to monitor neural activity elicited by humorous
    versus neutral pictures in NC (patients) and healthy
    volunteers (controls)
Test Subjects:
 Sleep Tests
• Epworth Sleepiness Scale (0-24)
• Stanford cataplexy questionnaire (>32.5%)
• Ullanlinna Narcolepsy Scale (>10)
• Swiss-Narcolepsy Scale (<00
• Multiple Sleep Latency Test (MSLT)
  • Measures the time it takes from the start of a daytime
    nap period to the first signs of sleep, called sleep
    latency. The test is based on the idea that the sleepier
    people are, the faster they will fall asleep.
  • Can be used to test for narcolepsy, to distinguish
    between physical tiredness and true excessive daytime
    sleepiness.
 Humor judgment paradigm
 Mini-sequences with neutral picture followed by
  same pic with either neutral or humorous
  element
 Humor intensity scale 0-3
 fMRI-ed 39 funniest pics w/neutral counterparts
   Patients judged whether they found these funny or
    not
Neutral
Humorous
Results- Group

 Patients and controls did not differ in the
  proportion of images judged as humorous
 Patients had slower rxn times indicating
  excessive daytime sleepiness
 fMRI revealed (+) in amygdala and insula and
  frontal regions known to be recruited by the
  affective content of humorous inputs and
  experiences
Results- Controls

 Tested for regions showing ↑fMRI signal
  during humourous trials in controls but not in
  patients
   Controls showed a maximal activity difference in
    R- hypothalmus
     Consistent with hypothesis that patients would have
      decreased hypothalamic activity
   Controls also showed increased activity in other
    areas associated with emotional regulation
     Increased response to humour in right hypothalamus,
   medial prefrontal and cingulate cortex for controls relative
                         to NC patients




                  Schwartz, S. et al. Brain 2008 131:514-522; doi:10.1093/brain/awm292




Copyright restrictions may apply.
Results- NC patients

 NC patients showed ↑ response to humorous
  stimuli in the R-amygdala
 ↑ activity in R- Inferior parietal and in fusiform
  cortex
   May reflect impact of top-down influences from
    amydgala on sensory pathways
 Increased amygdala response to humour in NC patients
                compared to controls




Increased fMRI signal in left insula and nucleus accumbens
            in NC-patients (but not in controls)
  Conclusion
• Narcolepsy is associated with increased amygdalar
  activity together with reduced medial prefrontal and
  hypothalamic activity during humor processing
  – Regions associated with emotional processing
  – Also found increased activity in L-Nucleus accumbens
    • Involved in humor processing
• Findings provide evidence for an implication of
  amygdalar circuits in the pathophysiology of human
  narcolepsy and abnormal responses to positive
  emotions in patients
Cataplectic patient in Reiss study

  Dramatic reduction in hypothalamic activity
    Similar to sleep state
  Initial overdrive and compensatory shutdown
   of the hypothalamus resulting in catalplectic
   attack?
    Massive supression of hypothalamic activity may
     be an essential component of a cascade of neural
     events leading to muscle atonia
  [all trials after attack were not modeled]
Additional Conclusions by Reiss

 Patients rated significantly fewer humorous
  cartoons as funny compared to controls
   Funny cartoons rated as less funny
 Patients showed ↑activity in hypothamus*
   Cataplectic patient- ↓activity
 Patients had ↑ activation of R-inferior frontal
  gyrus
   Patients train themselves to suppress laughter and
    avoid humorous material
09-23-09

Dear Inger,

Please find attached a
ppt with a humor & a
neutral mini-sequence.

Good luck for your
presentation!

Sophie

								
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