1. CCHS. Some data from patients and animals
Ha Trang, MD PhD
Center of reference for CCHS, Paris, France
5th International CCHS Conference
June Saint-Louis, MO

2. CORTICAL VOLUNTARY BEHAVIORAL SUBCORTICAL AUTONOMIC CHEMICAL CONTROL
Spinal
motoneurons
Diaphragm
Intercostal muscles
CONTROL
OF BREATHING
Cortex
Central
chemoreceptors
Peripheral
Pulmonary
mecanoreceptors
Chestwall
receptors
Phrenic Nerve

3. Structures involved in control of breathing
VLM
AP, area postrema; LRt, lateral reticular nucleus; NAd, nucleus ambiguus, dorsal division; Pn, ventral pontine nucleus; SO, IO, superior and inferior olivary complexes; SP5, spinal trigeminal nucleus; V, motor nucleus of the trigeminal nerve; V4, fourth ventricle; XII, hypoglossal motor nucleus. VLM, Ventro-Lateral Medullary surface

4. Hypoventilation during sleep, mainly during NREM sleep
Girl, Day 8
CCHS hallmarks
Hypoventilation during sleep, mainly during NREM sleep
Abnormal Hypercapnic and Hypoxic VR in all states of vigilance
As shown here in a baby, the CCHS hallmarks are present at birth
presence of hypoventilation, most important during sleep, mainly during quiet sleep
And abnormal ventilatory responses to hypercapnia or to hypoxia in all states of vigilance
Ventilation minute is very low during quiet sleep with reduced tidal volume and reduced respiratory rate
Although abnormal chemical RV during wake, the baby was able to maintain normal ventialtion with normal tidal volume and normal RR

5. Which drives to breathe during wakefulness ? in CCHS patients ?
Despite abnormal chemical RV during wakefulness, most CCHS patients breathe normally while awake
A « cortical breathing » is likely to be determinant to maintain ventilation in awake CCHS patients

6. Which drives to breathe during wakefulness ?
The SMA plays an important role in modulating breathing :
in awake normal humans
in awake patients with NeuroMuscular Diseases (Georges et al, 2016)

7. 7 CCHS patients (5F, 20-30yrs) of the French cohort 8 Control healthy individuals
Methods:
Recordings of EEG and breathing
Measurement of Pre-inspiratory potentials
Tested in 3 conditions
Resting spontaneous breathing
CO2 inhalation
Inspiratory forced
breathing
Tremoureux et al 2014

8. Control
CCHS

9. Has cortical breathing any clinical consequences ?
Pre-inspiratory « cortical activity » was detected in awake CCHS patients during resting breathing
This provides a neurophysiological evidence for SMA to contribute to the « cortical drive to breathe » in awake CCHS patients during SB
Questions:
Possibility to stimulate the cortical breathing for therapeutic purpose ?
Has cortical breathing any clinical consequences ?
Tremoureux et al 2014

10. Gait parameters differently affected by concurrent smartphone-based activities with scaled levels of cognitive effort Caramia et al, PLOS One 2017

11. EEG to ensure stable wakefulness 2 Tasks
1 adult CCHS patient
Functional MRI
EEG to ensure stable wakefulness
2 Tasks
Stream of Consciouness Test (SCT)
External awareness / Internal awareness
Paced Auditory Serial Addition Test (PASAT)
A neuropsychological test used to assess information processing and sustained executive attention.
During Mech Vent (MV) vs Spontaneous Breathing (SB)
“Stream of consciouness” test. “During the next minutes, we ask you to keep your eyes closed and to avoid prolonged structured thinking, such as counting or singing. When you hear a beep, please indicate me first the intensity of ‘external awareness’ ongoing prior to the beep by reporting a number orally from 1 to 4, and then indicate me the intensity of ‘internal awareness’ ongoing prior to the beep by reporting a number orally from 1 to 4. ‘External’ is here defined as the perception of environmental sensory stimuli (e.g., auditory, visual, olfactory, or somesthetic). ‘Internal’ here refers to all environmental stimuli-independent thoughts (e.g., inner speech, autobiographical memories, or wandering thoughts).”
Paced Auditory Serial Addition Test (PASAT) working memory and sustained executive attention, The PASAT test is a neuropsychological test used to assess capacity and rate of information processing and sustained and divided attention.
Sharman et al 2014

12. During stable wakefulness
Sharman et al 2014

13. 1. Executive functioning was better during MV than during SB
SCT.
Higher subjective intensity of spontaneous external and internal awareness during MV than SB
PASAT.
More correct answers during MV than SB
Sharman et al 2014

14. 2. DMN (default mode network) was restored during MV as compared to SB
Sharman et al 2014

15. 3. Functional connectivity patterns of brain activity differ during MV and SB
Sharman et al 2014

16. suggests the benefit of MV use while executing cognitive tasks
This observation :
suggests the benefit of MV use while executing cognitive tasks
shows the different brain functioning during MV and SB.
Data should be obtained in larger groups of CCHS patients with different ages and degrees of respiratory deficiency
“Stream of consciouness” test. “During the next minutes, we ask you to keep your eyes closed and to avoid prolonged structured thinking, such as counting or singing. When you hear a beep, please indicate me first the intensity of ‘external awareness’ ongoing prior to the beep by reporting a number orally from 1 to 4, and then indicate me the intensity of ‘internal awareness’ ongoing prior to the beep by reporting a number orally from 1 to 4. ‘External’ is here defined as the perception of environmental sensory stimuli (e.g., auditory, visual, olfactory, or somesthetic). ‘Internal’ here refers to all environmental stimuli-independent thoughts (e.g., inner speech, autobiographical memories, or wandering thoughts).”
Paced Auditory Serial Addition Test (PASAT) working memory and sustained executive attention, The PASAT test is a neuropsychological test used to assess capacity and rate of information processing and sustained and divided attention.
Sharman et al 2014

17. Two CCHS adult female patients were incidentally found to have increased HVR while using desogestrel

18. Do we know more about Desogestrel?
In CCHS patients: There are responders and non-responders
Two patients had higher resting ventilation (higher RR and lower PetCO2) when using DSG (vs cessation of DSG)
DSG increased fR in rats
Neuropharmacology 2016

19. Ex-vivo CNS preparations
Neuroscience Letters, 2014
Ex-vivo CNS preparations
-DBS
-MS

20. Etonogestrel produces higher increase of fR in response to acidosis in DBS > MS preps
>> Progestins may act via mechanisms involving supramedullary structures
DMSO dimethyl sulfoxide
ETO etonogestrel
MS medullary spinal cord preps
DMS diencephalon brainstem spinal cord preps

21. Etonogestrel increased fR
In MS preps
Etonogestrel increased fR
Cellular activity found increased in VLM (using c-fos-labeling)
Pre-BotC ??
No activity in RTN/pFRG
Joubert et al 2016

22. Etonogestrel is likely to have ventilatory effects via serotoninergic pathways
Joubert et al 2016

23. Etonogestrel modifies the efficiency of GABAA-mediated modulation of fR
Joubert et al 2016

24. Etonogestrel modifies the efficiency of NMDA-mediated modulation of fR
Joubert et al 2016

25. Hope for a better life with CCHS
Ongoing research on humans and animals
We need a better understanding of mechanisms underlying control of breathing in normal and in CCHS humans
We need a better understanding of mechanisms by which substances (drugs) may act on control of breathing