Sleep-disordered breathing-

Impact on the brain and body

function

Ronald M. Harper, Ph.D.

Distinguished Professor of NeurobiologyDavid Geffen School of Medicine, UCLA

rharper@ucla.edu

Objectives

• What types of sleep disordered breathing

• Effects on cardiovascular control, memory,

cognition, mood, hormonal, metabolic

control (diabetes)

• How does this happen

• What interventions are useful?

Obstructive Sleep Apnea – Loss of tone in upper

airway, continued movement of the diaphragm

Tongue genioglossal activity during sleep

Harper and Sauerland, 1978

If muscle tone is lost during REM sleep…..

But, not the only mechanism in OSA

A = no; pein = to breathe (Greek)

Apnea: failure to breathe

Obstructive sleep apnea: upper airway blocked,

diaphragm keeps going

A prime

candidate:

Some characteristics

• Obese males, higher risk

• Pre-menopausal women, lower risk

• High sensitivity to alcohol intake

• Upper airway malformations or functional increased resistance, higher risk

• Neural injury, especially cerebellar injury, stroke, higher risk

• Continuous positive airway pressure (CPAP) –Gold standard intervention

Obstructive sleep apnea

• It’s not just obese, adult males

• Pediatric cases; often hypertrophied

tonsilar tissue

• Maldevelopment of facial structures,

micrognathia, can be a factor

• Childhood obesity an increasingly major

concern

Upper Airway Resistance Syndrome (UARS)

Increased airway resistance (not complete

blockage, as in OSA), similar muscle relaxation

Usually evaluated by esophageal pressure;

increased esophageal pressure, followed by arousals

Arousals- sympathetic activation, hypertension

Abnormal sleep architecture (from arousals), snoring,

daytime sleepiness, hypertension (hypotension also)

Intervention similar; CPAP, mandibular devices

Periodic or Cheyne-Stokes Breathing

-often found in heart failure, sometimes in

OSA

A coordination issue- matching peripheral CO2 sensing with central chemoreception

Similar O2 desaturation and reperfusion concerns!

Why hypertension in OSA?

Resting sympathetic nervous activity is

exaggerated in OSA, even during waking states!

Sympathetic discharge can be recorded from peroneal nerve

OSA

3- fold risk of developing hypertension

In addition, OSA increases atrial fibrillation

Heart failure patients have OSA and Cheyne-Stokes breathing, show substantial brain injury, especially in right insular cortices, just like OSA patients

Insular

cortex

Insular

cortex

Right insular cortex regulates sympathetic tone)

Right insular damage

The structural damage has consequences; the insular

cortex responds improperly in OSA

3 Valsalva efforts (blood pressure challenge; breathe

against a resistance): OSA patients vs Controls

From: Henderson et al., J. Appl. Physiol., 94:1063-1074, 2003

Obstructive Sleep Apnea: gray matter loss in

cerebellum and hippocampus

Macey et al., 2002

Cerebellar injury will affect blood pressure

regulation (keeps blood pressure from

falling too low or elevating too high); injury

will also affect motor coordination

(including breathing!!) – coordination is

what the cerebellum does!

How can cerebellar injury

affect physiology?

Distorted amplitude & timing- fMRI signals in

OSA to 3 Valsalva pressor maneuvers

It’s not just structural injury-functional impairment

From: Henderson et al., J. Appl. Physiol., 94:1063-1074, 2003

Cerebellar fastigial (“autonomic”) nucleus

Blue=control

Red=OSA

Brain stem areas also affected: ventrolateral

medulla, essential for breathing and blood pressure

regulation, injured in OSA (Mean Diffusivity)

Kumar et

al., 2012

More pathologies with sleep-

disordered breathing

• Recent memory deficits

• Cognitive planning, spatial orientation deficits

• Enhanced propensity for depression and anxiety

• Hormonal, metabolic problems

Many of affected brain structures also assist inspiratory drive!

Hippocampus Mammillary body

Fornix

Image by Acerland International, 2009

0.05

0.1

0.15

P value

Regional volume reduction in

hippocampus of OSA patients

10 OSA

vs

10 Controls

Mammillary volume loss- thiamine deficiency

(chronic alcoholics, Beriberi), but how about OSA?

• Thiamine deficiency - common in those with high fluid

loss, malnutrition, diuresis, malabsorption, sulfites,

thiaminase in raw fish

• B12 deficiency- fluid loss, other meds- proton pump

inhibitor antiacids, metformin, antibiotics,

• Diabetics- urination, HF patients often subjected to

dialysis and diuretics; HF patients, frequent

malabsorption,

• OSA patients frequently diabetic, often have fluid

regulation issues- profuse nocturnal sweating

With high fluid release (sweating,

diuresis, urination)……..

• Essential vitamins can be flushed from the body

• Potassium

• Magnesium

• Thiamine (Vitamin B1)

Thiamine is necessary to transport carbohydrates

into cells. If cells become too excited (through

hypoxia), and insufficient thiamine is present,

cells can die.

Damage in brain sites which regulate depression: hippocampus, anterior cingulate

Cingulate cortex plays a role in depression; electrical stimulation can rapidly reverse symptoms.

The cingulate cortex shows structural injury and functional deficits in OSA

Depression and anxiety associated with OSA

Anterior cingulate gray matter and

cingulate bundle (axonal) injury in OSA

From Macey et al., AJRCCM, 2002; Sleep, 2008

Voxel-based morphometry Fractional anisotropy

OSA patients with depressive signs (BDI>10)

(n=13) vs OSA without depression (n=27)

Cross et al.,

2008

Obstructive Sleep Apnea, hormones, and

Diabetes75% of obese Type II diabetics- moderate-to-

severe OSA!

Remainder- mild OSA!

Two hrs sleep deprivation- 50 mg/dl rise in glucose

OSA- neural injury in areas influencing

hypothalamus, potential for hormonal

dysruption

OSA: significant decline in testosterone

Enhanced injury

in Type II

diabetics

with OSA over

OSA patients

without

diabetes (T2

relaxation time)

Harper et al., 2009

An OSA treatment intervention

The Australian

didgeridoo- a

native instrument

requiring precise

neural control

over upper airway

muscles.

Relearning of cerebellar and motor circuits!

Not just a small airway!

Summary

• Sleep disordered breathing affects cardiovascular, cognitive, memory, pain, mood, and hormonal regulatory sites; a result of brain injury in condition

• Three types: OSA, UARS, Cheyne Stokes

• Cerebellar injury - loss of breathing and cardiovascular coordination in OSA

• Hormonal dysregulation in sleep-disordered breathing, likely via hypothalamic injury

• Close association, OSA with diabetes

• Interventions are available, and Dentistry can make significant contributions!

Acknowledgments

These studies were supported by the National

Institutes of Health, through multiple institutes,

including the Heart, Lung and Blood Institute, the

Nursing Institute, and the National Institutes of

Child Health and Human Development. Dr. R.

Kumar, Dr. P. Macey, Dr. M. Woo, Dr. J. Ogren,

Dr. R. Cross, and Dr. F. Yan-Go contributed

substantially to the work.