Central Nervous System Physiology,
Behavior & Stress
AnS 536
Spring 2014
Timing of the Development of the Brain
and CNS
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Last half of gestation
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“Critical period”
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Time sensitive, irreversible decision point in the
development of the neural structure or system
Rapid and/or dramatic changes in one or more of the
structural, neurochemical, or molecular parameters
Developmental changes occur largely in the last
half of gestation
Growth and development continue to occur
beyond the neonatal period
Timing of the Development of the Brain
and CNS
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Brain size during gestation
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The growth of the brain is not a linear process
Development of different parameters may peak at different
times
Weeks 29-41 of gestation: Brain size increases at a rate of
15 mL per week
Week 28: Brain is 13% of term brain volume
Week 34: Brain is 64% of term brain
Weeks 35-41: Five fold increase of white matter volume
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Increasing neuronal connectivity, dendritic arborizatoin and
connectivity, increasing synaptic junctions, and the maturation
of neurochemical and enzymatic processes
Mediating the Development of the
Brain and CNS
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Prenatal development
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Neurotrophic factors and guidance factors
mediate the successful targeting and steering of
axons
Axons are projected to neurons over long
distances to reach their final targets
CNS myelin proteins might also help preserve an
appropriate CNS neuronal network
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Prevents an overly exuberant axonal sprouting with
misconnections
Brain Injury at Birth
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Very rare in the term infant (1 in 1,000 live births)
Most often secondary to:
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Hemorrhage
Focal cerebral infarction
Hypoxic-ischemia cerebral injury
Other causes:
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Metabolic disturbances related to inborn errors of metabolism
Hypoglycemia
Hyperbilirubinemia
Infection/meningitis
Brain Injury at Birth
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Clinical expression:
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Subtle
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Severe
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Mild hypotonia or hyperalert state
Stupor or coma
Severity and extent of damage dictate short
and long-term consequences
Brain Injury at Birth
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Intracranial hemorrhage
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Subarachnoid hemorrhage
Subdural hemorrhage
Epidural hemorrhage
Intracerebral hemorrhage
Brain Injury at Birth
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Subarachnoid hemorrhage
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Primary
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Hemorrhage in the subarachnoid space
Most common form of intracranial bleeding in term neonates
Rupture of small veins bridging the leptomeninges is most
common occurrence
Secondary
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Extension of subdural, intraventricular, or intraparenchymal
hemorrhages
Occur less often
Trauma, coagulation disorders and rupture of intracranial
aneurysm or arteriovenous malformation can be responsible
Brain Injury at Birth
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Subdural hemorrhage
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Categorized by origin and direction of spread (supratentorial and
infratentorial)
Tears in the falx and tentorium or bridging cortical veins
secondary to stretching can cause significant hemorrhage
Most likely to occur during difficult vaginal deliveries
Symptoms include: increased intracranial pressure, seizures,
focal neurological deficits, herniation of the temporal lobe over
the tentorial edge causing ipsilateral third nerve paralysis, large
movements, decreased responsiveness, metabolic acidosis,
hypoglycemia, anemia and hypotension
Brain Injury at Birth
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Epidural hemorrhage
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Rare lesion in the neonate (~2% of all cases)
Hemorrhage occurs from branches of the middle
meningeal artery or from major veins or venous
sinuses
Progressive neurological dysfunction and death
are common results unless epidural hemorrhage
is evacuated and further bleeding stopped
Brain Injury at Birth
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Intracerebral Hemorrhage
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Uncommon occurrence
Blood can be found within the germinal matrix, ventricles or
parenchyma
Thalamus is a common site of hemorrhage
Predisposing factors include prior hypoxic–ischemic cerebral
injury, sepsis, and coagulopathy
Can be observed in association with subarachnoid or subdural
hemorrhage
Symptoms:
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Sudden onset of marked neurologic abnormalities,
Signs of seizures, evidence of increased intracranial pressure and
downward eye deviation
Brain Injury at Birth
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Cerebral infarction (perinatal stroke)
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Occurs 1 in 4,000 births
Causes:
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May occur from both embolic and thrombotic phenomena
Intrapartum asphyxia , deficiency of one of the systemic
coagulation inhibitors (ie, protein C or protein S), primary
hemorrhage with vasospasm, meningitis, polycythemia, or
ECMO
Etiology is unclear
Symptoms:
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Seizures or apnea, usually on the 2nd postnatal day
Brain Injury at Birth
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Hypoxia–ischemia cerebral injury
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The brain injury that develops is an evolving process beginning at
the insult and extends into the recovery period (reperfusion
phase)
Causes severe, long term neurological deficits in children (i.e.
cerebral palsy)
Impaired cerebral blood flow (CBF) in principle pathogenetic
mechanism
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Interruption of placental blood flow and gas exchange (asphyxia)
Fetal acidemia
Cellular energy failure, acidosis, glutamate release, intracellular Ca+2
accumulation, lipid peroxidation and nitric oxide neurotoxicity serve
to disrupt essential components of the cell with its ultimate death
Extracorporeal Membrane Oxygenation
(ECMO)
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What is ECMO?
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Method of treatment for newborn, pediatric and
adult patients in respiratory and cardiac failure
Most patients are placed on ECMO therapy due
to severe hypoxemia
Used as a last resort in high risk infants with an
anticipated mortality rate of 80-85%
Survival rate in infants using EMCO ~84%
Extracorporeal Membrane Oxygenation
(ECMO)
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Modified heart-lung machine combined with
a membrane oxygenator to provide
cardiopulmonary support
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Catheterization of right common carotid artery
and internal jugular vein
Venous blood is drained from the infant and gas
exchange occurs in a machine outside of the
body
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Both O2 and CO2
Blood is warmed before returning to host
Extracorporeal Membrane Oxygenation
(ECMO)
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Potential detrimental effects on the developing brain:
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Severe morbidity in patients treated with ECMO due to
neurologic alterations
Brain responds to hypoxia by increasing cerebral blood flow,
resulting in a maintenance of cerebral oxygen transport, and
cerebral oxygen metabolism
Prolonged periods of severe hypoxia result in a loss of
cerebral autoregulation leading to the loss of the brain’s ability
to maintain oxygen transport and oxygen metabolism = brain
injury
Extracorporeal Membrane Oxygenation
(ECMO)
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Cerebral microcirculation is vulnerable to
alterations in blood pressure when systemic
insults occur (i.e. severe asphyxia, hypoxia,
and hypercarbia)
ECMO can lead to cerebral hemorrhage in
an injured brain due to the loss of
autoregulation and systemic heparinization
Intracranial hemorrhage
Fetal & Neonatal Pain Perception
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Can the fetus feel pain in utero similar to adults?
Critical cortico-thalamic connections appear to be
present by 24-28 weeks of gestation
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Suggests that the fetus can potentially feel pain by the third
trimester
Nociceptive stimuli elicit physiological stress-like responses
in the human fetus in utero
Physiologic processing of nociceptive stimulus and
perceiving a nociceptive stimulus as painful are not
the same
Fetal & Neonatal Pain Perception
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There is both a physiological and emotional
or cognitive aspect of pain perception
Processing can be independent of perception
(i.e. surgeries under general anesthesia)
Nociceptive stimuli can elicit subcortically
mediated physiological stress responses
despite unconsciousness
To emotionally experience pain, we must be
cognitively aware of the stimulus = we must
be conscious
Fetal & Neonatal Pain Perception
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Is the fetus ever conscious or aware?
Consciousness occurs when all the incoming
information from the external and internal
environment are available to all parts of the cortex at
the same time
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Sleep is an arousable state of unconsciousness
It is possible to be awake and not conscious
It is possible to be awake and conscious
It is NOT possible to be asleep and conscious
No strong evidence that the fetus is ever awake
Fetal & Neonatal Pain Perception
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The fetus is actively kept asleep (unconscious) by a
variety of endogenous inhibitory factors:
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Adenosine, allopregnanolone and pregnanolone,
prostaglandin D2, a placental nerual inhibitor, warmth,
buoyancy, and cushioned tactile stimulation
Nociceptive pathways are intact from around midgestation, however, the critical aspect of cortical
awareness in the process of pain perception is
missing
No direct evidence to suggest subcortical effects of
nociceptor input in the fetus can alter neural
development and have adverse affects
Fetal & Neonatal Pain Perception
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Post parturition
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Substantial withdrawal of the neuroinhibitors
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Involvement of neuroactivators:
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Adenosine
17β-estradiol, noradrenaline, and sensory information (air, cold surfaces)
Animals must be sentient and conscious for suffering to occur
Consciousness occurs for the first time after birth
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Breathing oxygenates the newborn enough to remove the dominant
adenosine inhibition of brain function
Newborns that do not breathe will die without suffering
Newborns that do breathe, but not sufficiently to remove adenosine will
die without suffering
Most farm animals become conscious within minutes of birth and have
the potential to suffer
Assessing Fetal and Neonatal Wellbeing
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Measurements of fetal well-being:
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Movement
Sleep states
Behavioral arousal
Fetal O2 and CO2 status
Fetal progesterone and estrogen status
Fetal thermal status
Fetal tactile stimulation
Assessing Fetal and Neonatal Wellbeing
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Objective signs of neonatal well-being
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Heart rate (100-140 bpm)
Respiratory effort (apneic, irregular, shallow
ventilation, or crying lustily)
Reflex irritability (response to a form of stimuli)
Muscle tone (flaccid, or resisting extension)
Color (cyanotic or pink – not as straightforward
due to infants high affinity for oxygen, foreign
material covering the skin, and skin pigmentation
due to race)
Neonatal Abstinence Syndrome
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Occurs in infants exposed to opiates in utero
due to maternal drug abuse during
pregnancy
Somewhere between 48-94% of infants
exposed to opiates in utero develop clinical
signs of withdrawal
Severity of neonatal psychomotor behavior
remains controversial
Neonatal Abstinence Syndrome
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Health institutions should adopt an abstinence scoring
method
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Lipsitz tool
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Finnegan
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Simple numeric system using a value of >4 for significant signs of
withdrawal
Weighted scoring of 31 items
Neonates with psychomotor behavior are difficult to
determine, and vary among institutions
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Inconsistent diagnosis and treatment
Appropriate treatment?
Neonatal Abstinence Syndrome
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Primary line of management:
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Pharmacologic treatment
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Sedative-hypnotic withdrawal
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Opioids
Methadone
Phenobarbital
Secondary line of management:
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Intravenous morphine, clonidine, diazepam, oral
morphine, phenobarbital, methadone, and tincture
of opium
Circadian Rhythms
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An internal time-keeping system, the “biological
clock”
Suprachiasmatic nucleus (SCN) is the site of the
master pacemaker controlling circadian rhythms
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Develops early in gestation
Is present in the fetus and newborn
Functional rhythms do occur during fetal life
The clock of the SCN oscillates with a near 24-hour period
Solar day/night is regulated by light
Circadian Rhythms
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12 hour light cycling conditions influences the
repetitive oscillations in hormone levels that
are very regular and cycle once every 24
hours
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Cortisol levels follow the biological clock
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Cortisol levels ↑ to peak levels at night during rest
Cortisol levels continually ↓ during the day
Circadian Rhythms
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Individual components of the circadian system
develops postnatally
Early postnatal period
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The developing circadian system is synchronized by
maternal cues
Disturbing diurnal rhythms do have an effect on
developing neonates
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Constant light trials show that disturbances in biological
rhythms and sleep states and inhibition of weight gain and
visual development occur