central nervous system physiology, behavior & stress ans 536 spring 2014

Central Nervous System Physiology, Behavior & Stress

AnS 536Spring 2014

Timing of the Development of the Brain and CNS

Last half of gestation – “Critical period”

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

Brain size during gestation– 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

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

Prenatal development– 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

Prevents an overly exuberant axonal sprouting with misconnections

Brain Injury at Birth

Very rare in the term infant (1 in 1,000 live births) Most often secondary to:

– Hemorrhage– Focal cerebral infarction– Hypoxic-ischemia cerebral injury

Other causes:– Metabolic disturbances related to inborn errors of metabolism– Hypoglycemia– Hyperbilirubinemia– Infection/meningitis


Clinical expression:– Subtle

Mild hypotonia or hyperalert state– Severe

Stupor or coma

Severity and extent of damage dictate short and long-term consequences


Intracranial hemorrhage– Subarachnoid hemorrhage– Subdural hemorrhage– Epidural hemorrhage

Intracerebral hemorrhage


Subarachnoid hemorrhage– Primary

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

Extension of subdural, intraventricular, or intraparenchymal hemorrhages

Occur less often Trauma, coagulation disorders and rupture of intracranial

aneurysm or arteriovenous malformation can be responsible


Subdural hemorrhage– 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


Epidural hemorrhage– 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


Intracerebral Hemorrhage– 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:

Sudden onset of marked neurologic abnormalities, Signs of seizures, evidence of increased intracranial pressure and

downward eye deviation


Cerebral infarction (perinatal stroke)– Occurs 1 in 4,000 births– Causes:

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:

Seizures or apnea, usually on the 2nd postnatal day


Hypoxia–ischemia cerebral injury– 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

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)

What is ECMO?– 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%


Modified heart-lung machine combined with a membrane oxygenator to provide cardiopulmonary support– 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

Both O2 and CO2

– Blood is warmed before returning to host


Potential detrimental effects on the developing brain:– 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


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

Can the fetus feel pain in utero similar to adults? Critical cortico-thalamic connections appear to be

present by 24-28 weeks of gestation– 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


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


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

– 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


The fetus is actively kept asleep (unconscious) by a variety of endogenous inhibitory factors:

– Adenosine, allopregnanolone and pregnanolone, prostaglandin D2, a placental nerual inhibitor, warmth, buoyancy, and cushioned tactile stimulation

Nociceptive pathways are intact from around mid-gestation, 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


Post parturition– Substantial withdrawal of the neuroinhibitors

Adenosine– Involvement of neuroactivators:

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

– 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 Well-being

Measurements of fetal well-being:– 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 Well-being

Objective signs of neonatal well-being– 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

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


Health institutions should adopt an abstinence scoring method

– Lipsitz tool Simple numeric system using a value of >4 for significant signs of

withdrawal– Finnegan

Weighted scoring of 31 items Neonates with psychomotor behavior are difficult to

determine, and vary among institutions– Inconsistent diagnosis and treatment– Appropriate treatment?


Primary line of management:– Pharmacologic treatment

Opioids Methadone

– Sedative-hypnotic withdrawal Phenobarbital

Secondary line of management:– Intravenous morphine, clonidine, diazepam, oral

morphine, phenobarbital, methadone, and tincture of opium

Circadian Rhythms

An internal time-keeping system, the “biological clock”

Suprachiasmatic nucleus (SCN) is the site of the master pacemaker controlling circadian rhythms

– 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

12 hour light cycling conditions influences the repetitive oscillations in hormone levels that are very regular and cycle once every 24 hours– Cortisol levels follow the biological clock

Cortisol levels ↑ to peak levels at night during rest Cortisol levels continually ↓ during the day

Circadian Rhythms

Individual components of the circadian system develops postnatally

Early postnatal period– The developing circadian system is synchronized by

maternal cues Disturbing diurnal rhythms do have an effect on

developing neonates– Constant light trials show that disturbances in biological

rhythms and sleep states and inhibition of weight gain and visual development occur

central nervous system physiology, behavior & stress ans 536 spring 2014

Documents