Chapter 12 - The Central Nervous System*

 

I.     Introduction

 

A.     The brain is the largest, most complex portion of the nervous system, containing 100 billion multipolar neurons.

B.      It provides for voluntary movements, interpretation and integration of sensation, consciousness, and cognitive function.

C.      It is responsible for processing sensory information, producing sensations, storing memory, integrating information, reasoning, controlling visceral activities, providing personality, generating emotions, and initiating motor activities.

D.     Protection of the brain and spinal cord is provided both by bone and by the  membranes called meninges that surround these structures.

 

II. Embryonic Development of the Brain

 

A. Brain structure in the adult reflects the way the brain forms in the embryo.

B. The brain develops from the rostral portion of the embryonic neural tube.

C.   The early brain begins as a part of the neural tube where there are three cavities at one end:

1.       Forebrain or prosencephalon (cerebral hemispheres and diencephalon);

2.      Midbrain or mesencephalon ;

3.      Hindbrain or rhombencephalon (pons, medulla, and cerebellum)

D.  The cavities persist as ventricles and the tissue surrounding them differentiates into the structural and functional regions of the brain.

E.  Cephalization results in the envelopment of the diencephalon and superior brain stem by the cerebral hemispheres.

 

III.Regions and Organization of the Brain 

A.     The adult brain is divided into the:

1.       Cerebral hemispheres

a.       Have gray matter nuclei (cell bodies) surrounded by white matter and an outer cortex of gray matter.

2.      Diencephalon

3.      Brain stem

4.      Cerebellum

a.       Have gray matter nuclei (cell bodies) surrounded by white matter and

an outer cortex of gray matter.

 

IV. Ventricles of the Brain

  1. The brain contains four ventricles filled with cerebrospinal fluid.

1.       The two lateral ventricles are in the cerebral hemispheres;

2.      The third ventricle is in the diencephalon; and

3.      The fourth ventricle is in the brain stem and connects with the central canal of the spinal cord.

(* Human Anatomy & Physiology, 6 Ed.; Marieb, 2004)

V. The Cerebral Hemispheres

 

A. Structure of the Cerebrum

1.  The cerebrum is the largest portion of the mature brain, consisting of two cerebral hemispheres.

2.  A deep ridge of nerve fibers called the corpus callosum connects the hemispheres, and the falx cerebri of the dura mater separates them.

3.  The two cerebral hemispheres exhibit gyri, sulci, and fissures.

a.       Gyri (convolutions) are outward folds of the surface of the cerebral cortex.

b.      Sulci are shallow furrows on the brain, less deep than fissures.

c.   Fissures are deep furrows on the brain.

            4. The longitudinal fissure partially separates the hemispheres

5.  Other fissures or sulci subdivide each hemisphere into lobes.

6.  The lobes of the brain are named according to the bones they underlie and include the frontal lobe, parietal lobe, temporal lobe, occipital lobe, and insula (Island of Reil).

7. Each cerebral hemisphere consists of the:

a.       Cerebral cortex  - A thin layer of gray matter that lies on the outside of the cerebrum and contains 75% of the cell bodies in the nervous system.

b.      Cerebral white matter - made up of myelinated nerve fibers connecting the cell bodies of the cortex with the rest of the nervous system.

c.       Basal nuclei (ganglia)

8.      Each cerebral hemisphere receives sensory impulses from, and dispatches motor impulses to, the opposite side of the body.

a.       The body is represented in a upside-down fashion in the sensory and motor cortices.

 

B.  Functions of the Cerebrum

1.  The cerebrum provides higher brain functions, such as interpretation of sensory input, initiating voluntary muscular movements, memory, and integrating information for reasoning.

            2.  Functional Regions of the Cerebral Cortex

a.       The functional areas of the brain have been established using a variety of techniques.

b.       Functional areas of the cerebral cortex:

1)      Motor areas include primary motor and premotor areas of the frontal lobe, the frontal eye field, and Broca's area in the frontal lobe of one hemisphere (usually the left).

a)  The primary motor areas lie in the frontal lobes, anterior to the  central sulcus and in its anterior wall.

b)     Broca's area, anterior to the primary motor cortex, is usually in the left cerebral hemisphere and coordinates muscular activity to make speech possible.

 

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c) Above Broca's area is the frontal eye field that controls the voluntary movements of the eyes and eyelids

 

2) Sensory Areas:

a.)    The sensory area responsible for receiving impulses for temperature, pressure, pain, smell, and taste lies posterior to the central sulcus and in its posterior wall.

b.)    Primary somatosensory cortex, somatosensory association cortex, and the gustatory (taste) area lie in the parietal lobe

c)  Olfactory and auditory areas lie in the temporal lobe

d)  Sensory areas for sight lie within the occipital lobe.

e)  Vestibular area lies in the insula

f)  Sensory and motor fibers alike cross over in the spinal cord or brain stem so centers in the right hemisphere are interpreting or controlling the left side of the body, and vice versa.

 

                        3)  Association Areas

a)  The various association areas of the brain analyze and interpret sensory impulses and function in reasoning, judgment, emotions, verbalizing ideas, and storing memory.

b)  A general interpretive area is found at the junction of the parietal, temporal, and occipital lobe on one side (usually the left), and plays the primary role in complex thought processing.

c) Association areas located in the prefrontal cortex in the frontal lobe

d)  Language areas, including the lateral prefrontal cortex, a large portion of the temporal lobe, Broca's area, Wernicke's areas in one hemisphere (temporal lobe) only, usually the left, and affective language areas in one hemisphere (usually the right).

 

3.  Hemisphere Dominance

a.  Both cerebral hemispheres function in receiving and analyzing sensory input and sending motor impulses to the opposite side of the body.

b.  The cerebral hemispheres show lateralization of cortical function

1)      Most people exhibit left hemisphere dominance for mathematical skills and  language-related activities of speech, writing, and reading.

a)  The left hemisphere is dominant in 90% of the population, although some individuals have the right hemisphere as dominant, and others show equal dominance in both hemispheres.

 

2) The right hemisphere is more concerned with visual-spatial skills and creative endeavors.

 

 

 

 

 

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4.      Fiber tracts of the cerebral white matter include:

a.       Commissures;

b.      Association fibers; and

c.       Projection fibers

 

5.  Basal Ganglia

a.       The basal ganglia are masses of gray matter (subcortical nuclei) located deep within the cerebral hemispheres that relay motor impulses from the cerebrum and help to control motor activities (muscular movements) by producing inhibitory dopamine.  (Parkinson’s disease occurs when dopamine is not produced in adequate amounts.)

b.      The paired basal nuclei (also called basal ganglia) develop from the forebrain and include the:

1)       Lentiform nucleus (globus pallidus and putamen); and

2)      Caudate nucleus

c.       Functionally, they are closely associated with the substantia nigra of the midbrain.

 

6.  Ventricles and Cerebrospinal Fluid

a.       The ventricles are a series of connected cavities within the cerebral hemispheres and brain stem.

b.      The ventricles are continuous with the central canal of the spinal cord, and are filled with cerebrospinal fluid.

c.  Choroid plexuses, specialized capillaries from the pia mater, secrete cerebrospinal fluid.

1)      Cerebrospinal fluid is a clear fluid that has nutritive as well as protective (cushioning) functions

2)     Specialized ependymal cells, joined by tight junctions, regulate the composition of the cerebrospinal fluid.

3)     Most cerebrospinal fluid arises in the lateral ventricles; humans secrete 500 milliliters daily.

4)     Cerebrospinal fluid is reabsorbed through arachnoid granulations.

 

VI. The Diencephalon

A. The diencephalon lies above the brain stem, encloses the third ventricle, and

contains the thalamus, hypothalamus, and epithalamus

 

1.  The thalamus functions in sorting and directing sensory information arriving from other parts of the nervous system, performing the services of both messenger and editor.

a.       The thalamus may transmit sensory information by synchronizing action potentials.

 

 

 

 

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b.      The thalamus is the major station for:

1) Sensory impulses ascending to the sensory cortex;

2) Inputs from subcortical  motor nuclei and the cerebellum traveling to the cerebral motor cortex; and

3)Impulses traveling to association cortices from lower centers

2.  The hypothalamus maintains homeostasis by regulating a wide variety of visceral activities and by linking the endocrine system with the nervous system.

a.       It is an important autonomic nervous system control center and a pivotal part of the limbic system;

b.      The hypothalamus regulates heart rate and arterial blood pressure, body temperature, water and electrolyte balance, thirst, hunger, eating behavior, body weight, movements and secretions of the digestive tract (gastrointestinal activity), activity of the anterior pituitary gland, growth and reproduction, and sleep and wakefulness.

 

             3. The epithalamus consists of the:

a.       Pineal gland; and

b.      Choroid plexus of the third ventricle.

 

4. Other portions of the diencephalon are the:

a.       Optic tracts and optic chiasma;

b.      The infundibulum (attachment for the pituitary);

c.       The posterior pituitary; and

d.      Mammillary bodies;

 

5.      The limbic system consists of numerous structures that encircle diencephalon,

a.       The limbic system controls emotional experience and expression;

b.      It is the “emotional-visceral brain”

c.       By generating pleasant or unpleasant feelings about experiences, the limbic system guides behavior that may enhance the chance of survival.

d.      It also plays a role in memory.

                                                           

 VII. Brain Stem

A.     The brain stem lies at the base of the cerebrum, and connects the brain to the spinal cord. The brain stem includes the:

1.       Midbrain;

2.      Pons; and

3.      Medulla Oblongata

 

 

 

 

 

 

 

 

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B.      Functions of the brain stem components:

 

1.    Midbrain

a.  The midbrain, located between the diencephalon and pons, contains bundles of myelinated nerve fibers that convey impulses to and from higher parts of the brain, and masses of gray matter that serve as reflex centers.

 

b.  The midbrain contains centers for auditory and visual reflexes as well as reflexes that maintain posture.

 

c. The midbrain contains the:

1)      Corpora quadrigemina (visual and auditory reflex centers);

2)     Red nucleus (subcortical motor centers); and

3)     Substantia nigra.

4)     The periaqueductal gray matter elicits the fear response and contains the motor nuclei of cranial nerves III and IV.

5)     The cerebral peduncles on its ventral face house the pyramidal fiber tracts.

6)     The midbrain surrounds the cerebral aqueduct.

 

            2.  Pons

a.       The pons, lying between the midbrain and medulla oblongata,

b.      It transmits impulses between the brain and spinal cord; it is mainly a conduction area;

c.   It contains centers that regulate the rate and depth of breathing; its nuclei (cell bodies) contribute to regulation of respiration and cranial nerves V-VII.

 

3. Medulla Oblongata

 a. Transmits all ascending and descending impulses between the brain and spinal cord.

b.  It also houses nuclei that control visceral functions, including the cardiac center that controls heart rate, the vasomotor center for blood pressure control, and the respiratory center that works, along with the pons, to control the rate and depth of breathing (respiratory rhythm).

c. The olivary nucleus and cough, sneezing, swallowing, and vomiting centers are in the medulla.

d. Important nuclei in the medulla serve cranial nerves VIII-XII.

e. The pyramids (descending corticospinal tracts) form the ventral face of the medulla oblongata.

f. These fibers cross over (decussation of the pyramids) before entering the spinal cord.

 

 

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4. Reticular Formation

a.  Throughout the brain stem, hypothalamus, cerebrum, cerebellum, and basal ganglia, is a complex network of nerve fibers connecting tiny islands of gray matter; this network is the reticular formation.

b.  Decreased activity in the reticular formation results in sleep;

c.  Increased activity results in wakefulness; thus maintaining the alert state of the cerebral cortex (RAS)

d.  The reticular formation filters incoming sensory impulses.

 

VIII. The Cerebellum

 

A. The cerebellum is made up of two hemispheres, marked by convolutions, and connected by a vermis.

B.  A thin layer of gray matter lies outside a core of white matter.

C.   The cerebellum communicates with other parts of the central nervous system through cerebellar peduncles.

D.  It is connected to the brain stem by superior, middle, and inferior peduncles

 

E.   Functions of the cerebellum

1.       The cerebellum functions to integrate sensory information about the position of body parts and coordinates skeletal muscle activity and maintains posture.

2.      It processes and interprets impulses from the motor cortex and sensory pathways;

3.      It coordinates motor activity so that smooth, well-timed movements occur.

4.      It also plays a poorly understood role in cognition.

 

IX. Higher Mental Functions of the Brain

 

 A.  Brain Wave Patterns and the EEG 

1. Brain waves are patterns of electrical activity of the brain.

a.       An electroencephalogram (EEG) is a record of brain wave activity.

b.      Brain wave patterns (identified by their frequencies) include:

1) Alpha waves – indicate a brain that is “idling” – a calm, relaxed state of

                            wakefulness

2) Beta waves – occur when you are awake and mentally alert;  concentrating on some problem or visual stimulus

3) Theta waves – common in children; however, considered abnormal in adults who are awake

4) Delta waves – seen during sleep and when the reticular activating system is damped, such as during anesthesia.  In awake adults, delta waves indicate brain damage.

 

2. Epilepsy results from abnormal electrical activity of brain neurons.

a.       Involuntary muscle contractions and sensory auras are typical during epileptic seizures.

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B. Consciousness

1. Consciousness includes:

a.  Sensory perception;

b.  Initiation and control of voluntary movement;

c.  Higher mental processing capabilities.

 

2. Consciousness is described clinically on a continuum from alertness to drowsiness to stupor and finally to coma.

 

3. Human consciousness is thought to involve holistic information processing, which is:

a. Not localizable;

b. Superimposed on other types of neural activity; and

c. Totally interconnected.

 

4. Fainting (syncope) is a temporary loss of consciousness that usually reflects inadequate blood delivery to the brain.

 

5. Coma is loss of consciousness in which the victim is unresponsive to stimuli.

 

C. Sleep and Sleep-Awake Cycles

 

1. Sleep is a state of altered consciousness from which one can be aroused by stimulation.

 

2. The two major types of sleep are:

a. Slow wave or Non-Rapid Eye Movement (NREM) sleep; and

b. Rapid eye movement (REM) sleep.

                                                                                   

3. NREM Sleep:

a.  Slow-wave sleep (NREM) occurs for 70 to 90 minutes when the person is very tired, and results from decreasing activity in the reticular formation.

b. During stages 1-4, brain waves become more irregular; and

c.  Brain waves increase in amplitude until delta wave sleep (stage 4) is achieved.

d. Slow-wave sleep (stage 4 of NREM) appears to be restorative.

   e. Time spent in slow-wave sleep declines steadily throughout life.

 

4. REM Sleep:

a.  During REM sleep, certain areas of the brain are active and dreaming; eye movements and irregular heart and breathing rates occur.

b. During REM, the eyes move rapidly under the lids.

c. REM sleep is important for emotional stability.

d. REM occupies half of an infant's sleep time and then declines to about 25% of sleep time by the age of ten years.

 

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5.      NREM and REM sleep alternate throughout the night.

 

6.      Narcolepsy is involuntary lapses into sleep that occur without warning during waking periods.

 

7.      Insomnia is a chronic inability to obtain the amount or quality of sleep needed to function adequately.

 

8.      Sleep apnea is a temporary cessation of breathing during sleep due to hypoxia (a deficiency of oxygen reaching the tissues of the body).

 

D. Memory

 

1.  Memory is the ability to recall one's thoughts

a. It is essential for learning;

b. It is part of consciousness.

                                                                                   

2. Memory storage has two stages:

a. Short-term memory (STM) which is mostly electrical in nature; and

b. Long-term memory (LTM).

1) In long-term memory, synaptic connections between neurons are established and remain unchanged for years.

2)  According to the long-term synaptic potentiation theory, memory consolidation (conversion of short-term memory into long-term) occurs as repeated stimulation of the same synapses strengthens them.

 

3. Transfer of information from STM to LTM takes minutes to hours, but more time is required for LTM consolidation.

                                                                                   

4.      Fact memory is the ability to learn and consciously remember information.

a. Fact (declarative) memory appears to involve the following:

1) Hippocampus;

2) Amygdala;

3) Diencephalon;

4) Basal forebrain; and

5) Prefrontal cortex.

 

5.      Skill memory is the learning of motor skills, which are then performed without conscious thought.

a. Skill (declarative) memory pathways are mediated by the corpus striatum.

 

6.      The nature of memory traces in the human brain is not fully known, but NMDA receptors (essentially calcium channels), activated sequentially by depolarization and glutamate binding, play a major role in long-term potentiation (LTP).

a. The calcium influx that follows NMDA receptor activation mobilizes enzymes that mediate events necessary for memory consolidation.

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X. Protection of the Brain

 

  1. The brain is protected by bone, meninges, cerebrospinal fluid, and the blood-brain barrier.

 

1.Meninges: 

a. The meninges from superficial to deep are the:

1) Dura mater;

2) Arachnoid mater; and

3) Pia mater.

 

b.      The meninges enclose the brain and spinal cord and their blood vessels.

 

c. Functions of the various meninges:

 

1) The outermost meninx is made up of tough, white dense connective tissue, contains many blood vessels, and is called the dura mater.

a) It forms the inner periosteum of the skull bones.

       b) In some areas, the dura mater forms partitions between lobes of the brain, and in others, it forms dural sinuses.   

c)The sheath around the spinal cord is separated from the vertebrae by an   epidural space.

d) Inward folds of the inner layer of the dura mater secure the brain to the skull.

                                                                                                               

2) The middle meninx, the arachnoid mater, is thin and lacks blood vessels.

a) It does not follow the convolutions of the brain.

b) Between the arachnoid and pia maters is a subarachnoid space containing cerebrospinal fluid.

 

3) The innermost pia mater is thin and contains many blood vessels and nerves.

a) It is attached to the surface of the brain and spinal cord and follows their contours.

 

2.  Cerebrospinal Fluid (CSF)

a. Is formed by the choroid plexuses from blood plasma;

b. Circulates through the ventricles and into the subarachnoid space;

c. Returns to the dural venous sinuses via the arachnoid villi;

d. Supports and cushions the brain and spinal cord; and

e.  Helps to nourish the brain and spinal cord.

 

 

 

 

 

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3.  The Blood-Brain Barrier

a. Reflects the relative impermeability of the epithelium of capillaries of the brain.

b. Allows water, respiratory gases, essential nutrients, and fat soluble molecules to enter the neural tissue,  but

 c. Prevents entry of other water-soluble, potentially harmful substances.

 

B. Homeostatic Imbalances of the Brain

 

1.       Head trauma may cause brain injuries called concusions (reversible damage) or contusions (irreversible damage).

a.       When the brain stem is affected, unconsciousness (temporary or permanent) occurs.

b.  Trauma-induced brain injuries may be aggravated by intracranial hemorrhage or cerebral edema, both of which compress brain tissue.

 

2.      Cerebrovascular accidents (strokes) result when blood circulation to brain neurons is impaired and brain tissue dies.

a. The result may be hemiplegia (paralysis of one side of the body), sensory deficits, or speech impairment.

 

3.      Alzheimer's disease is a degenerative brain disease in which beta amyloid peptide deposits and neurofibrillar tangles appear.

a. Marked by a deficit of acetylcholine (ACh),

b. Results in slow, progressive loss of memory and motor control and increasing dementia.

                                               

4.      Neurodegenerative disorders of the basal nuclei involve abnormalities of the neurotransmitter dopamine (too little or too much secreted) and are characterized by abnormal movements:

a.  Parkinson's disease

b. Huntington's disease.

 

XI. Spinal Cord

 

  1. Embryonic Development of the Spinal Cord 

1.       The spinal cord develops from the neural tube.

2.      Its gray matter forms from the alar and basal plates.

3.      Fiber tracts form the outer white matter.

4.      The neural crest forms the sensory (dorsal root) ganglia.

 

  1. Gross Anatomy and Protection of the Spinal Cord 

 

1.       The spinal cord is a two-way impulse conduction pathway and a reflex center.

2.      It resides within the vertebral column

3.      It is protected by meninges and cerebrospinal fluid.

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4.      It extends from the base of the brain (foramen magnum) and extends as a slender cord to the intervertebral disk between the first and second lumbar vertebrae.

5.      The spinal cord consists of 31 segments, each of which gives rise to a pair of spinal nerves.

6.      The cord is enlarged in the cervical and lumbar regions.

a.       A cervical enlargement gives rise to nerves leading to the upper limbs,

b.      A lumbar enlargement gives rise to nerves innervating the lower limbs.

7.  The spinal cord ends at the conus medullaris and continues as a thin cord of connective tissue called the filum terminale.

                                                                       

  1. Cross-Sectional Anatomy of the Spinal Cord

1.       Two deep longitudinal grooves (anterior median fissure and posterior median sulcus) divide the cord into right and left halves.

 

2.      The central gray matter of the spinal cord is H shaped.

a.       Composition of the horns of the gray matter:

            1) Anterior horns mainly contain somatic motor neurons.

            2) Lateral horns contain visceral (autonomic) motor neurons.

3)     Posterior horns contain interneurons.

 

b.      Axons of motor neurons of the lateral and anterior horns emerge in common from the spinal cord via the ventral roots.

 

c.       Axons of sensory neurons (with cell bodies located in the dorsal root ganglion) enter the posterior aspect of the cord and from the dorsal roots.

 

3.      White matter, made up of bundles of myelinated nerve fibers, surrounds a butterfly-shaped core of gray matter of the spinal cord housing interneurons.

 

a.       Each side of the white matter of the spinal cord has posterior, latera, and anterior columns (funiculi);

b.      Each funiculus contains a number of ascending and descending tracts.

c.       All tracts are paired and most decussate (cross over)

d.      A central canal contains cerebrospinal fluid.

 

  1. Functions of the Spinal Cord

1.       The spinal cord has two major functions:

a.       To transmit impulses to and from the brain via ascending and descending nerve tracts, and

b.      To house spinal reflexes.

 

 

 

 

 

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2.  Ascending tracts include:

a.       Fasciculi gracilis and fasciculi cuneatus conduct sensory impulses from the skin, muscles, tendons, and joints to the brain.

b.  Spinothalamic tracts transmit impulses concerning pain, temperature, touch, and pressure.

c.       Spinocerebellar tracts carry impulses from the lower limbs and help coordinate muscular movements.

 

3. Descending tracts include:

a.   The pyramidal tracts (anterior and lateral corticospinal tracts) conduct impulses to skeletal muscles to control voluntary movements.

b.   Reticulospinal tracts control muscular activity and activity of sweat glands.

c.   Rubrospinal tracts carry motor impulses to skeletal muscles to coordinate muscles and control posture.

                                   

4.  Reflex Arcs

a.  A reflex arc includes a sensory receptor, a sensory neuron, an interneuron in the spinal cord, a motor neuron, and an effector.

b. Reflexes whose arcs pass through the spinal cord are called spinal reflexes.

 

            5. Reflex Behavior

a.  Reflexes are automatic, subconscious responses to stimuli that help maintain homeostasis (heart rate, blood pressure, etc.) and carry out automatic responses (vomiting, sneezing, swallowing, etc.).

b. The knee-jerk reflex (patellar tendon reflex) is an example of a monosynaptic reflex (no interneuron).

c.  The withdrawal reflex involves sensory neurons, interneurons, and motor neurons.

1)      While the flexor muscles contract to withdraw the hand, a crossed extensor reflex causes extensors in the other arm to contract.

 

E. Spinal Cord Trauma and Disorders

1.       Injury to the anterior horn neurons or the ventral roots results in flaccid paralysis.

2.       Injury to the upper motor neurons in the brain results in spastic paralysis.

3.       If a dorsal root or sensory tract is damaged, paresthesia (abnormal sensation, such as burning, prickling or tactile hallucination) occurs.

4.       Poliomyelitis results from inflammation and destruction of the anterior horn neurons by the poliovirus. 

a.       Paralysis and muscle atrophy follow.

5.       Amyotrophic lateral sclerosis results from destruction of the anterior horn neurons and the pyramidal tract.

a.       The victim loses the ability to swallow, speak and breathe.

b.      Death occurs within 5 years.

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F. Diagnostic Procedures for Assessing CNS Dysfunction 

1.       Diagnostic procedures used to assess neurological condition and function range from routine reflex testing to sophisticated techniques such as pneumoencephalography, cerebral angiography, CT scans, MRI scans, and PET scans.

 

G.Developmental Aspects of the Central Nervous System

 

1.   Maternal and environmental factors may impair embryonic brain development.

a.    Oxygen deprivation destroys brain cells.

b.    Severe congenital brain diseases include cerebral palsy, anencephaly, hydrocephalus, and spina bifida.

2.      Premature babies have trouble regulating body temperature because the hypothalamus is one of the last brain areas to mature prenatally.

3.      Development of motor control indicates progressive myelination and maturation of a child's nervous system.

4.      Brain growth ends in young adulthood.

a.       Neurons die throughout life and are not replaced

b.       Brain weight and volume decline with age

5.      Healthy elders maintain nearly optimal intellectual function

a. Disease (particularly cardiovascular disease) is the major cause of declining mental function with age.                  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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