Month: May 2022

Although a given hormone may travel throughout the body in the bloodstream, it will affect the activity only of its target cells; that is, cells with receptors for that particular hormone. Once the hormone binds to the receptor, a chain of events is initiated that leads to the target cell’s response. Hormones play a critical role in the regulation of physiological processes because of the target cell responses they regulate. These responses contribute to human reproduction, growth and development of body tissues, metabolism, fluid, and electrolyte balance, sleep, and many other body functions. The major hormones of the human body and their effects are identified in Table 17.2.Endocrine Glands and Their Major Hormones

Endocrine gland	Associated hormones	Chemical class	Effect
Pituitary (anterior)	Growth hormone (GH)	Protein	Promotes growth of body tissues
Pituitary (anterior)	Prolactin (PRL)	Peptide	Promotes milk production
Pituitary (anterior)	Thyroid-stimulating hormone (TSH)	Glycoprotein	Stimulates thyroid hormone release
Pituitary (anterior)	Adrenocorticotropic hormone (ACTH)	Peptide	Stimulates hormone release by adrenal cortex
Pituitary (anterior)	Follicle-stimulating hormone (FSH)	Glycoprotein	Stimulates gamete production
Pituitary (anterior)	Luteinizing hormone (LH)	Glycoprotein	Stimulates androgen production by gonads
Pituitary (posterior)	Antidiuretic hormone (ADH)	Peptide	Stimulates water reabsorption by kidneys
Pituitary (posterior)	Oxytocin	Peptide	Stimulates uterine contractions during childbirth
Thyroid	Thyroxine (T4), triiodothyronine (T3)	Amine	Stimulate basal metabolic rate
Thyroid	Calcitonin	Peptide	Reduces blood Ca2+ levels
Parathyroid	Parathyroid hormone (PTH)	Peptide	Increases blood Ca2+ levels
Adrenal (cortex)	Aldosterone	Steroid	Increases blood Na+ levels
Adrenal (cortex)	Cortisol, corticosterone, cortisone	Steroid	Increase blood glucose levels
Adrenal (medulla)	Epinephrine, norepinephrine	Amine	Stimulate fight-or-flight response
Pineal	Melatonin	Amine	Regulates sleep cycles
Pancreas	Insulin	Protein	Reduces blood glucose levels
Pancreas	Glucagon	Protein	Increases blood glucose levels
Testes	Testosterone	Steroid	Stimulates development of male secondary sex characteristics and sperm production
Ovaries	Estrogens and progesterone	Steroid	Stimulate development of female secondary sex characteristics and prepare the body for childbirth

Table17.2

Types of Hormones:

The hormones of the human body can be divided into two major groups on the basis of their chemical structure. Hormones derived from amino acids include amines, peptides, and proteins. Those derived from lipids include steroids (Figure 17.3). These chemical groups affect a hormone’s distribution, the type of receptors it binds to, and other aspects of its function.

Figure 17.3Amine, Peptide, Protein, and Steroid Hormone Structure

Amine Hormones:

Hormones derived from the modification of amino acids are referred to as amine hormones. Typically, the original structure of the amino acid is modified such that a –COOH, or carboxyl, group is removed, whereas the −NH+3−NH3+, or amine, group remains.

Amine hormones are synthesized from the amino acids tryptophan or tyrosine. An example of a hormone derived from tryptophan is melatonin, which is secreted by the pineal gland and helps regulate circadian rhythm. Tyrosine derivatives include the metabolism-regulating thyroid hormones, as well as the catecholamines, such as epinephrine, norepinephrine, and dopamine. Epinephrine and norepinephrine are secreted by the adrenal medulla and play a role in the fight-or-flight response, whereas dopamine is secreted by the hypothalamus and inhibits the release of certain anterior pituitary hormones.

Peptide and Protein Hormones:

Whereas the amine hormones are derived from a single amino acid, peptide and protein hormones consist of multiple amino acids that link to form an amino acid chain. Peptide hormones consist of short chains of amino acids, whereas protein hormones are longer polypeptides. Both types are synthesized like other body proteins: DNA is transcribed into mRNA, which is translated into an amino acid chain.

Examples of peptide hormones include antidiuretic hormone (ADH), a pituitary hormone important in fluid balance, and atrial-natriuretic peptide, which is produced by the heart and helps to decrease blood pressure. Some examples of protein hormones include growth hormone, which is produced by the pituitary gland, and follicle-stimulating hormone (FSH), which has an attached carbohydrate group and is thus classified as a glycoprotein. FSH helps stimulate the maturation of eggs in the ovaries and sperm in the testes.

Steroid Hormones:

The primary hormones derived from lipids are steroids. Steroid hormones are derived from the lipid cholesterol. For example, the reproductive hormones testosterone and the estrogens—which are produced by the gonads (testes and ovaries)—are steroid hormones. The adrenal glands produce the steroid hormone aldosterone, which is involved in osmoregulation, and cortisol, which plays a role in metabolism.

Like cholesterol, steroid hormones are not soluble in water (they are hydrophobic). Because blood is water-based, lipid-derived hormones must travel to their target cell bound to a transport protein. This more complex structure extends the half-life of steroid hormones much longer than that of hormones derived from amino acids. A hormone’s half-life is the time required for half the concentration of the hormone to be degraded. For example, the lipid-derived hormone cortisol has a half-life of approximately 60 to 90 minutes. In contrast, the amino acid–derived hormone epinephrine has a half-life of approximately one minute.

Pathways of Hormone Action:

The message a hormone sends is received by a hormone receptor, a protein located either inside the cell or within the cell membrane. The receptor will process the message by initiating other signaling events or cellular mechanisms that result in the target cell’s response. Hormone receptors recognize molecules with specific shapes and side groups, and respond only to those hormones that are recognized. The same type of receptor may be located on cells in different body tissues, and trigger somewhat different responses. Thus, the response triggered by a hormone depends not only on the hormone, but also on the target cell.

Once the target cell receives the hormone signal, it can respond in a variety of ways. The response may include the stimulation of protein synthesis, activation or deactivation of enzymes, alteration in the permeability of the cell membrane, altered rates of mitosis and cell growth, and stimulation of the secretion of products. Moreover, a single hormone may be capable of inducing different responses in a given cell.

Pathways Involving Intracellular Hormone Receptors:

Intracellular hormone receptors are located inside the cell. Hormones that bind to this type of receptor must be able to cross the cell membrane. Steroid hormones are derived from cholesterol and therefore can readily diffuse through the lipid bilayer of the cell membrane to reach the intracellular receptor (Figure 17.4). Thyroid hormones, cross the cell membrane by a specific carrier-mediated mechanism that is energy and Na⁺ dependent.

The location of steroid and thyroid hormone binding differs slightly: a steroid hormone may bind to its receptor within the cytosol or within the nucleus. In either case, this binding generates a hormone-receptor complex that moves toward the chromatin in the cell nucleus and binds to a particular segment of the cell’s DNA. In contrast, thyroid hormones bind to receptors already bound to DNA. For both steroid and thyroid hormones, binding of the hormone-receptor complex with DNA triggers transcription of a target gene to mRNA, which moves to the cytosol and directs protein synthesis by ribosomes.

Figure 17.4Binding of Lipid-Soluble Hormones A steroid hormone directly initiates the production of proteins within a target cell. Steroid hormones easily diffuse through the cell membrane. The hormone binds to its receptor in the cytosol, forming a receptor–hormone complex. The receptor–hormone complex then enters the nucleus and binds to the target gene on the DNA. Transcription of the gene creates a messenger RNA that is translated into the desired protein within the cytoplasm.

Pathways Involving Cell Membrane Hormone Receptors:

Hydrophilic, or water-soluble, hormones are unable to diffuse through the lipid bilayer of the cell membrane and must therefore pass on their message to a receptor located at the surface of the cell. Except for thyroid hormones, which are lipid-soluble, all amino acid–derived hormones bind to cell membrane receptors that are located, at least in part, on the extracellular surface of the cell membrane. Therefore, they do not directly affect the transcription of target genes, but instead initiate a signaling cascade that is carried out by a molecule called a second messenger. In this case, the hormone is called a first messenger.

The second messenger used by most hormones is cyclic adenosine monophosphate (cAMP). In the cAMP second messenger system, a water-soluble hormone binds to its receptor in the cell membrane (Step 1 in Figure 17.5). This receptor is associated with an intracellular component called a G protein, and binding of the hormone activates the G-protein component (Step 2). The activated G protein in turn activates an enzyme called adenylyl cyclase, also known as adenylate cyclase (Step 3), which converts adenosine triphosphate (ATP) to cAMP (Step 4). As the second messenger, cAMP activates a type of enzyme called a protein kinase that is present in the cytosol (Step 5). Activated protein kinases initiate a phosphorylation cascade, in which multiple protein kinases phosphorylate (add a phosphate group to) numerous and various cellular proteins, including other enzymes (Step 6).

Figure 17.5Binding of Water-Soluble Hormones Water-soluble hormones cannot diffuse through the cell membrane. These hormones must bind to a surface cell-membrane receptor. The receptor then initiates a cell-signaling pathway within the cell involving G proteins, adenylyl cyclase, the secondary messenger cyclic AMP (cAMP), and protein kinases. In the final step, these protein kinases phosphorylate proteins in the cytoplasm. This activates proteins in the cell that carry out the changes specified by the hormone.

The phosphorylation of cellular proteins can trigger a wide variety of effects, from nutrient metabolism to the synthesis of different hormones and other products. The effects vary according to the type of target cell, the G proteins and kinases involved, and the phosphorylation of proteins. Examples of hormones that use cAMP as a second messenger include calcitonin, which is important for bone construction and regulating blood calcium levels; glucagon, which plays a role in blood glucose levels; and thyroid-stimulating hormone, which causes the release of T₃ and T₄ from the thyroid gland.

Overall, the phosphorylation cascade significantly increases the efficiency, speed, and specificity of the hormonal response, as thousands of signaling events can be initiated simultaneously in response to a very low concentration of hormone in the bloodstream. However, the duration of the hormone signal is short, as cAMP is quickly deactivated by the enzyme phosphodiesterase (PDE), which is located in the cytosol. The action of PDE helps to ensure that a target cell’s response ceases quickly unless new hormones arrive at the cell membrane.

Importantly, there are also G proteins that decrease the levels of cAMP in the cell in response to hormone binding. For example, when growth hormone–inhibiting hormone (GHIH), also known as somatostatin, binds to its receptors in the pituitary gland, the level of cAMP decreases, thereby inhibiting the secretion of human growth hormone.

Not all water-soluble hormones initiate the cAMP second messenger system. One common alternative system uses calcium ions as a second messenger. In this system, G proteins activate the enzyme phospholipase C (PLC), which functions similarly to adenylyl cyclase. Once activated, PLC cleaves a membrane-bound phospholipid into two molecules: diacylglycerol (DAG) and inositol triphosphate (IP₃). Like cAMP, DAG activates protein kinases that initiate a phosphorylation cascade. At the same time, IP₃ causes calcium ions to be released from storage sites within the cytosol, such as from within the smooth endoplasmic reticulum. The calcium ions then act as second messengers in two ways: they can influence enzymatic and other cellular activities directly, or they can bind to calcium-binding proteins, the most common of which is calmodulin. Upon binding calcium, calmodulin is able to modulate protein kinase within the cell. Examples of hormones that use calcium ions as a second messenger system include angiotensin II, which helps regulate blood pressure through vasoconstriction, and growth hormone–releasing hormone (GHRH), which causes the pituitary gland to release growth hormones.

Factors Affecting Target Cell Response:

You will recall that target cells must have receptors specific to a given hormone if that hormone is to trigger a response. But several other factors influence the target cell response. For example, the presence of a significant level of a hormone circulating in the bloodstream can cause its target cells to decrease their number of receptors for that hormone. This process is called downregulation, and it allows cells to become less reactive to the excessive hormone levels. When the level of a hormone is chronically reduced, target cells engage in upregulation to increase their number of receptors. This process allows cells to be more sensitive to the hormone that is present. Cells can also alter the sensitivity of the receptors themselves to various hormones.

Two or more hormones can interact to affect the response of cells in a variety of ways. The three most common types of interaction are as follows:

• The permissive effect, in which the presence of one hormone enables another hormone to act. For example, thyroid hormones have complex permissive relationships with certain reproductive hormones. A dietary deficiency of iodine, a component of thyroid hormones, can therefore affect reproductive system development and functioning.
• The synergistic effect, in which two hormones with similar effects produce an amplified response. In some cases, two hormones are required for an adequate response. For example, two different reproductive hormones—FSH from the pituitary gland and estrogens from the ovaries—are required for the maturation of female ova (egg cells).
• The antagonistic effect, in which two hormones have opposing effects. A familiar example is the effect of two pancreatic hormones, insulin and glucagon. Insulin increases the liver’s storage of glucose as glycogen, decreasing blood glucose, whereas glucagon stimulates the breakdown of glycogen stores, increasing blood glucose.

Regulation of Hormone Secretion:

To prevent abnormal hormone levels and a potential disease state, hormone levels must be tightly controlled. The body maintains this control by balancing hormone production and degradation. Feedback loops govern the initiation and maintenance of most hormone secretion in response to various stimuli.

Role of Feedback Loops:

The contribution of feedback loops to homeostasis will only be briefly reviewed here. Positive feedback loops are characterized by the release of additional hormone in response to an original hormone release. The release of oxytocin during childbirth is a positive feedback loop. The initial release of oxytocin begins to signal the uterine muscles to contract, which pushes the fetus toward the cervix, causing it to stretch. This, in turn, signals the pituitary gland to release more oxytocin, causing labor contractions to intensify. The release of oxytocin decreases after the birth of the child.

The more common method of hormone regulation is the negative feedback loop. Negative feedback is characterized by the inhibition of further secretion of a hormone in response to adequate levels of that hormone. This allows blood levels of the hormone to be regulated within a narrow range. An example of a negative feedback loop is the release of glucocorticoid hormones from the adrenal glands, as directed by the hypothalamus and pituitary gland. As glucocorticoid concentrations in the blood rise, the hypothalamus and pituitary gland reduce their signaling to the adrenal glands to prevent additional glucocorticoid secretion (Figure 17.6).

Figure 17.6Negative Feedback Loop The release of adrenal glucocorticoids is stimulated by the release of hormones from the hypothalamus and pituitary gland. This signaling is inhibited when glucocorticoid levels become elevated by causing negative signals to the pituitary gland and hypothalamus.

Role of Endocrine Gland Stimuli:

Reflexes triggered by both chemical and neural stimuli control endocrine activity. These reflexes may be simple, involving only one hormone response, or they may be more complex and involve many hormones, as is the case with the hypothalamic control of various anterior pituitary–controlled hormones.

Humoral stimuli are changes in blood levels of non-hormone chemicals, such as nutrients or ions, which cause the release or inhibition of a hormone to, in turn, maintain homeostasis. For example, osmoreceptors in the hypothalamus detect changes in blood osmolarity (the concentration of solutes in the blood plasma). If blood osmolarity is too high, meaning that the blood is not dilute enough, osmoreceptors signal the hypothalamus to release ADH. The hormone causes the kidneys to reabsorb more water and reduce the volume of urine produced. This reabsorption causes a reduction of the osmolarity of the blood, diluting the blood to the appropriate level. The regulation of blood glucose is another example. High blood glucose levels cause the release of insulin from the pancreas, which increases glucose uptake by cells and liver storage of glucose as glycogen.

An endocrine gland may also secrete a hormone in response to the presence of another hormone produced by a different endocrine gland. Such hormonal stimuli often involve the hypothalamus, which produces releasing and inhibiting hormones that control the secretion of a variety of pituitary hormones.

In addition to these chemical signals, hormones can also be released in response to neural stimuli. A common example of neural stimuli is the activation of the fight-or-flight response by the sympathetic nervous system. When an individual perceives danger, sympathetic neurons signal the adrenal glands to secrete norepinephrine and epinephrine. The two hormones dilate blood vessels, increase the heart and respiratory rate, and suppress the digestive and immune systems. These responses boost the body’s transport of oxygen to the brain and muscles, thereby improving the body’s ability to fight or flee.

Communication is a process in which a sender transmits signals to one or more receivers to control and coordinate actions. In the human body, two major organ systems participate in relatively “long distance” communication: the nervous system and the endocrine system. Together, these two systems are primarily responsible for maintaining homeostasis in the body.

Neural and Endocrine Signaling:

The nervous system uses two types of intercellular communication—electrical and chemical signaling—either by the direct action of an electrical potential, or in the latter case, through the action of chemical neurotransmitters such as serotonin or norepinephrine. Neurotransmitters act locally and rapidly. When an electrical signal in the form of an action potential arrives at the synaptic terminal, they diffuse across the synaptic cleft (the gap between a sending neuron and a receiving neuron or muscle cell). Once the neurotransmitters interact (bind) with receptors on the receiving (post-synaptic) cell, the receptor stimulation is transduced into a response such as continued electrical signaling or modification of cellular response.

The target cell responds within milliseconds of receiving the chemical “message”; this response then ceases very quickly once the neural signaling ends. In this way, neural communication enables body functions that involve quick, brief actions, such as movement, sensation, and cognition.

In contrast, the endocrine system uses just one method of communication: chemical signaling. These signals are sent by the endocrine organs, which secrete chemicals—the hormone—into the extracellular fluid. Hormones are transported primarily via the bloodstream throughout the body, where they bind to receptors on target cells, inducing a characteristic response. As a result, endocrine signaling requires more time than neural signaling to prompt a response in target cells, though the precise amount of time varies with different hormones. For example, the hormones released when you are confronted with a dangerous or frightening situation, called the fight-or-flight response, occur by the release of adrenal hormones—epinephrine and norepinephrine—within seconds. In contrast, it may take up to 48 hours for target cells to respond to certain reproductive hormones.

In addition, endocrine signaling is typically less specific than neural signaling. The same hormone may play a role in a variety of different physiological processes depending on the target cells involved. For example, the hormone oxytocin promotes uterine contractions in women in labor. It is also important in breastfeeding, and may be involved in the sexual response and in feelings of emotional attachment in both males and females.

In general, the nervous system involves quick responses to rapid changes in the external environment, and the endocrine system is usually slower acting—taking care of the internal environment of the body, maintaining homeostasis, and controlling reproduction (Table 17.1). So how does the fight-or-flight response that was mentioned earlier happen so quickly if hormones are usually slower acting? It is because the two systems are connected. It is the fast action of the nervous system in response to the danger in the environment that stimulates the adrenal glands to secrete their hormones. As a result, the nervous system can cause rapid endocrine responses to keep up with sudden changes in both the external and internal environments when necessary. Endocrine and Nervous Systems

	Endocrine system	Nervous system
Signaling mechanism(s)	Chemical	Chemical/electrical
Primary chemical signal	Hormones	Neurotransmitters
Distance traveled	Long or short	Always short
Response time	Fast or slow	Always fast
Environment targeted	Internal	Internal and external

Table17.1

Structures of the Endocrine System:

The endocrine system consists of cells, tissues, and organs that secrete hormones as a primary or secondary function. The endocrine gland is the major player in this system. The primary function of these ductless glands is to secrete their hormones directly into the surrounding fluid. The interstitial fluid and the blood vessels then transport the hormones throughout the body. The endocrine system includes the pituitary, thyroid, parathyroid, adrenal, and pineal glands (Figure 17.2). Some of these glands have both endocrine and non-endocrine functions. For example, the pancreas contains cells that function in digestion as well as cells that secrete the hormones insulin and glucagon, which regulate blood glucose levels. The hypothalamus, thymus, heart, kidneys, stomach, small intestine, liver, skin, female ovaries, and male testes are other organs that contain cells with endocrine function. Moreover, adipose tissue has long been known to produce hormones, and recent research has revealed that even bone tissue has endocrine functions.

Figure 17.2Endocrine System Endocrine glands and cells are located throughout the body and play an important role in homeostasis.

The ductless endocrine glands are not to be confused with the body’s exocrine system, whose glands release their secretions through ducts. Examples of exocrine glands include the sebaceous and sweat glands of the skin. As just noted, the pancreas also has an exocrine function: most of its cells secrete pancreatic juice through the pancreatic and accessory ducts to the lumen of the small intestine.

Other Types of Chemical Signaling:

In endocrine signaling, hormones secreted into the extracellular fluid diffuse into the blood or lymph, and can then travel great distances throughout the body. In contrast, autocrine signaling takes place within the same cell. An autocrine (auto- = “self”) is a chemical that elicits a response in the same cell that secreted it. Interleukin-1, or IL-1, is a signaling molecule that plays an important role in inflammatory response. The cells that secrete IL-1 have receptors on their cell surface that bind these molecules, resulting in autocrine signaling.

Local intercellular communication is the province of the paracrine, also called a paracrine factor, which is a chemical that induces a response in neighboring cells. Although paracrines may enter the bloodstream, their concentration is generally too low to elicit a response from distant tissues. A familiar example to those with asthma is histamine, a paracrine that is released by immune cells in the bronchial tree. Histamine causes the smooth muscle cells of the bronchi to constrict, narrowing the airways. Another example is the neurotransmitters of the nervous system, which act only locally within the synaptic cleft.

Figure 17.1A Child Catches a Falling Leaf Hormones of the endocrine system coordinate and control growth, metabolism, temperature regulation, the stress response, reproduction, and many other functions.

You may never have thought of it this way, but when you send a text message to two friends to meet you at the dining hall at six, you’re sending digital signals that (you hope) will affect their behavior—even though they are some distance away. Similarly, certain cells send chemical signals to other cells in the body that influence their behavior. This long-distance intercellular communication, coordination, and control is critical for homeostasis, and it is the fundamental function of the endocrine system.

The role of the cerebellum is a subject of debate. There is an obvious connection to motor function based on the clinical implications of cerebellar damage. There is also strong evidence of the cerebellar role in procedural memory. The two are not incompatible; in fact, procedural memory is motor memory, such as learning to ride a bicycle. Significant work has been performed to describe the connections within the cerebellum that result in learning. A model for this learning is classical conditioning, as shown by the famous dogs from the physiologist Ivan Pavlov’s work. This classical conditioning, which can be related to motor learning, fits with the neural connections of the cerebellum. The cerebellum is 10 percent of the mass of the brain and has varied functions that all point to a role in the motor system.

Location and Connections of the Cerebellum:

The cerebellum is located in apposition to the dorsal surface of the brain stem, centered on the pons. The name of the pons is derived from its connection to the cerebellum. The word means “bridge” and refers to the thick bundle of myelinated axons that form a bulge on its ventral surface. Those fibers are axons that project from the gray matter of the pons into the contralateral cerebellar cortex. These fibers make up the middle cerebellar peduncle (MCP) and are the major physical connection of the cerebellum to the brain stem (Figure 16.14). Two other white matter bundles connect the cerebellum to the other regions of the brain stem. The superior cerebellar peduncle (SCP) is the connection of the cerebellum to the midbrain and forebrain. The inferior cerebellar peduncle (ICP) is the connection to the medulla.

Figure 16.14Cerebellar Peduncles The connections to the cerebellum are the three cerebellar peduncles, which are close to each other. The ICP arises from the medulla—specifically from the inferior olive, which is visible as a bulge on the ventral surface of the brain stem. The MCP is the ventral surface of the pons. The SCP projects into the midbrain.

These connections can also be broadly described by their functions. The ICP conveys sensory input to the cerebellum, partially from the spinocerebellar tract, but also through fibers of the inferior olive. The MCP is part of the cortico-ponto-cerebellar pathway that connects the cerebral cortex with the cerebellum and preferentially targets the lateral regions of the cerebellum. It includes a copy of the motor commands sent from the precentral gyrus through the corticospinal tract, arising from collateral branches that synapse in the gray matter of the pons, along with input from other regions such as the visual cortex. The SCP is the major output of the cerebellum, divided between the red nucleus in the midbrain and the thalamus, which will return cerebellar processing to the motor cortex. These connections describe a circuit that compares motor commands and sensory feedback to generate a new output. These comparisons make it possible to coordinate movements. If the cerebral cortex sends a motor command to initiate walking, that command is copied by the pons and sent into the cerebellum through the MCP. Sensory feedback in the form of proprioception from the spinal cord, as well as vestibular sensations from the inner ear, enters through the ICP. If you take a step and begin to slip on the floor because it is wet, the output from the cerebellum—through the SCP—can correct for that and keep you balanced and moving. The red nucleus sends new motor commands to the spinal cord through the rubrospinal tract.

The cerebellum is divided into regions that are based on the particular functions and connections involved. The midline regions of the cerebellum, the vermis and flocculonodular lobe, are involved in comparing visual information, equilibrium, and proprioceptive feedback to maintain balance and coordinate movements such as walking, or gait, through the descending output of the red nucleus (Figure 16.15). The lateral hemispheres are primarily concerned with planning motor functions through frontal lobe inputs that are returned through the thalamic projections back to the premotor and motor cortices. Processing in the midline regions targets movements of the axial musculature, whereas the lateral regions target movements of the appendicular musculature. The vermis is referred to as the spinocerebellum because it primarily receives input from the dorsal columns and spinocerebellar pathways. The flocculonodular lobe is referred to as the vestibulocerebellum because of the vestibular projection into that region. Finally, the lateral cerebellum is referred to as the cerebrocerebellum, reflecting the significant input from the cerebral cortex through the cortico-ponto-cerebellar pathway.

Figure 16.15Major Regions of the Cerebellum The cerebellum can be divided into two basic regions: the midline and the hemispheres. The midline is composed of the vermis and the flocculonodular lobe, and the hemispheres are the lateral regions.

Coordination and Alternating Movement:

Testing for cerebellar function is the basis of the coordination exam. The subtests target appendicular musculature, controlling the limbs, and axial musculature for posture and gait. The assessment of cerebellar function will depend on the normal functioning of other systems addressed in previous sections of the neurological exam. Motor control from the cerebrum, as well as sensory input from somatic, visual, and vestibular senses, are important to cerebellar function.

The subtests that address appendicular musculature, and therefore the lateral regions of the cerebellum, begin with a check for tremor. The patient extends their arms in front of them and holds the position. The examiner watches for the presence of tremors that would not be present if the muscles are relaxed. By pushing down on the arms in this position, the examiner can check for the rebound response, which is when the arms are automatically brought back to the extended position. The extension of the arms is an ongoing motor process, and the tap or push on the arms presents a change in the proprioceptive feedback. The cerebellum compares the cerebral motor command with the proprioceptive feedback and adjusts the descending input to correct. The red nucleus would send an additional signal to the LMN for the arm to increase contraction momentarily to overcome the change and regain the original position.

The check reflex depends on cerebellar input to keep increased contraction from continuing after the removal of resistance. The patient flexes the elbow against resistance from the examiner to extend the elbow. When the examiner releases the arm, the patient should be able to stop the increased contraction and keep the arm from moving. A similar response would be seen if you try to pick up a coffee mug that you believe to be full but turns out to be empty. Without checking the contraction, the mug would be thrown from the overexertion of the muscles expecting to lift a heavier object.

Several subtests of the cerebellum assess the ability to alternate movements, or switch between muscle groups that may be antagonistic to each other. In the finger-to-nose test, the patient touches their finger to the examiner’s finger and then to their nose, and then back to the examiner’s finger, and back to the nose. The examiner moves the target finger to assess a range of movements. A similar test for the lower extremities has the patient touch their toe to a moving target, such as the examiner’s finger. Both of these tests involve flexion and extension around a joint—the elbow or the knee and the shoulder or hip—as well as movements of the wrist and ankle. The patient must switch between the opposing muscles, like the biceps and triceps brachii, to move their finger from the target to their nose. Coordinating these movements involves the motor cortex communicating with the cerebellum through the pons and feedback through the thalamus to plan the movements. Visual cortex information is also part of the processing that occurs in the cerebrocerebellum while it is involved in guiding movements of the finger or toe.

Rapid, alternating movements are tested for the upper and lower extremities. The patient is asked to touch each finger to their thumb, or to pat the palm of one hand on the back of the other, and then flip that hand over and alternate back-and-forth. To test similar function in the lower extremities, the patient touches their heel to their shin near the knee and slides it down toward the ankle, and then back again, repetitively. Rapid, alternating movements are part of speech as well. A patient is asked to repeat the nonsense consonants “lah-kah-pah” to alternate movements of the tongue, lips, and palate. All of these rapid alternations require planning from the cerebrocerebellum to coordinate movement commands that control the coordination.

Posture and Gait:

Gait can either be considered a separate part of the neurological exam or a subtest of the coordination exam that addresses walking and balance. Testing posture and gait addresses functions of the spinocerebellum and the vestibulocerebellum because both are part of these activities. A subtest called station begins with the patient standing in a normal position to check for the placement of the feet and balance. The patient is asked to hop on one foot to assess the ability to maintain balance and posture during movement. Though the station subtest appears to be similar to the Romberg test, the difference is that the patient’s eyes are open during station. The Romberg test has the patient stand still with the eyes closed. Any changes in posture would be the result of proprioceptive deficits, and the patient is able to recover when they open their eyes.

Subtests of walking begin with having the patient walk normally for a distance away from the examiner, and then turn and return to the starting position. The examiner watches for abnormal placement of the feet and the movement of the arms relative to the movement. The patient is then asked to walk with a few different variations. Tandem gait is when the patient places the heel of one foot against the toe of the other foot and walks in a straight line in that manner. Walking only on the heels or only on the toes will test additional aspects of balance.

Ataxia:

A movement disorder of the cerebellum is referred to as ataxia. It presents as a loss of coordination in voluntary movements. Ataxia can also refer to sensory deficits that cause balance problems, primarily in proprioception and equilibrium. When the problem is observed in movement, it is ascribed to cerebellar damage. Sensory and vestibular ataxia would likely also present with problems in gait and station.

Ataxia is often the result of exposure to exogenous substances, focal lesions, or a genetic disorder. Focal lesions include strokes affecting the cerebellar arteries, tumors that may impinge on the cerebellum, trauma to the back of the head and neck, or MS. Alcohol intoxication or drugs such as ketamine cause ataxia, but it is often reversible. Mercury in fish can cause ataxia as well. Hereditary conditions can lead to degeneration of the cerebellum or spinal cord, as well as malformation of the brain, or the abnormal accumulation of copper seen in Wilson’s disease.

Connections between the body and the CNS occur through the spinal cord. The cranial nerves connect the head and neck directly to the brain, but the spinal cord receives sensory input and sends motor commands out to the body through the spinal nerves. Whereas the brain develops into a complex series of nuclei and fiber tracts, the spinal cord remains relatively simple in its configuration (Figure 16.12). From the initial neural tube early in embryonic development, the spinal cord retains a tube-like structure with gray matter surrounding the small central canal and white matter on the surface in three columns. The dorsal, or posterior, horns of the gray matter are mainly devoted to sensory functions whereas the ventral, or anterior, and lateral horns are associated with motor functions. In the white matter, the dorsal column relays sensory information to the brain, and the anterior column is almost exclusively relaying motor commands to the ventral horn motor neurons. The lateral column, however, conveys both sensory and motor information between the spinal cord and brain.

Figure 16.12Locations of Spinal Fiber Tracts

Sensory Modalities and Location:

The general senses are distributed throughout the body, relying on nervous tissue incorporated into various organs. Somatic senses are incorporated mostly into the skin, muscles, or tendons, whereas the visceral senses come from nervous tissue incorporated into the majority of organs such as the heart or stomach. The somatic senses are those that usually make up the conscious perception of the how the body interacts with the environment. The visceral senses are most often below the limit of conscious perception because they are involved in homeostatic regulation through the autonomic nervous system.

The sensory exam tests the somatic senses, meaning those that are consciously perceived. Testing of the senses begins with examining the regions known as dermatomes that connect to the cortical region where somatosensation is perceived in the postcentral gyrus. To test the sensory fields, a simple stimulus of the light touch of the soft end of a cotton-tipped applicator is applied at various locations on the skin. The spinal nerves, which contain sensory fibers with dendritic endings in the skin, connect with the skin in a topographically organized manner, illustrated as dermatomes (Figure 16.13). For example, the fibers of eighth cervical nerve innervate the medial surface of the forearm and extend out to the fingers. In addition to testing perception at different positions on the skin, it is necessary to test sensory perception within the dermatome from distal to proximal locations in the appendages, or lateral to medial locations in the trunk. In testing the eighth cervical nerve, the patient would be asked if the touch of the cotton to the fingers or the medial forearm was perceptible, and whether there were any differences in the sensations.

Figure 16.13Dermatomes The surface of the skin can be divided into topographic regions that relate to the location of sensory endings in the skin based on the spinal nerve that contains those fibers. (credit: modification of work by Mikael Häggström)

Other modalities of somatosensation can be tested using a few simple tools. The perception of pain can be tested using the broken end of the cotton-tipped applicator. The perception of vibratory stimuli can be testing using an oscillating tuning fork placed against prominent bone features such as the distal head of the ulna on the medial aspect of the elbow. When the tuning fork is still, the metal against the skin can be perceived as a cold stimulus. Using the cotton tip of the applicator, or even just a fingertip, the perception of tactile movement can be assessed as the stimulus is drawn across the skin for approximately 2–3 cm. The patient would be asked in what direction the stimulus is moving. All of these tests are repeated in distal and proximal locations and for different dermatomes to assess the spatial specificity of perception. The sense of position and motion, proprioception, is tested by moving the fingers or toes and asking the patient if they sense the movement. If the distal locations are not perceived, the test is repeated at increasingly proximal joints.

The various stimuli used to test sensory input assess the function of the major ascending tracts of the spinal cord. The dorsal column pathway conveys fine touch, vibration, and proprioceptive information, whereas the spinothalamic pathway primarily conveys pain and temperature. Testing these stimuli provides information about whether these two major ascending pathways are functioning properly. Within the spinal cord, the two systems are segregated. The dorsal column information ascends ipsilateral to the source of the stimulus and decussates in the medulla, whereas the spinothalamic pathway decussates at the level of entry and ascends contralaterally. The differing sensory stimuli are segregated in the spinal cord so that the various subtests for these stimuli can distinguish which ascending pathway may be damaged in certain situations.

Whereas the basic sensory stimuli are assessed in the subtests directed at each submodality of somatosensation, testing the ability to discriminate sensations is important. Pairing the light touch and pain subtests together makes it possible to compare the two submodalities at the same time, and therefore the two major ascending tracts at the same time. Mistaking painful stimuli for light touch, or vice versa, may point to errors in ascending projections, such as in a hemisection of the spinal cord that might come from a motor vehicle accident.

Another issue of sensory discrimination is not distinguishing between different submodalities, but rather location. The two-point discrimination subtest highlights the density of sensory endings, and therefore receptive fields in the skin. The sensitivity to fine touch, which can give indications of the texture and detailed shape of objects, is highest in the fingertips. To assess the limit of this sensitivity, two-point discrimination is measured by simultaneously touching the skin in two locations, such as could be accomplished with a pair of forceps. Specialized calipers for precisely measuring the distance between points are also available. The patient is asked to indicate whether one or two stimuli are present while keeping their eyes closed. The examiner will switch between using the two points and a single point as the stimulus. Failure to recognize two points may be an indication of a dorsal column pathway deficit.

Similar to two-point discrimination, but assessing laterality of perception, is double simultaneous stimulation. Two stimuli, such as the cotton tips of two applicators, are touched to the same position on both sides of the body. If one side is not perceived, this may indicate damage to the contralateral posterior parietal lobe. Because there is one of each pathway on either side of the spinal cord, they are not likely to interact. If none of the other subtests suggest particular deficits with the pathways, the deficit is likely to be in the cortex where conscious perception is based. The mental status exam contains subtests that assess other functions that are primarily localized to the parietal cortex, such as stereognosis and graphesthesia.

A final subtest of sensory perception that concentrates on the sense of proprioception is known as the Romberg test. The patient is asked to stand straight with feet together. Once the patient has achieved their balance in that position, they are asked to close their eyes. Without visual feedback that the body is in a vertical orientation relative to the surrounding environment, the patient must rely on the proprioceptive stimuli of joint and muscle position, as well as information from the inner ear, to maintain balance. This test can indicate deficits in dorsal column pathway proprioception, as well as problems with proprioceptive projections to the cerebellum through the spinocerebellar tract.

Muscle Strength and Voluntary Movement:

The skeletomotor system is largely based on the simple, two-cell projection from the precentral gyrus of the frontal lobe to the skeletal muscles. The corticospinal tract represents the neurons that send output from the primary motor cortex. These fibers travel through the deep white matter of the cerebrum, then through the midbrain and pons, into the medulla where most of them decussate, and finally through the spinal cord white matter in the lateral (crossed fibers) or anterior (uncrossed fibers) columns. These fibers synapse on motor neurons in the ventral horn. The ventral horn motor neurons then project to skeletal muscle and cause contraction. These two cells are termed the upper motor neuron (UMN) and the lower motor neuron (LMN). Voluntary movements require these two cells to be active.

The motor exam tests the function of these neurons and the muscles they control. First, the muscles are inspected and palpated for signs of structural irregularities. Movement disorders may be the result of changes to the muscle tissue, such as scarring, and these possibilities need to be ruled out before testing function. Along with this inspection, muscle tone is assessed by moving the muscles through a passive range of motion. The arm is moved at the elbow and wrist, and the leg is moved at the knee and ankle. Skeletal muscle should have a resting tension representing a slight contraction of the fibers. The lack of muscle tone, known as hypotonicity or flaccidity, may indicate that the LMN is not conducting action potentials that will keep a basal level of acetylcholine in the neuromuscular junction.

If muscle tone is present, muscle strength is tested by having the patient contract muscles against resistance. The examiner will ask the patient to lift the arm, for example, while the examiner is pushing down on it. This is done for both limbs, including shrugging the shoulders. Lateral differences in strength—being able to push against resistance with the right arm but not the left—would indicate a deficit in one corticospinal tract versus the other. An overall loss of strength, without laterality, could indicate a global problem with the motor system. Diseases that result in UMN lesions include cerebral palsy or MS, or it may be the result of a stroke. A sign of UMN lesion is a negative result in the subtest for pronator drift. The patient is asked to extend both arms in front of the body with the palms facing up. While keeping the eyes closed, if the patient unconsciously allows one or the other arm to slowly relax, toward the pronated position, this could indicate a failure of the motor system to maintain the supinated position.

Reflexes:

Reflexes combine the spinal sensory and motor components with a sensory input that directly generates a motor response. The reflexes that are tested in the neurological exam are classified into two groups. A deep tendon reflex is commonly known as a stretch reflex, and is elicited by a strong tap to a tendon, such as in the knee-jerk reflex. A superficial reflex is elicited through gentle stimulation of the skin and causes contraction of the associated muscles.

For the arm, the common reflexes to test are of the biceps, brachioradialis, triceps, and flexors for the digits. For the leg, the knee-jerk reflex of the quadriceps is common, as is the ankle reflex for the gastrocnemius and soleus. The tendon at the insertion for each of these muscles is struck with a rubber mallet. The muscle is quickly stretched, resulting in activation of the muscle spindle that sends a signal into the spinal cord through the dorsal root. The fiber synapses directly on the ventral horn motor neuron that activates the muscle, causing contraction. The reflexes are physiologically useful for stability. If a muscle is stretched, it reflexively contracts to return the muscle to compensate for the change in length. In the context of the neurological exam, reflexes indicate that the LMN is functioning properly.

The most common superficial reflex in the neurological exam is the plantar reflex that tests for the Babinski sign on the basis of the extension or flexion of the toes at the plantar surface of the foot. The plantar reflex is commonly tested in newborn infants to establish the presence of neuromuscular function. To elicit this reflex, an examiner brushes a stimulus, usually the examiner’s fingertip, along the plantar surface of the infant’s foot. An infant would present a positive Babinski sign, meaning the foot dorsiflexes and the toes extend and splay out. As a person learns to walk, the plantar reflex changes to cause curling of the toes and a moderate plantar flexion. If superficial stimulation of the sole of the foot caused extension of the foot, keeping one’s balance would be harder. The descending input of the corticospinal tract modifies the response of the plantar reflex, meaning that a negative Babinski sign is the expected response in testing the reflex. Other superficial reflexes are not commonly tested, though a series of abdominal reflexes can target function in the lower thoracic spinal segments.

Comparison of Upper and Lower Motor Neuron Damage:

Many of the tests of motor function can indicate differences that will address whether damage to the motor system is in the upper or lower motor neurons. Signs that suggest a UMN lesion include muscle weakness, strong deep tendon reflexes, decreased control of movement or slowness, pronator drift, a positive Babinski sign, spasticity, and the clasp-knife response. Spasticity is an excess contraction in resistance to stretch. It can result in hyperflexia, which is when joints are overly flexed. The clasp-knife response occurs when the patient initially resists movement, but then releases, and the joint will quickly flex like a pocket knife closing.

A lesion on the LMN would result in paralysis, or at least partial loss of voluntary muscle control, which is known as paresis. The paralysis observed in LMN diseases is referred to as flaccid paralysis, referring to a complete or partial loss of muscle tone, in contrast to the loss of control in UMN lesions in which tone is retained and spasticity is exhibited. Other signs of an LMN lesion are fibrillation, fasciculation, and compromised or lost reflexes resulting from the denervation of the muscle fibers.

The twelve cranial nerves are typically covered in introductory anatomy courses, and memorizing their names is facilitated by numerous mnemonics developed by students over the years of this practice. But knowing the names of the nerves in order often leaves much to be desired in understanding what the nerves do. The nerves can be categorized by functions, and subtests of the cranial nerve exam can clarify these functional groupings.

Three of the nerves are strictly responsible for special senses whereas four others contain fibers for special and general senses. Three nerves are connected to the extraocular muscles resulting in the control of gaze. Four nerves connect to muscles of the face, oral cavity, and pharynx, controlling facial expressions, mastication, swallowing, and speech. Four nerves make up the cranial component of the parasympathetic nervous system responsible for pupillary constriction, salivation, and the regulation of the organs of the thoracic and upper abdominal cavities. Finally, one nerve controls the muscles of the neck, assisting with spinal control of the movement of the head and neck.

The cranial nerve exam allows directed tests of forebrain and brain stem structures. The twelve cranial nerves serve the head and neck. The vagus nerve (cranial nerve X) has autonomic functions in the thoracic and superior abdominal cavities. The special senses are served through the cranial nerves, as well as the general senses of the head and neck. The movement of the eyes, face, tongue, throat, and neck are all under the control of cranial nerves. Preganglionic parasympathetic nerve fibers that control pupillary size, salivary glands, and the thoracic and upper abdominal viscera are found in four of the nerves. Tests of these functions can provide insight into damage to specific regions of the brain stem and may uncover deficits in adjacent regions.

Sensory Nerves:

The olfactory, optic, and vestibulocochlear nerves (cranial nerves I, II, and VIII) are dedicated to four of the special senses: smell, vision, equilibrium, and hearing, respectively. Taste sensation is relayed to the brain stem through fibers of the facial and glossopharyngeal nerves. The trigeminal nerve is a mixed nerve that carries the general somatic senses from the head, similar to those coming through spinal nerves from the rest of the body.

Testing smell is straightforward, as common smells are presented to one nostril at a time. The patient should be able to recognize the smell of coffee or mint, indicating the proper functioning of the olfactory system. Loss of the sense of smell is called anosmia and can be lost following blunt trauma to the head or through aging. The short axons of the first cranial nerve regenerate on a regular basis. The neurons in the olfactory epithelium have a limited life span, and new cells grow to replace the ones that die off. The axons from these neurons grow back into the CNS by following the existing axons—representing one of the few examples of such growth in the mature nervous system. If all of the fibers are sheared when the brain moves within the cranium, such as in a motor vehicle accident, then no axons can find their way back to the olfactory bulb to re-establish connections. If the nerve is not completely severed, the anosmia may be temporary as new neurons can eventually reconnect.

Olfaction is not the pre-eminent sense, but its loss can be quite detrimental. The enjoyment of food is largely based on our sense of smell. Anosmia means that food will not seem to have the same taste, though the gustatory sense is intact, and food will often be described as being bland. However, the taste of food can be improved by adding ingredients (e.g., salt) that stimulate the gustatory sense.

Testing vision relies on the tests that are common in an optometry office. The Snellen chart (Figure 16.7) demonstrates visual acuity by presenting standard Roman letters in a variety of sizes. The result of this test is a rough generalization of the acuity of a person based on the normal accepted acuity, such that a letter that subtends a visual angle of 5 minutes of an arc at 20 feet can be seen. To have 20/60 vision, for example, means that the smallest letters that a person can see at a 20-foot distance could be seen by a person with normal acuity from 60 feet away. Testing the extent of the visual field means that the examiner can establish the boundaries of peripheral vision as simply as holding their hands out to either side and asking the patient when the fingers are no longer visible without moving the eyes to track them. If it is necessary, further tests can establish the perceptions in the visual fields. Physical inspection of the optic disk, or where the optic nerve emerges from the eye, can be accomplished by looking through the pupil with an ophthalmoscope.

Figure 16.7The Snellen Chart The Snellen chart for visual acuity presents a limited number of Roman letters in lines of decreasing size. The line with letters that subtend 5 minutes of an arc from 20 feet represents the smallest letters that a person with normal acuity should be able to read at that distance. The different sizes of letters in the other lines represent rough approximations of what a person of normal acuity can read at different distances. For example, the line that represents 20/200 vision would have larger letters so that they are legible to the person with normal acuity at 200 feet.

The optic nerves from both sides enter the cranium through the respective optic canals and meet at the optic chiasm at which fibers sort such that the two halves of the visual field are processed by the opposite sides of the brain. Deficits in visual field perception often suggest damage along the length of the optic pathway between the orbit and the diencephalon. For example, loss of peripheral vision may be the result of a pituitary tumor pressing on the optic chiasm (Figure 16.8). The pituitary, seated in the sella turcica of the sphenoid bone, is directly inferior to the optic chiasm. The axons that decussate in the chiasm are from the medial retinae of either eye, and therefore carry information from the peripheral visual field.

Figure 16.8Pituitary Tumor The pituitary gland is located in the sella turcica of the sphenoid bone within the cranial floor, placing it immediately inferior to the optic chiasm. If the pituitary gland develops a tumor, it can press against the fibers crossing in the chiasm. Those fibers are conveying peripheral visual information to the opposite side of the brain, so the patient will experience “tunnel vision”—meaning that only the central visual field will be perceived.

The vestibulocochlear nerve (CN VIII) carries both equilibrium and auditory sensations from the inner ear to the medulla. Though the two senses are not directly related, anatomy is mirrored in the two systems. Problems with balance, such as vertigo, and deficits in hearing may both point to problems with the inner ear. Within the petrous region of the temporal bone is the bony labyrinth of the inner ear. The vestibule is the portion for equilibrium, composed of the utricle, saccule, and the three semicircular canals. The cochlea is responsible for transducing sound waves into a neural signal. The sensory nerves from these two structures travel side-by-side as the vestibulocochlear nerve, though they are really separate divisions. They both emerge from the inner ear, pass through the internal auditory meatus, and synapse in nuclei of the superior medulla. Though they are part of distinct sensory systems, the vestibular nuclei and the cochlear nuclei are close neighbors with adjacent inputs. Deficits in one or both systems could occur from damage that encompasses structures close to both. Damage to structures near the two nuclei can result in deficits to one or both systems.

Balance or hearing deficits may be the result of damage to the middle or inner ear structures. Ménière’s disease is a disorder that can affect both equilibrium and audition in a variety of ways. The patient can suffer from vertigo, a low-frequency ringing in the ears, or a loss of hearing. From patient to patient, the exact presentation of the disease can be different. Additionally, within a single patient, the symptoms and signs may change as the disease progresses. Use of the neurological exam subtests for the vestibulocochlear nerve illuminates the changes a patient may go through. The disease appears to be the result of accumulation, or over-production, of fluid in the inner ear, in either the vestibule or cochlea.

Tests of equilibrium are important for coordination and gait and are related to other aspects of the neurological exam. The vestibulo-ocular reflex involves the cranial nerves for gaze control. Balance and equilibrium, as tested by the Romberg test, are part of spinal and cerebellar processes and involved in those components of the neurological exam, as discussed later.

Hearing is tested by using a tuning fork in a couple of different ways. The Rinne test involves using a tuning fork to distinguish between conductive hearing and sensorineural hearing. Conductive hearing relies on vibrations being conducted through the ossicles of the middle ear. Sensorineural hearing is the transmission of sound stimuli through the neural components of the inner ear and cranial nerve. A vibrating tuning fork is placed on the mastoid process and the patient indicates when the sound produced from this is no longer present. Then the fork is immediately moved to just next to the ear canal so the sound travels through the air. If the sound is not heard through the ear, meaning the sound is conducted better through the temporal bone than through the ossicles, a conductive hearing deficit is present. The Weber test also uses a tuning fork to differentiate between conductive versus sensorineural hearing loss. In this test, the tuning fork is placed at the top of the skull, and the sound of the tuning fork reaches both inner ears by travelling through bone. In a healthy patient, the sound would appear equally loud in both ears. With unilateral conductive hearing loss, however, the tuning fork sounds louder in the ear with hearing loss. This is because the sound of the tuning fork has to compete with background noise coming from the outer ear, but in conductive hearing loss, the background noise is blocked in the damaged ear, allowing the tuning fork to sound relatively louder in that ear. With unilateral sensorineural hearing loss, however, damage to the cochlea or associated nervous tissue means that the tuning fork sounds quieter in that ear.

The trigeminal system of the head and neck is the equivalent of the ascending spinal cord systems of the dorsal column and the spinothalamic pathways. Somatosensation of the face is conveyed along the nerve to enter the brain stem at the level of the pons. Synapses of those axons, however, are distributed across nuclei found throughout the brain stem. The mesencephalic nucleus processes proprioceptive information of the face, which is the movement and position of facial muscles. It is the sensory component of the jaw-jerk reflex, a stretch reflex of the masseter muscle. The chief nucleus, located in the pons, receives information about light touch as well as proprioceptive information about the mandible, which are both relayed to the thalamus and, ultimately, to the postcentral gyrus of the parietal lobe. The spinal trigeminal nucleus, located in the medulla, receives information about crude touch, pain, and temperature to be relayed to the thalamus and cortex. Essentially, the projection through the chief nucleus is analogous to the dorsal column pathway for the body, and the projection through the spinal trigeminal nucleus is analogous to the spinothalamic pathway.

Subtests for the sensory component of the trigeminal system are the same as those for the sensory exam targeting the spinal nerves. The primary sensory subtest for the trigeminal system is sensory discrimination. A cotton-tipped applicator, which is cotton attached to the end of a thin wooden stick, can be used easily for this. The wood of the applicator can be snapped so that a pointed end is opposite the soft cotton-tipped end. The cotton end provides a touch stimulus, while the pointed end provides a painful, or sharp, stimulus. While the patient’s eyes are closed, the examiner touches the two ends of the applicator to the patient’s face, alternating randomly between them. The patient must identify whether the stimulus is sharp or dull. These stimuli are processed by the trigeminal system separately. Contact with the cotton tip of the applicator is a light touch, relayed by the chief nucleus, but contact with the pointed end of the applicator is a painful stimulus relayed by the spinal trigeminal nucleus. Failure to discriminate these stimuli can localize problems within the brain stem. If a patient cannot recognize a painful stimulus, that might indicate damage to the spinal trigeminal nucleus in the medulla. The medulla also contains important regions that regulate the cardiovascular, respiratory, and digestive systems, as well as being the pathway for ascending and descending tracts between the brain and spinal cord. Damage, such as a stroke, that results in changes in sensory discrimination may indicate these unrelated regions are affected as well.

Gaze Control:

The three nerves that control the extraocular muscles are the oculomotor, trochlear, and abducens nerves, which are the third, fourth, and sixth cranial nerves. As the name suggests, the abducens nerve is responsible for abducting the eye, which it controls through contraction of the lateral rectus muscle. The trochlear nerve controls the superior oblique muscle to rotate the eye along its axis in the orbit medially, which is called intorsion, and is a component of focusing the eyes on an object close to the face. The oculomotor nerve controls all the other extraocular muscles, as well as a muscle of the upper eyelid. Movements of the two eyes need to be coordinated to locate and track visual stimuli accurately. When moving the eyes to locate an object in the horizontal plane, or to track movement horizontally in the visual field, the lateral rectus muscle of one eye and medial rectus muscle of the other eye are both active. The lateral rectus is controlled by neurons of the abducens nucleus in the superior medulla, whereas the medial rectus is controlled by neurons in the oculomotor nucleus of the midbrain.

Coordinated movement of both eyes through different nuclei requires integrated processing through the brain stem. In the midbrain, the superior colliculus integrates visual stimuli with motor responses to initiate eye movements. The paramedian pontine reticular formation (PPRF) will initiate a rapid eye movement, or saccade, to bring the eyes to bear on a visual stimulus quickly. These areas are connected to the oculomotor, trochlear, and abducens nuclei by the medial longitudinal fasciculus (MLF) that runs through the majority of the brain stem. The MLF allows for conjugate gaze, or the movement of the eyes in the same direction, during horizontal movements that require the lateral and medial rectus muscles. Control of conjugate gaze strictly in the vertical direction is contained within the oculomotor complex. To elevate the eyes, the oculomotor nerve on either side stimulates the contraction of both superior rectus muscles; to depress the eyes, the oculomotor nerve on either side stimulates the contraction of both inferior rectus muscles.

Purely vertical movements of the eyes are not very common. Movements are often at an angle, so some horizontal components are necessary, adding the medial and lateral rectus muscles to the movement. The rapid movement of the eyes used to locate and direct the fovea onto visual stimuli is called a saccade. Notice that the paths that are traced in Figure 16.9 are not strictly vertical. The movements between the nose and the mouth are closest, but still have a slant to them. Also, the superior and inferior rectus muscles are not perfectly oriented with the line of sight. The origin for both muscles is medial to their insertions, so elevation and depression may require the lateral rectus muscles to compensate for the slight adduction inherent in the contraction of those muscles, requiring MLF activity as well.

Figure 16.9Saccadic Eye Movements Saccades are rapid, conjugate movements of the eyes to survey a complicated visual stimulus, or to follow a moving visual stimulus. This image represents the shifts in gaze typical of a person studying a face. Notice the concentration of gaze on the major features of the face and the large number of paths traced between the eyes or around the mouth.

Testing eye movement is simply a matter of having the patient track the tip of a pen as it is passed through the visual field. This may appear similar to testing visual field deficits related to the optic nerve, but the difference is that the patient is asked to not move the eyes while the examiner moves a stimulus into the peripheral visual field. Here, the extent of movement is the point of the test. The examiner is watching for conjugate movements representing proper function of the related nuclei and the MLF. Failure of one eye to abduct while the other adducts in a horizontal movement is referred to as internuclear ophthalmoplegia. When this occurs, the patient will experience diplopia, or double vision, as the two eyes are temporarily pointed at different stimuli. Diplopia is not restricted to failure of the lateral rectus, because any of the extraocular muscles may fail to move one eye in perfect conjugation with the other.

The final aspect of testing eye movements is to move the tip of the pen in toward the patient’s face. As visual stimuli move closer to the face, the two medial recti muscles cause the eyes to move in the one nonconjugate movement that is part of gaze control. When the two eyes move to look at something closer to the face, they both adduct, which is referred to as convergence. To keep the stimulus in focus, the eye also needs to change the shape of the lens, which is controlled through the parasympathetic fibers of the oculomotor nerve. The change in focal power of the eye is referred to as accommodation. Accommodation ability changes with age; focusing on nearer objects, such as the written text of a book or on a computer screen, may require corrective lenses later in life. Coordination of the skeletal muscles for convergence and coordination of the smooth muscles of the ciliary body for accommodation are referred to as the accommodation–convergence reflex.

A crucial function of the cranial nerves is to keep visual stimuli centered on the fovea of the retina. The vestibulo-ocular reflex (VOR) coordinates all of the components (Figure 16.10), both sensory and motor, that make this possible. If the head rotates in one direction—for example, to the right—the horizontal pair of semicircular canals in the inner ear indicate the movement by increased activity on the right and decreased activity on the left. The information is sent to the abducens nuclei and oculomotor nuclei on either side to coordinate the lateral and medial rectus muscles. The left lateral rectus and right medial rectus muscles will contract, rotating the eyes in the opposite direction of the head, while nuclei controlling the right lateral rectus and left medial rectus muscles will be inhibited to reduce antagonism of the contracting muscles. These actions stabilize the visual field by compensating for the head rotation with opposite rotation of the eyes in the orbits. Deficits in the VOR may be related to vestibular damage, such as in Ménière’s disease, or from dorsal brain stem damage that would affect the eye movement nuclei or their connections through the MLF.

Figure 16.10Vestibulo-ocular Reflex If the head is turned in one direction, the coordination of that movement with the fixation of the eyes on a visual stimulus involves a circuit that ties the vestibular sense with the eye movement nuclei through the MLF.

Nerves of the Face and Oral Cavity:

An iconic part of a doctor’s visit is the inspection of the oral cavity and pharynx, suggested by the directive to “open your mouth and say ‘ah.’” This is followed by inspection, with the aid of a tongue depressor, of the back of the mouth, or the opening of the oral cavity into the pharynx known as the fauces. Whereas this portion of a medical exam inspects for signs of infection, such as in tonsillitis, it is also the means to test the functions of the cranial nerves that are associated with the oral cavity.

The facial and glossopharyngeal nerves convey gustatory stimulation to the brain. Testing this is as simple as introducing salty, sour, bitter, or sweet stimuli to either side of the tongue. The patient should respond to the taste stimulus before retracting the tongue into the mouth. Stimuli applied to specific locations on the tongue will dissolve into the saliva and may stimulate taste buds connected to either the left or right of the nerves, masking any lateral deficits. Along with taste, the glossopharyngeal nerve relays general sensations from the pharyngeal walls. These sensations, along with certain taste stimuli, can stimulate the gag reflex. If the examiner moves the tongue depressor to contact the lateral wall of the fauces, this should elicit the gag reflex. Stimulation of either side of the fauces should elicit an equivalent response. The motor response, through contraction of the muscles of the pharynx, is mediated through the vagus nerve. Normally, the vagus nerve is considered autonomic in nature. The vagus nerve directly stimulates the contraction of skeletal muscles in the pharynx and larynx to contribute to the swallowing and speech functions. Further testing of vagus motor function has the patient repeating consonant sounds that require movement of the muscles around the fauces. The patient is asked to say “lah-kah-pah” or a similar set of alternating sounds while the examiner observes the movements of the soft palate and arches between the palate and tongue.

The facial and glossopharyngeal nerves are also responsible for the initiation of salivation. Neurons in the salivary nuclei of the medulla project through these two nerves as preganglionic fibers, and synapse in ganglia located in the head. The parasympathetic fibers of the facial nerve synapse in the pterygopalatine ganglion, which projects to the submandibular gland and sublingual gland. The parasympathetic fibers of the glossopharyngeal nerve synapse in the otic ganglion, which projects to the parotid gland. Salivation in response to food in the oral cavity is based on a visceral reflex arc within the facial or glossopharyngeal nerves. Other stimuli that stimulate salivation are coordinated through the hypothalamus, such as the smell and sight of food.

The hypoglossal nerve is the motor nerve that controls the muscles of the tongue, except for the palatoglossus muscle, which is controlled by the vagus nerve. There are two sets of muscles of the tongue. The extrinsic muscles of the tongue are connected to other structures, whereas the intrinsic muscles of the tongue are completely contained within the lingual tissues. While examining the oral cavity, movement of the tongue will indicate whether hypoglossal function is impaired. The test for hypoglossal function is the “stick out your tongue” part of the exam. The genioglossus muscle is responsible for protrusion of the tongue. If the hypoglossal nerves on both sides are working properly, then the tongue will stick straight out. If the nerve on one side has a deficit, the tongue will stick out to that side—pointing to the side with damage. Loss of function of the tongue can interfere with speech and swallowing. Additionally, because the location of the hypoglossal nerve and nucleus is near the cardiovascular center, inspiratory and expiratory areas for respiration, and the vagus nuclei that regulate digestive functions, a tongue that protrudes incorrectly can suggest damage in adjacent structures that have nothing to do with controlling the tongue.

Motor Nerves of the Neck:

The accessory nerve, also referred to as the spinal accessory nerve, innervates the sternocleidomastoid and trapezius muscles (Figure 16.11). When both the sternocleidomastoids contract, the head flexes forward; individually, they cause rotation to the opposite side. The trapezius can act as an antagonist, causing extension and hyperextension of the neck. These two superficial muscles are important for changing the position of the head. Both muscles also receive input from cervical spinal nerves. Along with the spinal accessory nerve, these nerves contribute to elevating the scapula and clavicle through the trapezius, which is tested by asking the patient to shrug both shoulders, and watching for asymmetry. For the sternocleidomastoid, those spinal nerves are primarily sensory projections, whereas the trapezius also has lateral insertions to the clavicle and scapula, and receives motor input from the spinal cord. Calling the nerve the spinal accessory nerve suggests that it is aiding the spinal nerves. Though that is not precisely how the name originated, it does help make the association between the function of this nerve in controlling these muscles and the role these muscles play in movements of the trunk or shoulders.

Figure 16.11Muscles Controlled by the Accessory Nerve The accessory nerve innervates the sternocleidomastoid and trapezius muscles, both of which attach to the head and to the trunk and shoulders. They can act as antagonists in head flexion and extension, and as synergists in lateral flexion toward the shoulder.

To test these muscles, the patient is asked to flex and extend the neck or shrug the shoulders against resistance, testing the strength of the muscles. Lateral flexion of the neck toward the shoulder tests both at the same time. Any difference on one side versus the other would suggest damage on the weaker side. These strength tests are common for the skeletal muscles controlled by spinal nerves and are a significant component of the motor exam. Deficits associated with the accessory nerve may have an effect on orienting the head, as described with the VOR.

In the clinical setting, the set of subtests known as the mental status exam helps us understand the relationship of the brain to the body. Ultimately, this is accomplished by assessing behavior. Tremors related to intentional movements, incoordination, or the neglect of one side of the body can be indicative of failures of the connections of the cerebrum either within the hemispheres, or from the cerebrum to other portions of the nervous system. There is no strict test for what the cerebrum does alone, but rather in what it does through its control of the rest of the CNS, the peripheral nervous system (PNS), and the musculature.

Sometimes eliciting a behavior is as simple as asking a question. Asking a patient to state his or her name is not only to verify that the file folder in a health care provider’s hands is the correct one, but also to be sure that the patient is aware, oriented, and capable of interacting with another person. If the answer to “What is your name?” is “Santa Claus,” the person may have a problem understanding reality. If the person just stares at the examiner with a confused look on their face, the person may have a problem understanding or producing speech.

Functions of the Cerebral Cortex:

The cerebrum is the seat of many of the higher mental functions, such as memory and learning, language, and conscious perception, which are the subjects of subtests of the mental status exam. The cerebral cortex is the thin layer of gray matter on the outside of the cerebrum. On average, it is approximately 2.55 mm thick and highly folded to fit within the limited space of the cranial vault. These higher functions are distributed across various regions of the cortex, and specific locations can be said to be responsible for particular functions. There is a limited set of regions, for example, that are involved in language function, and they can be subdivided on the basis of the particular part of language function that each governs.

The basis for parceling out areas of the cortex and attributing them to various functions has its root in pure anatomical underpinnings. The German neurologist and histologist Korbinian Brodmann, who made a careful study of the cytoarchitecture of the cerebrum around the turn of the nineteenth century, described approximately 50 regions of the cortex that differed enough from each other to be considered separate areas (Figure 16.4). Brodmann made preparations of many different regions of the cerebral cortex to view with a microscope. He compared the size, shape, and number of neurons to find anatomical differences in the various parts of the cerebral cortex. Continued investigation into these anatomical areas over the subsequent 100 or more years has demonstrated a strong correlation between the structures and the functions attributed to those structures. For example, the first three areas in Brodmann’s list—which are in the postcentral gyrus—compose the primary somatosensory cortex. Within this area, finer separation can be made on the basis of the concept of the sensory homunculus, as well as the different submodalities of somatosensation such as touch, vibration, pain, temperature, or proprioception. Today, we more frequently refer to these regions by their function (i.e., primary sensory cortex) than by the number Brodmann assigned to them, but in some situations the use of Brodmann numbers persists.

Figure 16.4Brodmann’s Areas of the Cerebral Cortex On the basis of cytoarchitecture, the anatomist Korbinian Brodmann described the extensive array of cortical regions, as illustrated in his figure. Subsequent investigations found that these areas corresponded very well to functional differences in the cerebral cortex. (credit: modification of work by “Looie496”/Wikimedia Commons, based on original work by Korvinian Brodmann)

Area 17, as Brodmann described it, is also known as the primary visual cortex. Adjacent to that are areas 18 and 19, which constitute subsequent regions of visual processing. Area 22 is the primary auditory cortex, and it is followed by area 23, which further processes auditory information. Area 4 is the primary motor cortex in the precentral gyrus, whereas area 6 is the premotor cortex. These areas suggest some specialization within the cortex for functional processing, both in sensory and motor regions. The fact that Brodmann’s areas correlate so closely to functional localization in the cerebral cortex demonstrates the strong link between structure and function in these regions.

Areas 1, 2, 3, 4, 17, and 22 are each described as primary cortical areas. The adjoining regions are each referred to as association areas. Primary areas are where sensory information is initially received from the thalamus for conscious perception, or—in the case of the primary motor cortex—where descending commands are sent down to the brain stem or spinal cord to execute movements (Figure 16.5).

Figure 16.5Types of Cortical Areas The cerebral cortex can be described as containing three types of processing regions: primary, association, and integration areas. The primary cortical areas are where sensory information is initially processed, or where motor commands emerge to go to the brain stem or spinal cord. Association areas are adjacent to primary areas and further process the modality-specific input. Multimodal integration areas are found where the modality-specific regions meet; they can process multiple modalities together or different modalities on the basis of similar functions, such as spatial processing in vision or somatosensation.

A number of other regions, which extend beyond these primary or association areas of the cortex, are referred to as integrative areas. These areas are found in the spaces between the domains for particular sensory or motor functions, and they integrate multisensory information, or process sensory or motor information in more complex ways. Consider, for example, the posterior parietal cortex that lies between the somatosensory cortex and visual cortex regions. This has been ascribed to the coordination of visual and motor functions, such as reaching to pick up a glass. The somatosensory function that would be part of this is the proprioceptive feedback from moving the arm and hand. The weight of the glass, based on what it contains, will influence how those movements are executed.

Cognitive Abilities:

Assessment of cerebral functions is directed at cognitive abilities. The abilities assessed through the mental status exam can be separated into four groups: orientation and memory, language and speech, sensorium, and judgment and abstract reasoning.

Orientation and Memory:

Orientation is the patient’s awareness of his or her immediate circumstances. It is awareness of time, not in terms of the clock, but of the date and what is occurring around the patient. It is awareness of place, such that a patient should know where he or she is and why. It is also awareness of who the patient is—recognizing personal identity and being able to relate that to the examiner. The initial tests of orientation are based on the questions, “Do you know what the date is?” or “Do you know where you are?” or “What is your name?” Further understanding of a patient’s awareness of orientation can come from questions that address remote memory, such as “Who is the President of the United States?”, or asking what happened on a specific date.

There are also specific tasks to address memory. One is the three-word recall test. The patient is given three words to recall, such as book, clock, and shovel. After a short interval, during which other parts of the interview continue, the patient is asked to recall the three words. Other tasks that assess memory—aside from those related to orientation—have the patient recite the months of the year in reverse order to avoid the overlearned sequence and focus on the memory of the months in an order, or to spell common words backwards, or to recite a list of numbers back.

Memory is largely a function of the temporal lobe, along with structures beneath the cerebral cortex such as the hippocampus and the amygdala. The storage of memory requires these structures of the medial temporal lobe. A famous case of a man who had both medial temporal lobes removed to treat intractable epilepsy provided insight into the relationship between the structures of the brain and the function of memory.

Henry Molaison, who was referred to as patient HM when he was alive, had epilepsy localized to both of his medial temporal lobes. In 1953, a bilateral lobectomy was performed that alleviated the epilepsy but resulted in the inability for HM to form new memories—a condition called anterograde amnesia. HM was able to recall most events from before his surgery, although there was a partial loss of earlier memories, which is referred to as retrograde amnesia. HM became the subject of extensive studies into how memory works. What he was unable to do was form new memories of what happened to him, what are now called episodic memory. Episodic memory is autobiographical in nature, such as remembering riding a bicycle as a child around the neighborhood, as opposed to the procedural memory of how to ride a bike. HM also retained his short-term memory, such as what is tested by the three-word task described above. After a brief period, those memories would dissipate or decay and not be stored in the long-term because the medial temporal lobe structures were removed.

The difference in short-term, procedural, and episodic memory, as evidenced by patient HM, suggests that there are different parts of the brain responsible for those functions. The long-term storage of episodic memory requires the hippocampus and related medial temporal structures, and the location of those memories is in the multimodal integration areas of the cerebral cortex. However, short-term memory—also called working or active memory—is localized to the prefrontal lobe. Because patient HM had only lost his medial temporal lobe—and lost very little of his previous memories, and did not lose the ability to form new short-term memories—it was concluded that the function of the hippocampus, and adjacent structures in the medial temporal lobe, is to move (or consolidate) short-term memories (in the pre-frontal lobe) to long-term memory (in the temporal lobe).

The prefrontal cortex can also be tested for the ability to organize information. In one subtest of the mental status exam called set generation, the patient is asked to generate a list of words that all start with the same letter, but not to include proper nouns or names. The expectation is that a person can generate such a list of at least 10 words within 1 minute. Many people can likely do this much more quickly, but the standard separates the accepted normal from those with compromised prefrontal cortices.

Language and Speech:

Language is, arguably, a very human aspect of neurological function. There are certainly strides being made in understanding communication in other species, but much of what makes the human experience seemingly unique is its basis in language. Any understanding of our species is necessarily reflective, as suggested by the question “What am I?” And the fundamental answer to this question is suggested by the famous quote by René Descartes: “Cogito Ergo Sum” (translated from Latin as “I think, therefore I am”). Formulating an understanding of yourself is largely describing who you are to yourself. It is a confusing topic to delve into, but language is certainly at the core of what it means to be self-aware.

The neurological exam has two specific subtests that address language. One measures the ability of the patient to understand language by asking them to follow a set of instructions to perform an action, such as “touch your right finger to your left elbow and then to your right knee.” Another subtest assesses the fluency and coherency of language by having the patient generate descriptions of objects or scenes depicted in drawings, and by reciting sentences or explaining a written passage. Language, however, is important in so many ways in the neurological exam. The patient needs to know what to do, whether it is as simple as explaining how the knee-jerk reflex is going to be performed, or asking a question such as “What is your name?” Often, language deficits can be determined without specific subtests; if a person cannot reply to a question properly, there may be a problem with the reception of language.

An important example of multimodal integrative areas is associated with language function (Figure 16.6). Adjacent to the auditory association cortex, at the end of the lateral sulcus just anterior to the visual cortex, is Wernicke’s area. In the lateral aspect of the frontal lobe, just anterior to the region of the motor cortex associated with the head and neck, is Broca’s area. Both regions were originally described on the basis of losses of speech and language, which is called aphasia. The aphasia associated with Broca’s area is known as an expressive aphasia, which means that speech production is compromised. This type of aphasia is often described as non-fluency because the ability to say some words leads to broken or halting speech. Grammar can also appear to be lost. The aphasia associated with Wernicke’s area is known as a receptive aphasia, which is not a loss of speech production, but a loss of understanding of content. Patients, after recovering from acute forms of this aphasia, report not being able to understand what is said to them or what they are saying themselves, but they often cannot keep from talking.

The two regions are connected by white matter tracts that run between the posterior temporal lobe and the lateral aspect of the frontal lobe. Conduction aphasia associated with damage to this connection refers to the problem of connecting the understanding of language to the production of speech. This is a very rare condition, but is likely to present as an inability to faithfully repeat spoken language.

Figure 16.6Broca’s and Wernicke’s Areas Two important integration areas of the cerebral cortex associated with language function are Broca’s and Wernicke’s areas. The two areas are connected through the deep white matter running from the posterior temporal lobe to the frontal lobe.

Sensorium:

Those parts of the brain involved in the reception and interpretation of sensory stimuli are referred to collectively as the sensorium. The cerebral cortex has several regions that are necessary for sensory perception. From the primary cortical areas of the somatosensory, visual, auditory, and gustatory senses to the association areas that process information in these modalities, the cerebral cortex is the seat of conscious sensory perception. In contrast, sensory information can also be processed by deeper brain regions, which we may vaguely describe as subconscious—for instance, we are not constantly aware of the proprioceptive information that the cerebellum uses to maintain balance. Several of the subtests can reveal activity associated with these sensory modalities, such as being able to hear a question or see a picture. Two subtests assess specific functions of these cortical areas.

The first is praxis, a practical exercise in which the patient performs a task completely on the basis of verbal description without any demonstration from the examiner. For example, the patient can be told to take their left hand and place it palm down on their left thigh, then flip it over so the palm is facing up, and then repeat this four times. The examiner describes the activity without any movements on their part to suggest how the movements are to be performed. The patient needs to understand the instructions, transform them into movements, and use sensory feedback, both visual and proprioceptive, to perform the movements correctly.

The second subtest for sensory perception is gnosis, which involves two tasks. The first task, known as stereognosis, involves the naming of objects strictly on the basis of the somatosensory information that comes from manipulating them. The patient keeps their eyes closed and is given a common object, such as a coin, that they have to identify. The patient should be able to indicate the particular type of coin, such as a dime versus a penny, or a nickel versus a quarter, on the basis of the sensory cues involved. For example, the size, thickness, or weight of the coin may be an indication, or to differentiate the pairs of coins suggested here, the smooth or corrugated edge of the coin will correspond to the particular denomination. The second task, graphesthesia, is to recognize numbers or letters written on the palm of the hand with a dull pointer, such as a pen cap.

Praxis and gnosis are related to the conscious perception and cortical processing of sensory information. Being able to transform verbal commands into a sequence of motor responses, or to manipulate and recognize a common object and associate it with a name for that object. Both subtests have language components because language function is integral to these functions. The relationship between the words that describe actions, or the nouns that represent objects, and the cerebral location of these concepts is suggested to be localized to particular cortical areas. Certain aphasias can be characterized by a deficit of verbs or nouns, known as V impairment or N impairment, or may be classified as V–N dissociation. Patients have difficulty using one type of word over the other. To describe what is happening in a photograph as part of the expressive language subtest, a patient will use active- or image-based language. The lack of one or the other of these components of language can relate to the ability to use verbs or nouns. Damage to the region at which the frontal and temporal lobes meet, including the region known as the insula, is associated with V impairment; damage to the middle and inferior temporal lobe is associated with N impairment.

Judgment and Abstract Reasoning:

Planning and producing responses requires an ability to make sense of the world around us. Making judgments and reasoning in the abstract are necessary to produce movements as part of larger responses. For example, when your alarm goes off, do you hit the snooze button or jump out of bed? Is 10 extra minutes in bed worth the extra rush to get ready for your day? Will hitting the snooze button multiple times lead to feeling more rested or result in a panic as you run late? How you mentally process these questions can affect your whole day.

The prefrontal cortex is responsible for the functions responsible for planning and making decisions. In the mental status exam, the subtest that assesses judgment and reasoning is directed at three aspects of frontal lobe function. First, the examiner asks questions about problem solving, such as “If you see a house on fire, what would you do?” The patient is also asked to interpret common proverbs, such as “Don’t look a gift horse in the mouth.” Additionally, pairs of words are compared for similarities, such as apple and orange, or lamp and cabinet.

The prefrontal cortex is composed of the regions of the frontal lobe that are not directly related to specific motor functions. The most posterior region of the frontal lobe, the precentral gyrus, is the primary motor cortex. Anterior to that are the premotor cortex, Broca’s area, and the frontal eye fields, which are all related to planning certain types of movements. Anterior to what could be described as motor association areas are the regions of the prefrontal cortex. They are the regions in which judgment, abstract reasoning, and working memory are localized. The antecedents to planning certain movements are judging whether those movements should be made, as in the example of deciding whether to hit the snooze button.

To an extent, the prefrontal cortex may be related to personality. The neurological exam does not necessarily assess personality, but it can be within the realm of neurology or psychiatry. A clinical situation that suggests this link between the prefrontal cortex and personality comes from the story of Phineas Gage, the railroad worker from the mid-1800s who had a metal spike impale his prefrontal cortex. There are suggestions that the steel rod led to changes in his personality. A man who was a quiet, dependable railroad worker became a raucous, irritable drunkard. Later anecdotal evidence from his life suggests that he was able to support himself, although he had to relocate and take on a different career as a stagecoach driver.

A psychiatric practice to deal with various disorders was the prefrontal lobotomy. This procedure was common in the 1940s and early 1950s, until antipsychotic drugs became available. The connections between the prefrontal cortex and other regions of the brain were severed. The disorders associated with this procedure included some aspects of what are now referred to as personality disorders, but also included mood disorders and psychoses. Depictions of lobotomies in popular media suggest a link between cutting the white matter of the prefrontal cortex and changes in a patient’s mood and personality, though this correlation is not well understood.

The neurological exam is a clinical assessment tool used to determine what specific parts of the CNS are affected by damage or disease. It can be performed in a short time—sometimes as quickly as 5 minutes—to establish neurological function. In the emergency department, this rapid assessment can make the difference with respect to proper treatment and the extent of recovery that is possible.

The exam is a series of subtests separated into five major sections. The first of these is the mental status exam, which assesses the higher cognitive functions such as memory, orientation, and language. Then there is the cranial nerve exam, which tests the function of the 12 cranial nerves and, therefore, the central and peripheral structures associated with them. The cranial nerve exam tests the sensory and motor functions of each of the nerves, as applicable. Two major sections, the sensory exam and the motor exam, test the sensory and motor functions associated with spinal nerves. Finally, the coordination exam tests the ability to perform complex and coordinated movements. The gait exam, which is often considered a sixth major exam, specifically assesses the motor function of walking and can be considered part of the coordination exam because walking is a coordinated movement.

Neuroanatomy and the Neurological Exam:

Localization of function is the concept that circumscribed locations are responsible for specific functions. The neurological exam highlights this relationship. For example, the cognitive functions that are assessed in the mental status exam are based on functions in the cerebrum, mostly in the cerebral cortex. Several of the subtests examine language function. Deficits in neurological function uncovered by these examinations usually point to damage to the left cerebral cortex. In the majority of individuals, language function is localized to the left hemisphere between the superior temporal lobe and the posterior frontal lobe, including the intervening connections through the inferior parietal lobe.

The five major sections of the neurological exam are related to the major regions of the CNS (Figure 16.2). The mental status exam assesses functions related to the cerebrum. The cranial nerve exam is for the nerves that connect to the diencephalon and brain stem (as well as the olfactory connections to the forebrain). The coordination exam and the related gait exam primarily assess the functions of the cerebellum. The motor and sensory exams are associated with the spinal cord and its connections through the spinal nerves.

Figure 16.2Anatomical Underpinnings of the Neurological Exam The different regions of the CNS relate to the major sections of the neurological exam: the mental status exam, cranial nerve exam, sensory exam, motor exam, and coordination exam (including the gait exam).

Part of the power of the neurological exam is this link between structure and function. Testing the various functions represented in the exam allows an accurate estimation of where the nervous system may be damaged. Consider the patient described in the chapter introduction. In the emergency department, he is given a quick exam to find where the deficit may be localized. Knowledge of where the damage occurred will lead to the most effective therapy.

In rapid succession, he is asked to smile, raise his eyebrows, stick out his tongue, and shrug his shoulders. The doctor tests muscular strength by providing resistance against his arms and legs while he tries to lift them. With his eyes closed, he has to indicate when he feels the tip of a pen touch his legs, arms, fingers, and face. He follows the tip of a pen as the doctor moves it through the visual field and finally toward his face. A formal mental status exam is not needed at this point; the patient will demonstrate any possible deficits in that area during normal interactions with the interviewer. If cognitive or language deficits are apparent, the interviewer can pursue mental status in more depth. All of this takes place in less than 5 minutes. The patient reports that he feels pins and needles in his left arm and leg, and has trouble feeling the tip of the pen when he is touched on those limbs. This suggests a problem with the sensory systems between the spinal cord and the brain. The emergency department has a lead to follow before a CT scan is performed. He is put on aspirin therapy to limit the possibility of blood clots forming, in case the cause is an embolus—an obstruction such as a blood clot that blocks the flow of blood in an artery or vein.

Causes of Neurological Deficits:

Damage to the nervous system can be limited to individual structures or can be distributed across broad areas of the brain and spinal cord. Localized, limited injury to the nervous system is most often the result of circulatory problems. Neurons are very sensitive to oxygen deprivation and will start to deteriorate within 1 or 2 minutes, and permanent damage (cell death) could result within a few hours. The loss of blood flow to part of the brain is known as a stroke, or a cerebrovascular accident (CVA).

There are two main types of stroke, depending on how the blood supply is compromised: ischemic and hemorrhagic. An ischemic stroke is the loss of blood flow to an area because vessels are blocked or narrowed. This is often caused by an embolus, which may be a blood clot or fat deposit. Ischemia may also be the result of thickening of the blood vessel wall, or a drop in blood volume in the brain known as hypovolemia.

A related type of CVA is known as a transient ischemic attack (TIA), which is similar to a stroke although it does not last as long. The diagnostic definition of a stroke includes effects that last at least 24 hours. Any stroke symptoms that are resolved within a 24-hour period because of restoration of adequate blood flow are classified as a TIA.

A hemorrhagic stroke is bleeding into the brain because of a damaged blood vessel. Accumulated blood fills a region of the cranial vault and presses against the tissue in the brain (Figure 16.3). Physical pressure on the brain can cause the loss of function, as well as the squeezing of local arteries resulting in compromised blood flow beyond the site of the hemorrhage. As blood pools in the nervous tissue and the vasculature is damaged, the blood-brain barrier can break down and allow additional fluid to accumulate in the region, which is known as edema.

Figure 16.3Hemorrhagic Stroke (a) A hemorrhage into the tissue of the cerebrum results in a large accumulation of blood with an additional edema in the adjacent tissue. The hemorrhagic area causes the entire brain to be disfigured as suggested here by the lateral ventricles being squeezed into the opposite hemisphere. (b) A CT scan shows an intraparenchymal hemorrhage within the parietal lobe. (credit b: James Heilman)

Whereas hemorrhagic stroke may involve bleeding into a large region of the CNS, such as into the deep white matter of a cerebral hemisphere, other events can cause widespread damage and loss of neurological functions. Infectious diseases can lead to loss of function throughout the CNS as components of nervous tissue, specifically astrocytes and microglia, react to the disease. Blunt force trauma, such as from a motor vehicle accident, can physically damage the CNS.

A class of disorders that affect the nervous system are the neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), Creutzfeld–Jacob disease, multiple sclerosis (MS), and other disorders that are the result of nervous tissue degeneration. In diseases like Alzheimer’s, Parkinson’s, or ALS, neurons die; in diseases like MS, myelin is affected. Some of these disorders affect motor function, and others present with dementia. How patients with these disorders perform in the neurological exam varies, but is often broad in its effects, such as memory deficits that compromise many aspects of the mental status exam, or movement deficits that compromise aspects of the cranial nerve exam, the motor exam, or the coordination exam. The causes of these disorders are also varied. Some are the result of genetics, such as Huntington’s disease, or the result of autoimmunity, such as MS; others are not entirely understood, such as Alzheimer’s and Parkinson’s diseases. Current research suggests that many of these diseases are related in how the degeneration takes place and may be treated by common therapies.

Finally, a common cause of neurological changes is observed in developmental disorders. Whether the result of genetic factors or the environment during development, there are certain situations that result in neurological functions being different from the expected norms. Developmental disorders are difficult to define because they are caused by defects that existed in the past and disrupted the normal development of the CNS. These defects probably involve multiple environmental and genetic factors—most of the time, we don’t know what the cause is other than that it is more complex than just one factor. Furthermore, each defect on its own may not be a problem, but when several are added together, they can disrupt growth processes that are not well understand in the first place. For instance, it is possible for a stroke to damage a specific region of the brain and lead to the loss of the ability to recognize faces (prosopagnosia). The link between cell death in the fusiform gyrus and the symptom is relatively easy to understand. In contrast, similar deficits can be seen in children with the developmental disorder, autism spectrum disorder (ASD). However, these children do not lack a fusiform gyrus, nor is there any damage or defect visible to this brain region. We conclude, rather poorly, that this brain region is not connected properly to other brain regions.

Infection, trauma, and congenital disorders can all lead to significant signs, as identified through the neurological exam. It is important to differentiate between an acute event, such as stroke, and a chronic or global condition such as blunt force trauma. Responses seen in the neurological exam can help. A loss of language function observed in all its aspects is more likely a global event as opposed to a discrete loss of one function, such as not being able to say certain types of words. A concern, however, is that a specific function—such as controlling the muscles of speech—may mask other language functions. The various subtests within the mental status exam can address these finer points and help clarify the underlying cause of the neurological loss.

Figure 16.1Neurological Exam Health care professionals, such as this air force nurse, can rapidly assess the neurological functions of a patient using the neurological exam. One part of the exam is the inspection of the oral cavity and pharynx, which enables the doctor to not only inspect the tissues for signs of infection, but also provides a means to test the functions of the cranial nerves associated with the oral cavity.

A man arrives at the hospital after feeling faint and complaining of a “pins-and-needles” feeling all along one side of his body. The most likely explanation is that he has suffered a stroke, which has caused a loss of oxygen to a particular part of the central nervous system (CNS). The problem is finding where in the entire nervous system the stroke has occurred. By checking reflexes, sensory responses, and motor control, a health care provider can focus on what abilities the patient may have lost as a result of the stroke and can use this information to determine where the injury occurred. In the emergency department of the hospital, this kind of rapid assessment of neurological function is key to treating trauma to the nervous system. In the classroom, the neurological exam is a valuable tool for learning the anatomy and physiology of the nervous system because it allows you to relate the functions of the system to particular locations in the nervous system.

As a student of anatomy and physiology, you may be planning to go into an allied health field, perhaps nursing or physical therapy. You could be in the emergency department treating a patient such as the one just described. An important part of this course is to understand the nervous system. This can be especially challenging because you need to learn about the nervous system using your own nervous system. The first chapter in this unit about the nervous system began with a quote: “If the human brain were simple enough for us to understand, we would be too simple to understand it.” However, you are being asked to understand aspects of it. A healthcare provider can pinpoint problems with the nervous system in minutes by running through the series of tasks to test neurological function that are described in this chapter. You can use the same approach, though not as quickly, to learn about neurological function and its relationship to the structures of the nervous system.

Nervous tissue is different from other tissues in that it is not classified into separate tissue types. It does contain two types of cells, neurons and glia, but it is all just nervous tissue. White matter and gray matter are not types of nervous tissue, but indications of different specializations within the nervous tissue. However, not all nervous tissue performs the same function. Furthermore, specific functions are not wholly localized to individual brain structures in the way that other bodily functions occur strictly within specific organs. In the CNS, we must consider the connections between cells over broad areas, not just the function of cells in one particular nucleus or region. In a broad sense, the nervous system is responsible for the majority of electrochemical signaling in the body, but the use of those signals is different in various regions.

The nervous system is made up of the brain and spinal cord as the central organs, and the ganglia and nerves as organs in the periphery. The brain and spinal cord can be thought of as a collection of smaller organs, most of which would be the nuclei (such as the oculomotor nuclei), but white matter structures play an important role (such as the corpus callosum). Studying the nervous system requires an understanding of the varied physiology of the nervous system. For example, the hypothalamus plays a very different role than the visual cortex. The neurological exam provides a way to elicit behavior that represents those varied functions.

An important way to understand the effects of native neurochemicals in the autonomic system is in considering the effects of pharmaceutical drugs. This can be considered in terms of how drugs change autonomic function. These effects will primarily be based on how drugs act at the receptors of the autonomic system neurochemistry. The signaling molecules of the nervous system interact with proteins in the cell membranes of various target cells. In fact, no effect can be attributed to just the signaling molecules themselves without considering the receptors. A chemical that the body produces to interact with those receptors is called an endogenous chemical, whereas a chemical introduced to the system from outside is an exogenous chemical. Exogenous chemicals may be of a natural origin, such as a plant extract, or they may be synthetically produced in a pharmaceutical laboratory.

Broad Autonomic Effects:

One important drug that affects the autonomic system broadly is not a pharmaceutical therapeutic agent associated with the system. This drug is nicotine. The effects of nicotine on the autonomic nervous system are important in considering the role smoking can play in health.

All ganglionic neurons of the autonomic system, in both sympathetic and parasympathetic ganglia, are activated by ACh released from preganglionic fibers. The ACh receptors on these neurons are of the nicotinic type, meaning that they are ligand-gated ion channels. When the neurotransmitter released from the preganglionic fiber binds to the receptor protein, a channel opens to allow positive ions to cross the cell membrane. The result is depolarization of the ganglia. Nicotine acts as an ACh analog at these synapses, so when someone takes in the drug, it binds to these ACh receptors and activates the ganglionic neurons, causing them to depolarize.

Ganglia of both divisions are activated equally by the drug. For many target organs in the body, this results in no net change. The competing inputs to the system cancel each other out and nothing significant happens. For example, the sympathetic system will cause sphincters in the digestive tract to contract, limiting digestive propulsion, but the parasympathetic system will cause the contraction of other muscles in the digestive tract, which will try to push the contents of the digestive system along. The end result is that the food does not really move along and the digestive system has not appreciably changed.

The system in which this can be problematic is in the cardiovascular system, which is why smoking is a risk factor for cardiovascular disease. First, there is no significant parasympathetic regulation of blood pressure. Only a limited number of blood vessels are affected by parasympathetic input, so nicotine will preferentially cause the vascular tone to become more sympathetic, which means blood pressure will be increased. Second, the autonomic control of the heart is special. Unlike skeletal or smooth muscles, cardiac muscle is intrinsically active, meaning that it generates its own action potentials. The autonomic system does not cause the heart to beat, it just speeds it up (sympathetic) or slows it down (parasympathetic). The mechanisms for this are not mutually exclusive, so the heart receives conflicting signals, and the rhythm of the heart can be affected (Figure 15.13).

Figure 15.13Autonomic Connections to Heart and Blood Vessels The nicotinic receptor is found on all autonomic ganglia, but the cardiovascular connections are particular, and do not conform to the usual competitive projections that would just cancel each other out when stimulated by nicotine. The opposing signals to the heart would both depolarize and hyperpolarize the heart cells that establish the rhythm of the heartbeat, likely causing arrhythmia. Only the sympathetic system governs systemic blood pressure so nicotine would cause an increase.

Sympathetic Effect:

The neurochemistry of the sympathetic system is based on the adrenergic system. Norepinephrine and epinephrine influence target effectors by binding to the α-adrenergic or β-adrenergic receptors. Drugs that affect the sympathetic system affect these chemical systems. The drugs can be classified by whether they enhance the functions of the sympathetic system or interrupt those functions. A drug that enhances adrenergic function is known as a sympathomimetic drug, whereas a drug that interrupts adrenergic function is a sympatholytic drug.

Sympathomimetic Drugs:

When the sympathetic system is not functioning correctly or the body is in a state of homeostatic imbalance, these drugs act at postganglionic terminals and synapses in the sympathetic efferent pathway. These drugs either bind to particular adrenergic receptors and mimic norepinephrine at the synapses between sympathetic postganglionic fibers and their targets, or they increase the production and release of norepinephrine from postganglionic fibers. Also, to increase the effectiveness of adrenergic chemicals released from the fibers, some of these drugs may block the removal or reuptake of the neurotransmitter from the synapse.

A common sympathomimetic drug is phenylephrine, which is a common component of decongestants. It can also be used to dilate the pupil and to raise blood pressure. Phenylephrine is known as an α₁-adrenergic agonist, meaning that it binds to a specific adrenergic receptor, stimulating a response. In this role, phenylephrine will bind to the adrenergic receptors in bronchioles of the lungs and cause them to dilate. By opening these structures, accumulated mucus can be cleared out of the lower respiratory tract. Phenylephrine is often paired with other pharmaceuticals, such as analgesics, as in the “sinus” version of many over-the-counter drugs, such as Tylenol Sinus or Excedrin Sinus, or in expectorants for chest congestion such as in Robitussin CF.

A related molecule, called pseudoephedrine, was much more commonly used in these applications than was phenylephrine, until the molecule became useful in the illicit production of amphetamines. Phenylephrine is not as effective as a drug because it can be partially broken down in the digestive tract before it is ever absorbed. Like the adrenergic agents, phenylephrine is effective in dilating the pupil, known as mydriasis (Figure 15.14). Phenylephrine is used during an eye exam in an ophthalmologist’s or optometrist’s office for this purpose. It can also be used to increase blood pressure in situations in which cardiac function is compromised, such as under anesthesia or during septic shock.

Figure 15.14Mydriasis The sympathetic system causes pupillary dilation when norepinephrine binds to an adrenergic receptor in the radial fibers of the iris smooth muscle. Phenylephrine mimics this action by binding to the same receptor when drops are applied onto the surface of the eye in a doctor’s office. (credit: Corey Theiss / Vulegenda/Wikimedia Commons)

Other drugs that enhance adrenergic function are not associated with therapeutic uses, but affect the functions of the sympathetic system in a similar fashion. Cocaine primarily interferes with the uptake of dopamine at the synapse and can also increase adrenergic function. Caffeine is an antagonist to a different neurotransmitter receptor, called the adenosine receptor. Adenosine will suppress adrenergic activity, specifically the release of norepinephrine at synapses, so caffeine indirectly increases adrenergic activity. There is some evidence that caffeine can aid in the therapeutic use of drugs, perhaps by potentiating (increasing) sympathetic function, as is suggested by the inclusion of caffeine in over-the-counter analgesics such as Excedrin^®.

Sympatholytic Drugs:

Drugs that interfere with sympathetic function are referred to as sympatholytic, or sympathoplegic, drugs. They primarily work as an antagonist to the adrenergic receptors. They block the ability of norepinephrine or epinephrine to bind to the receptors so that the effect is “cut” or “takes a blow,” to refer to the endings “-lytic” and “-plegic,” respectively. The various drugs of this class will be specific to α-adrenergic or β-adrenergic receptors, or to their receptor subtypes.

Possibly the most familiar type of sympatholytic drug are the β-blockers. These drugs are often used to treat cardiovascular disease because they block the β-receptors associated with vasoconstriction and cardioacceleration. By allowing blood vessels to dilate, or keeping heart rate from increasing, these drugs can improve cardiac function in a compromised system, such as for a person with congestive heart failure or who has previously suffered a heart attack. A couple of common versions of β-blockers are metoprolol, which specifically blocks the β₁-receptor, and propanolol, which nonspecifically blocks β-receptors. There are other drugs that are α-blockers and can affect the sympathetic system in a similar way.

Other uses for sympatholytic drugs are as antianxiety medications. A common example of this is clonidine, which is an α-agonist. The sympathetic system is tied to anxiety to the point that the sympathetic response can be referred to as “fight, flight, or fright.” Clonidine is used for other treatments aside from hypertension and anxiety, including pain conditions and attention deficit hyperactivity disorder.

Parasympathetic Effects:

Drugs affecting parasympathetic functions can be classified into those that increase or decrease activity at postganglionic terminals. Parasympathetic postganglionic fibers release ACh, and the receptors on the targets are muscarinic receptors. There are several types of muscarinic receptors, M1–M5, but the drugs are not usually specific to the specific types. Parasympathetic drugs can be either muscarinic agonists or antagonists, or have indirect effects on the cholinergic system. Drugs that enhance cholinergic effects are called parasympathomimetic drugs, whereas those that inhibit cholinergic effects are referred to as anticholinergic drugs.

Pilocarpine is a nonspecific muscarinic agonist commonly used to treat disorders of the eye. It reverses mydriasis, such as is caused by phenylephrine, and can be administered after an eye exam. Along with constricting the pupil through the smooth muscle of the iris, pilocarpine will also cause the ciliary muscle to contract. This will open perforations at the base of the cornea, allowing for the drainage of aqueous humor from the anterior compartment of the eye and, therefore, reducing intraocular pressure related to glaucoma.

Atropine and scopolamine are part of a class of muscarinic antagonists that come from the Atropa genus of plants that include belladonna or deadly nightshade (Figure 15.15). The name of one of these plants, belladonna, refers to the fact that extracts from this plant were used cosmetically for dilating the pupil. The active chemicals from this plant block the muscarinic receptors in the iris and allow the pupil to dilate, which is considered attractive because it makes the eyes appear larger. Humans are instinctively attracted to anything with larger eyes, which comes from the fact that the ratio of eye-to-head size is different in infants (or baby animals) and can elicit an emotional response. The cosmetic use of belladonna extract was essentially acting on this response. Atropine is no longer used in this cosmetic capacity for reasons related to the other name for the plant, which is deadly nightshade. Suppression of parasympathetic function, especially when it becomes systemic, can be fatal. Autonomic regulation is disrupted and anticholinergic symptoms develop. The berries of this plant are highly toxic, but can be mistaken for other berries. The antidote for atropine or scopolamine poisoning is pilocarpine.

Figure 15.15Belladonna Plant The plant from the genus Atropa, which is known as belladonna or deadly nightshade, was used cosmetically to dilate pupils, but can be fatal when ingested. The berries on the plant may seem attractive as a fruit, but they contain the same anticholinergic compounds as the rest of the plant.Sympathetic and Parasympathetic Effects of Different Drug Types

Drug type	Example(s)	Sympathetic effect	Parasympathetic effect	Overall result
Nicotinic agonists	Nicotine	Mimic ACh at preganglionic synapses, causing activation of postganglionic fibers and the release of norepinephrine onto the target organ	Mimic ACh at preganglionic synapses, causing activation of postganglionic fibers and the release of ACh onto the target organ	Most conflicting signals cancel each other out, but cardiovascular system is susceptible to hypertension and arrhythmias
Sympathomimetic drugs	Phenylephrine	Bind to adrenergic receptors or mimics sympathetic action in some other way	No effect	Increase sympathetic tone
Sympatholytic drugs	β-blockers such as propanolol or metoprolol; α-agonists such as clonidine	Block binding to adrenergic drug or decrease adrenergic signals	No effect	Increase parasympathetic tone
Parasymphatho-mimetics/muscarinic agonists	Pilocarpine	No effect, except on sweat glands	Bind to muscarinic receptor, similar to ACh	Increase parasympathetic tone
Anticholinergics/muscarinic antagonists	Atropine, scopolamine, dimenhydrinate	No effect	Block muscarinic receptors and parasympathetic function	Increase sympathetic tone

Table15.2