Introduction to Central Nervous System Disorders

Cellular Dysfunction

Neuronal cell death is a hallmark of many disorders of the nervous system through the processes of necrosis and apoptosis. When cell death is caused by necrosis, there is cellular swelling, fragmentation, and cell disintegration. Necrosis causes the internal structure of the cell to swell as water enters the cell through osmosis and cell membranes to rupture. Lymphocytes and polynuclear cells can cause inflammatory cells to surround the necrotic debris, resulting in release of cytotoxic compounds and destruction of neighboring cells. Excitotoxicity results from the inappropriate activation of excitatory amino acid receptors leading to the entry of calcium ions into the cell. The calcium activates intracellular function. Damaged cells release excitotoxins that damage surrounding cells.¹⁶

Apoptosis is programmed cell death, or a type of cellular suicide, but apoptosis does not cause inflammatory responses. It is a more organized process with fragmentation of the cells and degradation of the DNA. It is common during the development of cells to eliminate the overproduction of one cell type. The biochemical pathway is present in all cells of the body and is used normally in the maturation and regulation of the nervous system with systematic removal of neurons from the brain. In apoptosis, the cell is removed by macrophages and leaves no residual damage to other components of the CNS. If the cell sustains genetic damage through neurodegenerative disease or injury and cannot be repaired by the system, the cell dies. Damage to the CNS can cause excessive apoptosis through the process of trophic factor withdrawal, oxidative insults, metabolic compromise, overactivation of glutamate receptors, and exposure to bacterial toxins.³⁶ These processes are described in the next paragraphs.

The intensity of cellular injury determines whether the cell dies or is able to survive. Very severe injury leads to the passive process of necrosis, less severe but irreparable injury leads to the active process of apoptosis, and survivable injury leads to reactive changes such as gliosis or scarring.

Free radical formation is a by-product of excitotoxicity. Free radicals are capable of destroying cellular components and triggering apoptosis. Free radicals are molecules with an odd number of electrons. The odd, or unpaired, electron is highly reactive as it seeks to pair with another free electron. Free radicals are generated during oxidative metabolism and energy production in the body. Free radicals are related to normal metabolism but can be the cause of oxidative stress in brain injury and disease. Oxidative stress refers to cells and tissues that have been altered by exposure to oxidants. Oxidation of lipids, proteins, and DNA leads to tissue injury. Nitrogen monoxide (nitric oxide [NO]) is a free radical generated by NO synthase (NOS). This enzyme modulates physiologic responses, such as vasodilation or signaling, in the brain. Oxidative stress, rather than being the primary cause, appears to be a secondary complication in many progressive disorders, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), as well as disorders of mental status. An enhanced antioxidant status is associated with reduced risk of several diseases.⁴⁴

The blood-brain barrier is made from endothelial cells and its tight junctions, so that substances can pass only through the cell and not in between cells. Drug entry into the CNS is determined by the drug’s lipid solubility. Glucose and amino acid cross the endothelial cell barrier via protein transporters.

The ependyma cells line the ventricles and spinal canal and regulate metabolism between the channels of the extracellular space and the ventricles. Ependyma forms the basis of the cerebral spinal fluid barrier. There is movement of molecules through the extracellular space with the possibility of long range and relatively diffuse actions of neurotransmitters released into the extracellular space. This type of signaling is known as volume transmission and may have a major role in setting large-scale neuronal excitability or inhibition.¹⁶

Dysfunction within the nervous system can affect either or both of the two main classes of cells: the glial cells and the neurons. Stem cells create new glia and new neurons. The region immediately beneath the ependymal cell layer produces new cells at a very low rate in the adult compared to the amount created during neurogenesis in early development. They migrate widely through the brain and conform phenotypically to the regions where they end up.

Sensory Disturbances

The skin, muscles, and joints contain a variety of receptors that create electrical activity as described previously^8,54 (see Chapter 39). The electrical input is carried to the CNS through the afferent axons via the spinal cord. The cell bodies rest in the ganglion of the dorsal root that lies adjacent to the spinal cord. The afferent fibers are arranged somatotopically in the spinal column and ascend to the brainstem and the sensory cortex. Fig. 28-8 shows the simplified synapse.⁴¹ A characteristic of the fibers that run in the dorsal column of the spinal cord is that they synapse at the level of the brainstem nuclei, where they cross over to the contralateral (opposite) hemisphere of the brain. This phenomenon is illustrated in Fig. 28-9.⁴¹ When there is a disorder of the brain that affects the afferent system above the level of the brainstem, symptoms occur on the side contralateral to the lesion.^26,41

The brainstem receives information from specialized senses. For example, vestibular information is received via cranial nerve VIII and integrated through the brainstem nuclei, contributing to postural control and locomotion. Disorders of the afferent nerve, dorsal columns of the spinal cord, and brainstem result in changes in the sensory input available. This can manifest as lack of cutaneous sensation, numbness, tingling, paresthesias, or dysesthesias in the distribution of the nerves affected. Sensory input from the joints and muscles is known as proprioception. When this sensory function is lost or disturbed, the person will have difficulty maintaining the body in the appropriate position for the voluntary and involuntary movements necessary for most functional activities, especially those required for postural control. Movements become ataxic or uncoordinated because of the loss of feedback on position from the joints.³

The nervous system has several pain-control pathways available, some of which suppress and some of which facilitate the experience of pain. Modulation of noxious stimuli is directed by the reticular formation. Noxious stimuli can be experienced as more or less painful, depending on the individual’s circumstances. If an individual is focused on a task during an injury, such as a soldier or athlete, the pain of the injury may be suppressed until the task is completed. When a lesion affects the midbrain areas that modulate and interpret sensory input, such as the thalamus, the result can cause exaggeration of sensory stimuli.

Disruption of the sensory input provided by the optic nerve is evident in some disorders of the brain and will result in loss of vision in some or all of a field of view. Visual-field cuts are common with stroke (see Chapter 32). Visual hallucinations can also be part of a CNS disorder when the optic radiations or occipital lobe is disrupted, which may also be caused by stroke or a degenerative disease such as multiple sclerosis.

Brainstem Dysfunction

The brainstem contains the lower motor neurons for the muscles of the head and does the initial processing of general afferent information concerning the head. The cranial nerves enter the system at the brainstem through the respective nuclei and provide sensation and motor control of the head and neck. An anatomic view of the cranial nerves and the relationship of the nuclei to central structures is provided in Fig. 28-10.⁴¹ The sensory and motor functions of the cranial nerves are outlined in Table 28-1. A working knowledge of the attributes of the cranial nerves assists in the understanding of the level and impact of lesions within the CNS.

Distinctive brainstem functions include a conduit for spinal cord activity in both ascending sensory tracts and descending motor tracts. The nuclei in the brainstem provide relay functions to divert the information to the appropriate higher level structures for further modification.

The brainstem has been divided into three major subdivisions related to a characteristic set of features. The medulla, attached directly to the spinal cord, houses the inferior olivary nucleus that has direct output connections to the cerebellum and gets direct input from the spinal cord and cerebellum. The pons extends from the medulla and is attached to the cerebellum through both the middle and superior cerebellar peduncles receiving major outflow from the cerebellum. Vestibular nuclei sit within the pons, making it the center for integration of vestibular input.

The third level of the brainstem, the midbrain, contains the red nucleus with fibers that connect the cerebellum to the thalamus. The substantia nigra found here connects to the basal ganglia structures and shares the dopamine pathway related to the initiation and control of movement. It is also connected to the cortex through the cerebral peduncle containing descending fibers.

The reticular formation is a diffuse network of neurons, extending through the brainstem to higher levels, and is important in influencing movement. The reticular regions are closely related to the cerebellum, basal ganglia, vestibular nuclei, and substantia nigra and involved with complex movement patterns. It is through the reticular formation that there is inhibition of flexor reflexes, so that only noxious stimulus can evoke the flexor response such as the reflexive pulling a hand away from a hot stove.

This is a brief reflection of the complexity of the brainstem and is not intended to be comprehensive. However, it is clear that advanced knowledge of the interface and connections of the brainstem helps the therapist understand the functions that are described throughout this text.

Movement Disorders

Control of movement is accomplished by the cooperative effort of many brain structures.^8,54 Activity initiated in the cerebral cortex triggers interneurons that regulate interaction of the lower motor neurons. The parietal and premotor areas of the cerebral cortex are involved in identifying targets in space, determining a course of action, and creating the motor program. The cortex determines strategies for movement. The brainstem and spinal cord are responsible for the execution of the task. The same signal may be processed simultaneously by many different brain structures for different purposes, showing parallel distributed processing. Various areas of the brain, such as the cerebellum and basal ganglia, interact to establish a motor program that modifies the hierarchic information going from the cortex to the spinal cord.

Abnormal movement patterns in neurologic disorders can result from lesions of the CNS at many levels. A simplified representation of the typical synaptic flow of neurons and interneurons is seen in Fig. 28-11. It is important to recognize that there are many synapses not represented here in the levels of the brainstem and central modulation centers of the basal ganglia and limbic lobes.

Damage at any level brings about the movement disorders that are related to the pathologies in the next chapters. Motor output is critically evaluated by the therapist, thus the knowledge of patterns of abnormal movement associated with disorders of the brain is part of the clinical expertise necessary to practice.

Disorders of Coordinated Movement

Lack of coordinated movement known as ataxia can occur with damage to a variety of structures of the nervous system, including sensory neuropathies, but is most commonly associated with cerebellar dysfunction. Damage to the input and output structures of the cerebellum, such as the thalamus and vestibular nuclei, can also cause ataxic movements.

Input regarding the position of the head, trunk, and extremities comes from the spinal cord in order to compare the resulting activity with the intended motor command. This input comes in rapidly because the relay involves only a few synapses. The input comes through the climbing fibers that connect the inferior olive to the Purkinje’s cell or from mossy fibers that relay the remaining information.⁵ The deep cerebellar nuclei are the structures that communicate information from the Purkinje’s cell to the various nuclei of the brainstem and thalamus.²⁶ The cerebellum has no direct synapse with the spinal cord but exerts its influence through the action on interneurons within the nuclei of the brainstem.

The medial region known as the vestibulocerebellum connects with the cortex and brainstem through both its ascending and descending projections. The cerebellum has influence on movement through the vestibulospinal and reticulospinal tracts. Lesions result in the inability to coordinate eye and head movement, postural sway, and delayed equilibrium responses.⁵ Postural tremor is present in some individuals with vestibulocerebellar lesions.

The spinocerebellum connects to the somatosensory tracts of the spinal cord. It receives input from the cortex regarding the ongoing motor command. Control of proximal musculature is achieved via the connections to the motor cortex. Lesions of the spinocerebellum can cause hypotonia and disruption of rhythmic patterns associated with walking. Precision of voluntary movements is lost when this area is dysfunctional.³⁸

The anterior lobe of the cerebellum is implicated in disorders of gait with loss of balance noted in stance. Proprioception may give inaccurate cues because the cerebellar relays become disrupted. Long loop reflexes lose adaptability and are unable to trigger appropriate responses in the lower leg to maintain balance when the body sways or the surface is moving. The ability to modify reflexes is lost even when there are repeated trials.⁶⁰

In the cerebrocerebellum, or posterior lobes, connections are made to the cortex through the pons. The posterior lobes are involved in complex motor, perceptual, and cognitive tasks. Lesions of the cerebrocerebellum lead to a decomposition of movement and timing.

Hypotonicity, or decreased muscle tone, can occur on the side of the lesion or bilaterally if the lesion is central and is seen primarily in the proximal muscle groups. The person with hypotonicity is unable to fixate the limb posturally, leading to incoordination with movement. Asthenia, or generalized weakness, is sometimes seen in the person with cerebellar lesions. Hypotonicity and asthenia, however, do not always occur together. It is believed that both disorders represent loss of input from the cerebellum to the cerebral cortex, but they may represent loss of input to different areas of the cortex.

Dysmetria, the underestimation or overestimation of a necessary movement toward a target, is commonly seen with cerebellar disorders. There is an error in the production of force necessary to perform an intended movement. The initiation of movement is prolonged compared to normal, and the ability to change directions rapidly is impaired. The resulting overshoot and undershoot during movement are known as an intention tremor. Dysdiadochokinesia, the inability to perform rapidly alternating movements, is related to the inability to stop ongoing movement. The movement becomes slow, without rhythm or consistency.

Decomposition of movement is seen in persons with cerebellar dysfunction. Instead of performing a movement in one smooth motion, the person will move in distinct sequences to accomplish the motion. Multijoint movements are more affected than single-joint movements. Disruption in force and extent of movement will result in difficulty with grip control and maintaining static hold against resistance. When the resistance is removed, for example, the extremity will oscillate because of lack of feedback regarding position and force needed to maintain static hold.

Scanning speech is a component of cerebellar dysfunction representing complexity of the motor activity. Word selection is not affected, but the words are pronounced slowly and without melody, tone, or rhythm. This reflects the incoordination or hypotonicity of the muscles of the larynx in controlling the voice.

Eye movements are disrupted in the person with cerebellar dysfunction, in both a static head and eye position and with movement of the head. Gaze-evoked nystagmus, or nonvoluntary rhythmic oscillation of the eye, occurs when the cerebellum is unable to hold the gaze on an object, especially a lateral position. When looking at a lateral target, the eyes drift back toward midline and then immediately back to the target. Eyes flickering on and off the target, eyes fluttering around the target, or spastic bursts of eye oscillations may be present when there is brainstem or midline cerebellar lesions.

Ocular dysmetria is similar to the dysmetria seen in the extremities. This dysmetria is seen in cerebellar lesions when the eyes are moving from one target to another (known as saccadic movement) or when attempting to follow a target (known as smooth pursuit).

Vestibuloocular function is disrupted in medial lesions, and the ability to maintain eye stability during head movement is affected. See the section on Vestibular Dysfunction in Chapter 38 for more information on vestibuloocular dysfunction.

Gait disturbance is another disorder related to dysfunction of the cerebellum. The gait becomes wide based and staggering without typical arm swing. The step length is uneven, the step widths are inconsistent, and the feet are often lifted higher than necessary. Stance and swing become irregular, and there is loss of adaptation to changes in terrain. It becomes difficult to perform heel-to-toe walking or walking a straight line, which is the standard sobriety test. In some persons, there is a surprising ability to avoid a fall, although the standing balance is abnormal. When the person is able to perform compensatory movements of the upper body and limbs, falls can be avoided.¹⁹

The cerebellum plays a major role in motor learning. The cerebellum is vital in anticipatory, or feed-forward, activity and modification of response.³⁰ The cerebellum learns or memorizes small movements that are integrated into complex activity. During the acquisition phase of motor learning, the cerebellum is active.²⁴ Increased activity has also been noted during mental imagery or mental rehearsal of a motor program.⁴⁶ The cerebellum is active during cognitive and emotional processes, and lesions can cause difficulty in shifting attention from one sensory or thought domain to another.

Deficits of Higher Brain Function

The cortex has a great deal to do with the abilities and activities that are a part of the highest development in humans, including language and abstract thinking. Perception, movement, and adaptive response to the outside world depends on an intact cerebral cortex. As with other parts of the CNS, it is subdivided for ease of understanding the separate functions, although the structure and function is full of overlap. Fig. 28-12 represents some of the functional specialization of the brain. Fig. 28-13 describes the lobar relationship to the cerebellum and brainstem.

The frontal lobe is the largest single area of the brain, constituting nearly one-third of the brain’s cortical surface. It is phylogenetically the youngest area of the brain and has major connections with all other areas of the brain. The frontal lobe is responsible for the highest levels of cognitive processing, control of emotion, and behavior. An individual’s personality is established as a frontal lobe function, and one of the most disturbing deficits seen with lesions affecting the frontal lobe is change from the person’s premorbid personality. A person’s character and temperament are changed by damage to the frontal lobe. Slow processing of information, lack of judgment based on known consequences, withdrawal, and irritability can be the result of an insult to the frontal lobe. Lack of inhibition and apathy are common clinical problems related to frontal lobe damage. The person with a frontal lobe disorder may lack insight into the deficits, and therefore behavior can be difficult to control.

The right hemisphere syndrome represents the inability to orient the body within external space and generate the appropriate motor responses. Hemineglect is one of the most common deficits seen with right hemisphere lesions. The individual does not respond to sensory stimuli on the left side of the body and does not respond to the environment surrounding the left side. Hemineglect is evident in the involved extremities and trunk during mobility and self-care activities. The ability to draw in two and three dimensions is lost along with other drawing skills, such as perspective and accurate copying. Spatial disorientation can result, with the person losing familiarity with the environment and becoming lost in areas that should be familiar. Inability to read and follow a map can be an indication of right hemisphere deficit.¹³

Disorders of emotional adjustment often follow a lesion in the right hemisphere. These disorders are primarily in the affective domain of interpersonal relationships and socialization. Cortical control of the limbic system is believed to be responsible, but the exact mechanism of control of more complex emotional behavior is not completely understood at this time. There appears to be hemispheric lateralization of emotions with suggestions that the right hemisphere is the dominant hemisphere in controlling emotions.

Language is one of the higher functions of the brain that is affected in many disorders of the CNS. Speech is a more elementary capacity than language and refers to the mechanical act of uttering words using the neuromuscular structures responsible for articulation. Dysarthria, a disturbance in articulation, and anarthria, the lack of ability to produce speech, are disorders of speech not language. One common language disorder is expressive aphasia, a deficit in speech production or language output, accompanied by a deficit in communication, in which speech comes out as garbled or inappropriate words.

Localization of speech production in the left frontal lobe and impaired language comprehension in the temporal lobe demonstrate how higher functions can be related to brain regions. However, language control may be in different areas for different persons, and therefore damage to the same area of the brain may produce aphasia in some individuals whereas others may be spared. Left hand–dominant people may have right hemisphere dominance for language.³¹

Alexia is another symptom of higher brain dysfunction. It is the acquired inability to read. Alexia is typically caused by lesions in the left occipital lobe and the corpus callosum that prevent incoming visual information from reaching the angular gyrus for linguistic interpretation. Agraphia can be caused by lesions located anywhere in the cerebrum. Because writing is a motor skill, lesions of the corticospinal tract, basal ganglia, and cerebellum; myopathies; and peripheral nerve injuries can all cause abnormal or clumsy writing. These disorders may be seen in addition to neurobehavioral syndromes. Typically the features of agraphia tend to parallel the characteristics of aphasia.

Apraxia is an acquired disorder of skilled purposeful movement that is not a result of paresis, akinesia, ataxia, sensory loss, or comprehension. Ideomotor apraxia is the most common type and represents the inability to carry out a motor act on verbal command. Ideomotor apraxia appears to be caused by a lesion in the arcuate fasciculus. The anterior connection from the left parietal lobe may be disrupted, preventing the motor system from receiving the command to act. A lesion in the left premotor area can cause apraxia by directly interrupting the motor act. Damage to the anterior corpus callosum can lead to apraxia that is evident in the left hand only. Ideational apraxia is failure to perform a sequential act even though each part of the act can be performed individually. The lesion causing ideational apraxia appears to be in the left parietal lobe, as in hemiparesis, or in the frontal lobe, as in Alzheimer’s disease. The syndrome is seen as well with diffuse cortical damage associated with degenerative dementia.

Agnosia is the inability to recognize an object; the previously acquired meaning of an object is no longer attached to it. Agnosia is associated with lesions of the sensory cortices involved with seeing, hearing, and feeling and with the loss of one sensory modality. It is difficult to assess because the person is often easily able to compensate. Although the ability to recognize an object by vision is gone, the ability to recognize that same object by hearing or feeling is retained.

Altered States of Consciousness

Alteration of consciousness is not considered an independent disease entity but a reflection of some underlying disease or abnormal state of brain function. The human brain possesses a mechanism that allows a waking and sleeping state (arousal), as well as a separate ability to focus awareness on relevant environmental stimuli (attention).^13,37 To achieve a state of consciousness the cerebral cortex must be activated by the ascending reticular formation fibers in the brainstem. The fibers extend to the thalamus, limbic system, and cortex. The upper part of this system acts as an on/off switch for consciousness and controls the sleep-wake cycle. The lower part controls respiration.

Disturbances of arousal and attention can range from coma after brainstem injury (see Chapter 33) to confusional states caused by drug intoxication. Metabolic or systemic disorders generally cause depressed consciousness without focal neurologic findings.⁵⁹ CNS disorders may or may not have concomitant focal signs. Table 28-2 compares metabolic and drug-induced coma with coma caused by space-occupying lesions.

Clinical disorders of arousal may result in hyperaroused states and can appear as restlessness, agitation, or delirium. This is presumably a result of the loss of hemispheric inhibition of brainstem function. Hypoarousal can be described on a spectrum ranging from drowsiness to stupor and coma. Stupor is a state of unresponsiveness that requires vigorous stimulation to bring about arousal. Coma is a state of unarousable unresponsiveness. Small and restricted lesions of the brainstem can result in stupor and coma. Massive bilateral hemispheric lesions are necessary to cause coma.

Damage to the cerebral cortex can be caused by loss of blood flow, subarachnoid hemorrhage, anesthetic toxicity, hypoglycemia, hypothermia, or status epilepticus (see the section on Epilepsy in Chapter 36). If the link to the brainstem is destroyed, the person will remain in a persistent vegetative state (PVS). Although the person may make random movements and the eyes may open, mentation remains absent. Akinetic mutism, similar to PVS, reflects damage to the mediofrontal lobe and results in lack of motivation to perform any motor or mental activity (abulia). In the locked-in syndrome, there is damage to the pons resulting most often from thrombosis of the basilar artery. This is a remarkable impairment, involving no mental deficit at all but resulting in inability to move anything but the eyes. It is in essence the opposite of PVS.

Supratentorial lesions that cause increased pressure, such as hemorrhage, cerebral edema, or neoplasm, can cause coma by producing tentorial herniation and subsequent compression of the brainstem. There is usually a hemiparesis with a dilated pupil on the side of the lesion because of central compression involving the third cranial nerve by the herniation.

In infratentorial lesions, brainstem damage can be related to drugs, hemorrhage, infarction, or compression from the posterior fossa. Disruption of ocular movements is an early sign of brainstem involvement.⁶⁵ There is loss of the pupillary reaction to light while the corneal reflex remains intact.

Brain death relates to destruction of both the upper and lower parts of the reticular formation in the brainstem, which will eventually lead to death. Cortical electrical activity and spinal reflexes may be preserved, but these are of no consequence because they are unable to be used for thought or movement.

Attention is more difficult to relate to specific brain structure than arousal. However, the acute confusional state is one of the most common neurologic disorders encountered. Although there is not a clear understanding of the mechanism of attention from the neuroanatomic perspective, there appears to be a major role played by the parietal and frontal lobes. Frontal and prefrontal areas of the brain are responsible for mental control, concentration, vigilance, and performance of meaningful activity. Cognition and emotional control are established by extensive white matter connections between the frontal lobes and the remainder of the cerebrum.⁴⁸ Diseases that affect the white matter, such as multiple sclerosis, can affect the level of attention without decreasing arousal. Psychiatric disease has an effect on both arousal and attention³⁷. The acute confusional state may be the result of a number of causes. Intoxicants, metabolic disorders, infections, epilepsy, blood flow disorders, traumatic injuries, and neoplasms can all be responsible for the change in orientation or attention.

Emotional Instability

The orbital prefrontal region is especially expanded in the right cortex and is dominant for selectively attending to facial expressions. It has extensive connections with limbic and subcortical regions, important in regulation of emotional information and mediation of pleasure and pain. Primitive emotions that serve fundamental motivational and social communication functions and nonverbal affects are spontaneously expressed on the face. Psychic systems process unconscious information. Empathetic cognition and the perception of the emotional states of other human beings are developed within the first 3 years of life. Control of vital functions enable the individual to cope actively with stress and external challenge. Self-regulation functions are learned through this region.⁴⁹

Although the limbic system defies exact definition, it is recognized as the area of control of human behavior and is widely studied in behavioral neurology. The limbic system, sometimes referred to as the limbic lobe, is generally considered to encompass part of the cortical, diencephalon, and brainstem structures. This system includes the orbitofrontal cortex, hippocampus, parahippocampal gyrus, cingulate gyrus, dentate gyrus, amygdala, septal area, hypothalamus, and portions of the thalamus. The limbic lobe structures are seen in Fig. 28-14.⁴¹ Working together, these structures provide the essential, need-directed motor activity necessary for survival. This is the area that integrates the motivation and intentional drive to trigger a motor act. Both the automatic and somatic systems are influenced by the limbic system.⁶² Limbic syndromes involve the primary emotions, which are those associated with pain, pleasure, anger, and fear. The processing of the limbic system is responsible for the fact that emotionally charged experiences will be more easily remembered than those with less emotional stimulation.¹³ In lower animals, the limbic system is concerned primarily with the sense of smell, and it is a common observation that smells can trigger a strong emotional response in humans.

The amygdala are nuclei located in the medial temporal lobe anterior to the hippocampus as illustrated in Fig. 28-15. The amygdala is involved in sensory processing and determining the value of the information received. The patterns of emotional memories are formed here, and this is the area that establishes the anxiety and panic or the pleasure that is unconsciously related to an experience that may or may not be remembered.³ The amygdala is richly connected with the prefrontal cortex, the thalamus, hypothalamus, and brainstem as seen in Fig. 28-16.⁴¹ Not represented here is the influence that the prefrontal cortex has on the amygdala, which is thought to be inhibitory. The amygdala is the central structure associated with the learning of fear, fearful responding, and associated autonomic and behavior responses.

Kindling is a term originally used to describe how subthreshold seizure activity becomes increasingly active and severe with successive seizures. Partial kindling also can occur in the amygdala, and it appears related to increased defensive responses and anxiety-like behavior in animals. In humans the amygdala is involved in integrating emotional and contextual information that are parts of the human stress response. Amygdaloidal lesions result in hampered fear conditioning, whereas amygdaloidal stimulation results in classic fear responses such as defensive and aggressive behavior and autonomic reactivity. It has been demonstrated that the amygdala plays a role in conditioned fear responding in general and the startle response in particular.

Perhaps the best example of an anxiety disorder that seems to follow the classic fear-conditioning model is posttraumatic stress disorder (PTSD). Greater amygdala activations were identified in persons with PTSD than in healthy controls. Activations in the amygdala correlated with weakened activation of the medial prefrontal cortex and hippocampus.³⁹ The prefrontal cortex is thought to be hypoactivated in PTSD, particularly during trauma memory activation. It is possible that such prefrontal cortex hypoactivation may be related to startle responses that are larger in PTSD when exposed to contexts in which they know they will be exposed to reminders of their trauma. Recent positron emission tomography (PET) studies have found that the amygdala is clearly active when individuals are thinking about their trauma.²⁸ The amygdala and the hippocampus play a crucial role in the pathophysiology of social phobia.

The thalamus is a two-lobed medial structure that that sits just above the brainstem and is bounded on its dorsal surfaces by the lateral ventricles. The thalamus consists of multiple nuclei receiving input from sensory receptors and brainstem arousal systems and then relays this information to the frontal cortex, the cingulate gyrus, the amygdala, and the hippocampus. With the exception of olfaction, all sensory input goes through thalamic nuclei before being sent onto the cortex. The thalamus affects the quantity and quality of sensory processing. The fact that basic sensory information and arousal signals converge in the thalamus explains why even basic sensory signals can be distorted under conditions of high arousal. Although moderate arousal may facilitate transmission, conditions of high stress likely will distort or hinder transmissions to target structures throughout the brain.

Dissociative symptoms are common among survivors of trauma, and maladaptive levels of dissociation can develop alongside other pathologic responses to trauma. Dissociation is defined as a disruption in the usually integrated functions of consciousness, memory, identity, or perception of the environment, and the term dissociative symptoms in the literature have been used to capture a range of symptoms that can include changes in time perception, altered sensory perception, flashbacks, psychogenic amnesia, reduction in awareness, affective blunting, feelings of detachment, depersonalization, multiple identities, and derealization.^15,28

Although severe disturbances in sensory processing may occur under conditions of extreme stress, more subtle changes may occur even at baseline. The thalamus has rich bidirectional connections with the cingulate gyrus and the frontal cortex, two of the structures responsible for the prioritization and shifting of attention. During the extreme stress of an actual trauma, it is likely that the thalamus impairs rather than facilitates the processing of environmental stimuli. In this sense, the thalamus has a role to play in amnesia for traumatic events. For example, disruption in the relay of contextual and traumatic information could contribute to the fragmentation and inaccuracies associated with traumatic memory. Unlike the role the hippocampus might play in fragmenting sensory elements of the memory, however, thalamic interference would result in an initial interference with basic stimulus encoding.²⁸

Levels of emotion that are generated and advanced by the limbic system, or more specifically the amygdala, can be described on a continuum. An emotion can be triggered as fear or frustration, which when heightened can manifest as anger. If the neurochemical activity continues to build and leads to internal chaos or conflict, it becomes rage. The motor response will become violent if there is a sufficient trigger. Genetics and environmental history will lead to differences in how a person moves from fear to violence. When there is damage to the area of the limbic lobe that results from injury or disease, there can be an increase in rage and easy progression to violence. The diffuse axonal damage of head injury can cause a tendency to become easily frustrated or to have unsubstantiated fears.

The different symptom dimensions of obsessive compulsive disorder and other anxiety disorders are likely to share common neural substrates dedicated to general threat detection and emotional arousal because these reactions are adaptive and useful to deal with different kinds of threat. Research suggests that syndrome-specific neural substrates may have evolved to deal with specific threats. In evolutionary terms, general anxiety, which is common to individuals who have obsessive compulsive disorder and other anxiety disorders, may have evolved to deal with nonspecific threats, for example, cleanliness is important for protection against infections; harming obsessions and checking rituals keep people safe; and hoarding helps people survive periods of scarcity The neuroimaging findings, showing increased activation of limbic and ventral frontal-striatal regions in obsessive compulsive disorder, could reflect exaggerations of normal emotional responses to biologically relevant stimuli rather than fundamentally abnormal neuronal responses.³⁵

Borderline personality disorder (BPD), including affective dysregulation, identity disturbance, and self-mutilating behaviors, were originally thought to involve a disorder of character. In recent studies, it appears that BPD individuals are compromised significantly in executive skill and/or other frontal lobe functions, visuomotor speed, attention, and verbal memory. These fairly consistent neuropsychologic findings in adults are supported by developmental studies of children with borderline features. These children appear to have greater difficulty with executive skills, including planning, organizing, and sequencing; perceptual motor functioning; and memory proficiency.³⁹

Fear conditioning is a fast process, with a long-lasting effect, but repeated exposure to the conditioned stimulus in the absence of the unconditioned stimulus can lead to extinction. Extinction reduces the likelihood that the conditioned stimulus will elicit the fear response. The medial prefrontal and anterior cingulate cortices have been implicated in extinction learning. Understanding how learned fears are diminished and how extinction learning is changed in individuals who have anxiety disorders might be an important step in translating neurobiologic research to diagnosis and treatment of these individuals.

Memory Problems

Memory is associated with various areas of the brain, and a particular area may be responsible for different aspects of memory. The hippocampus, the thalamus, and the basal forebrain are critical to the performance of recent memory (Table 28-3). Fig. 28-17 shows the relationship of learning strategies and brain regions. For immediate auditory memory, left and right temporal-parietal cortices mediate auditory verbal and nonverbal material. Neurogenesis has been observed in the dentate gyrus of the hippocampus throughout the lives of many species, including humans. Not all newly generated hippocampal neurons survive, but hippocampal-dependent memory tasks can enhance the survival of these neurons.²¹ Inflammatory cytokines reduce hippocampal neurogenesis and impair the ability to maintain long-term potentiation in the hippocampus, which is a critical physiologic process involved in memory consolidation.²⁰

Working memory, the ability to hold information in short-term storage while permitting other cognitive operations to take place, appears to depend on the prefrontal cortex. Keeping a spatial location in mind may involve a right frontal area that directs the maintenance of that information in a right parietal area, whereas keeping a word in mind may involve a left frontal area that directs the maintenance of that information in a left temporal or parietal area. Specific basal ganglia and cerebellar areas appear to support the working memory capacity of particular frontal regions.

Disorders of recent memory, known as amnesia, are a significant neurobehavioral phenomenon and common in persons after traumatic brain injury. Declarative memory is retention of facts and events of a prior experience or the memory of what has occurred and is related to explicit learning. Procedural memory describes the learning of skills and habits, or how something is done. Implicit learning is based on procedural memory. The relationship to memory and relearning motor skills is discussed in the Special Implications for the Physical Therapist: Motor Learning Strategies in this chapter.

Anterograde amnesia is the failure of new learning or formation of new memory. Retrograde amnesia is the loss of ability to recall events. The inability to acquire new learning is often accompanied by confabulation, the fabrication of information in response to questioning. Traumatic amnesia refers to an individual’s inability to recall significant aspects of their traumatic experience. Traumatic memories are reported to be fragmented, compartmentalized, and disintegrated, suggesting that the hippocampus still may have a role to play in the phenomena of traumatic amnesia. Dysregulation in the hippocampal system has the potential to generate narratives of traumatic events that are spotty and unreliable.

Neuromodulators, such as norepinephrine, have the potential to affect hippocampal functioning in a more dynamic fashion. The locus ceruleus, located in the brainstem, for example, projects directly to the hippocampus and modulates its functioning through norepinephrine release. The effects of such a network are unclear, although the implications are that stress-related memory alterations might occur on a split-second basis and deficient or extreme locus ceruleus input may disrupt normal hippocampal processing severely. Given that the hippocampus plays a role in integrating input from diverse sources when encoding memory, disruptions in its functioning may lead to memories that seem fragmented and nonlinear. Over time, fragments of the memory may become consolidated, vivid, and easily recalled, while other fragments rarely are accessed.²⁸

The role of stress in neurologic disease often is overlooked. Several chronic neurologic disease states, such as Alzheimer’s disease, are associated with elevated secretion of stress hormones, in particular cortisol, which results from overactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The stress or perceived threat activates the hypothalamus, triggering release of hormones that cause increased adrenal output of cortisol.⁴⁷ Stress also can trigger or exacerbate symptom onset and perhaps progression of chronic illness such as Parkinson’s disease. Stress hormones also can mitigate the impact of acute neurotrauma; for example, there is a positive correlation between cortisol levels and mortality after head injury. Thus neurologic disease states can occur within a context of elevated glucocorticoids, which may have profound influences on recovery and neuroplasticity. In addition, abnormal regulation of glucocorticoid release is associated with many affective disorders, such as depression and PTSD, that are overrepresented in populations with neurologic disease; Parkinson’s disease is a prime example. Acute and sustained glucocorticoid release also can precipitate changes in peripheral and central immune signaling, resulting in cytokine profiles that may be deleterious for functional recovery in the face of neurologic challenge.²³

Accumulation of risk is another concept that plays a pivotal role in the life-course model of chronic diseases. Allostasis is defined as the ability to achieve stability through change. The price of this accommodation to stress has been defined as the allostatic load. It follows that acute stress (the “fight, flight, or freeze” response) and chronic stress resulting from the cumulative load of minor day-to-day stresses can add to the allostatic load and have long-term consequences. Subacute stress is defined as an accumulation of stressful life events over a duration of months and includes emotional factors, such as hostility and anger, as well as affective disorders such as major depression and anxiety disorders. Chronic stressors include factors, such as low social support, work stress, marital stress, and caregiver strain, and present as feelings of fatigue, lack of energy, irritability, and demoralization.

The link between chronic psychologic distress and adverse behavior, such as overeating, may be centrally mediated. Normally, glucocorticoids help end acute stress responses by exerting negative feedback on the HPA axis. The combination of chronic stress and high glucocorticoid levels seems to stimulate a preferential desire to ingest sweet and fatty foods, presumably by affecting dopaminergic transmission in areas of the brain associated with motivation and reward.¹⁷

Brain areas associated with reward are linked with those that sense physical pain. Chronic pain can cause depression, and depression can increase pain. Most individuals who have depression also present with physical symptoms. Studies using functional magnetic resonance imaging (fMRI) have shown that social rejection lights up brain areas that are also key regions in the response to physical pain. The area of the anterior cingulate cortex that is activated by visceral pain also is activated in cases of social rejection.

Disturbances of neurologic function can result in behavioral disturbances that mimic disturbances of mental function in psychiatric disorders. Delusions, or fixed false beliefs, have been reported in a great variety of neurologic conditions and appear to be associated with the limbic system. Paranoid delusions are common in disorders of the medial temporal lobe or a combination of the frontal and right parietal lobes. Hallucinations are sensory experiences without external stimulation. Visual hallucinations generally suggest neurologic involvement; auditory hallucinations imply psychiatric disease. Midbrain lesions in the cerebral peduncles can cause hallucinations involving animals. Temporal lesions can cause recurrent auditory experiences.¹³

Rapid-eye movement (REM) sleep behavior disorder is characterized by loss of muscular atonia and prominent motor behaviors during REM sleep. Sleep behavior disorder can cause sleep disruption. The disorder is strongly associated with neurodegenerative diseases such as multiple-system atrophy, Parkinson’s disease, dementia with Lewy bodies, and progressive supranuclear palsy. The symptoms of sleep behavior disorder precede other symptoms of these neurodegenerative disorders by several years. Furthermore, several recent studies have shown that sleep behavior disorder is associated with abnormalities of electroencephalographic (EEG) activity; cerebral blood flow; and cognitive, perceptual, and autonomic functions. Sleep behavior disorder might be a stage in the development of neurodegenerative disorder. Box 28-2 includes the areas of the brain that play a role in sleep behavior.¹⁸

Lesions of the hemispheres or lobes may cause loss of the functions that each hemisphere controls. Because diseases and damage caused by trauma will often affect one area of the brain, the associated syndromes for the main areas of the brain are described.³³

Autonomic Nervous System

The term autonomic nervous system was introduced to describe the system of nerves that controls the unstriated tissue, the cardiac muscle, and the glandular tissue of mammals involved in the control of autonomic function. The autonomic CNS neurons are located at many levels from the cerebral cortex to the spinal cord. Efferent autonomic pathways are organized in two major outflows: the sympathetic and parasympathetic. Finally, the enteric nervous system, which is considered a separate and independent division of the autonomic nervous system, is located in the walls of the gut. The schematic diagram of the autonomic nervous system is seen in Fig. 28-18.

Neurons in the cerebral cortex, basal forebrain, hypothalamus, midbrain, pons, and medulla participate in autonomic control. The central autonomic network integrates visceral, humoral, and environmental information to produce coordinated autonomic, neuroendocrine, and behavioral responses to external or internal stimuli. A coordinated response is generated through interconnections among the amygdala and the neocortex, forebrain, hypothalamus, and autonomic and somatic motor nuclei of the brainstem. The insular and medial prefrontal cortices (paralimbic areas) and nuclei of the amygdala are the higher centers involved in the processing of visceral information and the initiation of integrated autonomic responses. The central nucleus of the amygdala projects to the hypothalamus, periaqueductal gray (PAG), and autonomic nuclei of the brainstem to integrate autonomic, endocrine, and motor responses to emotionally relevant stimuli.

The hypothalamus integrates the autonomic and endocrine responses that are critical for homeostasis. The PAG matter of the midbrain is the site of integrated autonomic, behavioral, and antinociceptive stress responses. It is organized into separate columns that control specific patterns of response to stress. The lateral PAG mediates sympathoexcitation, opioid-independent analgesia, and motor responses consistent with the fight-or-flight reaction. The ventrolateral PAG produces sympathoinhibition, opioid-dependent analgesia, and motor inhibition.

Neurons in the medulla are critical for the control of cardiovascular, respiratory, and gastrointestinal functions. The medullary nucleus of the solitary tract is the first relay station for the arterial baroreceptors and chemoreceptors, as well as cardiopulmonary and gastrointestinal afferents.

Preganglionic sympathetic neurons are organized into different functional units that control blood flow to the skin and muscles, secretion of sweat glands, skin hair follicles, systemic blood flow, as well as the function of viscera. Selectivity is refined by the release of different neurotransmitters. Acetylcholine is the neurotransmitter of the sympathetic and parasympathetic preganglionic neurons. The main postganglionic sympathetic neurotransmitter is norepinephrine.

Visceral afferents transmit conscious sensations (e.g., gut distention and cardiac ischemia) and unconscious visceral sensations (e.g., blood pressure and chemical composition of the blood). Their most important function is to initiate autonomic reflexes at the local, ganglion, spinal, and supraspinal levels. Visceral sensation is carried primarily by the spinothalamic and spinoreticular pathways, which transmit visceral pain and sexual sensations. Brainstem visceral afferents are carried by the vagus and glossopharyngeal nerves. Brainstem visceral afferents are important in complex automatic motor acts such as swallowing, vomiting, and coughing.²¹

Traumatic spinal cord injury, particularly injury above the T5 level, is associated with severe and disabling cardiovascular, gastrointestinal, bladder, and sexual dysfunction. These individuals have both supine and orthostatic hypotension and are at risk of developing bradycardia and cardiac arrest during tracheal suction or other maneuvers that activate the vagovagal reflexes.

Pure autonomic failure with no other neurologic deficits is rare. More often, autonomic failure occurs in combination with other neurologic disorders, such as Parkinson’s disease, and multiple system atrophy In these individuals, it is important for the examiner to inquire about abnormalities in gait, changes in facial expression, the presence of dysarthria, difficulty in swallowing, and balance problems. Autonomic failure also occurs in individuals with some peripheral neuropathies such as those associated with diabetes. Because autonomic failure may be caused by lesions at different levels of the nervous system, a history of secondary trauma, cerebrovascular disease, tumors, infections, or demyelinating diseases should be established. Additionally, because the most frequent type of autonomic dysfunction encountered in medical practice is pharmacologic, there should be a thorough review of medication use, especially antihypertensive and psychotropic drugs.

Some conditions may be confused with autonomic failure, including neurally mediated syncope, which is referred to as vasovagal, vasodepressor, or reflex syncope. This condition is caused by a paroxysmal reversal of the normal pattern of autonomic activation that maintains blood pressure in the standing position; these individuals do not have autonomic failure. A detailed history is important to differentiate this disorder. In contrast to individuals with chronic autonomic failure in whom syncope appears as a gradual fading of vision and loss of awareness, individuals with neurally mediated syncope often have signs and symptoms of autonomic overactivity such as diaphoresis and nausea before the event. This distinction and the episodic nature of neurally mediated syncope should be part of a thorough clinical history.

The complexity of the nervous system cannot be overstated. The information provided in this overview of the components of the CNS is meant to illuminate the many facets of the system that can be affected by pathologic processes. Fig. 28-19 shows the relationship of the areas that have been described here.⁴¹ Familiarity with this relationship is the basis of attempting to understand the pathologies that will be considered in the next chapters. To understand pathology, one must have a good working knowledge of brain structure and function. The Whole Brain Atlas web site provides dynamic images of the brain integrating imaging techniques that link anatomy and pathology.⁶⁶

Aging and the Central Nervous System

Senescence, or aging, results from changes in DNA, RNA, and proteins. Errors in the duplication of DNA increase with age because of random damage over time. There may be a specific genetic program for senescence. Fibroblasts from an older individual double fewer times than those of an embryo.

Age-related reduction in adult brain weight represents loss of brain tissue. There is highly selective atrophy of brain tissue in the aging CNS. It is not clear how much of the change represents actual loss of nerve cells, since the changes in vascular tissue and glial cells may represent some of the loss. Simple loss of cells is common, Nerve cell shrinking, causing possible changes in functional efficiency, may be a more important effect of old age than cell loss. Nerve conduction velocity decreases with age in both the motor and sensory systems. By the eighth decade there is an average loss of 15% of the velocity in the myelinated fibers.³²

The inner structure of the nerve cell changes with aging. The presence of lipofuscin, or wear and tear pigment, a pigmented lipid found in the cytoplasm, may interfere with normal cell function via pressure on the cell nucleus. The pigmented nuclei of the brainstem catecholaminergic neurotransmitter accumulates with age. Damage to an axon close to the neuronal cell body results in changes in the area of the cell body and is referred to as an axonal reaction. The mechanism and relationship to dysfunction are still not clearly understood. The deposition of amyloid-β protein creating plaques in the cerebral cortex is found in many but not all older people. Neuritic, or senile, plaques are found outside the neuron filled with degenerating axons, dendrites, astrocytes, and amyloid. They represent damage to brain tissue. The neuritic plaques are thought to occur most often in the cortex and hippocampus and have been associated with dementia and Alzheimer’s disease.¹⁴

Neurofibrillary tangles, or abnormal neurologic fibers that displace and distort the cell body, are found in higher concentrations in the older brain. Neurofibrillary tangles and amyloid are also found in higher concentrations in people with Alzheimer’s disease (see Chapter 31).

The blood supply also diminishes during aging, with a net reduction of 10% to 15%. The relationship of cerebral blood flow, the resultant decrease in the glucose supply to the brain, and decreased metabolism are not well-established as to cause and effect. All three are noted in the aging brain.⁴⁴

Morphologic changes in the aging brain are accompanied by neurochemical changes. Changes in neurotransmitter activity are seen with aging and are an area of great interest at this time. There is a decrease in the number of some of the receptors, as well as decreases in synthesis of some of the neurotransmitters. Enzymes involved in synthesis of transmitters, such as dopamine, norepinephrine, and acetylcholine, are decreased with age. Changes in these neurotransmitters may be reflected in decreased control over visceral functions, emotions, and attention. Serotonin, involved in central regulatory activities of respiration, thermoregulation, sleep, and memory, appears to be reduced in the older brain. Depression in the older adult may be related to increased production of MAO, which breaks down catecholamines and results in a loss of the feeling of well-being.²⁷

Other changes in the brain related to neurotransmission, such as Parkinson’s and Alzheimer’s disease, are described in the chapters that follow. Mood and depressive symptoms also are common in elderly individuals who are ill and are associated with increased morbidity and mortality. There is a relationship between inflammatory cytokines and depressive disorders. Age-associated alterations in immunity are apparent in the innate immune cells of the brain. There is an elevated inflammatory profile in the aging brain consisting of an increased population of reactive glia. A potential consequence of a reactive glial cell population in the brain is an exaggerated inflammatory response to innate immune activation. Even in the absence of detectable disease, the glia population undergoes an age-related transformation that creates a more sensitive brain environment.

An amplified and prolonged inflammatory response in the aged brain promotes protracted behavioral and cognitive impairments and the behavioral consequences of illness and infection in the elderly, if prolonged, can have deleterious affects on mental health. There is an increased prevalence of delirium in elderly individuals who present to the emergency department as a result of infections unrelated to the CNS. Viral or bacterial pneumonia in the aged frequently presents clinically as delirium, even in the absence of classic pneumonia symptoms.²⁰

The central mechanisms that are involved in the control of balance do not appear to change excessively with age but are more likely to be affected by degenerative neurologic diseases such as Parkinson’s or Alzheimer’s disease. Age-related changes in the peripheral vestibular system include hair cell receptors that begin to decrease at the age of 30 years, and by 55 to 60 years, there is a loss of the vestibular receptor ganglion cells. The myelinated nerve cells of the vestibular system show up to a 40% loss. Partial loss of vestibular function in the older population can lead to complaints of dizziness, with less ability of the nervous system to accommodate the loss compared with younger persons.

In addition to vestibular losses, there is concomitant loss of other sensory inputs relating to balance and mobility: vision and somatosensation. Maintaining equilibrium, or balance, requires a multimodal system integrating vestibular, visual, and somatosensory signals. The integration of these signals in the CNS coordinates multiple output responses: eye movement, postural correction, motor skill, and conscious awareness of spatial orientation. There are longer response latencies and delayed reaction times. Vision changes include loss of acuity, decreased peripheral fields, and loss of depth perception. The loss of input from this combination is slow, with compensation developing through the years.¹¹ Eventually a loss of functional reserve, or redundant function, that is normally present in virtually all physiologic systems is seen with aging. There is an apparent decrease in the ability to integrate conflicting sensory information to determine appropriate postural responses. Changes occur as well in motor output that may contribute to the loss of balance and mobility.¹⁰ Although the response patterns are the same in young and old people, with responses being activated in the stretched ankle muscle and radiating up to the thigh, in some older people, this response is disrupted with the proximal muscles being activated before the distal muscles. In the older person, there appears to be more co-contraction of muscles around the ankle as a result of perturbation.⁵³

Neurologic disease is more prevalent in older persons, as is the risk of neurologic sequelae as a result of intracranial hemorrhage, subdural hematoma, and neoplasms. Awareness of the signs and symptoms of these disorders is essential. The therapist may be the person able to identify a disease or the potential for a disorder that may manifest during a treatment session.

Clinical Localization

Clinical localization is the first step to differential diagnosis for a individual with neurologic disease. Coupling the time course of the illness with the clinical localization is the essence of neurology. The history of the onset and nature of the symptoms is critical to establish the diagnosis related to the neurologic disorder. In many cases, based on the history and symptoms, the clinician is able to generate a hypothesis regarding the site in the nervous system that has been affected and the nature of the lesion. A complete history of the nature of the symptoms is also critical to determining which diagnostic tools will provide the most accurate differential diagnosis and best determine the cause.

The examination of the client with neurologic dysfunction often begins with mental status changes. Alterations of consciousness and disturbances of higher brain function give the clinician clues about the nature of the disease process and the location of damage within the brain⁵⁹ (Table 28-4).

Motor and sensory changes will also reflect the type, level, and extent of damage to the system in the case of both disease and trauma. Understanding the typical motor and sensory changes associated with a particular disease or disorder leads the evaluation. For example, knowing that ALS involves both upper and lower motor signs may help the clinician when this otherwise perplexing condition presents in the clinic. Understanding the functional deficits related to each condition can also lead the clinician to a diagnosis. Gait disorders are often representative of the level or location of damage within the nervous system.

The diagnosis of neurologic disorders remains a clinical specialty, although the use of sophisticated imaging and measurement of neural function have provided insight into the pathologic state of the nervous system. The following are examples of diagnostic test currently performed.

Computed Tomography

Computed tomography (CT) scans allows a snapshot of the CNS, and damage within tissue can be identified. Disorders affecting blood flow, multiple sclerosis, neoplasm, and infection can be identified with these scans. CT is an excellent study to evaluate for acute intracranial hemorrhage, particularly in the subarachnoid space. Active bleeding may be detected in either epidural or subdural hemorrhages as a relative lucency, which is commonly referred to as the “swirl sign.” Edema from excitotoxic damage associated with infarct or diffuse anoxia can be seen representing intracellular fluid, and vasogenic edema is the abnormal accumulation of extracellular fluid in the white matter that looks like fingers following the white matter tracts. Evaluation of ventricular size can be done by CT. Enlargement of the temporal horns out of proportion to the lateral ventricular bodies is helpful in recognizing early hydrocephalus. CT can be helpful to follow ventricular size after shunting.

CT is very useful for detecting intracranial calcifications such as those seen in congenital infections, vascular lesions, and metabolic disease. The location and distribution of calcifications is helpful in differentiating these various causes. The identification of calcification in a neoplasm aids in differential diagnosis.²¹

Magnetic Resonance Imaging

MRI signal patterns are recognizable with common diseases such as cerebral edema, neoplasm, abscess, infarcts, or demyelinating processes. MRI is the study of choice to evaluate all lesions in the brain and spine. CT, however, is more sensitive than MRI for the evaluation of calcifications, subtle fractures, and remains pivotal in the diagnosis of acute subarachnoid hemorrhage. Additionally, MRI cannot be performed in individuals who have intraorbital foreign bodies, pacemakers, or non-MRIcompatible implants, such as artificial heart valves, vascular clips, cochlear implants, or ventilators. The use of MRI is the modality of choice for detecting congenital malformations. Infection of the spine is better evaluated by MRI.

Functional Magnetic Resonance Imaging

fMRI is based on blood oxygenation level–dependent (BOLD) imaging of the brain and provides functional data of cerebral activation during any given task (e.g., motor, visual, or cognitive). This method allows for a quantitative nonclinical method for assessing changes in cerebral function as related to cerebral activities (i.e., performance of physical or cognitive tasks). The BOLD fMRI technique allows for detection of minute changes in cerebral oxygenation. fMRI studies of various pathways of the brain, including the language, memory, and visual pathways, will enhance our ability to connect activity to changes in the brain. For example, frontal and lateral three-dimensional (3D) fMRI renderings show functional activity in the occipital lobe secondary to a visual stimulus.

Positron Emission Tomography

Positron emission tomography (PET) and single-photon emission CT (SPECT) scanning can show cellular activity via regional blood flow in the brain and are now used to monitor changes in the brain with functional activity. Both techniques can be used to depict the regional density of a number of neurotransmitters, allowing researchers to better understand the role of different parts of the brain during activity.

Electroencephalography

Cerebral ischemia produces neuronal dysfunction, leading to slowing of frequencies or reduced amplitude in the EEG tracing. These changes may be generalized (global ischemia) or regional (focal ischemia). The depth of ischemia is associated with the severity of EEG changes. EEG cannot assess the whole cerebral cortex, however, and is less reliable at assessing subcortical structures.

Brainstem Auditory Evoked Potentials

Potentials generated in the auditory nerve and in different regions of the auditory pathways in the brainstem can be recorded. The attention of the subject is not required. Because the brainstem auditory evoked potential (BAEP) is of very low voltage, between 1000 and 2000 responses are generally recorded so that the BAEP can be extracted by averaging from the background noise. Wave III probably arises in the region of the superior olive, whereas waves IV and V arise in the midbrain and inferior colliculus. Waves VI and VII are of uncertain origin and little clinical utility because of their inconsistency in normal subjects. The most consistent components are waves I, III, and V, and it is to these that attention is directed when BAEPs are evaluated for clinical purposes.

The BAEP is an important means of evaluating function of the cranial nerve VIII and the central auditory pathways in the brainstem. In infants, young children, and adults who are unable to cooperate for behavioral testing, BAEPs can be used to evaluate hearing. The wave V component of the response is generated by auditory stimuli that are too weak to generate other components. The BAEP is also useful in assessing the integrity of the brainstem. The presence of normal BAEPs in comatose individuals suggests either that the coma is due to bihemispheric disease or that it relates to metabolic or toxic factors; abnormal BAEPs in this context imply brainstem pathology and a poorer prognosis than otherwise. When coma is due to brainstem pathology, the BAEP findings help in localizing the lesion.

BAEPs have been used to detect subclinical brainstem pathology in individuals with suspected multiple sclerosis. However, the yield in this circumstance is less than with the visual or somatosensory evoked potentials, possibly because the auditory pathway is relatively short or is more likely to be spared. Cerebral ischemia results in delay in the arrival of or reduction in amplitude of evoked responses.²¹

Transcranial Doppler Ultrasonography

Transcranial Doppler ultrasonography uniquely measures local blood flow velocity in the proximal portions of large intracranial arteries. Hemodynamic compromise is inferred when there is reduction in mean flow velocities or when there is slow flow acceleration. In addition, transcranial Doppler ultrasonography can detect cerebral microembolic signals, reflecting the presence of gaseous or particulate matter in the cerebral artery. Solid, fat, gas, or air materials in flowing blood are larger and of different composition and, thus, have different acoustic impedance than surrounding red blood cells. Thus the Doppler ultrasound beam is both reflected and scattered at the interface between the embolus and blood, resulting in an increased intensity of the received Doppler signal. A completely accurate and reliable characterization of embolus size and composition, however, is not yet possible with current technology.

Near-Infrared Spectroscopy

In brain tissue, the venous oxygen saturation predominates (70% to 80%), and cerebral oximetry relies on this fact. Near-infrared spectroscopy (NIRS) uses light optical spectroscopy in the near-infrared range to evaluate brain oxygen saturation by measuring regional cerebral venous oxygen saturation. Table 28-5 describes the use of various imaging techniques correlated to anatomic site.

Methods to Control Central Nervous System Damage

Damage or disease of the nervous system often results in changes in the production and uptake of neurotransmitters. Many important drugs that alter nervous system function act by selective interaction with neurotransmitter receptors. Drugs that act at synapses either enhance or block the action of these neurotransmitters. Most neurotransmitters with a prominent role in brain function produce very brief receptor-mediated actions at specific groups of synapses. A few neurotransmitters are more prolonged and act more widely throughout the extracellular space. The combined action of both a briefly acting and a more enduring neurotransmitter produces a modulation of postsynaptic neuronal activity. Pharmacologic strategies are currently aimed at modulation of neurotransmitter synthesis, release, reuptake, and degradation.²⁵ Some drugs mediate inhibition of neurotransmitter release by acting at presynaptic receptors. Opiates are one group of drugs that act by the inhibition of neurotransmitter release. Drugs used to control excessive tone in specific muscle groups often work by inhibiting neurotransmitter release. Anesthetic drugs modify the actions of neurotransmitter receptors by changing the membranes of cells on or within which the receptors are located.

Drug therapy can stimulate neurotransmitter release. Drugs aimed at maintaining neurotransmitter activity in the synaptic cleft can be useful in neuromuscular junction diseases. Another way to regulate the level of neurotransmitters is to influence the rate of chemical degradation. Drugs can inhibit the breakdown of certain elements that may be broken down by natural processes such as oxidation. One action of these drugs is to prolong the efficacy of released neurotransmitters by inhibiting their degradation.⁶¹ An example of this process is the regulation dopamine. Dopamine activity can be increased by four mechanisms:

Synthesis of the neurotransmitter can be increased by giving dopa because it is the product beyond the rate-limiting enzyme and there is ordinarily an abundant amount of aromatic amino acid decarboxylase in the CNS. When dopa is combined with a peripherally active decarboxylase inhibitor, more dopa is delivered across the blood-brain barrier and can be used to synthesize central dopamine. Drugs, such as cocaine, amphetamine, and methylphenidate, can increase release.

The normal metabolism of dopamine involves reuptake of dopamine into the presynaptic cell, with subsequent metabolism by two enzymes, MAO and COMT. Prolongation of dopamine activity can be effected by blocking reuptake or altering enzyme activity. Amantadine and possibly some tricyclic antidepressant medications operate on the dopaminergic system through blockade of reuptake. MAO inhibitors and COMT inhibitors for human use also increase dopaminergic activity. Finally, direct activation of the dopamine receptors on the striatal cell can be induced by agonists like bromocriptine, pergolide, and other drugs. Importantly, orally administered dopamine itself has no place in altering the CNS dopamine levels, because, being a positively charged molecule, it cannot cross the blood-brain barrier.²¹

Other drugs protect the cell membrane in the presence of toxins that act on the membrane such as the toxic effects of the free radicals produced in brain tissue after hypoxia, ischemia, and seizures. Damage to the neuron occurs when the free radical is allowed to penetrate the membrane.⁴⁵ The best defense is to prevent penetrance. Antioxidant therapies are being examined for a variety of neurodegenerative disorders and the sequelae of stroke and spinal cord injury. It is believed that the toxicity of glutamate can be blocked by various antioxidants. Vitamin E, a free radical scavenger, is an antioxidant that has been tested widely. However, it does not pass easily through the blood-brain barrier, and as a fat-soluble vitamin, it can be toxic in large doses. Estrogen can work as an antioxidant through intrinsic neurotrophic activities. Ongoing studies are looking at the natural substances noted above as well as manufactured substances that will provide antioxidant or free radical scavenging. There is great hope that substances that will slow down the destruction related to oxidative stress will prove to be curative for progressive diseases of the CNS, as well as other degenerative processes associated with connective tissue, neoplasm, and aging.⁷ Specific drugs used for primary neurologic disorders are described in the next chapters.

Exciting new advancements in the field of molecular genetics have begun to identify novel candidate genes that may be involved in many inherited or acquired neurologic disorders. The basic principle of gene therapy is to transfer exogenous genes into specific cell types within the human body to correct a pathologic disorder. Currently, gene therapies are based on simple nucleic acid sequences or derived from unique viruses. Researchers have attempted to use the power of viruses to essentially hijack cells for gene expression of appropriate therapeutic molecules.

Stem cells are unspecialized living cells that have the capacity to renew themselves for long periods of time through cell division. Under certain physiologic or experimental conditions, they can be induced to become cells with special functions such as the beating cells of the heart muscle or the insulin-producing cells of the pancreas. Embryonic stem cells are derived from embryos that develop from eggs that have been fertilized in vitro and then donated for research purposes with the informed consent of the donors. The embryos from which human embryonic stem cells are derived are typically 4 or 5 days old and consist of a hollow microscopic collection of cells called the blastocyst. An adult stem cell is an undifferentiated cell found among differentiated cells in a tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Some researchers now use the term somatic stem cell instead of adult stem cell. Unlike embryonic stem cells, which are defined by their origin, the origin of adult stem cells in mature tissues is unknown. A single adult stem cell could have the ability generate a line of genetically identical cells, or clones.²

There is evidence for the impact of immune system dysfunction in these diseases despite the blood-brain barrier protection of the CNS from the direct effects of autoimmune responses. Identification of immune system elements is leading researchers toward an understanding of the role of the immune system in diseases such as multiple sclerosis, ALS, Parkinson’s disease, and Alzheimer’s disease.

Use of catheters to deliver drugs directly into the cerebrospinal fluid or brain tissue has enhanced the ability to deliver drugs that act directly on the neuron. Although the catheters have been made more sophisticated and can deliver the drugs in measured doses, complications of administration and uneven levels of absorption continue to be limiting factors.

Treatment of Nonneural Dysfunction

Many drugs used to treat neurologic disorders influence nonneuronal tissue, including cerebral blood vessels and glia. Cerebral edema can increase the permeability of the blood-brain barrier, causing an increase in fluid within the brain. The resulting compression of brain tissue can be life-threatening. Drugs, such as mannitol, that control cerebral edema, or drugs that provide diuresis can help preserve neuronal function. In demyelinating disease, antiinflammatory and immunosuppressive drugs are used to preserve the function of the glial cells that produce the myelin sheath.

For some of the viruses that invade the CNS there is replication of cells in nonneural tissue. Use of drugs that inhibit RNA or DNA synthesis can prevent viral replication without disrupting neuronal integrity. Acyclovir, used in the treatment of herpes encephalitis, is an example of this type of drug.

In infants and children, there is an altered drug metabolism that should be considered whenever administering drugs that act on the nervous system. Concomitant illness and fever will further alter drug metabolism. An immature blood-brain barrier can also affect the absorption of drugs into brain tissue. When anticonvulsants are administered, close monitoring of blood levels is necessary.

Physiologic Basis for the Recovery of Function

After injury to the nervous system, there are changes in the structure and function of the neurons. In some instances the changes can lead to further damage, whereas other changes facilitate recovery.

Diaschisis, or neural shock, occurs when there is injury to a nerve and disruption of the neural pathway that extends a distance from the site of injury. When the neurons distal to the injury regain function, which may be soon after the injury, partial function may return.

Injury may be secondary to either swelling of the axon or edema in the surrounding tissue that blocks synaptic activity in the injured neurons, as well as that in the surrounding area. With reduction of the edema, function may return. This is the reason that medications that reduce edema are often given in the context of diffuse brain swelling.

When there is a loss of presynaptic function in one area, the postsynaptic target cells for that area may become more sensitive to neurotransmitters that are now produced in lower concentrations. The compensatory mechanism is known as denervation supersensitivity. Regenerative synaptogenesis occurs when injured axons begin sprouting. Collateral sprouting is the process of neighboring axons sprouting to connect with sites that were previously innervated by the injured axon.

Suppression of a response to a stimulus is considered habituation, whereas sensitization is an increased response to a stimulus, usually related to noxious stimuli or pain. Adaptation is the ability to modify a motor response based on changes in the sensory environment or input received.

Long-term potentiation occurs when a weak input and a strong input arrive at a dendrite at the same time. The weak stimulus is enhanced by the strong stimulus. With repeated activation of combined stimuli, there is an increase in the presynaptic transmitter associated with the stimulus. After the long-term potentiation has been established, the weak input will elicit a stronger response than it had initially.³¹

The characteristics of a lesion will have a profound effect on recovery from a brain injury. Small lesions of the brainstem may in fact be as devastating as large lesions of the cerebral cortex. Cerebellar damage can affect both learning and memory of movements. Lesions that occur gradually appear to cause less disruption of function than lesions that occur all at once such as with strokes. Advanced age will adversely affect the return of function. Studies show that a person’s prior level of activity and environment will affect the rate and extent of recovery. An enriched environment will positively affect recovery when it is available either before the insult or during the recovery period.

Redistribution of cortical mapping is seen after a lesion in the brain.⁹ These changes may involve unmasking of previously nonfunctional synaptic connections from adjacent areas, or the ability of the neighboring inputs may take over. It is clear that both sensory and motor maps in the cortex are constantly changing according to input from the environment. In addition, the brain appears to increase use of ipsilateral pathways after a lesion that affects one side of the brain.

Recovery of function by strict definition is the return to original processes for an activity. When alternative processes are used to complete the task, it is considered compensation. Neural modifiability may be seen as a change in the organization of connections among neurons and is often referred to as plasticity. Some of the recovery after CNS damage is considered spontaneous. Forced recovery is the result of specific interventions that create change in the neural structure.⁵³ Constraint-induced training makes use of this action.

Physiologic studies suggest that motor relearning and recovery of function may be accomplished through the same neural mechanisms and reflect the plasticity of the brain. Learning alters our capability to perform the appropriate motor act by changing both the effectiveness of the neural pathways used and the anatomic connections.

Learning involves storage of memory and can occur in all parts of the brain with both parallel and hierarchic processing. The area of representation within the brain becomes specialized for both inputs and outputs. Areas of the brain used during the early phase of learning movement are different from those used once a skill is learned. Initially, more areas of the brain are active, since skill develops both the number of neurons firing and location of activity change. The use of sensory input is increased in the early stages of learning. The prefrontal areas are also more active in the learning phase and become less active during automatic movements.⁹ The stimuli repeatedly excite cortical neuron populations, and the neurons progressively grow in numbers. Repetition will lead to greater specificity, and the responses become stronger. With skill acquisition, sensory feedback appears to be less critical.

Control of learning comes from many areas of the CNS working together. The area involved may depend on a number of variables associated with the type of learning taking place and is influenced by the environment. The cortex is involved in learning through sensorimotor integration. It is postulated that there are widely distributed groups of neurons acting as a cortical engram, composed of multiple functional groupings. Thus, when an activity is repeated and stored in memory, the engrams are available to trigger groups of cells that fire synchronously during movement. The engrams appear to influence the precision, speed, and accuracy of movement.³¹

The limbic system is critical to the learning phase because it generates need-directed motor activity and communicates the intent to the rest of the brain. The limbic system is a critical part of the neural representation necessary for memory that includes the cortex and thalamus.

The cerebellum appears to be active during procedural learning. A possible mechanism is through the influence of the climbing fibers on the mossy fibers with eventual change in the output fibers, the Purkinje fibers.⁵⁸ The lateral cerebellum affects cognition through its relationship to the frontal areas active during cognitive processes.⁴⁶

The basal ganglia appear to be highly involved in the cognitive aspects of motor behavior although the level of contribution remains unclear. Habit formation appears to be associated with functions of the basal ganglia, and the control of internally generated movement here appears to be a part of the motor learning continuum.³¹

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